Tuberculosis in Children PDF

Essentials of
TUBERCULOSIS IN CHILDREN
Essentials of
4th Edition
Vimlesh Seth MD FAMS FCAI FISCD

Senior Consultant
Formerly, Senior Professor and Head
Department of Pediatrics and
Chief Division of Tuberculosis, Pulmonology
Rheumatology and Intensive Care Unit
All India Institute of Medical Sciences (AIIMS)
New Delhi, India
SK Kabra MD DNB
Professor and Incharge
Division of Tuberculosis and Pulmonology
All India Institute of Medical Sciences (AIIMS)
New Delhi, India
Foreword
Peter R Donald
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Essentials of Tuberculosis in Children

© 2011, Jaypee Brothers Medical Publishers
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First Edition : 1997

Second Edition : 2001
Third Edition : 2006
Fourth Edition : 2011
ISBN 978-93-5025-252-9
Typeset at JPBMP typesetting unit
Printed at
Dedicated to
My husband
Professor SD Seth
for his constant encouragement
and moral support
My grandchildren Ushmita and Udbhav
for helping me proactively
to become computer friendly
for easing my editorial
work for the book
Contributors
AK Gupta MD Ashok Rattan MD BN Upendra MS

Professor and Head Chief Executive Assistant Professor
Department of Radiodiagnosis Fortis Clinical Research Ltd Department of Orthopedics
All India Institute of Medical Advisor, Religare SRL, Fortis All India Institute of Medical
Sciences Escorts, Delhi and NCR Sciences, New Delhi, India
New Delhi, India E-mail:
E-mail: arun676@hotmail.com ashok.rattan@fortis.cro.com, BR Thapa MD
ashok.rattan@srl.in Professor and Chief
Division of Pediatric
Alexey Kruk MD
Ashu Seith Bhalla MD Gastroenterology Hepatology and
Department of Public Health
Associate Professor Nutrition
Oxford University
Department of Radiodiagnosis Postgraduate Institute of Medical
United Kingdom Education and Research (PGIMER)
All India Institute of Medical
E-mail: bjmarais@sun.acza Chandigarh, India
Sciences
New Delhi, India E-mail: brthapa1@yahoo.co.in
A Maheshwari MD
E-mail: ashubhalla1@yahoo.com
Assistant Professor Daphne Ling
Department of Pediatrics Department of Epidemiology
Atin Kumar MD
Kalawati Saran Children Hospital and Biostatistics
Assistant Professor
Lady Hardinge Medical College Radiodiagnosis MC Gill University , Quebec, Canada
New Delhi, India JPNA Trauma Centre
E-mail: anejas@hotmail.com All India Institute of Medical Donald A Enarson MD, FRCP (Edin)
Sciences International Union Against
Alka Beotra PhD New Delhi, India Tuberculosis and Lung Disease
Scientific Director E-mail: dratinkumar@gmail.com 68 boulvard Saint-Michel
National DOPE Testing Laboratory Paris 75006 France
JN Stadium, Lodi Road E-mail: union@iuatld.org
Bansidhar Tarai MD
New Delhi, India Formerly Chair in Clinical
Lab Manager
E-mail: drabeotra@rediffmail.com Pharmacology
Microbiology, Immunology and
Indian Council of Medical Research
Molecular Biology
and Professor and Head
Anju Seth MD Quest Diagnostics India Private
Department of Pharmacology
Professor Limited
All India Institute of Medical Sciences
Division of Endocrinology Gurgaon
New Delhi, India
Department of Pediatrics Haryana, India
E-mail: drsdseth@yahoo.com
Kalawati Saran Children Hospital E-mail: bansisss@gmail.com
drsdseth@gmail.com
Lady Hardinge Medical College
New Delhi, India Ben J Marais MRCP FCP M (Med) H Simon Schaaf MBChB (Stell) MMed
E-mail: anju_seth@yahoo.com Professor Ped (Stell) DCM (Stell) MD Ped (Stell)
Department of Pediatrics and Child Professor of Pediatrics
Arvind Bagga MD FIAP FAMS Health Desmond Tutu TB Centre
Professor Faculty of Health Sciences, Department of Pediatrics and Child
Department of Pediatrics Tygerberg Hospital Health, and Tygerberg Children’s
All India Institute of Medical Health Sciences, Stellenbosch Hospital, Faculty of Health Sciences
University Stellenbosch University
Sciences
PO Box No. 19063 PO Box 19063, 7505 Tygerberg
New Delhi, India
7505 Tygerberg, South Africa South Africa
E-mail: arvindbagga@hotmail.com
E-mail: bjmarais@sun.ac.za E-mail hss@sun.ac.za
viii
Harleen MS Grewal MD PhD DTMH LS Chauhan MD Neena Khanna MD

Professor and Senior Consultant Senior Dy Director-General (TB) Professor
The Grade Institute Section for Central TB Division Department of Dermatology and
Microbiology and Immunology Directorate General of Health Venereology
University of Bergen, Norway Services and Family Welfare All India Institute of Medical Sciences
E-mail: harleen.grewal@cih.uib.no Government of India New Delhi, India
Nirman Bhawan, New Delhi, India E-mail: neena_aiims@yahoo.co.in
Heidi Syre PhD E-mail: ddgtb@rntcp.org
Scientist, The Grade Institute Section Nimrat Bawa
for Microbiology and Immunology Madhukar Pai MD PhD Diplomat of American Boards
University of Bergen, Norway Assistant Professor and CIHR New (Pathology)
E-mail: harleen.grewal@cih.uib.no Investigator Director Technical Affairs
Department of Epidemiology and Auroprobe Laboratories
J Cunningham MD FRCP Biostatistics C-229, Defence Colony
McGill University 1020 Pine Ave New Delhi, India
Medical Officer, WHO/CDS/TDR/PRD
West E-mail: auro@auroprobelab.com,
Unicef/UNDP/World Bank/WHO
Montreal, QC H3A IA2, Canada drbawa@hotmail.com
Special Program for Research in
E-mail: madhukar.pai@mcgill.ca.
Tropical Diseases, 20 Appia Ave
Nulda Beyers MBChB(Stell) FCP(SA)
Geneva-27, Switzerland
Madhulika Kabra MD PhD(Stell) MSc(Med)(UCT)
E-mail: cunninghamj@who.int Professor TB/Community Project
Additional Professor
Department of Pediatrics International Union Against
JB Sharma MD DNB FRCOG All India Institute of Medical Tuberculosis and Lung Disease
Associate Professor Sciences 68 boulevard Saint-Michel
Department of Obstetrics and New Delhi, India Paris, France
Gynecology E-mail: E-mail: nb@sun.ac.za
All India Institute of Medical Sciences madulikakabra@hotmail.com
New Delhi, India OP Semwal MBBS DCH
E-mail: jbsharma2000@gmail.com Manju Ghosh PhD Former, Research Associate
Research Scientist Department of Pediatrics
JL Stanford MD Division of Genetics All India Institute of Medical Sciences
Head, Division of Bacteriology Department of Pediatrics New Delhi, India
School of Pathology All India Institute of Medical Now: Senior Consultant Pediatrics
University College and Sciences E-mail: semwalop@gmail.com
Middlesex School of Medicine New Delhi, India
63-67, Riding House Street E-mail: Pawan Rawal MD DM
London WIP 7PP, UK mghosh_aims@rediffmail.com Senior Research Associate
Division of Pediatric
K Gopinath PhD Md Khurshid Alam Hyder Gastroenterology Hepatology and
Scientist Medical Officer (TB) Nutrition
Division of Clinical Microbiology Tuberculosis Control Postgraduate Institute of Medical
World Health Organization Education and Research (PGIMER)
Department of Laboratory Medicine
Regional Office for South-East Asia Chandigarh, India
All India Institute of Medical Sciences
World Health House E-mail: drrawal2005@yahoo.co.in
New Delhi, India
Indraprastha Estate
E-mail: kgnath@gmail.com
Mahatma Gandhi Marg PK Dave MS
New Delhi, India Senior Consultant
Kusum Verma MD E-mail: hyderk@searo.who.int Department of Orthopedics and
Senior Pathologist
Director
Sir Ganga Ram Hospital, New Delhi Nani Nair MD Rockland Hospital, New Delhi
Formerly Dean, Professor and Head Regional Adviser TB Former Director and Professor of
Department of Pathology World Health Organization Orthopedics
All India Institute of Medical Sciences Regional Office for South-East Asia All India Institute of Medical Sciences
New Delhi, India New Delhi-110002, India Ansari Nagar, New Delhi, India
E-mail: ic_verma@vsnl.com E-mail: nairn@searo.who.int E-mail: prakash_kotwal@hotmail.com
ix
Contributors
Contents
PM Udani (Late) MD DCH Rakesh Lodha MD S Rasool MBBS

Professor Emeritus Assistant Professor Research Officer
Department of Pediatrics Department of Pediatrics Regional Research
Institute of Child Health, JJ Group All India Institute of Medical Institute of Unani Medicine
of Hospitals Sciences Jamia Nagar
Mumbai, Maharashtra, India New Delhi, India New Delhi, India
E-mail: rlodha1661@gmail.com
PP Kotwal MS Sandeep R Mathur MD
Professor and Head Ravi Angara MD Assistant Professor
Department of Orthopedics Senior Resident Department of Pathology
All India Institute of Medical Sciences Division of Pediatric All India Institute of Medical Sciences
New Delhi, India Gastroenterology Hepatology and New Delhi, India
E-mail:
E-mail: prakash_kotwal@hotmail.com Nutrition
drsunnymathur@yahoo.com
Postgraduate Institute of Medical
PR Donald MBChB (Stell) DCH (Glasg) Education and Research
Sangeeta Sharma MD
DTM&H (Lond) FCP(SA) FRCP (Edin) MD Chandigarh, India
Specialist and Head
(Stell) E-mail: brthapa1@yahoo.co.in
Emeritus Professor of Pediatrics Department of Pediatrics
Desmond Tutu TB Centre LRS Institute of TB and Respiratory
Robert P Gie MD
Department of Pediatrics and Child Desmond Tutu TB Center and Diseases
Health Department of New Delhi, India
and Tygerberg Children’s Hospital Pediatric and Child Health
Faculty of Health Sciences Faculty of Health Sciences Sarman Singh MD
Stellenbosch University Stellenbosh University Professor
PO Box 19063 South Africa Clinical Microbiology Division
7505 Tygerberg, South Africa E-mail: bjmarais@sun.ac.za Department of Laboratory Medicine
E-mail: prd@sun.ac.za All India Institute of Medical
Rohit Sarin DTCD MD Sciences
Prashant Mathur DCH DNB PhD Head New Delhi, India
Scientist ‘D’ Department of TB Control and E-mail- ssingh56@hotmail.com
Division of Noncommunicable Training
Diseases Lala Ram Sarup Institute of
Indian Council of Medical Research Tuberculosis and Related Diseases S Aneja MD
New Delhi, India Sri Aurobindo Marg Director Professor
E-mail: mathurp@icmr.org.in, New Delhi, India Department of Pediatrics
drprashant.mathur@gmail.com E-mail: drsarin@yahoo.com Kalawati Saran Children Hospital
Lady Hardinge Medical College
Rachna Seth DCH DNB Roli Mathur PhD New Delhi, India
Scientist ‘C’ E-mail: anejas@hotmail.com
Assistant Professor
Division of Basic Medical Sciences
Department of Pediatrics
Indian Council of Medical Research
All India Institute of Medical Sciences SD Seth MD
New Delhi, India
New Delhi, India Advisor Clinical Trials Registry –
E-mail: rolimat@yahoo.com,
E-mail: India
rolimat@gmail.com
drsandeepseth@hotmail.com National Institute of Medical Statistics
Ruchi Sood PhD Indian Council of Medical Research
Rajni Sharma Research Scientist-Infectious New Delhi, India
Assistant Professor Diseases
Division of Endocrinology New Drug Discovery Research Seemab Gulati MD
Department of Pediatrics Ranbaxy Research Laboratories Associate Professor
Kalawti Saran Children Hospital Plot No. 20, Sector 18 Department of Pediatrics
Lady Hardinge Medical College Udyog Vihar, Industrial Area All India Institute of Medical Sciences
New Delhi, India Gurgaon, Haryana, India New Delhi, India
E-mail: anju_seth@yahoo.com E-mail: ruchi.sood@ranbaxy.com Email: sheefaligulati@gmail.com
x
S Mukhopadhyaya MD S Kumar IP Apollo Hospital

Senior Radiologist Head of Laboratories Sarita Vihar, New Delhi
Formerly Professor and Head Auroprobe Laboratories Email: kalra_veena@hotmail.com
Department of Radiodiagnosis E-mail: eduprobe@gmail.com
All India Institute of Medical Sciences Vimlesh Seth MD
New Delhi, India S Kuhn MD Senior Consultant in Pediatrics
E-mail:mukherjee@touchtelindia.net Consultant in Pediatrics Formerly Senior Professor and
Infectious diseases at Head
Alberta Children’s Hospital Department of Pediatrics
SK Kabra MD DNB 1820 Richmond Road SW All India Institute of Medical
Professor Calgargy, Alberta, Canada Sciences
Department of Pediatrics E-mail: New Delhi, India
All India Institute of Medical Sciences susan.kuhn@calgaryhealthregion.ca E-mail: vimleshseth@gmail.com,
New Delhi, India vimleshseth@yahoo.com
E-mail: skkabra@rediffmail.com Tahmeed Ahmed MBBS PhD
Senior Scientist and Head YK Amdekar MD
Suneeta Mittal MD FRCOG Nutrition Programm Senior Consultant Pediatrics
Professor and Head Dhaka, Bangladesh 151, Tushar, 14th Road
Department of Obstetrics and E-mail: tahmeed@icddrb.org Chembur, Mumbai, Maharashtra,
Gynecology India
All India Institute of Medical Sciences V Kalra MD E-mail: ykasya@gmail.com
New Delhi, India Senior Consultant
E-mail: suneeta_mittal@yahoo.com Pediatric Neurology
Foreword
The epidemic proportions of tuberculosis in many countries was identified as a global emergency in 1993. Despite a
considerable increase in international efforts aimed at tuberculosis control and investment in tuberculosis research,
the perverse influence of HIV-infection combined with the effects of poverty and economic recession have combined
to ensure that the failure to control tuberculosis remains a cause for concern for National Tuberculosis Control
Managers in many countries. The magnitude of the problem is daunting and has been exacerbated by the appearance
of an increasing proportion of MDR-TB and the threat of XDR TB; under the lengthening shadow of HIV, the dream
of controlling, not to speak of eradicating TB has moved far into the future. Against this background, childhood
tuberculosis may appear to be a minor problem, but the percentage of tuberculosis occurring in children is estimated
to vary between 15% in low income countries to below five percent in United States and European countries, while
in high density peri-urban slums, the proportion may rise to much more than 20% in some cases. Even in developed
countries, MDR and XDR tuberculosis are an ever-present threat due to the increasing mobility of people across
international boundaries.
The problem of the diagnosis of tuberculosis in children remains a significant obstacle and is worsened in
severe forms of extrapulmonary diseases such as osteoarticular disease and meningeal tuberculosis. The lack of
standard case definitions and low priority accorded to childhood tuberculosis in the public health agendas of many
countries are persistent problems. Nonetheless, it is pleasing that the problems of childhood tuberculosis have recently
received increasing attention from the various agencies including the World Health Organization (WHO).
The belief that tuberculosis in children is not a significant cause of transmission of infection is also not true if
viewed from a long-term perspective; a significant proportion of children in the younger and vulnerable age group
who are infected by an adult source case will very often not receive preventive therapy and will later develop
infectious adult-type tuberculosis, especially during adolescence and this is particularly likely to happen in
communities with a high incidence of HIV-infection. Globally, it is estimated that 1.5 million new cases and 130,000
deaths due to tuberculosis per year occur in young children. Of the total deaths due to tuberculosis, 95% occur in
developing countries. It has been rightly emphasized that tuberculosis control programs should recognize tuberculosis
as a disease of the family and community rather than only the individual and that tuberculosis infection and disease
in children of all ages should be managed simultaneously with the evaluation and management of other family
members and members of the extended family and household and not in isolation.
It is thus pleasing that children are now specially included in the Revised National Tuberculosis Control
Programme (RNTCP) and that antituberculosis agents will become available on a weight-for-age basis. Suboptimal
dosing still remains possible and the lack of child-friendly preparations makes the accurate treatment of under-five-
year-old children difficult and it is this group that is subject to more serious forms of disseminated disease. Within
financial constraints, active contact tracing of under-five-year-old children is now recommended and will be facilitated
by a family or household-orientated approach.
In addition to these welcome innovations, the early diagnosis and management by directly observed short-
course treatment (DOTS) of all sputum microscopy smear-positive patients, whether children, adolescents or adults,
remains an important cornerstone of any tuberculosis control program as does the administration of BCG to infants.
Although BCG vaccination has a limited effect and prevents mainly disseminated forms of tuberculosis, efforts to
develop a new improved vaccine are gathering momentum.
One of the characteristics of tuberculosis in children, in contrast to adults, is the wide spectrum of manifestations
and there is a great need to create a greater understanding of this spectrum to fully appreciate the specific problems of
childhood tuberculosis. This book should thus be welcomed by the childhood tuberculosis community throughout the
world. In this book, Vimlesh Seth, herself a well-known international figure in this field, has brought together
63 eminent scientists and clinicians who have contributed 44 outstanding chapters that address most of the manifestations
of childhood tuberculosis. Dr Seth has made a considerable contribution to the better management of childhood
tuberculosis; included in her many activities are participation in two consensus reports (1997 and 2004) and a third that
appears in this book that summarizes the deliberations of pediatricians, program managers and laboratory workers
relating to childhood tuberculosis.
xii
In addition, attention is drawn to the neglected areas of tuberculosis in girls at adolescence and in children with
cancer and two chapters discuss pitfalls in diagnosis and management of childhood tuberculosis, and lacunae and
experience of managing children under the National Program (DOTS). The place of contact surveillance has been
highlighted and forms of extrapulmonary tuberculosis, such as neurotuberculosis, have been illustrated with a large
number of clinical pictures from children of various ages in the different stages of disease. The chapter on imaging
is exhaustive and based on data of pediatric TB clinic over five decades at All India Institute of Medical Sciences
(AIIMS), New Delhi, India.
The book is a valuable resource not only for the pediatric fraternity but also for all practitioners who treat children;
and it should find a place not only in libraries of medical colleges but also in Pediatric and Community Medicine
Departments. It is very reader-friendly and organized for easy consultation by both undergraduates and postgraduates
who need to know more about childhood tuberculosis. Appropriately in an age when the epidemic of HIV continues
to spread, there is a chapter on the organization of a pediatric and HIV clinic in the pediatric department of medical
college and how this can contribute to the collection of information about tuberculosis and HIV for the National Data
Base about disease in children and so influence the design of future policies for diagnosis and management. Frequently
asked questions relating to childhood tuberculosis and BCG are addressed and this is of great practical value. Dr Seth
is to be congratulated on the successful compilation of a formidable compendium of information about childhood
tuberculosis which will be of value, throughout the world wherever tuberculosis is a significant problem.
Peter R Donald
MBChB (Stell) DCH (Glasg) DTM&H (Lond) FCP(SA) FRCP (Edin) MD (Stell)
Emeritus Professor of Pediatrics
Desmond Tutu TB Centre
Department of Paediatrics and Child Health
and Tygerberg Children’s Hospital
Faculty of Health Sciences
Stellenbosch University
Tygerberg, South Africa
Preface to the Fourth Edition
Tuberculosis (TB) continues to be the world’s most important infectious cause of morbidity and mortality among
adults. Nearly nine million people develop tuberculous disease each year and 1.7 million die every year (WHO,
2007). Detection rates are low and morbidity and mortality is high in children also. Over the last five years, the
incidence and prevalence of TB in children has not decreased. The reason is that on the preventive front, the same
strategies: (i) diagnosis and treating sputum smear-positive cases in adults and (ii) mass BCG vaccination of newborns
and infants are being practised. These have not proved effective to a significant extent because of the concurrent
addition of HIV/AIDS infection, MDR-TB and even XDR-TB. The latter two conditions need aggressive treatment in
children along with their source cases, which are usually adults in the family.
On the diagnostic front, with the significant advances at molecular level, there has not emerged a single test for
diagnosis, that too are not cost-effective requiring huge finances and high level of technical expertise. At best, they
are categorized only supportive tests.
In the contact survey, addition of IGRAs, with the basis of release of interferon – γ after incubation of whole
blood or separated T-cells with CFT 10 peptides and ESAT-609 antigen of tubercle bacilli has been well researched.
The two tests are quantiFERON-γ. TB and T-SPOT.TB; ELISPOT. These again cannot be used as the tests for diagnosis
as they emphasize that they are only comparable to the existing tuberculin test, the advantages over tuberculin test
are: (i) require only one visit of the patient, (ii) previous BCG vaccination does not interfere and, (iii) presence of
nontuberculous mycobacteria in the environment does not vitiate the results. However, their main advantage is
their use in contact tracing for which they have been extensively used.
In the basic format of the book there are seven sections. In each section a number of new chapters have been
added, contributed by specialists in their respective field. In total there are 44 chapters with 63 contributors from
India and abroad. In the 1st three sections namely history, epidemiology and microbiology and immunopathogenesis,
the chapters have been updated including the latest details at the molecular level in all aspects. In the clinical spectrum,
for TB and HIV coinfection there are two chapters with one giving detailed dosage schedule of antiretroviral drugs.
The other significant additions are tuberculosis at adolescence, particularly in female children in whom it can
be a prelude to the development of sterelity later in life. Chapters on cutaneous and endocrine manifestations are the
other additions. The chapter on TB in children with cancer has highlighted the point why TB is not a scurge in these
children. However, one should be in the lookout for this, particularly when the presentation of complications in
cancer are unusual and do not improve with conventional antibiotics used for the commonly occurring superadded
infections. In the management section, the chapters on antituberculosis drugs have been completely revised and
updated to facilitate the readers to understand various regimens used in the clinical spectrum of TB in children
specially HIV/TB coinfection and MDR-TB. Pharmacokinetics of all antituberculosis drugs have been updated from
literature review along with the experience at Pediatric department of All India Institute of Medical Sciences (AIIMS)
with 1st-line agents. Chapter on lacunae and experience of DOTS in the management of children has been included.
The Indian Academy of Pediatrics (IAP) in the third Consensus Statement has highlighted some reservations about
management of HIV and TB coinfection and MDR-TB by general pediatricians. They have emphasized that these
two aspects need management by experts in the field. Advances up to 2010 have been included making all the
chapters well referenced with the latest literature.
The book will be useful to both undergraduates and postgraduates. Departments of Community Medicine of
Medical colleges and Tuberculosis Hospital will also benefit from the efforts of the authors. It will be a useful reference
book for Program Managers of the Tuberculosis Division of Ministry of Health and Family Welfare, Government of
India; Departments of Health Research and Indian Council of Medical Research, Biotechnology of the Government
of India. Chapters on research priorities and ethics involved in clinical trial will facilitate pediatricians to write high
quality scientific projects on TB in children to have research grant from funding agencies. Details of how to get
National Data Base of TB and its coinfection with HIV/AIDS are necessary. This will help in making changes in
policies in their management from time to time. Further, it will help to make some facilities exclusively for children
such as medicine boxes in the four to five weight categories as per age. A chapter exclusively for how to organize a
TB/HIV clinic for pediatrics has been elucidated with detailed case record forms and instruction for the junior
doctors attending the clinic to achieve goal in this direction. In toto, this book will serve as a very useful treatise
regarding all aspects of TB in children.
Vimlesh Seth
SK Kabra
Preface to the First Edition
The prevalence of active tuberculosis in India is 15 to 25 per 1,000 population, of which 25 percent are infectious.
About 3.4 million children in the country have tuberculosis of which 94 million are at risk of infection. Nearly 40
percent of the children by the age of 6 years and 80 percent by the age of 16 years develop tubercular infection. The
annual rate of infection is 3 percent.
There is resurgence of tuberculosis both in the developed and developing countries due to the increasing
occurrence of HIV/AIDs, even children being not spared. With the availability of effective chemotherapeutic agents,
a large number of children with pulmonary primary complex are overtreated and badly planned regimens are given
to children with tuberculous meningitis, as there are no specific guidelines for the management of tuberculosis in its
varied clinical spectrum. Ultimate control of tuberculosis rests on the development of shorter courses of chemotherapy,
and availability of vastly improved diagnostic methods.
Trinity of functions of the faculty of All India Institute of Medical Sciences is patient care, teaching and research.
For all this, there is always a need to have literature on the latest developments about epidemiology, diagnosis
(newer investigations) and treatment of any disease. Tuberculosis is one of the world’s most neglected health crises.
In this treatise, attempt has been made to address the problem of tuberculosis stating from epidemiology in
various settings (hospital and community), review of recent diagnostic methods, particularly the role of nonculture
techniques in the diagnosis of paucibacillary tuberculosis of children. Based on my work in the immunology in
children having tuberculosis, a clinico-immunoradiological profile has been defined. Work on the pharmacokinetics
conducted in my laboratory has helped me to design antituberculosis drug regimens for varied clinical spectrum on
sound scientific basis. The chapters on BCG vaccination and tuberculin test have exhaustively reviewed. There is a
chapter on practical problems in the form of questions and their answers. There is a whole lot of data on Indian
children practically about all aspects of tuberculosis in this book.
The book is intended to be used by general practitioners treating children, pediatricians in practice, faculty of
pediatrics and community medicine of medical colleges, postgraduate students and the policy makers of the
Government of India for its National Tuberculosis Control Program. Specific guidelines on diagnosis and management
of the children of an infectious adult can be formulated which should be incorporated in the National Tuberculosis
Control Program of Government of India and other developing countries.
My most sincere and grateful thanks are due to all the contributors from India and abroad for having presented
the various topics in a comprehensive and authoritative manner. My special thanks are due to Dr OP Semwal for his
painstaking effort and assistance in giving finishing touch to the book.
Able secretarial assistance of Miss Rita Sharma, Mrs Kanta Chawla and Mr Ashok Kumar is gratefully
acknowledged.
Thanks are also due to Shri JP Vij, Chairman and Managing Director of M/s Jaypee Brothers Medical Publishers
Pvt. Ltd., for the publication of this book. I gratefully acknowledge the sincere efforts of Mr Ghuman, Production
Manager, for ensuring a very high quality of the book and bringing it out in such a short-time.
Vimlesh Seth
Acknowledgments
I owe my gratitude to all the contributors for their painstakingly written chapters in an excellent, simple and lucid
style, very well referenced and updated with thorough illustrations.
We acknowledge the efforts of Shri Jitendar P Vij, Chairman and Managing Director of M/s Jaypee Brothers
Medical Publishers (P) Ltd, for publishing the book. We also acknowledge the meticulous work and sincere efforts
of Mr Tarun Duneja (Director–Publishing) and Mrs Samina Khan, for ensuring quality of this edition. We are thankful
to Mr Bir Singh for his untiring secretarial assistance. He worked even on weekends to meet the deadline.
About the Review of the Previous
Edition of the Book
The appearance of the book and contents are really outstanding.
Peter R Donald
Emeritus Professor of Pediatrics
Faculty of Health Sciences
Stellenbosch University
7505 Tygerberg, South Africa
E-mail: prd@sun.ac.za
No Western books on pediatrics have provided a comprehensive update on the subject of childhood tuberculosis,
especially in the context of the developing world.
Professor Vimlesh Seth herself has written most of the early chapters on epidemiology, diagnosis,
immunopathogenesis, and the immunology of BCG vaccination and the tuberculin test. These chapters are readable,
comprehensive, and well referenced. There have been many recent advances in mycobacterial immunology and it is
to Professor Seth's credit that she has managed to be so concise. This is an excellent book.
Anthony Costello
Senior Lecturer
Archives of Disease of Children 1991; 66: 1006
Contents
Section 1: Introduction
1. History of Tuberculosis ............................................................................................................... 3

Vimlesh Seth, SK Kabra
• History of Tuberculosis ......................................................................................................................................... 3
• History of Tuberculosis Control in India ............................................................................................................ 4
• Sanatoria in India ....................................................................................................................................................5
• Tuberculosis Association of India ........................................................................................................................ 5
• Tuberculosis Control Program in Independent India ....................................................................................... 5
• History and Development of International Cooperation in the Conquest of Tuberculosis ........................ 6
Section 2: Epidemiology
2. Global Epidemiology of Pediatric Tuberculosis .................................................................. 11

Md Khurshid Alam Hyder, Nani Nair, Tahmeed Ahmed
• Presentation of Pediatric TB ................................................................................................................................ 11
• TB in the World .....................................................................................................................................................13
• Effect of Migration ................................................................................................................................................16
3. Interaction of Epidemiological Factors................................................................................... 19

Donald A Enarson, Nulda Beyers
• Determinants of Tuberculosis in Children ........................................................................................................ 21
• Evaluation of Interventions with Reference to Children ................................................................................ 21
• Eradication of Tuberculosis .................................................................................................................................22
4. Epidemiology: Special Reference to Children ...................................................................... 26

• Pyramid of Childhood Tuberculosis .................................................................................................................. 26
• Disease Burden in Children ................................................................................................................................ 28
• Determinants of Infection and Disease ..............................................................................................................30
• Drug-resistant Tuberculosis ................................................................................................................................ 32
• Trends in Tubercular Disease .............................................................................................................................33
• HIV and Tuberculosis .......................................................................................................................................... 34
• Molecular Epidemiology ..................................................................................................................................... 34
• Actions Being Taken in India .............................................................................................................................. 36
xviii
Section 3: Microbiology and Immunopathogenesis
5. Mycobacterium Tuberculosis ................................................................................................... 41

Sarman Singh, K Gopinath, Ruchi Sood, Ashok Rattan
• Taxonomy ..............................................................................................................................................................41
• Description of the Genus ..................................................................................................................................... 42
6. Nontuberculous Mycobacteria ................................................................................................. 57

Sarman Singh, K Gopinath, Ashok Rattan
• Taxonomy ..............................................................................................................................................................57
• Classification of NTM on the Basis of Pigment Production ........................................................................... 57
7. Immunology of Tuberculosis: Basic Aspects and Relevance for

Immunodiagnostic Tests ........................................................................................................... 66
Heidi Syre, Harleen MS Grewal
• The Immune System .............................................................................................................................................66
8. Clinicoimmunological Profile .................................................................................................. 90

Vimlesh Seth
• Immune Reconstitution Disease Associated with Mycobacterial Infections ...............................................96
Section 4: Clinical Spectrum
9. Pulmonary Tuberculosis ......................................................................................................... 101

• Transmission .......................................................................................................................................................101
• Pathophysiology ................................................................................................................................................. 101
• Risk of Infection to Disease in Infants and Young Children ........................................................................102
• Natural History of Tubercular Infections........................................................................................................102
• Principles of Disease .......................................................................................................................................... 102
• Clinical Features ................................................................................................................................................. 107
• Clinical Features/Scoring Systems .................................................................................................................. 108
• Methods to Diagnose Latent Tuberculosis Infection ..................................................................................... 115
• Diagnostic Algorithm for Pulmonary Tuberculosis ......................................................................................115
10. Tuberculous Lymphadenitis .................................................................................................. 122

Ben J Marais, PR Donald
• Epidemiology ...................................................................................................................................................... 122
• Pathogenesis ........................................................................................................................................................123
• Clinical Findings and Diagnosis .......................................................................................................................123
• Treatment ............................................................................................................................................................. 126
11. Abdominal Tuberculosis ......................................................................................................... 128

BR Thapa, Pawan Rawal, Ravi Angara
• Causative Organisms .........................................................................................................................................128
• Ulcerative Type ...................................................................................................................................................130
• Stricturous/Hypertrophic type ........................................................................................................................130
xix
Contents
• Presentation According to Site of Involvement .............................................................................................131

• Techniques for Definitive Diagnosis ................................................................................................................132
• Abdominal Ultrasound ......................................................................................................................................137
• CT Abdomen .......................................................................................................................................................139
• Newer Modalities ...............................................................................................................................................142
• Differentiating ATB from Inflammatory Bowel Disease (IBD) .................................................................... 143
12. Neurotuberculosis ................................................................................................................... 150

12.1. Pathology and Pathogenesis .................................................................................................. 150
PM Udani
• Magnitude, Changing Clinical Patterns and Syndromes Specially in BCG-vaccinated Children .........150
• Abdominal Tuberculosis ...................................................................................................................................150
• Pathological Aspects .......................................................................................................................................... 151
• Specific Conditions .............................................................................................................................................154
• Pathological Basis of Various Syndromes ...................................................................................................... 156
12.2. Clinical Manifestations, Diagnosis and Management ..................................................... 161

Satinder Aneja, A Maheshwari, Vimlesh Seth
• Special Scenarios ................................................................................................................................................. 174
• Tuberculoma of Brain .........................................................................................................................................175
• Spinal Tuberculosis in Children .......................................................................................................................177
12.3. Case Studies ............................................................................................................................... 180

PM Udani, S Gulati, Rachna Seth, V Kalra, Vimlesh Seth
• Profile of TBM in Children Modified by BCG—Dr PM Udani’s Experience .............................................180
• Profile of TBM: AIIMS Experience ...................................................................................................................185
13. Osteoarticular Tuberculosis ................................................................................................... 200

PP Kotwal, PK Dave, BN Upendra
• Joint Involvement ...............................................................................................................................................200
• Tuberculosis of the Hip Joint ............................................................................................................................204
• Tuberculosis of the Knee Joint ..........................................................................................................................206
• Tuberculosis of the Ankle and Elbow ..............................................................................................................207
• Tuberculosis of the Short Long Bones ............................................................................................................. 207
• Tuberculosis of the Spine (Pott’s Spine) ..........................................................................................................207
14. Genitourinary Tuberculosis ................................................................................................... 214

Arvind Bagga
• Clinical Presentation .......................................................................................................................................... 214
• Diagnosis ..............................................................................................................................................................215
• Therapy ................................................................................................................................................................215
15. Tuberculosis and the HIV Infection ..................................................................................... 218
15.1. TB in HIV Infected Children.................................................................................................. 218

BJ Marais, PR Donald
• Epidemiology ...................................................................................................................................................... 218
• Tuberculosis and the HIV Infection .................................................................................................................218
• Diagnosis ..............................................................................................................................................................219
• Treatment ............................................................................................................................................................. 219
xx
15.2. Tuberculosis and HIV Infection ............................................................................................ 222

Vimlesh Seth, Rakesh Lodha
• Epidemiology of HIV-tuberculosis .................................................................................................................. 222
• Prevalence of Tuberculosis in HIV-infected Children ..................................................................................223
• Pathogenesis ........................................................................................................................................................224
• Differential Diagnosis ........................................................................................................................................227
• Treatment of TB ..................................................................................................................................................230
• Treatment of Children........................................................................................................................................231
• Prognosis ..............................................................................................................................................................234
16. Tuberculosis and Childhood Malignancy ........................................................................... 241

Rachna Seth
• Immunology of Tubercular Infection ..............................................................................................................241
• Risk Factors ..........................................................................................................................................................243
• Diagnosis..............................................................................................................................................................243
• Pulmonary Tuberculosis and Bone Marrow Transplant (BMT) Recipients ...............................................244
• Short-course Chemotherapy and Reactivation of TB ....................................................................................245
• Clinical Characteristics and Treatment Responses of Tuberculosis in
Patients with Malignancy Receiving Anticancer Therapy ...........................................................................245
17. Unusual Manifestations of Tuberculosis............................................................................. 248

Vimlesh Seth
• Tuberculosis of Eye and Conjunctiva ..............................................................................................................248
• Hematological Complications ..........................................................................................................................249
• Esophageal Tuberculosis ...................................................................................................................................250
• Tuberculous Otitis Media and Mastoiditis .....................................................................................................250
• Isolated Hepatic Inferior Vena Cava Thrombosis in a Case of Tuberculosis ............................................251
• Cement kidney: Renal Tuberculosis ................................................................................................................251
• Primary Tuberculosis Clinically Presenting as Gingival Enlargement: A Case Report ...........................251
• Simultaneous Tuberculous Meningoencephalitis in Two Siblings ............................................................. 251
• Childhood Tuberculosis Diagnosed and Managed as Asthma: A Case Report ........................................252
• Tuberculosis of the Breast in an Adolescent Girl ...........................................................................................252
• Esophageal Stent Improves Ventilation in a Child with a Bronchoesophageal
Fistula Caused by Mycobacterium tuberculosis................................................................................................. 252
• Pituitary Stalk Tuberculosis .............................................................................................................................. 252
• Multifocal Skeletal Tuberculosis ......................................................................................................................252
• BCG Related Complications .............................................................................................................................. 253
18. Cutaneous Tuberculosis .......................................................................................................... 255

Neena Khanna, Seemab Rasool
• Epidemiology ...................................................................................................................................................... 255
• Etiology ................................................................................................................................................................255
• Pathogenesis ........................................................................................................................................................255
• Classification .......................................................................................................................................................255
• Unusual Patterns of Tuberculosis ....................................................................................................................259
• Diagnosis of Cutaneous Tuberculosis ............................................................................................................. 259
• Treatment of Cutaneous Tuberculosis ............................................................................................................. 260
xxi
Contents
19. Adolescent Tuberculosis: Prelude to Future Infertility .................................................... 263

Suneeta Mittal, JB Sharma, Sangeeta Sharma
• Treatment ............................................................................................................................................................. 269
20. Endocrine Manifestations of Tuberculosis ......................................................................... 273

Anju Seth, Rajni Sharma
• Endocrine Effects of Tuberculosis Due to Chronic Systemic Disease .........................................................273
• CNS Tuberculosis ...............................................................................................................................................273
• Adrenal Tuberculosis .........................................................................................................................................274
• Thyroid Tuberculosis .........................................................................................................................................275
• Pancreatic Tuberculosis ..................................................................................................................................... 275
• Genital Tuberculosis ...........................................................................................................................................275
21. Congenital Tuberculosis ......................................................................................................... 277

Vimlesh Seth
• Pathophysiology ................................................................................................................................................. 277
• Diagnostic Criteria for Congenital Tuberculosis ...........................................................................................279
• Investigations ...................................................................................................................................................... 280
• Treatment ............................................................................................................................................................. 281
Section 5: Diagnosis
22. Pitfalls in Diagnosis and Treatment of Childhood Tuberculosis ................................... 287

YK Ambdekar, Vimlesh Seth
• Pitfalls in History Analysis ...............................................................................................................................287
23. Tuberculin Test ......................................................................................................................... 296

• History .................................................................................................................................................................. 297
• Tuberculins ..........................................................................................................................................................297
• Composition ........................................................................................................................................................ 297
• Immune Basis of Tuberculin Reactivity ..........................................................................................................298
• Tuberculosis and Immune System ...................................................................................................................299
• Administration of Tuberculin Test ...................................................................................................................300
• Infection with Nontuberculous Mycobacteria ................................................................................................301
• BCG Vaccination ................................................................................................................................................. 301
• Variables Affecting Interpretation ...................................................................................................................302
24. Newer Tuberculins: Profile in Developing Countries ...................................................... 310

JL Stanford
• The Reagents .......................................................................................................................................................310
• Skin Test and the Assessment of Vaccine Efficacy ........................................................................................314
• Development of New Vaccines ........................................................................................................................315
• New Tuberculins and Diagnosis of Mycobacterial Disease ......................................................................... 315
• Studies of Close Contacts of Patients with Disease .......................................................................................316
• Detection of Risk Factor ..................................................................................................................................... 317
• Prevaccination Skin Tests ..................................................................................................................................318
xxii
25. Laboratory Diagnosis of Mycobacterial (Tuberculosis) Infection in Children ............ 322
25.1. Conventional Methods ............................................................................................................ 322

Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
• The Diagnostic Challenges ................................................................................................................................322
• Tuberculin Skin Test (Mantoux Test)...............................................................................................................323
• Radiology-based Approaches ...........................................................................................................................324
• Fine Needle Aspiration Cytology (FNAC) .....................................................................................................324
• Conventional Lab Diagnosis .............................................................................................................................324
• Immune-based Diagnosis ..................................................................................................................................329
• Novel Culture Systems and Detection Methods ............................................................................................331
• Diagnosis of TB in HIV Infected Children ...................................................................................................... 331
25.2. Molecular Diagnostic Methods .............................................................................................. 332

S Kumar, Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
• Commercially Available Assays.......................................................................................................................334
• Identification of Mycobacterial Species from Culture by Molecular Methods.......................................... 336
• Molecular Methods for Detecting Drug Resistance in Mycobacterial Strains ...........................................337
26. Imaging of Tuberculosis in Children ................................................................................... 344

Ashu Seith Bhalla, A Kumar, AK Gupta, S Mukhopadhyaya
• Pulmonary Tuberculosis ....................................................................................................................................344
• Imaging Modalities ............................................................................................................................................344
• Imaging Findings ................................................................................................................................................345
• Prediction of Activity of Tuberculous Lesion ................................................................................................. 353
• Follow-up ............................................................................................................................................................. 353
• Intracranial Tuberculosis ...................................................................................................................................354
• Urinary Tract Tuberculosis ...............................................................................................................................358
• Abdominal Tuberculosis ...................................................................................................................................361
• Osteoarticular Tuberculosis .............................................................................................................................. 362
27. Pathologic Spectrum ................................................................................................................ 368

Sandeep R Mathur, Kusum Verma
• Pathologic Spectrum of Tuberculosis in Children .........................................................................................368
• Spectrum of Morphologic Changes .................................................................................................................373
28. New Approaches to TB Diagnosis in Children .................................................................. 380

Ben J Marais, Daphne Ling, Madhukar Pai
• Screening Child Contacts for Active Disease ................................................................................................. 380
• Approaches to Confirm Active Disease ..........................................................................................................382
Section 6: Management
29. Principles of Therapy ............................................................................................................... 395

• Microbiological Principles .................................................................................................................................395
xxiii
Contents
30. Antituberculosis Drugs: First-line Agents ........................................................................... 403

Vimlesh Seth, SD Seth, OP Semwal
• Classification of Drugs .......................................................................................................................................404
• Acute Toxicity of Isoniazid ...............................................................................................................................409
• Rifampicin (Rifampin) .......................................................................................................................................410
• Streptomycin .......................................................................................................................................................412
• Pyrazinamide ...................................................................................................................................................... 414
• Ethambutol ..........................................................................................................................................................415
31. Antituberculosis Drugs: Second-line and Newer Agents ................................................ 427

• Second-line Agents .............................................................................................................................................427
• Fluoroquinolones ................................................................................................................................................430
• Newer Rifamycin Derivatives ..........................................................................................................................434
• Beta-Lactams with Beta-Lactamase Inhibitors ...............................................................................................436
• Tuberactinomycin ...............................................................................................................................................436
• Macrolides ...........................................................................................................................................................436
• Phenazines ...........................................................................................................................................................437
• Cycloserine ..........................................................................................................................................................438
• Aminoglycosides ................................................................................................................................................439
• Capreomycin .......................................................................................................................................................439
• Miscellaneous Agents ........................................................................................................................................440
• Phenothiazines ....................................................................................................................................................441
• Nitroimidazopyrans ...........................................................................................................................................441
• Oxazolidinones ...................................................................................................................................................442
• The New Investigational Drugs .......................................................................................................................442
32. Antituberculosis Drugs: Pharmacokinetics ......................................................................... 449

Vimlesh Seth, Alka Beotra, SD Seth, OP Semwal
• General Aspects ..................................................................................................................................................449
• Factors Responsible for Altered Drug Response in Children ......................................................................452
• Various Factors which Change Pharmacokinetics ........................................................................................453
• Pharmacokinetics of Antitubercular Drugs in Relation to Various Factors ...............................................458
• Isoniazid ...............................................................................................................................................................461
• Rifampicin ............................................................................................................................................................463
• Pyrazinamide ...................................................................................................................................................... 464
33. Pharmacogenetics of Tuberculosis ........................................................................................ 471

Manju Ghosh, Madhulika Kabra
• What is Pharmacogenetics? ...............................................................................................................................471
34. Management of Tuberculosis ................................................................................................. 476

• Commonly Used Drugs ..................................................................................................................................... 476
• Drug Regimens ...................................................................................................................................................476
• Categories and Drugs Regimen under DOTS ................................................................................................478
• Corticosteroids in Tuberculosis ........................................................................................................................478
• Monitoring of Treatment ...................................................................................................................................479
• Monitoring for Side Effects ...............................................................................................................................480
xxiv
35. Consensus Statement on Childhood Tuberculosis— 2010 IAP

Working Group on Tuberculosis........................................................................................... 484
YK Ambdekar
• Objectives ............................................................................................................................................................. 485
• Recommendations ..............................................................................................................................................485
• Current Trends in Chemotherapy of TB under Revised National TB ........................................................490
• Management of a Neonate Born to a Mother with Tuberculosis ................................................................493
• Gaps in Knowledge ............................................................................................................................................493
36. Drug-resistant Tuberculosis in Children ............................................................................. 497

36.1. Drug-resistant Tuberculosis ................................................................................................... 497
HS Schaaf, PR Donald
• The Development of Drug-resistance and Discovery of Basic Principles of
Drug-resistant Tuberculosis .............................................................................................................................. 497
• Drug-resistant Tuberculosis in Children .........................................................................................................497
36.2. Multidrug-resistant Tuberculosis ......................................................................................... 504

• Epidemiology ...................................................................................................................................................... 506
• Management of Patients who have Drug-resistant Disease ......................................................................... 511
37. Organization of Pediatric Tuberculosis and HIV Clinic .................................................. 522

Vimlesh Seth
• Starting Tuberculosis Clinic for Children .......................................................................................................523
• Instructions for Resident Doctor ......................................................................................................................524
• Flow of Patients in TB Clinic .............................................................................................................................525
• New Cases ...........................................................................................................................................................525
• Check List for the Senior Resident Doctor on Follow-up Visit ....................................................................526
• Annexure I ...........................................................................................................................................................529
• Annexure II ..........................................................................................................................................................537
• Annexure III
• Annexure IV ........................................................................................................................................................541
• Annexure V ..........................................................................................................................................................546
Section 7: Prevention and Control of Tuberculosis
38. Bacillus Calmette-Guerin (BCG) ........................................................................................... 555

38.1. Bacillus Calmette-Guerin (BCG) Vaccination .................................................................... 555
• Need for BCG Vaccination ................................................................................................................................555
• Bacillus Calmette-Guerin (BCG) .......................................................................................................................555
38.2. BCG Vaccination—Frequently Asked Questions .............................................................. 574

Vimlesh Seth
• Annexure
• Instruction Sheet for BCG Immunization Section .......................................................................................... 574
xxv
Contents
39. Latent Tuberculosis ................................................................................................................. 589
39.1. Latent Tuberculosis in Children and Adolescents............................................................. 589

Vimlesh Seth, J Cunningham, SM Kuhn
• Latent Tuberculosis ............................................................................................................................................ 589
• Approach to Latent Tuberculosis Infection ....................................................................................................595
• Treatment of Latent Tuberculosis Infection ....................................................................................................597
39.2. Symptoms-based Screening of Child Tuberculosis Contacts—

Improved Feasibility in Resource Limited Settings .......................................................... 602
Alexey Kruk, Robert P Gie, H Simon Schaaf, Ben J Marais
40. Tuberculosis Control Program in Children—Lacunae and Experiences ....................... 612

Rohit Sarin, Sangeeta Sharma
• Issues and Lacunae .............................................................................................................................................612
41. Prospective of Prevention, Diagnosis and Management of

Tuberculosis in the National Program ................................................................................. 616
LS Chauhan
• Burden of Disease ...............................................................................................................................................616
42. Frequently Asked Questions about Tuberculosis .............................................................. 634

• The Broad Status of Tuberculosis at Present in the World ...........................................................................634
• Practical Point ...................................................................................................................................................... 639
• Treatment of TB Patients ...................................................................................................................................646
43. Ethical Issues and Concerns about Tuberculosis Research in Children ....................... 652
Roli Mathur, Prashant Mathur, Vimlesh Seth
• Ethics, Human Health and Research ...............................................................................................................652
• Tuberculosis Diagnosis, Treatment, Control, Prevention, Eradication and Ethics ...................................657
44. Tuberculosis in Children: Research Priorities .................................................................... 661

Vimlesh Seth
• Research in Pediatric Practice ...........................................................................................................................661
• Tuberculosis in Children: Research Priorities ................................................................................................661
• Epidemiology ...................................................................................................................................................... 662
• Diagnosis ..............................................................................................................................................................662
• Treatment ............................................................................................................................................................. 663
• Contact-Screening and Management ...............................................................................................................663
Index ............................................................................................................................................ 665

SECTION 1
INTRODUCTION
• History of Tuberculosis
1 History of Tuberculosis
INTRODUCTION Fracastonius of Verona (1478-1553) reserved the term

phthisis exclusively for pulmonary consumption.4
Tuberculosis, described with different names— King’s evil, There have been many other names used over the
phthisis, Rajyakshma, Tapedic, etc. appears to be a disease centuries for M.tuberculosis-related diseases. The term
as old as human history. Bones of prehistoric man dating tuberculosis relates to the “tubercles” which were first
back to 8000 BC have shown typical changes of associated with the disease in the 17th century, in Holland
tuberculosis.1 A bone from Neolithic period (5000 BC) by Franciseus de la Boe, better known as Dr Sylvius.
found in the region of Heidelberg, likewise shows evidence
of tuberculous changes.2 It has been described in India as Consumption Tuberculosis
early as 3000 BC. In Rigveda which is dated 2000 BC,
King’s evil Tuberculosis of neck and
tuberculosis has been described as Yakshma. Sushruta
lymph glands
described the disease and observed it was difficult to treat.3 Long/lung sickness Tuberculosis
Findings in certain Egyptian mummies clearly indicate Lupus vulgaris Tuberculosis of the skin
that spinal caries existed around 2400 BC.3 Mesenteric disease Tuberculosis of lymph
The oldest legal text in the world formulated by the glands inside the abdomen.
Babylonian monarch Hammurabi in 1948 to 1905 BC and An illness of children
engraved in cuneiform script on a stone pillar, now kept caused by drinking milk
at the Louvre in Paris mentions a chronic lung disease from TB infected cows.
which was probably tuberculosis.4 A unique bacterio- Now uncommon as milk
logical finding of acid-fast bacilli in smears taken from is pasteurized/ boiled in
India
psoas abscess in the astonishingly well preserved
Phthisis Chronic wasting away,
mummy of an Inca child from around 700 BC, clearly
the original Greek name
documents a case of tuberculosis of the lumbar spine.5 for tuberculosis
In Greek, literature description of tuberculosis Pott’s disease Tuberculosis of spine
appears around the time of Hippocrates (460-377 BC). Scrofula Tuberculosis of neck
He first described tubercle (Phymata) in the tissues of lymph glands,
cattle, sheep and pigs. The Hippocratic school considered progresses slowly with
pulmonary pthisis a hereditary rather than infectious abscesses and fistulas
disease.2 develop. Young person’s
Aristotle (384-322 BC) described scrofula on the skin disease
of phthisic pigs. He believed phthisis to be contagious White plaque Tuberculosis
White swelling Tuberculosis of the bone.
even though general opinion at that time tended to the
alternative theory that the disease was hereditary.6
Around the start of the common era, Aretaeus of In the previous era, tuberculosis was aptly named as
Capadocia described pulmonary consumption as a ‘captain of the ship of death.’ Many great literary and art
disease with purulent chronic sputum and generally poor figures died of tuberculosis and millions of victims never
prognosis. Galen (131-201) suspected contagious nature lived long enough to acquire fame. Its most famous victim
of phthisis and warned against intimate contact with was English poet John Keats who died in 1821 at the age of
consumptives. Caelius Aurelianus, a Roman physician 26 years. Some other famous victims of tuberculosis
of 5th century, described clinical details of phthisis. include French painter Antoin Walteare (1684-1721),
Reviewing consumption over the course of history, American philosopher Henry David Thoreu (1817-1862),
it is clear that upsurges of the disease have always Russian writer Antoin Chekhov (1860-1904), Polish composer
followed the development of new urban structures Frederic Chopin and South American liberator Simon Bolivar
drawing large numbers of people into confined space. (1783-1830). The renowned Indian personalities who died
4
Section 1 Introduction
of this disease include KL Sehgal, the famous singer of Soon after the establishment of WHO in 1947, TB was
yesteryear and Kamla Nehru, wife of the first Prime given the highest priority with a focus on BCG
Minister of India, Jawahar Lal Nehru. These deaths vaccination that was the only widely available control
occurred before the availability of chemotherapy.7 measure at that time. In late 1950s, WHO resources
The term ‘tubercle’ was coined by Franciseus Sylvius assisted in the establishment of vertical programs in high
(1614-1672). He noticed tubercles in the lungs of people incidence countries. Beginning 1980s with various control
with ‘phthisis.’ The term ‘tuberculosis’ was introduced by measures it was hoped that TB will finally get controlled.
Laurent Bayle (1774-1816) whereas Benjamin Martin (1720) However, in early 1990s, TB began its resurgence in
suggested that tuberculosis may be an infectious disease. several indus-trialized countries. In 1993 report, the
Frascatorious (1483-1553) postulated that this disease Director General of WHO declared TB to be a global
maybe transmitted in human population by air-borne public health emergency. In subsequent years, Directly
living particles. This particle was named ‘contagium Observed Treatment—Short-course (DOTS) emerged as
vivium.’ In 1868, Villemin (1827-1892) demonstrated in a public health breakthrough measure. Millennium
series of experiments that tuberculosis was caused by a Development Goals (MDGs) for TB Control envisage to
specific agent and that it could be transmitted from man reduce TB prevalence by half by year 2015. To create more
to animals by inoculation with infected material. Robert awareness World TB day is celebrated every year on 24th
Koch in 1882 identified this specific agent of Villemin. March all over world.8
However, the generic name Mycobacterium was proposed Though there is lot of effort to control tuberculosis,
by Lehmann and Newman in 1896. Koch formulated the new challenges are also emerging. In 1980s, TB was
following four postulates (Koch’s postulates): considered to be well controlled illness in industrialized
• The given organism must be found regularly in the countries. With arrival of HIV infection, there was
diseased tissue of the infected person or animal. resurgence of TB.9,10
• The organism must be capable of being grown in pure Other major challenge that has emerged over last three
culture. decades include epidemic of HIV infection and HIV TB
• The pure culture must produce the disease when co-infection, these illnesses enhance progression of each
administered to experimental animals. other and due to drug interaction treatment becomes
difficult. 11,12 There is changing clinical spectrum of illness,
• The organisms must be found in the experimentally
relative increase in extrapulmonary tuberculosis has been
produced disease, and be capable of being recovered
documented.13 Another important challenge include
again in pure culture.7
emergence of multidrug resistant and extensively drug
resistant tuberculosis.14-17
In 1890, Koch discovered ‘tuberculin’ and called it a
Advances have occurred in the diagnostic tests for
remedy for tuberculosis, which was not to be.
tuberculosis. Important developments in microbiology
Nevertheless, tuberculin became an important diagnostic
include development of newer culture media. With better
tool. The theory of allergy, on which Albert Calmette and
understanding of immunology and molecular biology of
Camille Guerin subsequently developed Bacillus Calmette
Mycobacterium tuberculosis, newer diagnostic tests are being
Guerin (BCG) vaccine, was evolved by Koch’s
developed.18,19 Polymerase chain reaction and interferon
observation of the altered behavior of infected organisms gamma release assay (IGRA) are some of them that are
when challenged with subsequent infection (Koch’s going to play an important role in diagnosis of TB.
phenomenon). Koch thought that a successful vaccine
would be a living attenuated vaccine rather than an
HISTORY OF TUBERCULOSIS CONTROL IN INDIA
inactivated one, and various attempts were made by
many workers including Koch himself to obtain such India may be the birth place of one of the deadliest killers
attenuated strains. However, only the artificially of tuberculosis. In a first of its kind study called,
attenuated bovine strain of Calmette and Guerin (BCG) Predominance of Ancestral Lineages of Mycobacterium
was finally produced by subculturing for 13 years (about tuberculosis in India that examined the diversity for
230 times). BCG vaccine was first used in 1921 as a presence of TB strains, a joint team of Indian and French
preventive tool. The discovery of streptomycin by scientist found that ancestral strains of the TB bacterium
Waksman in 1944 revolutionized the treatment from was widespread in India. This is an indication that this
bed rest, good nutrition and fresh air to effective might be the reservoir for TB from which more recent
chemotherapy. In the subsequent three decades, the strains evolved and spread to other countries. Although
conventional long-term therapy was replaced by the India has the highest prevalence of TB world-wide, the
more effective short-course (6-9 months) chemotherapy, genetic diversity of the bacterium in India was largely
mainly with the discoveries of rifampicin, ethambutol, unknown. This made a joint team from the Institute
and ‘rediscovery’ of pyrazinamide in the early seventies. Pasteur, Paris, Center for DNA Finger Printing and
5
Chapter 1 History of Tuberculosis
Diagnostics, Hyderabad, Tuberculosis Research Center, followed by the one in Madanapalle in South India. Later,
Chennai, and the National JALMA Institute for Leprosy many sanatoria were opened by private societies. The
and Allied Mycobacterial Diseases, Agra. They collected Bhowali Sanatorium was established by the Government
91 isolates originating from 12 different regions spread of India in 1911, and was named King Edward Sana-
across the country. The samples were analyzed by torium. Subsequently, many tuberculosis dispensaries in
genotyping with several tests and found highly different parts of India were opened.20
congruent groupings. The four independent sets of
markers made possible a clear definition of the three TUBERCULOSIS ASSOCIATION OF INDIA
prevalent lineages which corresponded to the ancestral
strains, an East African Indian, Delhi and the more Tuberculosis Association of India was established on 23rd
modern and virulent Beijing genogroups. In order to February, 1939. The association set up information and
study this diversity, strains obtained from patients in statistical bureau. The main aim was to encourage the
India between 1997 and 2002 were analyzed. The establishment of the clinics, dispensaries, sanato-ria and
excellent congruence observed between the four education of the public.
independent sets of genetic markers used here lends In relation to pediatrics, Indian Academy of Pediatrics
strong support to the assignment of different prevalent (IAP) formed a Subspeciality Chapter of Tuberculosis in 1989
lineages. Sayed E. Hasmain said “We have over 2500 under the leadership of Late Dr PM Udani.21 Indian
strains of TB in their laboratory”. After short listing the Council of Medical Research (ICMR) has also formed a
91 signature samples, he found that most Indians are separate committee for defining priority areas of research
suffering from the treatable and less harmful ancestral in tuberculosis in children.
TB bacterium. This makes the scientists believe that India A multicentric study in the form of a Task Force
is the origin for the disease. The virulent modern strain, Project was established by ICMR with Vimlesh Seth as
Beijing strain, is present in very few numbers. This leads the Convenor for the various centers. Five centers were
to an important study of the migration of Indian suffering financed by Indian Council of Medical Research (now a
from TB to other countries. Scientists from CDC Atlanta, part of an Independent Department of Health Research
Division of Tuberculosis Elimination (ADTE) have of Government of India as an independent body in the
suggested that the US change its guidelines and make Ministry of Health with Director General of Council as
tests mandatory for all foreign- born nationals. Hence it Secretary Health Research since 2008).
is likely that all foreign born Nationals living in the The objectives of these centers were mainly two:
United States of America including Indians, would soon • To define the uniform criteria of diagnosis of
be undergoing regular test for latent tuberculosis. At tuberculosis in children.
present only those foreign born nationals who have • To do clinical trial of short-course chemotherapy
stayed in America for more than five years undergo TB according to the severity of tuberculosis in children.
skin testing and treatment of latent tuberculosis. An eight As a follow-up of these, under the auspices of
member committee headed by Kevin P. Cain, Director Tuberculosis Chapter in Indian Academy of Pediatrics
of the TB division at CDC Atlanta collected data on all three expert group meetings were held in 1997 22 ,
TB cases listed in the US National TB Surveillance 200423 and 2010.24 Guidelines/Consensus Statement
database to understand why the number of annual cases on Diagnosis and Management of Tuberculosis in
of TB reported in US born residents declined by 93% from Children were also formulated by the National
1993 to 2004, while those among foreign born cases Tuberculosis Control Program (RNTCP). It resulted in a
increased by 5%.India has reported 557 TB cases which joint statement of TB division of Ministry of Health and
figured predominantly in the list of countries of origin Family Welfare and experts from Indian Academy of
of immigrant residents which had the largest number of Pediatrics.25
TB cases in 2004 after Mexico (1976) and Philippines (829). The spade work has also been done by the
India was followed by China (352), Haiti (248), South International Union Against Tuberculosis and Lung
Korea (219), Guatemala (190), Ethiopia (69) and Peru (59). Disease (IUATLD), Paris, and by 1990, the International
Interestingly nearly 375 Indians who were diagnosed Conference guidelines by WHO have been laid down
with TB were living in US for more than five years. regarding the diagnosis and treatment of tuberculosis of
various types in children in 2006.26
SANATORIA IN INDIA
TUBERCULOSIS CONTROL PROGRAM
A christian mission formed the first open-air sanatorium IN INDEPENDENT INDIA
for the treatment and isolation of tuberculous patients
(girls from schools and orphanages) in 1906 near Ajmer. A Tuberculosis Division in the Directorate General
In 1908, another sanatorium of its kind for women and of Health Services of Ministry of Health and Family
girls was founded in Almora (Uttar Pradesh). This was Welfare, Government of India, headed by an Advisor in
6
Section 1 Introduction
Tuberculosis, was established in 1947. The major form of tuberculosis. However, later with realization of
emphasis was on control of the bacillary form of tuberculosis, limitation of the study on BCG and with the opinion of
and BCG vaccination. With the annual rate of infection of pediatricians, it was decided that mass BCG vaccination
3 to 4 percent in India, some 94 million children aged should be continued in infants because Chingleput study
did not include children below five years. Moreover,
between 0 to 4 years are exposed to the risk of infection
what causes morbidity and mortality in children is the
and 3.64 million in this age group are infected annually.26
hematogenous spread in the form of miliary and
These numbers will increase substantially because these meningeal tuberculosis as a complication of primary
estimates were projected when the population of India infection. There are ample studies in the medical
was taken as 700 million (1981 census) which is more literature (India) to prove that BCG vaccination does
than 1000 million at present. Hence, it is felt that simul- provide protection against these severe forms of
taneously, the attention needs to be given to child tuberculosis, though to variable extent. The advent of
population as well. To this effect, as mentioned above, most of the antituberculosis drugs around fifties has
ICMR, IUATLD and WHO are making efforts. changed the whole concept of treatment of tuberculosis
The other activities of the National Tuberculosis and with the introduction of rifampicin and
Program of the Government of India, besides BCG pyrazinamide, it was expected that tuberculosis would
vaccination, are: be controlled in the coming years. The concept of short-
• Establishment of clinics and domiciliary services course chemotherapy with rifampicin and killing of
• Establishment of training and demonstration centers ‘persister’ bacilli with pyrazinamide, has revolutionized
• Provision of beds for isolation and treatment the treatment. However, with the occurrence of
• Facilities for after care and research. concurrent infection with HIV, and poor compliance to
The activities in this direction have been in the form antitubercular drugs leading to the emergence of resistant
of undertaking National Surveys, establishment of strains, the problem of multidrug resistant tuberculosis
Tuberculosis Research Centre at Madras (Chennai) and (MDR-TB) is on the rise. This has to be kept in focus for
National Tuberculosis Institute at Bangalore (Bengaluru). the early suspicion and diagnosis of MDR-TB as well as
Besides, there are separate hospitals for tuberculosis in the proper drug therapy for adequate period. Another
major cities and tuberculosis dispensaries in districts. important challenge include emergence of extensively
Training of Community Health Workers and scheme to drug resistant tuberculosis (XDR-TB). The WHO global
provide ambulatory diagnostic and therapeutic services program committee and the concerned authorities in the
at the door step are also part of its activities. developed and developing countries are keeping vigil
It was reported by WHO in 1999 that by the existing on these aspects.
National Tuberculosis Control Program only 30 to 50
percent of those diagnosed with TB were being cured. REFERENCES
The rest were continuing to transmit the infection and 1. Ayvazian LF. History of tuberculosis. In Reichman LB
TB remained unattended in children. To tackle this Hershfield (Eds): Tuberculosis. New York: Dekker 1993.
problem now a committee has been formed involving 2. Herzog H. History of tuberculosis. Respiration 1998; 65:
WHO experts, program managers in the Health Ministry 5-15.
and renowned pediatricians from Indian Academy of 3. Menon MPS (Ed). History of tuberculosis. In Pulmonary
Pediatrics who have made guidelines for management Tuberculosis, 2nd edn. New Delhi: National Book Trust
of tuberculosis in children. India is one of the first 1987; 8-14.
countries in the world that included children in national 4. Keers RY. Pulmonary Tuberculosis. A Journey Down the
Centuries. London: Bailliere-Tindall 1978.
tuberculosis control programs. Now for children there
5. Dubos R. The romance of death. Am Lung Assoc Bull
are weightwise boxes of medicines. 1982; 68: 5-6.
6. Garrison FH. An Introduction to the History of Medicine.
HISTORY AND DEVELOPMENT OF INTERNATIONAL Philadelphia: Saunders 1913.
COOPERATION IN THE CONQUEST OF TUBERCULOSIS 7. Kanai K. History of tuberculosis and the related research.
With the birth of World Health Organization in 1947, a In Introduction to Tuberculosis and Mycobacteria.
global approach to tackle the problem of tuberculosis was SEAMIC publication no. 60. Tokyo, South-East Asian
Medical Information Center/ International Medical
made. BCG vaccination campaign which started
Foundation of Japan 1991; 1-3.
separately, is now a part of Universal Immunization 8. Yesudian HM, Raviglione MC. World Tuberculosis Day
Program and forms an important component of National 2009: partnership for TB care. Indian J Med Res 2009;
Health and Child Health services. There was a period of 129:215-8.
turmoil when, from Chingleput study in South India it 9. Glynn JR. Resurgence of tuberculosis and the impact of
was interpreted that BCG is not effective against bacillary HIV infection. Br Med Bull 1998; 54: 579-93.
7
Chapter 1 History of Tuberculosis
10. Centre for Disease Control and Prevention (CDC). Progress 19. Kabra SK, Lodha R, Seth V. Some current concepts on
toward the elimination of tuberculosis—United States, childhood tuberculosis. Indian J Med Res 2004; 120:
1998. MMWR Morb Mortal Wkly Rep 1999; 48:732-6. 387-97.
11. Rajasekaran S, Chandrasekar C, Mahilmaran A, et al. HIV 20. Rao KN. History of tuberculosis. In Rao KN (Ed): The
coinfection among multidrug resistant and extensively Textbook of Tuberculosis, 2nd edn. Vikas Publishing
drug resistant tuberculosis patients—a trend. J Indian House, New Delhi 1981;3-15.
Med Assoc 2009; 107: 281-2. 21. Udani PM. Tuberculosis of children in India. Paediatr
12. El-Sadr WM, Tsiouris SJ. HIV-associated tuberculosis: Clin, India 1983;18:11-42.
diagnostic and treatment challenges. Semin Respir Crit 22. Treatment of Childhood Tuberculosis. Consensus
Care Med 2008; 29: 525-31. Statement Recommendations of Indian Academy of
13. Kabra SK, Lodha R, Seth V. Tuberculosis in children— Pediatrics 1997, in Seth Vimlesh, Kabra SK (Eds) Essentials
what has changed in last 20 years? Indian J Pediatr 2002; of Tuberculosis in Children 3rd edn. Jaypee Brothers
69 Suppl 1:S5-10. Medical Publishers (P) Ltd, New Delhi 2006; 543-47.
14. Mohapatra PR, Khurana AK, Janmeja AK. MDR-TB in 23. IAP Working group Consensus Statement of IAP
children: need for clear guidelines. Int J Tuberc Lung Dis working group. Status report on diagnosis of childhood
2009;13:1578-9. tuberculosis. Indian Pediatrics 2004;41:146-55.
15. Schaaf HS, Moll AP, Dheda K. Multidrug- and 24. Amdekar YK. Consesus statement on childhood
extensively drug-resistant tuberculosis in Africa and tuberculosis and working group of Tuberculosis. Indian
South America: epidemiology, diagnosis and Academy of Pediatrics. Indian Pediatr 2010;47:41-55.
management in adults and children. Clin Chest Med 25. Management of Pediatric Tuberculosis under the revised
2009;30:667-83. National Tuberculosis Control Programme (RNTCP). A
16. Shenoi S, Friedland G. Extensively drug-resistant joint statement of the central TB Division, Directorate
tuberculosis: a new face to an old pathogen. Annu Rev General of Health Services, Ministry and experts from
Med 2009; 60:307-20. Indian Academy of Pediatrics, in Seth Vimlesh, Kabra
17. Banerjee R, Schecter GF, Flood J, et al. Extensively drug- SK (Eds): Essential of Tuberculosis in Children 3rd edn.
resistant tuberculosis: new strains, new challenges. Jaypee Brothers Medical Publishers P (Ltd.), New Delhi
Expert Rev Anti Infect Ther 2008; 6:713-24. 2006;543-8.
18. Pai M, O’Brien R. New diagnostics for latent and active 26. World Health Organisation. Guidance for National TB
tuberculosis: state of the art and future prospects. Semin programs on the management of tuberculosis in children.
Respir Crit Care Med 2008; 29: 560-8. WHO, Geneva, Switzerland WHO/ HTN/ TB/2006:371.
SECTION 2
EPIDEMIOLOGY
• Global Epidemiology of Pediatric Tuberculosis

• Interaction of Epidemiological Factors
• Epidemiology: Special Reference to Children
2 Global Epidemiology of Pediatric
Tuberculosis
Md Khurshid Alam Hyder, Nani Nair, Tahmeed Ahmed
INTRODUCTION It is not easy to estimate the TB burden in children.

Challenges for doing so include difficulties in establishing
Tuberculosis (TB) is one of the most widespread a definite diagnosis, the increased presence of
infections affecting almost one-third of the world’s extrapulmonary disease in young children, the lack of a
population. The disease is an important cause of standard case definition, and the lower priority given
morbidity and mortality among both adults and children, to childhood TB on the public health agenda compared
especially in developing countries. It is the first infectious to adult TB.3 WHO data for TB in children are specified
disease to be declared a global health emergency in 1993. only for smear-positive cases. Data available is only upto
According to the WHO report 2009,1 globally, there 2002 (Table 2.2). As children are rarely smear-positive,
were an estimated 9.27 million ancient cases of TB in 2007. except at adolescence as reported recently which
This is an increase from 9.24 million cases in 2006, 8.3 represents only a minor fraction of the total cases. The
million cases in 2000 and 6.6 million cases in 1990. Most focus on smear-positive cases under the DOTS strategy,
of the estimated numbers of cases in 2007 were in Asia also leads to underdiagnosis of TB in children. An
(55%) and Africa (31%), with small proportions of cases accurate rate of tuberculosis in children is therefore
in the Eastern Mediterranean Region (6%), the European unknown.
Region (5%) and the Region of the Americas (3%). The Early identification and successful treatment of cases
five countries that rank first to fifth in terms of total of TB is currently the most effective means to protect
number of cases in 2007 are India (2.0 million), China children from infection with M. tuberculosis. While the
(1.3 million), Indonesia (0.53 million), Nigeria (0.46 DOTS strategy is showing encouraging results in a few
million) and South Africa (0.46 million). Of the developing countries, there is much less evidence of
9.27 million incident TB cases in 2007, an estimated 1.37 a similar impact in low-income countries. Sustained
million (15%) were HIV-positive; 79% of these HIV- efforts in Beijing Municipality, China, where DOTS was
positive cases were in the African Region and 11% were introduced in 1978, have been able to reduce the
in the South-East Asia Region. Although the total number prevalence of TB in children, and particularly life-
of incident cases of TB is increasing in absolute terms as threatening forms such as TB meningitis.4
a result of population growth, the number of cases per
capita is falling. The rate of decline is slow, at less than
PRESENTATION OF PEDIATRIC TB
1% per year. Globally, rates peaked at 142 cases per
100000 population in 2004. In 2007, there were an Tuberculosis is caused by mycobacteria. M. tuberculosis
estimated 139 incident cases per 100 000 population. is the most frequently found organism, to a lesser extent
Incidence rates are falling in five of the six WHO regions also M. bovis and M. africanum. In most cases, the
(Table 2.1). infection is transmitted from pulmonary smear-positive
In 2000, 8.3 million incident cases of TB were reported; cases (“open” cases) to other people. Patients are
an estimated 11 percent were children and the reported classified as smear-positive if acid-fast bacilli (the
proportion of TB occurring in children ranged from 3-25 mycobacteria) can be demonstrated in sputum. Children
percent.2 The percentage of TB cases occurring in children are rarely smear-positive, hence are much less likely to
is estimated to be below 5 percent in the United States be a source of infection for others. However, children
and European countries.2 However, developed countries can transmit M. tuberculosis, as has been documented
have witnessed a resurgence in TB due to immigration in large school-based and community outbreaks.5,6 They
of people from countries with high incidence of are more likely to develop disease after infection and
tuberculosis. In the report in 2009 by WHO there is are significantly more likely to develop extrapulmo-
no separate mention of children as TB notification nary and severe disseminated disease than adults. These
even among new smear-positive cases in DOTS areas. clinical observations apparently reflect fundamental
These figures are available only for 2002, and given in differences in the immune systems of young children
Table 2.2. and adults.7
12
Table 2.1: Estimated epidemiological burden of TB, 2007
Incidencea Prevalencea Mortality

All forms Smear- all forms HIV HIV
positive negative positive
HIV Prev.
Per Per Per Per Per in incident
Population Number 100,000 Number 100,000 Number 100,000 Number 100,000 Number 100,000 TB casesb
1000s 1000s pop 1000s pop 1000s pop 1000s pop 1000s pop
per year per year per year per year per year %
1. India 1 169 016 1 962 168 873 75 3 305 283 302 26 30 2.5 5.3
2. China 1 328 630 1 306 98 585 44 2 582 194 194 15 6.8 0.5 1.9
3. Indonesia 231 627 528 228 236 102 566 244 86 37 5.4 2.4 3.0
4. Nigeria 148 093 460 311 195 131 772 521 79 53 59 40 27
5. South Africa 48 577 461 948 174 358 336 692 18 38 94 193 73
6. Bangladesh 158 665 353 223 159 100 614 387 70 44 0.4 0.3 0.3
7. Ethiopia 83 099 314 378 135 163 481 579 53 64 23 28 19
8. Pakistan 163 902 297 181 133 81 365 223 46 28 1.4 0.9 2.1
9. Philippines 87 960 255 290 115 130 440 500 36 41 0.3 0.3 0.3
10. DR Congo 62 636 245 392 109 174 417 666 45 72 6.0 10 5.9
11. Russian 142 499 157 110 68 48 164 115 20 14 5.1 3.6 16
Federation
12. Vietnam 87 375 150 171 66 76 192 220 18 20 3.1 3.5 8.1
13. Kenya 37 538 132 353 53 142 120 319 10 26 15 39 48
14. Brazil 191 791 92 48 49 26 114 60 5.9 3.1 2.5 1.3 14
15. UR Tanzania 40 454 120 297 49 120 136 337 12 29 20 49 47
16. Uganda 30 884 102 330 42 136 132 426 13 41 16 52 39
17. Zimbabwe 13 349 104 782 40 298 95 714 6.9 52 28 213 69
Section 2 Epidemiology
18. Thailand 63 884 91 142 39 62 123 192 10 15 3.9 6.0 17

19. Mozambique 21 397 92 431 37 174 108 504 10 45 17 82 47
20. Myanmar 48 798 83 171 37 75 79 162 5.4 11 0.9 1.9 11
21. Cambodia 14 444 72 495 32 219 96 664 11 77 1.8 13 7.8
22. Afghanistan 27 145 46 168 21 76 65 238 8.2 30 0.0 0 0
High-burden 4 201 761 7 423 177 3 245 77 11 301 269 1 058 25 339 8.1 14
countries
AFR 792 378 2 879 363 1 188 150 3 766 475 357 45 378 48 38
AMR 909 820 295 32 157 17 348 38 33 3.6 7.9 0.9 11
EMR 555 064 583 105 259 47 772 139 97 17 7.7 1.4 3.5
EUR 889 278 432 49 190 21 456 51 56 6.3 8.1 0.9 9.8
SEAR 1 745 394 3 165 181 1 410 81 4 881 280 497 28 40 2.3 4.6
WPR 1 776 440 1 919 108 859 48 3 500 197 276 16 15 0.8 2.7
Global 6 668 374 9 273 139 4 062 61 13 723 206 1 316 20 456 6.8 15
a
Incidence and prevalence estimates include TB in people with HIV.
b
Prevalence of HIV in incident TB cases of all ages.
Source: Ref. 1—Global Tuberculosis Control Report, 2009.
13
Chapter 2 Global Epidemiology of Pediatric Tuberculosis
Table 2.2: TB notification in children among new smear-positive cases in DOTS areas (2002)
WHO region Boys (0-14) Girls (0-14) Total (0-14) All ages % children
Africa 7 926 9 471 17 397 958 365 1.8
The Americas 834 988 1 822 134 267 1.4
Eastern Mediterranean 1 415 1 544 2 959 179 594 1.6
Europe 156 201 357 134 917 0.3
South-East Asia 2 741 4 540 7 281 954 727 0.8
Western Pacific 1 000 1 280 2 280 680 750 0.3
Total 14,072 18,024 32,096 3,042,620 1.1
The risk of developing TB disease after infection with disease, and with a normal chest X-ray.2 Diagnosis of TB
M. tuberculosis is, in the absence of HIV co-infection, disease in children, however, is difficult because (1)
estimated to be between 5 and 10 percent in adults, 15 routine sputum smear microscopy rarely identifies TB
percent in adolescents, 24 percent in children below five in children: children under the age of ten rarely
years and as high as 43 percent in children under one year.8 expectorate sputum for evaluation; if they do, they may
If children develop TB disease, it happens more often early be less subjected to sputum-microscopy; (2) the Mantoux
after infection (progressive primary infection). The factors test may be negative if the child is malnourished; (3) since
that determine a child’s risk of developing disease include cavitary lesions due to pulmonary TB are rare in children,
younger age, malnutrition, recently acquired infection, and chest X-rays are not always helpful except at adolescent
immune suppression, particularly due to measles or HIV age group.12 If sputum is tested, they are less likely to be
infection.2 The incubation time (time between infection and smear-positive compared to adults. Approximately 95
symptoms) generally varies between one to six months.9 percent of children of less than 12 years old with TB are
If they do not develop disease during childhood, infected smear-negative.13 Gastric aspirates have also a low
children represent part of the pool from which future adult specificity: they are positive on smear in 20 percent of
TB cases will arise. Children infected with TB also indicate the cases and on culture in 50 percent.14 Gastric aspirates
that recent transmission of TB has occurred in the are often limited to hospital settings in urban areas, as is
communities where they are living. the case with mycobacterial culture. This leads to an
underdiagnosis of TB in children as efforts to confirm a
Pulmonary Tuberculosis diagnosis are often not made. Cases diagnosed outside
public programs are also less likely to be reported. Case
As a result of exposure to TB, a primary parenchymal definitions for research or surveillance are rarely based
lesion called Ghon focus develops in the lung with spread on bacteriology. A number of scoring systems are used
to the regional lymph nodes. The disease process is based on clinical symptoms, Mantoux test, contact history
contained at this stage in most cases by the resultant cell- and X-ray film of chest. An autopsy study carried out in
mediated immunity. Progression of disease in some Zambia found that 20 percent of children dying of
children occurs by: 1) extension of the primary focus with respiratory disease had evidence of TB, which in many
or without cavitary lesions; 2) the pathological processes cases was only diagnosed post mortem.15
caused by the enlarging lymph nodes, or by 3) spread WHO does not routinely collect segregated age data
through lymphatic and/or hematogenous spread.10 for smear-negative and extrapulmonary cases. This
means that 80 percent of child TB cases cannot be
Extrapulmonary Tuberculosis retrieved in the reported data. The proportion of child
Extrapulmonary tuberculosis (EPTB) refers to TB of TB varies enormously between countries. In low-preva-
organs other than the lungs. EPTB is common among lence countries, this may be less than five percent,
children and the most common forms include TB whereas in some high prevalence countries, it could be
lymphadenopathy, TB meningitis, TB effusions (pleural, more than four times higher. Detailed information of TB
pericardial and peritoneal) and spinal TB. According to in children is available from few countries only.
WHO the ratio of pulmonary and EPTB in children is
usually around 1:3. However, a retrospective study in TB IN THE WORLD
Brazil found that among under-15 children, pulmonary
Europe
TB was most frequent (57.8%), EPTB occurred in 24.4%
of the cases, while both forms occurred together in Tuberculosis cases in the WHO European Region make
17.8%.11 up less than 5 percent of the global disease burden.16 Case-
Diagnosis of TB infection in children is based on a notification rates vary enormously between countries in
positive Mantoux test without signs or symptoms of the the Region: 3 per 100,000 in Cyprus and Iceland versus
14
178 per 100,000 in Kazakhstan. Most countries in Western pronounced, a similar pattern is visible in other urban
Europe have notification rates below 10 per 100,000, while centers in UK, with a greater proportion of cases
some countries in Eastern Europe including the former identified among ethnic minorities.
Soviet Union report case-detection rates of more than 100 Other countries in Western Europe report a similar
per 100,000 (Fig. 2.1). pattern. Child TB in Stockholm has risen from <1 per
Case-notification rates have fallen in France and UK 100 000 in 1991 to 5.8 per 100,000 in 1995.19 Fifty percent
since 1980 and remain fairly constant in the last five years. of the children with TB were born in Africa. A study from
Many Eastern European countries have steadily increasing Copenhagen carried out between 1984 and 1993, showed
TB notification rates. TB data on children are scarce. The that 70 percent of children diagnosed with TB had
region reported only 551 smear-positive patients in the immigrant parents.20
age group 0 to 14 years, in both DOTS and non-DOTS
areas. Fifty percent of those came from two countries: Africa
Kazakhstan and Romania. Childhood TB increased more
than threefold in Latvia: from 43 to 144 cases between 1991 TB case notification in the WHO Africa Region has
and 2000, or an increase in rate from 7.5 to 38.9 per 100,000. increased dramatically in recent years. This is to a large
In 2000, childhood TB accounted for 8.4 percent of all TB extent attributable to HIV/AIDS. Although the
cases in Latvia. TB incidence in children has also increased population base in African countries is relatively smaller
in the Russian Federation. than the large Asian countries, not less than nine African
Although the proportion of child TB cases is lower in countries are found among the 22 high-burden TB
Kazakhstan than in France, this may be due to countries (which carry 80% of the global TB burden).
underdiagnosis or underreporting. The substantially Several African countries have the largest estimated rates
higher share of young adults in Eastern Europe indicates for TB in the world, more than countries in Asia or the
that children are more exposed to TB from their parents Western Pacific.
or their caretakers. Younger TB patients are more likely Among African countries, South Africa notified the
than older TB patients to have young children sharing highest number of TB cases in 2002, both in absolute
their household environments.17 number and as a rate per 100000. The notification rates
Specific changes are also occurring in the pattern and in South Africa and Zimbabwe are almost three times
distribution of child TB cases in the United Kingdom.18 those of other high-burden countries. Countries in Sub-
While TB notifications have marginally increased in UK, Saharan Africa have witnessed a substantial increase in
they have substan-tially increased in London city. TB case notification over the last ten years.21 Two-thirds
London alone contributes now 40 percent of all TB cases of the countries with case rates among children of more
in UK. Some areas in London have TB notification rates than 5 per 100 000 are located in Sub-Saharan Africa.
of more than 100 per 100 000. Child TB has also increased In a recent cross sectional survey of latent TB infection
every year since 1988. There is also a shift towards more in Cape Town area, only 4.7% had low grade TST
TB in black African children in UK, whereas the pro- responses of 1-9 mm. The proportions of individuals with
portion of pediatric cases from the Indian subcontinent TST ≥ 10 mm was 28.0% in the 5-10 year age stratum and
has decreased (44% for black African and 21% for 88.0% in the 31-35 year age stratum.22
children from the Indian subcontinent in 1998, while it The incidence in children is much more difficult to
was 23% and 50% respectively in 1993). TB in children is estimate due to lack of systematically collected data. As
also dramatically increasing in UK due to immigration. most of the African countries have resource-poor health
Sixty-six percent of the African children with TB in UK services, accurate diagnosis of TB in children becomes
were born abroad, and developed the disease within five even more difficult. As part of the DOTS strategy, several
years after entering the country. Although less TB programs in the region rely entirely on sputum-smear
microscopy for diagnosis of TB. This indicates that TB in
children in Africa is both underdiagnosed and under-
reported. The validity of the scarcely available data is
also not guaranteed.
It is clear however that, in Sub-Saharan Africa, child
TB has a larger share in the overall TB case load compared
with other regions. A study published in 2002 estimates
that childhood TB may represent up to 20 percent of
all TB cases.23 Another study from an urban community
Fig. 2.1: Distribution of TB in the World, AFR-Africa, AMR-The Americas,
in the Western Cape Province, South Africa, found
EMR-Eastern Mediterranean, EUR-Europe, SEAR-South East Asia, that 39 percent of the total cases was younger than 14
WPR-Western Pacific (new smear-positive cases 2003) years.24
15
In the United Republic of Tanzania25 and Kenya,26 Brazil, the only country of this region belonging to
repeated surveys to estimate the annual risk of the 22 high-burden countries, is also seeing a steady
transmission of infection (ARTI) show an increase in areas decrease in case-notification since 1998. The US Centers
where TB notification was the highest. The areas with for Disease Control and Prevention (CDC) reported an
the high prevalence rates for TB had also high prevalence estimated overall TB rate in the USA of 5.6 per 100,000 in
rates of HIV infection. 2002. This is the lowest figure since reporting began more
than fifty years ago.31
South-East Asia Data on childhood TB are available mainly from USA,
thanks to the comprehensive notification system by
The WHO South-East Asia Region consists of six CDC.2 TB in children is based on a positive tuberculin
countries in South Asia (Bangladesh, Bhutan, India, skin test, a complete set of diagnostic investigations, signs
Maldives, Nepal and Sri Lanka), four countries in South- and symptoms compatible with TB, and treatment with
East Asia (Indonesia, Myanmar, Thailand and Timor- two or more anti-TB drugs. The USA experienced a rise
Leste) and one country in North-East Asia (DPR Korea). in the overall TB case rate from 1984 to 1992, in
With 26 percent of the global population, these 11 conjunction with the declining public health
countries carry 34 percent of the global TB burden. India, infrastructure and the rising epidemic of HIV. However,
Indonesia and Bangladesh are in the top four among the the number of pediatric TB cases rose in this period with
22 high burden countries. India alone had an estimated 40%, twice the increase reported for the population as a
1.7 million TB cases in 2002. Although Maldives has the whole.32 Later, pediatric TB fell from 3.1 in 1992 to 1.5
lowest TB rate, the rate of this island nation is still twice per 100,000 in 2001. However, the share of children
that of Western Europe. among all TB cases has remained unchanged at 6 percent
There is little information on rates of childhood TB in during this period. As in UK, children belonging to ethnic
the region. Rates of infection have also been used to minority groups have a disproportionate share. Children
estimate the disease burden in a community, given the belonging to the Hispanic, black, non-Hispanic and Asian
limitations of using notification data for this purpose.27 or Pacific Islander communities developed TB disease
A study by the TB Research Centre, Chennai found an
much more compared to Caucasian children.33,34
ARTI of 2 percent in Chingleput district, Tamil Nadu,
In 2001, half of the TB cases reported to CDC occurred
India.28 This figure has not changed for the last 30 years,
in individuals born outside the USA. In California, the
suggesting that the TB risk for children is not increasing.
overall rates of pediatric TB have been falling since 1992;
It is estimated that approximately ten million children
this decline was most important in children born
per year in India alone are at risk of being infected with
overseas. Foreign-born children accounted for 42 percent
TB because of close contact with a smear-positive adult.29
of all childhood TB in California between 1985 and 1995.
A survey in Indonesian health facilities showed
In San Diego, in over 90 percent of US-born children
pediatric cases ranging between 5 and 28 percent of all
under-5 with TB, a source case could be identified from
TB cases, with the median age of child TB between 4 and
a highly endemic country or had a primary household
7.7 years old.30
language different from english.35
Eastern Mediterranean Western Pacific
TB case notification rates in this part of the world have
Figures in the Western Pacific Region are dominated by
remained stable or have even fallen in recent years. one country, China. There were an estimated 1.5 million
Overall contribution of this region to the global TB TB cases in 2002 in China, ranking the country second in
disease burden is only 4 percent. the world, after India. The estimated TB rate however, is
Only two countries in this region belong to the 22 moderately high: 113 per 100,000. Most other countries
high burden countries: Afghanistan and Pakistan. Both in the region have estimated rates in the same range. Only
countries are severely under-reporting, with less than 20 Cambodia has rates comparable to Sub-Saharan African
percent of the estimated cases being notified to WHO. countries. Apart from China, countries in the region
Very little information from this region is available report very few smear-positive children to WHO: 2,280
with regard to childhood TB. of whom 1,881 are in China.
A study in Australia shows how immigration from
The Americas high-prevalence countries contributes significantly to the
The case-notification rates have remained fairly constant disease pattern within a low prevalence population.36
since 1980 or went even down in most recent years. It Notification rates were highest in children born overseas,
was 40 per 100,000 in the early eighties, while the current while 51 percent of Australian born children with TB
figure stands at 27 to 28 per 100,000. were from non-English speaking households.
16
EFFECT OF MIGRATION absolute number of smear-positive cases increases also

substantially, which enhances exposure to and spreading
The effect of migration from resource-poor countries to of the infection to HIV+ and HIV– people alike.46 HIV in
developed countries has been well studied with active adults may be an indirect risk factor for TB in children.47
TB surveillance programs. This movement has a TB diagnosis in HIV+ children is even more difficult
tremendous impact on TB in developed countries.
in resource-poor countries. Tuberculin skin test may
Tuberculosis has been dubbed a re-emerging epidemic,
become negative due to HIV-associated anergy. The
which was thought to have almost entirely disappeared
clinical presentation of pulmonary TB overlaps with other
from the developed countries. This has been documented
opportunistic pulmonary infections and HIV related
extensively in USA, Australia, UK and Canada. In this
illnesses and may therefore, also be overdiagnosed.48 The
last country, the overall risk of TB was found to be twelve
child may have TB and other pulmonary diseases
times higher in immigrants compared to people born in
concurrently, and thus initially improve with a broad-
Canada.37 Similar results have been documen-ted in
spectrum antibiotic course.40 The treatment outcomes of
Switzerland 38, Germany 39 and Spain.40 Molecular
HIV+ TB children are also worse due to a higher
epidemiological studies undertaken in Norway and UK
mortality. A study in Ethiopia showed that the mortality
suggest that many of the new TB cases in immigrants are
during TB treatment in HIV+ children was six times
due to reactivation of infections acquired abroad.41-43
higher than in HIV-negative children.49 Similar results
Immigrant children in developed countries are at
were obtained from studies in the Côte d’Ivoire. 50
much higher risk of developing TB com-pared to children
Children with TB and HIV coinfection also appear to have
born in the country. Recent arrivals may have been
higher relapse rates.
exposed to TB in their country of origin. Those children
A major difference between children and adults with
are more likely to be exposed to TB either by traveling
HIV is the time of infection. Most adults have been
back to their country of origin or because of living in
infected with M. tuberculosis prior to their HIV infection.
close contact with infectious adults within their homes.
Tuberculosis disease may thus represent a reactivation
of a latent infection. Most children are perinatally infected
HIV and TB
with HIV. Exposure to and infection with TB occurs
HIV has a tremendous effect on TB, particularly in Sub- usually later. TB in children with HIV may therefore,
Saharan Africa. TB rates have increased following an occur at a later age, as young children with HIV are at a
increase in HIV. HIV is known to increase the risk of high-risk of morbidity and mortality from other
developing TB disease after infection. It is considered one respiratory diseases before they are infected with TB.51
of the principal reasons for the resurgence of TB in this
region. MDR-TB
There is limited information on the impact of HIV on
pediatric TB rates. It seems likely that it has contributed Drug-resistant TB may be acquired due to inadequate
to the increasing rate of disease in children in high previous treatment episodes. Such failure cases may
prevalence countries. HIV disproportionately affects spread resistant bacilli. Primary resistance occurs in
young, economically active people who are more likely people who are resistant to anti-TB drugs without being
to have young children. treated. Resistant children generally are primary
The number of children with TB coinfected with HIV resistant, as they are less likely to have been treated
has also increased. A study from Rio de Janeiro, Brazil before.52 There were estimated 0.5 million cases of multi-
shows an increase from 23 to 31 percent between 1995 drug-resistant TB (MDR-TB) in 2007. The countries that
and 1999.44 A similar phenomenon has been documented rank first to fifth in terms of total number of MDR-TB
from South Africa, where 48 percent of children with cases are India (1,31,000), China (1,12,000), the Russian
culture proven pulmonary TB were coinfected with Federation (43,000), South Africa (16,000), and
HIV.45 Bangladesh (15,000). By the end of 2008, 55 countries and
While it is clear that HIV-positive children are more territories had reported at least one case of extensively
vulnerable for developing the disease after infection, it drug-resistant TB (XDR-TB).1 No such data is available
is not yet proven if HIV makes them more vulnerable of for children. It is however, very difficult to document
being infected. Increased childhood TB rates are drug resistance in children due to lower rates of
associated with increased rates of disease among HIV microbiological confirmation in children. The diagnosis
infected adults in the community. As TB is the most of resistant TB in children is often made on demonstrating
common opportunistic infection in HIV-infected adults, resistance in an adult index case. There may be a strong
those adults are more likely to progress to TB disease. correlation with a suspect index case in low risk countries.
Although HIV-positive TB patients show more smear- In high prevalence countries however, multiple exposure
negative pulmonary and extrapul-monary disease, the within the same household, with a drug-sensitive index
17
case, does not rule out primary drug resistance in a 3. Kabra SK, Lodha R, Seth Vimlesh. Childhood
child. tuberculosis: what has changed in last 20 year. Indian J
There is no evidence that drug resistant bacilli would Pediatr 2002; 69: S5-10.
lead to increased infectiousness or increased risk of 4. Enarson DA. Children and global tuberculosis situation.
progressing to disease after infection.53 In general, the Paediatr Respir Rev 2004; 5(Suppl A): S143-5.
5. Eamramond P, Jaramillo E. Tuberculosis in children:
incidence and types of resistant organisms found in
reassessing the need for improved diagnosis in global
children will reflect the resistance pattern of organisms
control strategies. Int J Tuberc Lung Dis 2001;5:594-603.
circulating in the community.54 A South African study
6. Curtis AB, Ridzon R, Vogel R, et al. Extensive
conducted between 1994 and 1998 found 5.6 percent transmission of Mycobacterium tuberculosis from a child.
isoniazid resistance and 1 percent multidrug resistance N Engl J Med 1999;341:1491-5.
(isoniazid and rifampicin) in culture-positive TB 7. Lewinsohn DA, Gennaro ML, Scholvinck L, et al.
children.55 These figures were similar to what was found Tuberculosis immunology in children: diagnostic and
in the adult population during the same period. Data therapeutic challenges and opportunities. Int J Tuberc
from UK also shows similar resistance patterns in Lung Dis 2004;8:658-74.
children and adults. 8. Miller F, Seal R, Taylor M. Tuberculosis in children.
Boston: Little Brown, 1963.
CONCLUSION 9. Feigin R, Cherry J. Textbook of Pediatric Infectious
Diseases, 4th edn. Philadelphia: WB Saunders; 1998.
Tuberculosis remains a major problem of public health 10. Guidance for national tuberculosis programmes on
with a high morbidity and mortality. The internationally the management of tuberculosis in children: World
recommended DOTS strategy focuses on identifying and Health Organization. Available at: WHO/HTM/TB/
treating smear-positive cases, as a way of prioritizing 2006.371.
infectious cases and focusing interventions on cutting the 11. Franco R, Santana A, Matos E, et al. Clinical and
transmission. radiological analysis of children and adolescents with
Yet little is known about the global impact of tuberculosis in Bahia, Brazil. Braz J Infect Dis 2003 ;7:
73-81.
childhood tuberculosis. The overall majority of TB in
12. Ahmed T, Sobhan F, Ahmed AMS, et al. Childhood
children is ignored when limiting our attention to smear
tuberculosis: a review of epidemiology, diagnosis and
or culture-positive cases only. The number of children management. Inf Dis J Pak 2008;17:52-60.
suffering or dying from TB is unknown. Data are rather 13. Jereb JA, Kelly GD, Porterfield DS. The epide-miology
scarce, and if available, they document mainly findings of tuberculosis in children. Sem Pediatr Infect Dis
in developed countries. Migration is the main reason for 1993;4:220-31.
the resurgence of TB in industrialized countries, while 14. Khan EA, Starke JR. Diagnosis of TB in children:
HIV is the main cause fuelling the TB epidemic in increased need for better methods. Emerg Infect Dis 1995;
resource-poor, high-burden TB countries. Most children 1: 115-23.
with TB are not identified through national surveillance 15. Chintu C, Mudenda V, Lucas S. Lung diseases at
systems; they often represent the more severe complica- necropsy in African children dying from respiratory
tions. TB in children is also a sentinel marker for active illnesses: a descriptive necropsy study. Lancet
transmission of TB within communities.56 2002;360:985-90.
16. WHO Report 2004. Global Tuberculosis Control.
Surveillance, Planning, Financing.
HIGHLIGHTS 17. Rieder HL. Epidemiology of tuberculosis in children.
• Childhood TB contributes 5 to 15 percent of total Annales Nestlé 1997;55:1-9.
TB cases. 18. Atkinson P, Taylor H, Sharland M, et al. Resurgence of
• Estimates of TB in children are gross under estimates pediatric tuberculosis in London. Arch Dis Child
as most surveys report smear-positive cases only. 2002;86:264-5.
19. Eriksson M, Bennet R, Danielsson N. Clinical
• Childhood TB has a larger share in Sub-Saharan
manifestations and epidemiology of childhood
Africa.
tuberculosis in Stockholm 1976-95. Scand J Infect Dis
• Immigrant children are more prone to develop TB 1997;29:569-72.
as compared to those born in that country. 20. Rosenfeldt V, Paerregaard A, Fuursted K, et al.
Childhood tuberculosis in a Scandinavian metropolitan
area 1984-93. Scand J Infect Dis 1998;30:53-7.
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23. Donald P. Childhood tuberculosis: out of control? Curr Spanish Children: A Three-Decade Review. Pediatr Infect
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25. Tanzanian tuberculin study collaboration, Tuberculosis 42. Hayward A, Goss S, Drobniewski F, et al. The molecular
control in the era of the HIV epidemic: risk of tuberculosis epidemiology of tuberculosis in inner London. Epidemiol
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2001;5:103-12. 43. Maguire H, Dale J, McHugh T, et al. Molecular
26. Odhiambo J, Borgdorff M, Kiambih F. Tuberculosis and epidemiology of tuberculosis in London 1995-1997
the HIV epidemic: increasing annual risk of tuberculosis showing low rate of active transmission. Thorax
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27. Styblo K. The relationship between the risk of co-infection in children under-15 years of age in Rio de
tuberculosis infection and the risk of developing Janeiro, Brazil. Int J Tuberc Lung Dis 2003;7:198-9.
tuberculosis. Bull Int Union Tuberc 1985;60:117-9. 45. Jeena P, Pillay P, Pillay T, et al. Impact of HIV-1
28. Tuberculosis Research Centre. Trends in the prevalence coinfection on presentation and hospital-related
and incidence of tuberculosis in South India. Int J Tuberc mortality in children with culture pulmonary
Lung Dis 2001;5:142-57. tuberculosis in Durban, South Africa. Int J Tuberc Lung
29. Chakraborty A. Problem of tuberculosis among children Dis 2002;6:672-8.
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of tuberculosis in India. Indian J Tuberc 1999;46:91-103. in human immunodeficiency virus-infected and human
30. Manissero D. Personal communication with author. immunodeficiency virus-exposed children in New York
31. CDC. Reported tuberculosis in the United States 2001. City. Pediatr Infect Dis J 2000;19:700-6.
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33. Ussery XT, Valway SE, McKenna M, et al. Epidemiology in HIV-infected African children. Int J Tuberc Lung Dis
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Pediatr Infect Dis J 1996;15:697-704. 49. Palme I, Gudetta B, Bruchfeld J. Impact of human
34. Saiman L, San Gabriel P, Schulte J, et al. Risk factors for immunodeficiency virus I infection on clinical
latent tuberculosis infection among children in New York presentation, treatment and survival in a cohort of
City. Paediatrics 2001;107: 993-1003. Ethiopian children with tuberculosis. Pediatr Infect Dis
35. Kenyon T, Driver C, Haas E, et al. Immigration and J 2002;21:1053-61.
tuberculosis among children in the United States— 50. Mukadi Y, Wiktor S, Coulibaly I, et al. Impact of HIV
Mexico, county of San Diego, California. Paediatrics infection on development, clinical presentation and
1999;104-8. outcome of tuberculosis among children in Abidjan, Côte
36. Heath T, Roberts C, Winks M, et al. The epidemiology of d’Ivoire. AIDS 1997;11:700-6.
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of immigration in a low-prevalence population. Int J insights into the interaction of childhood tuberculosis and
Tuberc Lung Dis 1998;2: 647-54. HIV in the Western Cape. S Afr J HIV Med 2000;7:33-5.
37. Long R, Sutherland K, Kunimoto D, et al. The 52. Schaaf HS, et al. Transmission of multidrugresistant
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persons in Alberta, Canada, 1989-1998: identification of 53. Tiexeira L, Perkins MH, Johnson J. Infection and disease
high-risk groups. Int J Tuberc Lung Sis 2002;6:615-21. among household contacts of patients with multi-drug-
38. Barrazone C, Hofer M, Nussle D, et al. Childhood resistant tuberculosis. Int J Tuberc Lung Dis 2001;5:321-8.
tuberculosis at a Swiss university hospital: a two year 54. Steiner P, Rao M. Drug-resistant tuberculosis in children.
study. Eur J Pediatr 1993;152:805-9. Sem Pediatr Infect Dis 1993;4:275-82.
39. Felten MK, Rath T, Magdorf K, et al. Childhood 55. Schaaf H, Gie R, Beyers N, et al. Primary drug-resistant
tuberculosis in Germany between 1985 and 1994: tuberculosis in children. Int J Tuberc Lung Dis
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Lung Dis 1998;2:797-803. 56. Bloch A, Snider D. How much tuberculosis in children
40. Del Rosal T, Baquero-Artigao F, García-Miguel MJ, et al. continue to be neglected? Am J Public Health 1986;76:
Impact of Immigration on Pulmonary Tuberculosis in 14-5.
3 Interaction of
Epidemiological Factors
Donald A Enarson, Nulda Beyers
INTRODUCTION Epidemiological Methods for Measuring

No one could say that tuberculosis is not a serious Tuberculosis
problem today. It is the most frequent cause of death from A variety of methods have been applied and standardized
a single disease in the world among those aged 15 to 49 for the measurement of tuber-culosis in epidemiological
years, and the main cause of death in people living with investigations, including mortality studies,39 studies of
HIV/AIDS. Deaths due to tuberculosis are equivalent to routine notifications,40-43 data from routine reporting and
the crash of a jumbo jet every hour of every day. recording practices, prevalence surveys of disease44 and
The distribution and trend of tuberculosis in the world of infection45-48 and cohort studies of risk factors of
has been extensively described in other publications.1-3 disease.49,50 Studies have employed clinical and/or radio-
The epidemiology of tuberculosis has been described over logical examination,51-55 bacteriological techniques56-60 and
many years by a series of eminent investigators.4-12 molecular techniques.61-67 Identification and isolation of
According to WHO report 2009,13 globally there were an the microorganism using routine bacteriological
estimated 9.27 million incident cases of TB in 2007. This techniques has been considered the ‘gold standard’ in
is an increase from 9.24 million cases in 2006; 8.3 million identifying a ‘case’ of tuberculosis. However, this has been
cases in 2000 and 6.6 million cases in 1990. Most of the reported to be insensitive in children from whom it is
estimated number of cases in 2007 were in Asia (55%) exceedingly difficult to isolate Mycobacterium tuberculosis
in the majority of cases.1 Because it is so difficult to isolate
and Africa (31%). The most important epidemiological
the microorganism, defining a case for study purposes is
factor is the HIV status of population. These publications
a great challenge. For this reason, tuberculous meningitis
have highlighted the fact that tuberculosis is less a disease
in children was often used as an indicator of disease as
of the individual and more strikingly a disease of the well as of recent infection.
family and of the community. This is even more the case The tuberculin skin test, the ‘gold standard’ for
with tuberculosis in children. indicating the presence of infection with Mycobacterium
tuberculosis has been used extensively, 68 and even
A Framework for Understanding the Epidemiology of predominantly, in children. This test identifies
Tuberculosis individuals who have been infected with Mycobacterium
species and does not indicate the presence of disease.
Understanding the epidemiology, natural history and
control of tuberculosis is much easier when the disease Distribution of Tuberculosis in Children
is considered as a series of transitions from being
susceptible to becoming ill and finally being cured, The distribution of a disease in a population is classically
becoming a chronic case or dying of the disease.14 presented by characteristics of person, place and time.
This model, originally proposed in the 1960s, has been
revisited recently15 and its evidence base outlined.16-35 Person
Key transitions relevant to tuberculosis in children are Several recent reviews69,70 have evaluated a series of
the transitions from being susceptible to becoming studies from the prechemotherapy era that describe the
infected (by way of being exposed)36-37 and transitions clinical course of tuberculosis in children. The variation
from having disease to being diagnosed with the disease in distribution of tuberculosis by age71,72 is particularly
(by way of accessing health services, being recognized significant in tuberculosis in children. The incidence of
as showing clinical features suggestive of the disease, to infection rises steadily from birth to the age of 9 years,
being confirmed, or at least confidently diagnosed, as a rises more slowly from ages 10 to 14 and then rises
case of tuberculosis).38 steeply. The probability of developing clinically
20
significant disease following infection also varies with impact on tuberculosis in children has been less clearly
age. It is highest in children under one year of age investigated. Some studies have suggested a role of
(occurring in an estimated 12%), declines to reach its genetic susceptibility.81-83 In many low income countries
lowest level from ages 4 to 9 years and then rises steadily there is a high prevalence of infection with both
until adulthood. This trend in risk of developing disease Mycobacterium tuberculosis and HIV. This will invariably
is accompanied by a substantially greater risk of lead to an increase in childhood TB cases, but even more
developing severe disease leading to death in the worrying also to an increase in infectious cases of TB in
youngest age group, under one year of age. The same adolescents and young adults, who are the very people
age distribution is seen in communities with very little
having young children and will transmit these infections
tuberculosis73 and in those with a very high prevalence
to their children.
of disease.74 The pattern of infection and disease by age
identifies two distinct groups of patients, those under
10 years of age (and particularly the youngest group) and
Place
those 10 years and older.75 Among those who will become Striking differences in tuberculosis notification rates
infected for the first time at some point in their lives, most among various countries have been shown to reflect
will acquire the infection during childhood, at least in differences in probability of exposure in those locations
countries where tuberculosis is steadily declining. The during the early years of life.84 Moreover, when children
greatest risk of progressing from infection to disease occurs born in low-burden communities of parents from high-
in children who are infected for the first time under the burden communities visit the latter communities, they
age of 2 years or during the adolescent period. increase their probability of becoming infected and
The site in the body where the disease appears also developing disease.85 This fact confirms much earlier
varies with age. A study of children admitted to studies of uninfected, mobile populations86-87 showing
sanatorium in the period prior to the advent of
their increasing risk of infection, disease and death as
chemotherapy76 showed that, among older children
they move into areas where their risk of exposure is
(5 years of age or older), the tuberculosis manifested itself
increased. In locations with a high burden of tuberculosis,
most frequently as pleurisy (one-quarter to one-third of
a high proportion of all existing cases are children
cases). This was not the case for the younger children
because they are at a high risk of becoming infected (and
(under 5). The frequent manifestation of tuberculosis as
rapidly developing disease), although they are frequently
pleurisy, is also observed among adults newly infected
in the course of their work,77 and raises the question of undetected due to limited access to and quality of health
whether this phenomenon is due to age, or due to time services.
elapsed since infection. Frost,6 in demonstrating mortality
rates in birth cohorts for 1880 to 1910, showed that Time
mortality was equal for boys and girls under 5 years of The change in age-specific incidence/mortality of
age but was greater for girls than for boys in children pulmonary tuberculosis has been examined in a variety
aged 5 to 9 years (relative risk 1.72) and aged 10 to 19 of locations. These investigations have shown an
years (relative risk 1.67). The occurrence of complications unchanging profile of age-specific occurrence of the
(including fatality) following primary tuberculosis in disease over time. The principal change is in the level of
children did not differ between girls and boys.74 Females the disease, and not in its essential age-specific curve. A
are slightly (approximately 20%) more likely to be similar study in the trend in prevalence of infection has
infected than males.78 However, among the very young been shown in the Netherlands,1 where systematic
(under 5 years), this ratio is the inverse with females being tuberculin tests have been carried out on military recruits.
less likely (about 30%) than males to be infected. This investigation shows an unvarying shape of the age-
Tuberculosis has traditionally been considered a specific curve; the variation with time is only in the level
‘disease of poverty’, the reason for the association being of the prevalence. These unchanging patterns have been
the increased risk of exposure to Mycobacterium termed a ‘cohort’ phenomenon; that is to say, each
tuberculosis due to crowding. However, even in a succeeding birth cohort has a similar pattern, although
homogeneously poor community, tuberculosis is varying level, of tuberculosis. Tuberculosis in children
demonstrably associated with socioeconomic factors has a seasonal variation88 with a peak in late winter/
indicating ‘relative’ disadvantage.79 early spring. This might be attributed to the increased
The importance of an intact immune system in exposure due to being indoors for a greater extent during
controlling Mycobacterium tuberculosis in people already the seasons of inclement weather, or due to the fact that
infected has been incontrovertibly shown.80 Its precise in winter children cough from a variety of causes and
21
Chapter 3 Interaction of Epidemiological Factors
this cough, often from other causes, may urge the parents of becoming infected is the duration of exposure,
to seek health care for the child-tuberculosis which might increased by delay in diagnosis in adult patients
otherwise have been undetected, is then diagnosed. carrying bacteria susceptible to antibiotics. Where the
The occurrence of tuberculosis is affected by social disease is essentially untreatable (multidrug resistant),
and political changes. This has been clearly demonstrated the potential for prolonged exposure increases the
for the impact of war.89,90 The impact of HIV infection on probability of transmission of the infection with these
the burden of tuberculosis in communities is dramatic.91 multidrug resistant bacteria.99,100
Other forms of socioeconomic change are associated with
a change in tuberculosis, such as a drastic reduction in
Time Since Infection
economies92 or of services.93 These effects have been
reflected promptly in the occurrence of disease in Tuberculosis disease is most likely to appear during the
children.94 The impact of socioeconomic conditions on time immediately following infection.20,21 One-fifth of the
tuberculosis is substantial and sufficient to lead some risk of subsequently developing disease occurs in the first
scientists to suggest that these conditions have equal or year following infection, if preventive chemotherapy is
greater impact than medical measures.95 not given.
The type of disease following infection also varies
with the time that has elapsed since infection. In a study
DETERMINANTS OF TUBERCULOSIS IN CHILDREN
of children admitted to hospital after exposure to their
Exposure parents who had tuberculosis, Wallgren19 identified that
sites of disease such as the peripheral lymph nodes and
If a person never encounters the Mycobacterium the pleura were affected when the disease occurred soon
tuberculosis, that person will never become infected and, after infection while genitourinary disease occurred only
therefore, can never develop the disease. While, many years following infection.
exposure has been measured directly, using live guinea
pigs,96 this technique is impractical for most studies. Host Immunity
Indirect estimations of exposure have been developed
The observation that only a minority of people develop
in contact studies. From these studies, the concentration disease after becoming infected with Mycobacterium
of bacteria in the environment, as indicated by the tuberculosis is explained by the effective functioning
concentration of bacteria in expectorated sputum of of cell-mediated immunity. The impact on tuberculosis
tuberculosis cases,97 and the intensity of the interaction of reducing immune function has been dramatically
between the susceptible person and the person with the illustrated by the epidemic of human immune
contagious disease have been identified as key deficiency virus (HIV).101 The reason for the unusual
predictors of becoming infected. The scenario outlined clinical features of some tuberculosis cases associated
in these studies identifies the household as the location with HIV in industrialized countries has been studied
where infection is most likely to occur and the in Los Angeles.22 This study showed clearly that the
transmission is from parent to child. In a study of variation in clinical appearance associated with HIV
tuberculous infection in a number of African countries infection was related to the level of cell-mediated
in the 1960s, Roelsgaard reported tuberculous infection immune function. This may explain both the difference
to be substantially more likely if there was a history of in clinical features of tuberculosis in small children as
contact with a case of tuberculosis.78 The risk ratio was compared with adults (‘primary’ tuberculosis) and the
substantially higher in younger children (risk ratios of higher rate of occurrence of tuberculosis in small
10.1 for 0 to 4-year-old, 3.9 for 5 to 9-year-old and 1.9 children that cannot likely be explained by an
for 10 to 14-year-old). The diminution in risk ratios with increased risk of exposure.
age were related to a higher prevalence of infection in
older age groups (6-fold higher in 5 to 9-year-old, EVALUATION OF INTERVENTIONS
compared with 0-4 year-olds and 2.2 times higher in 10 WITH REFERENCE TO CHILDREN
to 14-year-old compared with 5 to 9-year-old). In a
report from India it was observed that the prevalence Objectives of Intervention
of tuberculosis infection and clinical disease among Many have claimed that the current case management
children in household contact with adult patients is strategy for tuberculosis (directly-observed treatment
higher than in the general population, and risk is short-course, DOTS)102 does not take sufficient notice of
significantly increased by contact with sputum positive the needs of children. This is, at one and the same time,
adults.98 An additional factor increasing the probability true and false. Because of its emphasis on the smear-
22
positive pulmonary patient as the priority in the strategy routine reporting of smear-negative cases by age, and
and, as has been previously noted, children with thus the burden of childhood TB cases is not easily
tuberculosis are under represented among cases reported measurable. As with the DOTS strategy, where the focus
as only a minority of children has sputum smear-positive has been on the most potent sources of transmission,
tuberculosis. While the DOTS strategy focuses primarily policies aimed at efficient management of tuberculosis
on adults (smear-positive cases), its ultimate objective is in children must focus on priorities. Tuberculosis in
the prevention of infection in children. The goal is to children is a disease as much of setting as of agent;
create a generation of children free of infection. Many children need to be managed as part of their community
setting. Case-finding needs to focus on investigation of
industrialized countries have come close to achieving this
children in contact with known cases of tuberculosis.108
but many have suggested that this had already occurred
Moreover, a comprehensive approach is required in the
before the introduction of effective therapeutic
management of such children, stressing not only the
interventions. The evidence that a generation of children management of existing cases but the prevention of
free of infection can be achieved in high-burden or low- future cases through the use of comprehensive
income communities, through the introduction of preventive chemotherapy. Unfortunately, the feasibility
interventions, is comparatively rare. A substantial and efficiency of comprehensively applying this
reduction in prevalence of infection following promptly recommendation has not been demonstrated in high-
on introduction of chemotherapy in aboriginal burden communities. There is an urgent need to
communities in Alberta, Canada has been shown.43 A undertake an evaluation and revision of the
similar impact in Beijing municipality on the reduction recommendations regarding preventive chemotherapy
of tuberculous meningitis and the prevalence of in this setting.
tuberculous infection has been shown after introduction
of modern tuberculosis control policies into a community ERADICATION OF TUBERCULOSIS
with virtually no coherent policy of management prior
Will this strategy take us to the ultimate goal, a generation
to 1978.103,104
free of tuberculous infection, with the consequent
eradication of this disease? There are reasons to suspect
Aims of a Program that, in areas not heavily impacted by the HIV epidemic,
it should be possible to make important strides in this
The aims of programs for the management of tuberculosis
direction, even with the rather inadequate tools we have
are two-fold: to provide a high standard of clinical
currently available.109 Clearly, to achieve the final push
practice to the greatest proportion of tuberculosis patients
against tuberculosis, it will be necessary to reverse the HIV
and to find and render no longer infectious (through cure)
epidemic. The role of drug resistance in maintaining the
the most potent sources of transmission (the sputum
epidemic is controversial110 and the priority, for the
smear-positive cases).105
present, without question, is on effective management of
the drug-susceptible cases. What is clear is the need to
Case Management Priorities maintain political commitment for the duration of the fight
The DOTS strategy focuses on cure of adults with newly against tuberculosis, a challenge that may be difficult to
detected tuberculosis patients as the highest priority. This meet.
was a shift from previous policy that stressed case-finding
as the highest priority because it was shown that HIGHLIGHTS
treatment whose results were unsatisfactory was actually • Tuberculosis is less a disease of the individual and
worse from an epidemiological point of view than no more strikingly a disease of the family and of the
treatment at all,106,107 an observation that had been made community. This is even more the case with
early after the introduction of chemotherapy but that had tuberculosis in children
been ignored until highlighted by Grzybowski.107 The • Because it is so difficult to isolate the microorganism,
DOTS strategy has resulted in improvement of treatment defining a case for study purposes is a great
outcome, reducing the prevalence of tuberculosis patients challenge. For this reason, tuberculous meningitis
by curing them, and has also enhanced case-finding by in children has often been used as an indicator of
providing quality services close to the residence of the disease as well as of recent infection
patients, enhancing accessibility. • The variation in distribution of tuberculosis by age
Case management in children is hampered by the is particularly significant in tuberculosis in children
difficulty in case detection and diagnosis. In addition, • The household is the location where infection is most
although childhood cases are often recorded as smear- likely to occur and the transmission is from parent
negative cases in the TB register, there is usually no to child
23
17. Nissen Meyer S, Dahlstrom G. Tuberculosis in BCG

• While the DOTS strategy focuses primarily on adults
vaccinated and non vaccinated young adults. Acta Tuberc
(smear-positive cases), its ultimate objective is the Scand 1953;32(suppl).
prevention of infection in children. The goal is to 18. Daniels M, Ridehalgh F, Springett VH, et al. Tuberculosis
create a generation of children free of infection in young adults. London: Lewis. 1948.
• Case finding needs to focus on investigation of 19. Wallgren A. The time table of tuberculosis. Tubercle
children in contact with known cases of tuberculosis 1948;29:245-51.
• A comprehensive approach is required in the 20. Ferebee SH, Mount FW. Tuberculosis morbidity in a
management of such children, stressing not only the controlled trial of the prophylactic use of isoniazid among
management of existing cases but the prevention of household contacts. Am Rev Respir Dis 1962;85:490-510.
21. D’Arcy Hart P, Sutherland I. Final report of the Medical
future cases through the use of comprehensive
Research Council by its Tuberculosis Vaccines Clinical
preventive chemotherapy. Trials Committee. BCG and vole bacillus vaccines in the
prevention of tuberculosis in adolescence and early adult
life. Br Med J 1977; ii:293-5.
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4 Epidemiology:
Special Reference to Children
INTRODUCTION Group II
Tuberculosis as a disease is of great public health Majority of patients in this group have non-specific
importance in the developing countries. Childhood symptoms, some may have characteristic symptoms.
tuberculosis is a reflection of ongoing transmission of They are either undiagnosed, untreated or inadequately
Mycobacterium tuberculosis in a community. It has been treated.
described as the continuing scourge of India.1 Donald2
has defined tuberculosis in children as a hidden epidemic Group III
in developing countries and has quoted several Indian
studies.3,4 Its clinical profile is different in developing It constitutes the base of the pyramid. These children are
countries in comparison to countries of Europe and North either asymptomatic or have non-specific symptoms,
America. Global estimates of tuberculosis (TB) per year hence are usually undiagnosed and untreated. They
among children have been described elsewhere. The constitute the reservoir of primary infection from which
extent of tuberculosis in children is a reflection of various post primary complication (Gr I and II) develop.
Tuberculosis Control Program in a particular area. These are also forerunners of a large percentage of (i) adult
Epidemiological data regarding the extent of problem in type of TB disease among adolescent children and (ii)
children is lacking globally as well as in India. The reason chronic pulmonary tuberculosis in adults.
in India being that in the National sample survey done Children are usually infected with tuberculosis by an
in 1955 to 1958, children less than five years were adult4a or an older child with sputum smear-positive
excluded.3 It is due to difficulty in diagnosis. The two pulmonary tuberculosis, often a family member. They are
common parameters, tuberculin test and X-ray chest with less likely to be infected with a smear-negative contact.
history of contact, symptomatology are difficult to The best way to prevent tuberculosis in children has been
perform at operational level. Further, the pressing thought to be the proper identification and treatment of
problem which was emphasized at that time was to pick infectious patients. Case notification of tuberculosis in
up infectious adults and their treatment. In India very children usually has been 6 to 20 percent of all registered
few studies are available regarding the extent of problem TB cases with the National Tuberculosis Program (NTP).
of tuberculosis in children. The available data are on the In India, the prevalence of primary tubercular infection
basis of hospital studies.5 in pediatric population is alarming. The annual risk of
Udani5 has described tuberculosis in children as a tubercular infection is 1.5 in the country, and 40 percent
pyramid as follows: of children by 16 years acquire infection. Nearly 10
percent of infected eventually develop disease. Five
percent of these are expected to develop tuberculosis in
PYRAMID OF CHILDHOOD TUBERCULOSIS the first two years of life. This large pool of infected
children, means that TB will continue to be a major
Pediatric patients with tuberculosis can be placed in three
problem in the foreseable future. Data on the burden of
categories:
all forms of TB amongst children in India are not available.
Most surveys conducted have focused on pulmonary TB
Group I and no significant population based studies on extra-
These patients are admitted in the hospital and constitute pulmonary TB are available. Pulmonary TB is primarily
6 to 10 percent of total pediatric admissions, majority of an adult disease and it has been estimated that 0 to 19
them have serious disease like meningitis, miliary disease years old population con-tain only 7 percent of total
or severe pulmonary involvement. They constitute the prevalent cases.6,7
apex of the pyramid. The risk of infection in children depends on the extent
of exposure to infectious droplet nuclei. If a mother has
27
Chapter 4 Epidemiology: Special Reference to Children
sputum smear-positive pulmonary TB, her infant is more tuberculosis-infected migrants in these countries
at risk of developing the disease because of the chance of particularly in USA.11
inhaling a large number of infectious droplets. There is a Reviewing the situation in ‘90s, an update in Bulletin
high prevalence of infection among children in household of WHO,12 it was reported that approximately one-third
contact with adult cases of tuberculosis. The risk is higher of the world’s population (1700 million) is infected with
for contacts of sputum-positive patients, but is also M. tuberculosis. The majority of cases belong to Asia with
significant for contacts of sputum-negative patients. an increasing number of HIV infected individuals.
Severe malnutrition, younger age, and absence of BCG Though the overall prevalence of tuberculosis infection
vaccination are significant risk factors for the transmission is similar in both parts of the world, i.e. Sub-Saharan
of infection. Exposure to environmental tobacco smoke Africa and Europe (34% and 28% respectively), there is a
independently increases the risk of acquiring infection8. big difference in the age distribution. In Africa, the
The majority of infected children do not develop TB majority of infected individuals are below 50 years of age
disease in childhood. The only evidence of infection may (80%). In the African, South-east Asian and Western
be a positive tuberculin skin test. The likelihood of Pacific regions more than 50 percent of the adult
developing disease is greatest shortly after infection. This population aged >15 years is infected (54%, 52% and 62%
declines steadily with time. Infants and young children respectively). 12 The emergence of HIV infection in
under 5 years are at particular risk of developing disease. association with tuberculosis has resulted in dual
The majority of children will present with symptoms with infection of 3 million individuals. Majority of them (78%)
in one year of infection. For infants particularly, the time- are in Africa.
span between the infection and disease maybe as little as Based on data among children and adults generated
6 to 8 weeks. Various immunosuppressive illnesses by Tuberculosis Research Centre (TRC), Chennai, among
facilitate the progression of infection to disease such as children by National Tuberculosis Institute (NTI),
HIV-infection,8a measles, whooping cough and protein- Bengaluru, and the annual risk of tuberculosis infection
calorie malnutrition.
In the study by National Tuberculosis Institute,
Table 4.1: Prevalence rate (%) of infection in
Bengaluru,9 the prevalence of tuber culosis in children in
South India — 23-year period
the 0 to 4 years of age was found to be one percent. These
had not received BCG and were contacts of sputum Survey
smear-positive cases. The problem and its extent in the Age I II III IV V VI
age group of 0 to 4 years can be easily estimated. The 1962 1963 1965 1967 1977 1985
population of India by 2000 AD had reached 0-4 2.1 1.8 1.3 1.0 1.5 1.2
one billion mark. Applying the one percent prevalence, 5-9 7.9 7.6 7.0 6.4 6.0 5.3
it could be computed that by 2009 AD, about more than 10-14 16.5 16.9 16.1 15.4 12.1 9.2
one and a quarter million children in this age group 0-14 8.6 8.6 7.7 7.1 4.7 4.8
would have already got infected. In the various programs
Table 4.2: Annual risk rates among 0 to 14 years over
of WHO for control of tuberculosis, children have not
23 years in South India
received due importance except in the latest directly
observed treatment short course therapy (DOTS). The Annual risk rate (%)
reasons for neglect of children in the National Survey On observed On standardized
Tuberculosis Control Program in India and the world prevalence rate rate
over has been due to difficulty in its diagnosis. The latter I 1.12 1.12
because gold standard of diagnosis is isolation of II 1.12 1.12
Mycobacterium tuberculosis either by smear or culture. III 0.92 0.99
Thus, a survey conducted in South India between 1984 IV 0.86 0.92
and 1986 and its comparison with old surveys shows a V 0.55 0.80
23-year trend9 (Tables 4.1 and 4.2). VI 0.55 0.61
Annual incidence of primary infection described by
Table 4.3: Annual incidence and prevalence of
studies of National Institute of Tuberculosis (NIT),
tuberculosis (NTP Data)10
Bengaluru was 0.8 percent in children under 5 year, giving
an estimate of 1.9 million getting infected every year. Age (years) Annual incidence Prevalence of
of infection (%) infection (%)
Annual incidence and prevalence of tuberculosis in NTP
data is given in Table 4.3.10 <5 0.8 2.8
The recent epidemic of HIV has slowed down the 5-9 1.1 13.4
declining trend in the incidence of tuberculosis. This has 10-14 1.3 —
All ages 1.6 38.0
further been aggravated because of large number of
28
(ARTI) estimates from the nation-wide sample survey by in ARTI about 4 %.17 In another survey done to see effect
NTI and TRC the estimated number of bacillary cases of DOTS on tuberculosis infection revealed ARTI
was 3.8 million (95% CI: 2.8-4.7). The number of abacillary estimates in the three tuberculin surveys as 1.6%, 1.4%
cases was estimated to be 3.9 million and that for and 1.2%, respectively. There was a significant decline in
extrapulmonary cases was 0.8 million giving a total the trend of TB infection. The annual decline estimated
burden of 8.5 million (95% CI: 6.3-10.4) for 2000.13 from the first to the third survey was 6%.18
Using data from district tuberculosis registry it was
observed that diagnoses of tuberculosis peaked in DISEASE BURDEN IN CHILDREN
northern part of India between April and June, and
reached a nadir between October and December, whereas Estimating the burden of TB in children is challenging
no seasonality was reported in the south. Overall, rates for several reasons. No standard case definition exists that
of new smear-positive tuberculosis cases were 57 per 100 may be applied easily to childhood TB. In many countries,
000 population in peak seasons versus 46 per 100 000 in limited resources prohibit establishing a confirmed
trough seasons. This was after ruling out general health- diagnosis. Childhood TB is given a lower public health
seeking behavior artifact. Seasonality was highest priority as compared to adult disease. Although many
in pediatric cases, suggesting variation in recent countries collect and report TB surveillance data, these
transmission14 data are not always readily available, consistent, or
reported using standard age criteria.
In India, tuberculosis in children has been regarded
Prevalence and Annual Risk of Tuberculosis Infection
as a major health hazard.26 The ICMR Survey, the only
in Children in India National survey, did not include children below 6 years
Multiple surveys were carried out over last 10 years in of age. The methodology did not include tuberculin skin
different part of country. It suggests that the prevalence tests and hence neither the prevalence of infection in
varies from region to region. It was minimal in Kerala children nor the annual risk of infection could be
and maximum in western and north India. It was more measured at that time.27 The data gathered in the National
in tribals and people living in slums, more in urban as Sample Survey 1955-58, was an eye opener. The
compared to rural area. Nutritional status did not change prevalence was reported to range from 2 to 8 cases per
prevalence estimated by tuberculin test. In some studies 1000 population. The disease was distributed equally in
children who had received BCG had lesser prevalence of rural and urban areas. The infectious cases were mainly
TB infection but it was insignificant. The computed ARTI in adults and not in school children. Hence, there is no
in children from different survey has been given in National data on prevalence in children < 5 years of age.
Table 4.4. There are studies in localized areas reporting prevalence
A nationwide survey to estimate acute respiratory of infection based on Tuberculin testing. Ukit and
tract infection (ARTI) in children 1-9 years of age in Benjamin28 reported that prevalence of infection was age-
dependent. The incidence of infection in the groups
selected clusters of 26 districts in four defined zones of
treated with placebo in the Chingleput study, was 1.75,
India using tuberculin testing with ITU PPD RT23 with
2.4 and 4.03 percent in the age groups of 1-4, 5-9 and 10
Tween 80 was carried out. Prevalence of infection was
to 14 years respectively.29 Results of a longitudinal survey
estimated using the cut-off point method (Method I) and
conducted by National Institute of Tuberculosis,
the mirror-image technique (Method II) among children
Bengaluru reported an annual risk of infection to be 3.2
without BCG scar. The ARTI computed from estimated
percent,30 whereas studies in Chingleput have not shown
prevalence was found to be lowest in the southern zone
any evidence of decline in annual risk of infection over a
(Method I: 1.1%, Method II: 1.0%). It was higher in the period of 15 years. Their results were 1.7 percent in 1969,
eastern zone (1.3% by both methods) and highest in the 1.93 percent in 1979 and 1.73 percent in 1989.31
western (Method I: 1.8%, Method II: 1.6%) and northern In 1989, the WHO estimated that each year 1.3 million
zones (1.9% by both methods). The proportion of infected new cases of childhood TB occur and 450,000 children
children was found to be significantly higher in urban die from disease32 In 1994, there were estimated 7,500,000
than in rural areas in all zones.15 total TB cases, of which 650,000 (9%) occurred in
The overall estimates of average annual risk of children.33 These estimates are based on the assumption
infection in children 1-9 years of age in the country was that childhood TB parallels adult trends and accounts for
computed as 1.5%. It was higher in urban areas, at 2.2%, a predictable proportion of total disease. Although
than in rural areas, at 1.3%.16 There are not many surveys childhood TB usually represents less than 5 percent of
done in same setting with similar methods to judge trends disease in industrialized countries, the burden of disease
in TB infection in children. A survey done in same borne by children in less developed, resource-poor
population after 8.3 years in Bengaluru suggest a decline countries maybe as high as 39 percent.34 At a global level,
29
Table 4.4: Summary of tuberculosis surveys in different parts of India
Authors Population surveyed Methods used Prevalence Remarks

19
Kumar S 2009 4821, children 5-9 Tuberculin test using reactions > 10 mm: 5% Low proportion of
years in Kerala 1 TU PPD RT23 with reactions > 12 mm: 3%: reactors indicated a
Tween 80 reactions > 14 mm: 2% low level of
transmission of
infection in Kerala.
Rao et al 20 2008 5314 children 1-9 Tuberculin test using Overall prevalence 7.1% Overall ARTI 1.3%
years of age in 1 TU of PPD RT 23 1.3% (1.0-1.7%)
Jabalpur with tween 80 (95% CI: 5.5–8.8%)
Prevalence without ARTI in children
BCG scar: 6.8% (95% without BCG scar
CI: 4.8–8.9%) 1.3% (0.9–1.7%)
Prevalence with BCG ARTI in children
scar: 7.6% (95% CI: with BCG scar:
4.4–10.9%) 1.4% (95%CI 0.8–2.0%);
Gopi et al 21 7098 children Tuberculin test Overall prevalence: 10.5 % (ARTI of 2.0%)
2008 aged 1-9 years in using 1 TU of PPD
Chennai RT 23 with Tween 80
No difference in Prevalence slightly
relation to BCG scar higher in slums
(11.1%; ARTI 2.1%)
as compared to
non slum area
(8.9%; ARTI 1.7%);
Rao etal 22 2008 1341 children Tuberculin testing Overall prevalence: ARTI was 3.9%
aged 1-9 years of with 1 TU of PPD 20.4% (95% CI: 18.2- (95% CI 3.5- 4.3%).
Saharia community RT 23 with Tween 22.5%)
in MP 80
BCG scar negative: ARTI in BCG scar
21.1% (95% CI: 18.3- negative: 3.9%
23.8%) (95% CI: 3.4-4.5%)
BCG scar positive: ARTI among BCG
19.0% (95% CI 15.4- scar positive 4.0%
22.5%) (95% CI: 3.2-4.8%)
Chadha et al.23 3636 children Tuberculin tested Prevalence: 9.6% ARTI: 1.4% (95%
2007 5-9 years of age in using 1 TU PPD (95% CI: 8.0-11.2.) CI: 1.1-1.6)
Andhra Pradesh RT23 with Tween
80
Pulickal et al24 418 school children Tuberculin skin test Prevalence 15.5% No relation with
2007 aged 5-9 years in using 1 TU PPD RT nutritional status
Palakkad District, 23 with Tween 80
Kerala BCG unvaccinated
children (24%)
BCG vaccinated (9.7%)
Chadha et al16 8637 children Tuberculin testing 11.8% among children Children without
2005 Khammam tribal using ITU PPD RT without BCG scar and BCG Scar 1.6 %,
district between 23 with Tween 80 10.6% among children with BCG scar 1.5%
1-9 years with BCG scar
Kolappan et al24a 17,811 children tuberculin testing 5.9% (95% CI 4.0-7.7%); ARTI was 1.0%
2004 1-9 years from using ITU PPD (95% CI 0.7-1.4%)
south zone of India RT23 with Tween 80
without a BCG scar
Shashidharan 10, 191 children 1-9 tuberculin testers 6.9% ARTI 1.7-1.8%.
et al25 2004 years from 8 administered 0.1 ml More in urban as
districts of Orissa (1 TU) of PPD RT 23 compared to
with Tween 80 rural area
30
the WHO currently reports only smear-positive cases by occurring in children in India is estimated around 10.2
age. The International Union against TB and Lung Disease percent. These figures are available only upto 2002. In
(IUATLD) currently recommends stratifying the the latest report of WHO there is no data separately
reporting of smear-positive cases into two age categories: tabulated for children even in sputum-positive cases.
younger than 15 years of age and 15 years of age and In 2007, the countries with the highest prevalence were
older.35 Reporting of smear-positive cases is considered India (with 2.0 million cases), China (1.3 million),
a practical strategy that complements the Directly Indonesia (530,000), Nigeria (460,000), and South Africa
Observed Therapy (DOTS) strategy. Nonetheless, an (460,000); of the estimated 1.37 million cases in HIV-
estimated 1.2 cases of smear-negative TB occur for every positive persons, 79% were in Africa and 11% in Southeast
smear-positive case of TB.36 Furthermore, approximately Asia.39
95 percent of cases in children younger than 12 years of
age are smear-negative.37 Thus, the WHO policy of DETERMINANTS OF INFECTION AND DISEASE
reporting only smear-positive cases by age causes a gross
underestimation of the burden of TB in children. Corbett Tuberculosis differs from various other infectious
and colleagues have generated age-specific estimates diseases as it has a particular social and geographic
describing the global distribution of TB.38 These country- distribution.
specific estimates were based on the number of smear-
positive cases reported in 2000 and published estimates Determinants of Infection
of the proportion of cases expected to be smear-positive Tuberculosis has two stages: First is the stage of infection
by age group. This analysis estimated that 8.3 million new and this may then progress to the second stage of disease.
cases of TB occurred in 2000, of which 884,019 (10.7%) Both the stages have different risk factors. The
were in children. Of the total, 659,379 (75%) occurred in determinants of these two stages need to be considered
22 high-burden countries (Table 4.5). Case rates estimated separately.
through this analytic approach for India for all age group Bacilli are transmitted from one infected person to the
is 179 per 100,000 population and for 0 to 14 years age other as an aerosol. In some cases contaminated milk may
group is 53 per 100,000 children. The proportion of TB also be responsible. In Indian children, most often the
Table 4.5: Estimated burden of childhood tuberculosis in the 22 highest-burden countries
Countries No. of children TB occurring in Childhood TB TB case rate

with TB children (%) case rates (All ages)
Afghanistan 17,540 25.3 189 324
Bangladesh 33,166 10.2 61 236
Brazil 23,520 20.7 47 66
Cambodia 3,966 5.3 70 571
China 86,978 5.3 27 129
Democratic Republic of Congo 24,052 16.1 106 306
Ethiopia 28,675 16.1 95 272
India 185,233 10.2 53 179
Indonesia 15,691 2.7 23 263
Kenya 22,124 16.1 167 450
Mozambique 7,703 16.1 98 268
Myanmar 8,007 10.2 51 165
Nigeria 32,310 12.4 63 228
Pakistan 61,905 25.3 103 172
Philippines 12,167 5.3 43 304
Russian Federation 7,778 4.2 30 126
South Africa 35,449 16.1 237 501
Thailand 2,317 2.7 15 141
Uganda 12,099 16.1 103 320
United Republic of Tanzania 18,890 16.1 118 337
Vietnam 7,559 5.3 29 183
Zimbabwe 12,267 16.1 221 603
Total: 22 highest-burden countries 659,397 9.6
Corbett EL et al. Arch Intern Med 2003; 163: 1009-21.
31
primary infection is human in origin and pulmonary, still posed an appreciable, although greatly reduced, risk.
though involvement of other sites has also been The majority of older children who were infected did not
reported.40 The sharing of the space with an infectious person have a household source identified. Infants and
puts the other person at a higher risk. It will also depend adolescent were the groups at highest risk for
upon the nature of disease in the source case. If cough or development of disease and death following primary
sneezing produces infectious aerosols, the risk becomes infection. Children with primary infection at 5 to 10 year
higher. The source which is producing acid fast bacilli, of age had the lowest risk development of disease and
death.
on direct microscopic examination, has been shown to
Infection with tubercle bacilli does not result in disease
contain very small number of tubercle bacilli (>104 bacilli
in all the infected persons. Nearly 90 percent people may
per ml). The undiagnosed and untreated status of these
not develop disease at all. In rest of the 10 percent, only
patients makes them more dangerous as regards the spread half will progress to the disease in first five years. Rest of
of the disease. them develop disease much later in life and this delayed
The other important determinant is the exposure and disease is defined as reactivation of latent or remotely
degree of ventilation of the ambient environment. This explains acquired tuberculosis infection.43 This occurrence of
higher risk to family members of source person than to disease in early years has the following determinants.
casual controls and also higher recurrence in people
belonging to low socioeconomic status which forces them Recent versus Old Infection
to reside in overcrowded and ill-ventilated houses.
Whether the inhalation of bacilli will cause infection Results of several classic studies have been employed to
in the uninfected person or not is determined by innate develop a model estimating risk of acquiring TB among
defense mechanism of the individual. Recent observations persons with recent infection and persons with
suggest a role for genetic factors in the resistance to preexisting infec-tion. 44 This modeling clearly
demonstrates that children 0 to 5 years of age with recent
infection.41 Further evidence is available that human
infection have significant annual risk of developing
immunodeficiency virus (HIV) impairs the innate
disease (Table 4.6).44
resistance and favors the development of tuberculosis
infection.42
Nutrition
Determinants of Developing Tuberculosis Disease Tuberculosis is very severe in malnourished children.45
An improved diet with protein, energy and vitamins A,
Epidemiological concepts in childhood tuber-culosis has D and C reduce the incidence of progressive disease. As
been clarified by review of literature in the the disease may be acute or chronic in children, it may
prechemotherapy era. Reports describe the major lead to deterioration of the nutritional status of the child.
transition in tuberculosis, from exposure to infection and It may present as Kwashiorkor or severe Marasmus. Most
from infection to disease. Children with household of the pediatricians today will like to rule out tuberculosis
exposure to a sputum smear-positive source case had the in malnourished children.
greatest risk of becoming infected and developing
disease, particularly in a child less than two years of age. Intercurrent Infection
This age was also more vulnerable to develop disease
from infection even when exposed to sputum smear- The recurrent infection or intercurrent infection can lead
negative household source case. Nonhousehold exposure to decreased host resistance.40 Activation of tuberculosis
Table 4.6: Annual risk of reactivation TB
Tuberculin skin test induration in mm Age in years

0-5 6-15 16-35 36-55 > 56
• Persons with existing infection
5-9 0.06 0.04 0.12 0.07 0.07
10-14 0.19 0.08 0.15 0.10 0.10
> 15 0.24 0.14 0.19 0.12 0.12
• Persons with recent infection
5-9 0.29 0.06 0.30 0.23 0.12
10-14 0.37 0.12 0.37 0.28 0.15
> 15 0.54 0.12 0.56 0.42 0.17
Horsburgh CR Jr. Priorities for the treatment of latent tuberculosis infection in the United States. N Engl J Med 2004; 350:
2060-7.
32
with measles infection is a well documented rate of 2 percent per annum. Referring to situation in
phenomenon. Some experts feel that even pertussis can India, he states that the epidemic in India started in the
lead to activation of tuberculosis in a young child. mid-19th century when it was in the peak in Eastern
Europe.48
Length of Time after Acquiring Infection The ICMR survey has shown that in India the
prevalence of disease is more or less universally
It is one of the most important determinants of the risk of
distributed throughout the country. Its prevalence was
developing the disease. Unless manifested immediately
found to be equal both in rural and urban populations.27
after acquiring infection, the risk appears to decline with
Social factors are responsible for an uneven
passing years.
distribution in various classes of population. Poverty is
one of the important companions of tuberculosis.49 The
Age at Infection
social cost by using DALYs (Disability Adjusted Life
The natural evolution of TB is dependent on host and Years) has been reported to be highest in Asia where it
pathogen factors. In immune-competent children, the risk was 5.1 percent, in India it was 3.7 percent whereas it is
of developing TB and the clinical presentation are highly only 0.2 percent in industrialized countries.
age dependent, with younger children being at greatest risk
for developing TB and severe manifestations.46 Table 4.7 Secular Trends
shows average age specific risk for disease development
after untreated primary infection in children. After reaching Due to lack of good reporting system in developing
the age of 10 years, children are much more likely to manifest countries, it is difficult to assess the trend in tuberculosis
adult-type disease that is primarily pulmonary in focus.47 infection and disease in children. There were enough
reasons to believe that there was a naturally occurring
decline in tuberculosis in various countries of the world.
Host Resistance
But this decline became stationary in 1980s and the last
The immunocompetence is another important decade has witnessed an increase in various countries
determinant of the disease. This may be genetically now. The available data indicate towards a real increase
determined. in the incidence of disease and it is feared that this increase
may continue in future.50,51 With increase in number of
Distribution of TB Infection and Disease diseased adults and spread of HIV infection, the infection
rates in children are likely to increase.
Today the industrialized world has very low prevalence
of tuberculosis. According to Grzybowski, Britain and
Western Europe had peak of tuberculosis in first half of
Determinants of Outcome of Treatment of Tuberculosis
the 19th century and is now declining naturally at the There are not many studies in literature documenting
outcome of treatment of different type of tuberculosis in
Table 4.7: Average age-specific risk for disease
children. In a retrospective study including 541 children
development after untreated primary infection*
receiving treatment of tuberculosis revealed that the
Age at Manifestations Risk of major factor associated with treatment failure was non-
primary infection of disease disease (%) receipt of BCG vaccination during infancy and extra-
(years) pulmonary disease.52
<1 No disease 50
Pulmonary disease 30-40 DRUG RESISTANT TUBERCULOSIS
TBM or miliary disease 10-20
1-2 No disease 70-80 Resistance to commonly used drugs in the treatment has
Pulmonary disease 10-20 been observed and hence an increase in number of cases
TBM or miliary disease 2-5 is obvious. The exact burden of drug resistant TB in
2-5 No disease 95 children is not known. Pattern of drug resistance among
Pulmonary disease 5
TBM or miliary disease 0.5
children with TB tends to reflect that found among adults
5-10 No disease 98 in the same population. A 4-yr prospective study in the
Pulmonary disease 2 Western Cape province of South Africa evaluated 149
TBM or miliary disease <0.5 child contacts of 80 adult multidrug resistant (MDR)
> 10 No disease 80-90 pulmonary TB cases.53 Most of the childhood contacts of
Pulmonary disease 10-20 adults with MDR-TB were likely to be infected by these
TBM or miliary disease <0.5
MDR source cases despite their exposure to other drug-
*Tubercular meningitis (TBM).46 susceptible adults with TB in some instances.
33
In 2007, there were an estimated 500,000 cases of all of the tuberculosis patients diagnosed in these two
multidrug-resistant (MDR) tuberculosis globally surveys were those of tuberculous lymphadenopathy,
(including 289,000 new cases); of these, 131,000 were in either cervical or mediastinal. There were only a few
India, 112,000 in China, 43,000 in Russia, 16,000 in South patients of tuberculosis spine and sputum positive
Africa, and 15,000 in Bangladesh; 55 countries had pulmonary tuberculosis among those diagnosed.
reported cases of extensively drug resistant (XDR) Widespread coverage with BCG vaccine has possibly
tuberculosis by the end of 2008. These last figures are led to modification in the pattern of clinical manifestations.
reason for considerable concern and highlight a potential It has been suggested that BCG vaccination is responsible
for decrease in the occurrence of disseminated and severe
threat to our ability to treat tuberculosis, both in
disease. Localized forms of illness, e.g. intrathoracic
individual patients and in the context of a treatment
lymphadenopathy, and localized CNS disease have been
program.39
reported to occur with greater frequency.57,58 However,
In India (Delhi region), the prevalence of resistance
this observation needs confirmation from epidemiological
to any drug was 32.4 percent, while that of multidrug studies.
resistance was 13.3 percent during 1994 to 1997.54 A recent study from Spain reported an increase in
Data on drug resistance in children from India is number of children with single hilar adenopathy (32%
scarce. At AIIMS out of 1579 children registered in TB for the period 1978-1987 to 43.4% for the period 1988-
clinic over 8 years, 21 (1.32%) were diagnosed as MDR 1997) in comparison with those with parenchymal
tuberculosis and one was XDR TB. involvement or a mixed pattern (62% vs 45%).51 The
authors also reported a non-significant trend towards a
TRENDS IN TUBERCULAR DISEASE lower rate of tubercular meningitis in the last decade.59
At a referral hospital in India60 an increase in the
Mycobacterium tuberculosis enter body through lungs and
proportion of cases of extrapulmonary tuberculosis has
it spreads to other parts including lymph nodes, tissues
been observed over last four and a half decades (Fig. 4.1).
surrounding the brain and, osteoarticular and urogenital
The increase was predominantly due to increase in
system. Pulmonary involvement is the most common.
lymphnode tuberculosis (Fig. 4.2). The severe form of
Among the 0 to 14-year-old tribal children of Carnico-
tubercular meningitis decreased over last four decades
bar, the best estimate of all forms of tuberculosis was
(Table 4.8).
found to be 6 per thousand (n = 6125).55 The incidence of
The data are not a reflection of either prevalence or
all forms of tuberculosis disease was found to be 2.8 per
incidence of the type of tuberculosis which presents in
thousand among the 1 to 4-year-old children in Chennai
medical colleges. In those still the predominant
(observed over a four-year period of follow-up).56 Almost
presentation indoors is of tubercular meningitis, severe
Fig. 4.1: Proportion of pulmonary and extrapulmonary tuberculosis in TB clinic of AIIMS,

New Delhi, India over last 4 decades
34
Fig. 4.2: Types of extrapulmonary tuberculosis in TB clinic of AIIMS, New Delhi, India over last 4 decades
form of pulmonary disease such as miliary in younger The impact of the HIV epidemic on pediatric TB has been
infants and pleural effusion in older children. The same reported in several studies. A prospective cohort study
will be reflected in the outdoor TB clinics. In TB hospitals of children with TB diagnosed in Addis Ababa from
such as LRS Institute of Respiratory Disease and Allied December 1995 to January 1997 in which HIV-positive
Sciences, Delhi, most of the children will have adults type children were compared with HIV-negative children,
of sputum-positive or even multidrug resistant reported that HIV-positive children were younger, more
pulmonary tuberculosis, disseminated disease. However, underweight and had a 6-fold higher mortality than HIV-
at All India Institute of Medical Sciences New Delhi, India negative children.63 There are not many studies from
being a superspeciality tertiary care center, the patients India on proportion of children co-infected with HIV and
of TBM get admitted are usually in the stage III and often TB. In a small study from Mumbai, 64 18 percent of
present after having been treated for sufficient length of children with disseminated tuberculosis (N = 50) were
time in other hospitals with no or poor response and HIV seropositive. Reported co-infection of HIV and TB
neurological sequlae. in various Indian studies varies from 16 to 68 percent.65-
67
In the outdoor of AIIMS in Pediatric TB clinic the Since follow up data of HIV infected children are not
children who are treated are mostly non-infectious available, it is very difficult to estimate annual infection
pulmonary tuberculosis, symptomatic pulmonary rate of tuberculosis in HIV-positive patients.
primary complex and tubercular lymphadenitis who are
referred from Pediatric Surgery Department after FNAC MOLECULAR EPIDEMIOLOGY
confirmed diagnosis. This is because at AIIMS Pediatric
The continuous presence of tuberculosis pandemic
TB clinic gets a limited amount of TB drugs from a NGO
despite the introduction of curative anti-tuberculosis
and there is constraint of personnel. The other forms of
drugs for the last 50 years has stimulated research efforts
extrapulmonary tuberculosis such as osteoarticular, into the molecular epidemiology of tuberculosis. Burgos
genitourinary are treated in orthopedic department and and Pym 68 has highlighted the need of research in
pediatric surgery department respectively. Hence, this molecular epidemiology because the coexistence of HIV
data is not representative of a medical college in India. and tuberculosis is a great threat to the population in Asia
and Africa. This new discipline of molecular
HIV AND TUBERCULOSIS epidemiology began with the identification of IS6110, a
noval mycobacterial insertion sequence. This method is
It has been reported that HIV infection is probably one firmly established, but is still expensive, labor-intensive
of the most important factors for the resurgence of TB in and only applicable on viable culture material.
adults as well as in children. In the year 1990, 4.2 percent IS6110 restriction fragment length polymorphism
of tuberculosis cases worldwide occurred in HIV-infected (RELP) is exclusively present in M. tuberculosis complex
individuals and estimates for the year 2000 were around species, although strains of M. tuberculosis lacking this
14 percent.61 Adults with HIV infection are more likely element have also been described. IS6110-based typing
to develop tuberculosis from latent infection, and those is the most widely applied genotyping method in the
who encounter M. tuberculosis after HIV related immune molecular epidemiology of M. tuberculosis and is the gold
suppression have a more rapid progression to disease.62 standard to which other methods are compared.
Table 4.8: Changing spectrum of tuberculosis over last four and a half decades in pediatric TB clinic of a tertiary care referral hospital—AIIMS*
Type of TB 1966-70 1971-75 1976-80 1981-85 1986-90 1991-95 1996-00 2000-04 2005-08 1966-2008
N % N % N % N % N % N % N % N % N % N %
*Pulmonary 146 99 373 99 245 98 556 83 606 80 751 81 615 69 534 59 415 46 4241 73
*Extra-
pulmonary 1 1 1 5 2 110 17 146 20 172 19 277 31 384 41 46 54 1579 27
Total 147 100 374 100 250 100 666 100 752 100 923 100 892 100 918 100 898 100 5820 100
**Extra-
pulmonary
- TBL — — 1 20 71 65 152 90 167 97 225 81 256 66 204 42 1056 68
- Disseminated — — — — 7 5 5 3 27 10 46 11 100 21 185 13
- TBM 1 — 2 40 39 35 7 5 — 17 6 8 2 18 04 61 04
- Osteoarticular — 1 2 2 40 — — — 8 3 24 7 83 17 118 07
- Others 50 12 78 16 128 08
*All India Institute of Medical Sciences, New Delhi, India.
** The figures in number and percentages are out of the total of extrapulmonary cases
35
36
The application of molecular epidemiology can be the grassroot level. This can be achieved by laying more
used usefully to study the following: emphasis on the participation of community leaders who
• Dynamics of transmission with in population can influence the grassroot workers to have high index
• Epidemiological impact of subpopulation on of suspicion for diagnosis in cases with chronic cough.
tuberculosis transmission Uptil now the case finding through Maternity and Child
• Improving disease control by demonstrating the Health Services has been disappointing. At the same time
exclusive potential for tuberculosis to progress to the children, i.e. the contacts of both sputum smear-
disease and spread amongst HIV-infected persons positive and sputum smear-negative must be screened.
• Determining the potential for spread of drug-resistant To begin with the vulnerable age group of 1 to 6 years
strains among hospitalized patients must be thoroughly investigated. Age group of 5 to 9
• Quantification of the level of infectiousness among years need to be kept under surveillance. Again 10 to 15
smear-negative patients years age group needs greater attention as they are likely
• Development and transmission of MDR-TB, defined to develop adult type of disease.
as resistance to at least isoniazid and rifampicin.
HIGHLIGHTS
Tuberculosis Mortality • Epidemiology with special reference to children in
Mortality due to tuberculosis in children has been shown Indian and global context has been discussed.
to have a strong correlation with socioeconomic status of • The major reason for lack of data in epidemiology is
population and disease severity. Tuberculosis has been due to difficulty in diagnosis in children particularly
estimated to be responsible for 5 to 50 percent of crude less than 5 years
death rate in 1 to 4 year old in different parts of country. • Operational difficulty of carrying out tuberculin test
and X-ray chest in the National Program settings
• Factors responsible for different presentation in
ACTIONS BEING TAKEN IN INDIA
children are detailed
Uptil now the tuberculosis has been diagnosed, treated • Government of India is making efforts to include
entirely differently by pediatricians and TB specialists. children in the National Program of DOTS.
Tuberculosis Chapter of Indian Academy of Pediatrics • Three consensus statements have been made on
has defined two consensus statements, one on diagnosis69 diagnosis and treatment by Indian Academy of
and the other on treatment.70 Now under the Revised Pediatrics and one by joint effort of TB division of
National Tuberculosis Control Program (RNTCP) using Ministry of Health Government of India with experts
strategy of DOTS, due attention is being attempted with in TB and renowned members of Indian Academy
the concurrence of joint committee of members of Indian of Pediatrics.
Academy of Pediatrics, Program managers and TB • WHO office at New Delhi has included certain
experts.71 The latest Consensus Statement on Childhood features innumerated in the above consensus in the
Tuberculosis Working Group on Tuberculosis of Indian implementation of diagnosis and treating
Academy of Pediatrics (IAP) has been published in 2010 tuberculosis in children.
(discussed elsewhere). • Child friendly weight for use wise boxes of anti TB
As mentioned earlier, out of the various precipitating drugs have been made for inclusion in the program.
factors like measles, whooping cough, chronic diarrhea The draw back is that these are not available for
and severe malnutrition, for tuberculosis HIV-infection children weighing sixteen kilograms and less. This
and disease is the recent addition. Measles and whooping conveniently excludes children below two years of age.
cough are covered in the National Program of • Certain research studies have been designed by
Immunization in India. There is never 100 percent active participation of few members of Indian
coverage, hence there is a need to strengthen this Academy of Pediatrics to come to certain practical
program. For malnutrition there is a coordinated program solutions for the problems encountered in the
between the Ministry of Health and Family Welfare and implementation of DOTS for children.
Ministry of Social Welfare named as Integrated Child • Guidelines have been prepared for uniformity in the
Development Services Scheme (ICDS). This also needs a implementation of DOTS for Diagnosis and
better cover-age of the vulnerable (1-5 years) age group. Treatment.
Mitchison72 has very wisely summarized that inspite • Institutes like AIIMS have started treating resistant
of all the advances in understanding of immuno- TB on ambulatory basis after initial stabilization.
pathogenesis, availability of high tech diagnostic Preliminary data shows the commonest
techniques, the most important aspect which would manifestation of resistant TB in children is
determine the impact of all these is diagnosis in adults at extrapulmonary in the form of cervical adenitis.
37
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1. Prabhakar R. Tuberculosis: the continuing scourge of of a DOTS programme in South India. Int J Tuberc Lung
India. Indian J Med Res 1976;65:19-25. Dis 2006;10:346-8.
2. Donald PR. Childhood tuberculosis: the hidden epidemic. 19. Kumar S, Radhakrishna, Chadha VK, et al. Prevalence of
Int J Tuberc Lung Dis 2004;8:627-9. tuberculosis infection among school children in Kerala,
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Trends in the prevalence and incidence of tuberculosis 20. Rao VG, Gopi PG, Yadav R, et al. Annual risk of
in South India. Int J Tuberc Lung Dis 2001;5:142-57. tuberculosis infection among tribal population of Central
4. Seth V. Tuberculosis in children: epidemiology, diagnosis India. Trop Med Int Health 2008; 13: 1372-7.
and treatment. In Seth V, Puri RK, Suchdeva HPS (Eds): 21. Gopi PG, Prasad VV, Vasantha M, et al. Annual risk of
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8. Singh M, Mynak ML, Kumar L, et al. Prevalence and risk 24a. Kalappan C, Gopi PG, Subrami R, et al. Estimation of
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8a Cotton MF, Schaaf HS, Lottering G, et al. Tuberculosis 25. Shashidharan AN, Chadha VK, Jagannath PS, et al. The
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13. Gopi PG, Subramani R, Santha T, et al. Estimation of with tuberculosis. Tubercle Lung Dis 1992; 73: 213-8.
burden of tuberculosis in India for the year 2000. Indian J 31. Myurnath S, Vallishayee RS, Radhamani MP,
Med Res 2005;122:243-8. et al. Prevalence study of tuberculosis infection over
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15. Chadha VK, Agarwal SP, Chauhan LS, et al. Annual risk 32. WHO. Childhood tuberculosis and BCG vaccine: EPI
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16. Chadha VK, Kumar P, Jagannatha PS, et al. Average Health Organisation1994; 72: 213-20.
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France: International Union Against Tuberculosis and 55. Narmada R, Raj Narain, Raju VB, et al. Incidence of
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SECTION 3
MICROBIOLOGY AND
IMMUNOPATHOGENESIS
• Mycobacterium Tuberculosis
• Nontuberculous Mycobacteria
• Immunology of Tuberculosis: Basic Aspects and
Relevance for Immunodiagnostic Tests
• Clinicoimmunological Profile
5 Mycobacterium Tuberculosis
Sarman Singh, K Gopinath, Ruchi Sood, Ashok Rattan
INTRODUCTION M. bovis and M. africanum is clinically indistinguishable

from classical tuberculosis and treatment is the same for
The genus Mycobacteria includes species of bacteria all the infections. M. microti causes a tuberculosis like
responsible for tuberculosis and leprosy, diseases of disease in voles, but is not considered pathogenic for
antiquity which still affect millions. Tuberculosis remains humans while BCG is essentially nonpathogenic for
one of the deadliest diseases in the world. Tuberculosis humans.
(TB) is diagnosed in 9.2 million people every year, of
which 1.7 million died in 2006. India tops the list by
TAXONOMY
having highest burden of infected people.1 The main
driving force is the Human Immunodeficiency Virus Mycobacterium is the only genus in the family
(HIV) pandemic, which has allowed TB to reemerge so Mycobacteriaceae. The high Guanine + Cytosine [GC] ratio
dramatically.1,2 Of the total notified TB cases (0.7 million), in the DNA of Mycobacteria (62-70%) is similar to that of
0.2 million deaths occurred in HIV-TB coinfected cases,1 other mycolic acid producing bacteria—Nocardia (60-69%),
with a 100-fold higher risk of developing disease within Rhodococcus (59-69%) and Corynebacterium (51-59%). This
one year of infection than those infected with similarity may support the consolidation of these genera
M. tuberculosis alone.2 Robert Koch, a physician from into a single family.7 The genus Mycobacterium is responsible
Wolstein, Germany demonstrated that tuberculosis is for more suffering world-wide than all other bacterial
caused by a prokaryote. He was able to isolate pure genera combined. Currently, there are over 100 recognized
culture of tubercle bacilli and inoculated them into species of Mycobacteria. This genus contains obligate
healthy mice and guinea pigs which eventually became pathogenic, opportunistic and saprophytic species.
diseased with the pathogen. Table 5.1 gives the Koch’s According to Bergey’s manual of determinative
postulates. Thus, a far reaching discovery emerged after bacteriology, mycobacteria are classified in the category II
centuries of ignorance. Koch published his findings on (Gram-positive bacteria having cell wall) with the following
10th April 1882 after presenting these on 24th of March classification:
1882.3 Division: - Prokaryote
The bacterium was named Mycobacterium (Greek, Subdivision - Protophyta
Mykes, Fungus; bacterium; small rods) in 1896 by Class: - Shizomycetes
Lehmann and Neumann in reference to the mould-like Order: - Actinomycetales
pellicles formed by the bacteria on liquid medium. At Family: - Mycobacteriaceae
that time the genus contained only two species, Genus: - Mycobacterium
Mycobacterium tuberculosis and Mycobacterium leprae. Mycobacteria have been classified into fast and slow
M. tuberculosis is clinically the most important growing species by the seemingly arbitrary criteria of
member of the M. tuberculosis complex which includes whether or not they produce visible growth on subculture
M. tuberculosis, M. bovis and its BCG (bacille Calmette-
Guerin) variant, M. africanum and M. microti. The
members of this complex are closely related as seen by Table 5.1: Koch’s postulates
DNA homology.4 Each one of them, however, does • The bacterium should be constantly associated with the
possess signature sequences which can be differentiated lesion of the disease
by sequencing after PCR amplification of specific • It should be possible to isolate the bacterium in pure
hypervariable regions in the gene coding for the 16S culture from the lesion
rRNA.5,6 But for all practical purposes, the degree of • Inoculation of such pure culture into suitable laboratory
homology between the species of the complex suggests animals should reproduce the lesions of the disease
that the members of this complex might be more properly • It should be possible to reisolate the bacterium in pure
considered serovars or pathovars of the same species culture from the lesions produced in the experimental
animals.
rather than five different species. Disease caused by
42
Section 3 Microbiology and Immunopathogenesis
in 7 days. Recently, however, this criterion was shown weight of the cell envelope. The cord factor is another
to be remarkably valid taxonomically: all slow growing constituent responsible for serpentine growth of the
species have only one operon whereas all fast growing organism. It is toxic to mammalian cells and is also
species have two. A phylogenetic analysis based on the inhibitor of polymorphonuclear cell migration. The cord
16S rRNA sequences placed the fast and slow growing factor is most abundant in virulent strain of
species into two clear and separate branches of the M. tuberculosis. The robust cell wall also provides
evolutionary tree8 (Table 5.2). resistance to killing by acidic and alkaline compounds,
osmotic lysis via complement and resistance to common
DESCRIPTION OF THE GENUS antibiotics.
The Mycobacteria are nonmotile, nonspore forming,
slightly curved or straight bacilli, 0.2 to 0.6 by 1 to 10 µm Staining Reaction
in size, sometimes with branching. Filamentous or
The high lipid content of the cell wall provides unusual
mycelium like growth may occur, but it is easily
impermeability to aniline dyes and stains. Mycobacteria,
fragmented into rods or coccoid elements (Fig. 5.1A).
therefore, are not readily stained by the Gram-stain.
Mycobacteria have a unique cell wall responsible for
its virulence, diagnostic staining and treatment. The cell Special staining procedures are applied to promote the
wall has high (>60%) lipid content that includes a waxy uptake of a strong dye but once the Mycobacteria have
coat made of three major components: mycolic acids, cord taken the stain, they are not easily decolorized even with
factor, wax D, and sulfatids. The mycolic acids of acid-alcohol. This resistance to decolorization is called
Mycobacteria are unique alpha branched chains of acid fastness. The property of acid fastness is not absolute
hydroxyl-fatty acids. These are strong hydrophobic and and may be partly or completely lost at some stage of
significant determinants of virulence, as they prevent growth by some proportion of the cells of some species
attack on Mycobacteria by cationic proteins, lysozymes of Mycobacteria. Cells of the fast growing Mycobacteria
and oxygen radicals in the phagocytic cells. may be less than 10% acid fast.
They also protect the extracellular organisms from Koch (1882) stained the tubercle bacilli with hot
complement attack. The waxes make up 50% of the dry alkaline methylene blue as the primary stain and vesuvin
Table 5.2: Classification on the basis of growth rate (Also see Figs 5.1A to E)
Slow growing Rapid growing Species that do not have special Species with special
mycobacteria mycobacteria nutritional requirements growth requirements
M. tuberculosis complex M. fortuitum complex M. marinum M. paratuberculosis
M. fortuitum M. ulcerans M. haemophilum
M. tuberculosis M. chelonei subsp. chelonei M. malmoense M. lepraemurium
M. bovis M. chelonei subsp. abscessus M. leprae
M. africanum
M. microti
M. avium complex Nonphotochromogenic
M. avium M. agri
M. intracellulare M. chitae
M. xenopi M. smegmatis
M. scrofulaceum complex M. parafortuitum complex
M. scrofulaceum M. parafortuitum
M. simiae M. aurum
M. diernhoferi
M. vaccae
M. neoaurum
M. gordonae complex Thermotolerant strains
M. gordonae M. flavescens
M. szulgai M. phlei
M. asiaticum M. thermoresistible
M. kansasii complex Bovine farcy
M. kansasii M. farcinogens
M. gastri M. senegalense
M. terrae complex
M. terrae
M. nonchronogenium
M. triviale
43
Chapter 5 Mycobacterium Tuberculosis
as the decolorizer and counter stain.3 Ehrlich (1882) Decolorization with alcohol and cold staining techniques
discovered 3% acid fast property of the bacteria and as well as the use of fluorescent dyes (e.g. Auramin-O)
stained the bacilli with hot fuchsin in the presence of to visualize the Mycobacteria have also been developed.
aniline oil as a mordant and destaining with a dilute (Fig. 5.1E) It is not possible to differentiate M. tuberculosis
mineral oil. Ziehl (1883) changed the mordant to phenol from other acid fast atypical Mycobacteria. The property
and Neelsen (1884) combined the dye and mordant to of acid fastness, however, is not unique to Mycobacteria.
form carbol fuchsin. Thus, the acid fast staining It is shared with Nocardia, volutin granules of
technique, although, pioneered by Ehrlich, is now known Corynebacteria, Legionella micadadi, bacterial and fungal
as the Ziehl-Neelsen (ZN) method and has remained spores and cysts of the protozoan Cryptosporidium species,
essentially unchanged since 1884 (Figs 5.1B to D). if only 1% acid is used to decolorize.
Figs 5.1A to E: A. Scanning Electron Microscopical

observation of M.tuberculosis. B. Ziehl-Neelsen stained
M. tuberculosis cells, C. Typical serpentine growth (cord
factor) of M. tuberculosis culture grown in egg-based media
(Lowenstein-Jensen Medium), D. ZN stained cells
harvested from liquid culture (Middlebrook 7H9 broth), E.
Auramine Rhodamine (AR) stained M. tuberculosis cells.
The fluorescent staining method has higher sensitivity over
ZN method (For color version see Plate 1)
44
Mycobacterial Species not right to call the disease “tuberculosis” because of the
pronounced differences between the two infections in
The primary mycobacteriosis throughout the world is pathogenesis, epidemiology, prognosis and response to
tuberculosis. Its prevalence and severity prompted the treatment. The drug susceptibility of NTM, as measured
studies of Robert Koch and others on its etiology that by tetrazolium microplate assay, showed that the pattern
culminated in the discovery of the tubercle bacilli in 1882. of drug susceptibility is grossly different in NTM from
Before the end of the century the bovine, avian, reptilian, M. tuberculosis (Fig. 5.2). Runyon13 provided early
piscine and saprophytic varieties of Mycobacteria had leadership in the classification of these mycobacteria and
also been described. Despite sporadic reports of isolation on the basis of type of colony, rate of growth, pigment
of many varieties of nontuberculous mycobacteria from production and simple biochemical reactions divided
clinical specimens only M. tuberculosis and M. bovis were them into four groups. Subsequent workers have
taken seriously as a cause of human disease,9 while these suggested different biochemical tests and High
isolates were given dismissive epithets such as “atypical” Performance Liquid Chromatography (HPLC) analysis
“pseudotubercular” and “tuberculoid” bacilli. Also, as of species—specific mycolic acids in order to improve
their classification was in chaos, they were dubbed the identification of isolates but the basic format has
“anonymous” mycobacteria. Interest in their role as remained unchanged. From the clinical point of view,
pathogens of man commenced in earnest in the 1950s however, these mycobacteria are divisible into three
with the description of two distinct diseases, namely groups:
swimming pool granuloma and Buruli ulcer caused by • The obligate human pathogens
M. marinum and M. ulcerans, respectively. And also the • Species that have been definitely shown to cause human
demonstration of their etiological role in the tuberculosis- disease under certain circumstances, and
like pulmonary disease.10 • Those that rarely, if ever, do so.
The “atypical” mycobacteria isolated from clinical Opportunistic infections due to MOTT or NTM have
material have been called by many names—paratubercle, been on the increase, mainly as a consequence of the AIDS
pseudotubercle, anony-mous, atypical, nontuberculous epidemic.14-16 Among the mycobacterial species often
(NTM), environmental, opportunistic, tuberculoid and implicated in NTM infections are M. avium, M. intra-
mycobacteria other than tubercle (MOTT) bacilli. The cellulare complex, M. fortuitum, M. chelonae, M. abscesses,
diseases associated with them have been termed— M. kansasii , M. celatum, and M. xenopi.12,14,16,17
pseudotuberculosis, mycobacteriosis, nontuberculous,
mycobacterial infection and tuberculosis due to one of
Habitat
the specific mycobacterium by species name.
None of the proposed names is without criticism but Mycobacteria are not members of the normal bacterial
the most appropriate and least offensive, is nontubercular flora of man, but M. smegmatis and M. gastri can sometime
mycobacteria (NTM).9 Certainly, atypical, anonymous be isolated from the smegma and gastric contents,
and unclassified are no longer acceptable as each of the respectively.18
species is typical, for the genus Mycobacteria, when ana- M. tuberculosis is clearly not typical of the myco-
lyzed microbiologically and since species specific names bacteria since, the majority of these species are essentially
have been designated, opportunistic is also not entirely environmental saprophytes and do not cause disease or
appropriate, 10,11 but usually referred to describe such rarely do so. Thus, M. tuberculosis has been described as
infections in immunocompromised persons.12 It is also being the Wayward Son of Honorable Parents. The impli-
MIC GC MIC GC
Fig. 5.2: Antimycobacterial drug susceptibility by tetrazolium microplate assay. This method is rapid, quantitative but
feasible only in center with biocontainment facility (For color version see Plate 1)
45
cation is that M. tuberculosis probably evolved from an They have been used for primary isolation of
environmental organism to become the most successful M. tuberculosis from the clinical samples and they also
bacterial pathogen of all time utilizing successful tend to yield a higher percentage of positive results in
strategies to invade and persist within macrophages with comparison to agar based isolation media. Because of its
phases of dormancy. luxuriant growth on egg media, M. tuberculosis has been
Mycobacteria are most widely known as the cause of termed “eugonic”.
dreadful diseases. Less well known is their role as Agar based media are prepared from semi synthetic
thriving members of environmental ecosystems. In fact, basal medium and are enriched with defined
a large variety of complex organic synthetic and supplement. Since, the medium is transparent, it permits
degradative processes have been described recently for early microscopic detection of the colonies. Growth of
free living soil mycobacteria. Mycobacteria synthesize a M. tuberculosis on agar based medium like Middlebrook
variety of steroid hormones from cholesterol.19 Various 7H10 is enhanced by the presence of 5 to 10% of CO2 in
simple and complex hydrocarbons and other organics the incubation atmosphere. (Fig. 5.3A). The medium
can be degraded and these activities could be useful in should be made selective by incorporation of various
pollution control.20 antibiotics. For the best results both an agar and egg based
media should be used for primary isolation of
Cultural Characteristics mycobacteria. Most strains of mycobacteria causing
human disease can be isolated using media of two
The Mycobacteria are aerobic nonencapsulated, nonspore different basal composition. Diffusible pigment is seldom
forming, nonmotile bacilli. The M. tuberculosis is one of present, but colonies of some species are regularly,
the slowest growing (generation time in animal tissues variably yellow or orange. Some species require light to
~24 hours) Mycobacteria. Colony morphology varies form pigments (photochomogens) and other form
among the species, M. tuberculosis forms rough colonies pigment in either the light or dark (scotochromogens)
with bacilli compacted into curving strands (serpentine (Fig. 5.3B).
cords). In contrast, M. avium complex usually forms It is true that M. tuberculosis is best isolated from
smooth transparent colonies with the bacilli arranged in clinical specimens on rich and fairly complex media like
no definite pattern. Robert Koch isolated the organism Middlebrook 7H9, BACTEC- MGIT960 and MB-act-240,
on heat coagulated sheep serum culture medium devised (Figs 5.4A to C) but the apparent fastidiousness of some
by John Tyndall. Nocard later introduced glycerol-beef such isolates may be consequence of their injury by
broth which Koch used for his studies on tuberculin. conditions in host tissue or by the treatment employed
Mycobacteria are strictly aerobic and grow more for processing the clinical specimen. Once isolated, M.
slowly than most bacterial pathogens. The generation tuberculosis is capable of adapting to grow on extremely
time of the mycobacteria is more than 12 hours. simple medium, i.e. one containing, a simple source of
M. tuberculosis has the longest replication time of 20 to carbon and nitrogen plus some buffer salts and trace
22 hours. The growth of M. tuberculosis is enhanced by elements. A visible mass multiplication can be seen in
an atmosphere of CO2 between 5 and 10% for the first Middlebrook 7H9 broth (Fig. 5.4C).
few weeks of incubation. Mycobacterium requires a pH
between 6.5 and 6.8 for the growth medium and grows Mycobacterial Envelope
better at higher humidity.
Isolation of mycobacterium poses a special problem The cell envelope essentially distinguishes species of
for the laboratory. Mycobacteria require a prolonged mycobacterial genus from other prokaryotes.
time for replication [approximately 15 to 22 hours], Mycobacteria in general give a weakly positive response
whereas the generation time of other bacteria present in to the Gram-stain but are phylogenetically more closely
related to Gram-positive bacteria. Based on the recent
the specimen may be as short as 20 to 30 minutes. This
developments in the knowledge of the ultrastructure and
disproportionate rate of growth between mycobacteria
chemistry of mycobacteria, the mycobacterial cell
and other bacteria may result in rapid accumulation of
envelop possesses 3 structural components: (1) Capsule
metabolic acids that liquefy the culture medium, making
(2) Cell wall and (3) Plasma membrane.21 This skeleton
it unsatisfactory for the recovery of mycobacteria.
provides osmotic protection from outside environment
Therefore, the successful isolation of mycobacteria
and also helps transportation of ions and molecules
depends upon the selective suppression of contaminating
beside the mechanical support and shape to the bacteria.
bacteria.
Egg-based solid media like Lowenstein-Jensen or
Mycobacterial Capsule
American Tradeau Society medium are very rich and
contain phospholipids, and proteins that tend to bind The outermost compartment of the cell envelop consists
and/or neutralize toxic products in clinical specimens. of a mixture of polysaccharides, proteins and lipids, and
46
Figs 5.3A and B: A. Mycobacterium smegmatis cultured in Middlebrook7H10 agar and incubated at 37°C for 5 days,
B. Mycobacterial colony and phenotypic appearance on Lowenstein-Jensen (L-J) Medium incubated at 30-37°C in the
presence or absence of light (For color version see Plate 2)
A B C
Figs 5.4A to C: Middelbrook 7H9 broth containing OADC (Oleic Acid, Dextrose, Catalase) with antibiotic mixture (PANTA
– Polymyxin, Amphotericin, Nalidixic Acid, Trimethoprim and Azlocillin) to prevent other contaminants is being used in
automated culture system with higher sensitivity. The growth rate of M. tuberculosis is faster (12-17 days) than the solid
(22-30 days), egg based L-J (27-45 days) culture methods. (A) BACTEC MGIT-960 (Mycobacterial growth Indicator
Tube, Becton Dickinson, USA) growth detection based on fluorescence (B) MB-BacT-240 (Biomeurieux, France) growth
detection based on colorimetry (C) Laboratory mass multiplication of M. tuberculosis in Middlebrook7H9 broth (For color
version see Plate 2).
is called capsule. The earliest mention of mycobacterial has not been possible so far and many substances are
capsules was by Chapman in 1959, who called the space found in more than one envelop compartments.
between the phagosomal membrane of the infected cell However, electron microscopic studies have proved
and the wall of the enclosed Mycobacterium a capsular existence of capsule in mycobacteria. It is also established
space or halo. Chemically, a clear distinction between now that most part of the capsule is lost from the
the wall associated compounds and capsular constituents mycobacteria during the conventional processing of the
47
samples for microscopy. Most of the species of Escherichia coli. It is composed of glycan to which the
mycobacteria are known to possess the capsule, but the tetrapeptide is attached which in turn is crosslinked.
thickness varies from species to species. The ratio of Linker disaccharide: Carbon 6 of about 10% of muramic
protein to polysaccharides varies, according to the acid residues provide the point of attachment of
species. For example, the major constituent in M.
peptidoglycan to polysaccharide, arabinogalactan via a
tuberculosis, M. kansasii, and M. gastri are polysaccharides
linker disaccharide phosphate. This structure is unique
while M. phlei and M. smegmatis consist mainly of
to Mycobact- eria and Nocardia.
proteins.21
The major polysaccharides of mycobacterial capsule Arabinogalactan: Attached to simple linker dis-accharide
consists of mainly the glucan (an arabino-mannan) and unit is a complex polysaccharide, called arabinogalactan.
a mannan. Small amounts of other oligo- and Mycolic acids are attached to the 5 position of the terminal
polysaccharides are also found, which are still not arabinogalactan.
characterized. The capsular proteins are complex
mixture of polypeptides. These include superoxide Plasma Membrane
dismutase, alanine dehydrogenase, glutamine
In ultrathin sections, plasma membrane occur as classical
synthetase, alcohol dehydrogenase and thioredoxine.
bilayers with two electron dense layers separated by
Even though traditionally the mycobacteria have been
transparent layer.21 This appearance, coupled with their
considered to be surrounded by “thick waxy coat” but
known chemical composition22 indicates that these are
the recent findings are that the capsule indeed consists
normal biological membranes. Mycobacterial membranes do,
of mainly carbohydrates and proteins and the lipid
however, have some distinctive components, notably the
constituents are only 2 to 5%. The mycobacterial
lipopolysaccharide, LAM, a major bioactive constituent lipopolysaccharides lipoarabinomannan (LAM), lipom-
of mycobacterial cell wall is not detectable from the annan and phosphatidylinositol. The appearance of
capsule. Various phospholipids and some species specific mycobacterial plasma membrane is not symmetrical, the
lipids (e.g. Dimycocerosate of phthiocerol) and type outer, electron dense layer is thicker than the inner layer.
specific lipids of M. tuberculosis, such as PGL and This asymmetry is lost when cells are killed before
lipooligosaccharides are present on its surface, others like fixation. There is electron cytochemical evidence that the
trehalose dimycolates occur in the inner compartments extra thickness is associated with carbohydrate and
of the capsule.21 possible candidate molecules are phosphatidylinositol
The role of mycobacterial capsule in pathogenesis is mannosides of LAM. There appears to be space between
important at least for the first steps of internalization of outer of the plasma membrane and the inner layer of cell
bacteria, though not absolute. The capsule plays wall. If we hypothesize that the walls of M. tuberculosis
important role in adhesion and penetration into the host form permeability barriers somewhat analogous to the
cell through various cell receptors, binding proteins and outer membranes of gram negative bacteria, then the
adhesion molecules. space between the outer leaflet of the membrane and the
wall forms a compartment analogous to the periplasmic
Cell Wall Core space of the gram-negative bacteria.
The cell wall core is defined as the insoluble matrix of
the mycobacterial cell wall after the removal of all soluble Associated Molecules of the Cell Wall
proteins, lipids and carbohydrates. It is composed of three
covalently attached macromolecules. The outermost, the Lipoarabinomannan (LAM)
mycolic acids, are 70- to 90-carbon-containing, branched Lipoarabinomannan is a phosphatidylinositol-anchored
fatty acids which form an outer lipid layer in some ways lipoglycan composed of a manna core with oligoara-
similar to the classical outer membrane of gram-negative binosyl-containing side chains. It is found in all
bacteria. The mycolic acids are esterified to the middle mycobacteria including M. tuberculosis. While LAM lacks
component, arabinogalactan (AG), a polymer composed covalent association with the cell wall core, it is
primarily of D-galactofuranosyl and D-arabinofuranosyl nonetheless a crucial part of cell envelope also. LAM is a
residues. AG is connected via a linker disaccharide, a-L- molecule of profound interest and importance with
rhamnosy l- (1 → 3)-α-D-N-acetyl-glucosaminosyl-1- diverse biological activities. It has properties analogous
phosphate, to the 6 position of a muramic acid residue in to gram-negative O-antigenic LPS such as nonspecific
the peptidoglycan. The peptidoglycan is the innermost suppression of T lymphocyte activation and inhibition
of the three cell wall core macromolecules.21 of antigenic responsiveness of human peripheral blood
Peptidoglycan: It is the innermost layer adjacent to plasma leucocytes and inhibits antigenic presenting cells. LAM
membrane and is analogous to other bacteria such as also inhibit interferon gamma mediated activation of
48
macrophages. Thus, it may be implicated in the Metabolic Biosynthesis

interaction of the pathogen and the host cell in the down
regulation of T cell responses of various types. It may be Most mycobacteria are prototropic, i.e. they are going to
grow in a media containing only inorganic salts plus a
a harbinger of bad immunity (i.e. immunopathogenesis).
source of carbon. Occasional fastidious strains, however,
In addition, it is a major B cell immunogen.23 Three
are encountered, which could represent naturally
general classes of LAM have been described: (1)
occurring auxotrophic mutants. Optimal growth in
ManLAM, from the virulent strains Erdman and H37Rv;
synthetic medium is generally obtained with asparagine
(2) Phosphor-myo-inositol-capped LAM (PILAM) found
and glutamine for nitrogen and glycerol for carbon.
in rapidly growing mycobacteria, M. smegmatis and M.
Latency seen in pathogenic mycobacteria is explained
fortuitum and (3) AraLAM which was described in M.
by the metabolic shut down in the mycobacteria which
chelonae. Although, there is significant heterogeneity
is triggered and regulated by the host immune system.
between LAM molecules with respect to glycosylation
Though no clear genetic basis of dormancy and
and acylation, differences in biological activity between
reactivation has been described, it is expected to be
the major classes of LAM have been attributed to heavy
genetically programmed and controlled by intracellular
mannose capping. signalling pathway.
Trehalose-based Glycolipids
Susceptibility to Physical and Chemical Agents
Trehalose is a simple disaccharide of glucose similar in
some ways to common table sugar, which is found free Mycobacteria possess the same degree of susceptibility
and bearing various fatty acyl groups in M. tuberculosis to heat as other nonspore forming mycobacteria and this
and other mycobacteria. These acylated trehaloses are property is exploited for destruction of mycobacteria in
associated via hydrophobic interactions with the mycolic milk by pasteurization. They are however more resistant
acids of cell wall core and thus, are on outside edge of to acid, alkalis and chemical disinfectants due to heavy
cell envelope. The most studied amongst these is capsule, as described above. This property is also
trehalose dimycoate, commonly known as the cord factor. exploited by microbiologists by decontamination of
Various biological activities have been described most clinical samples in their attempt to isolate mycobacteria
of them seemingly related to their ability to induce in pure cultures from sites, e.g. sputum, where rapidly
cytokine-mediated events, such as systemic toxicity, growing commensal bacteria are present.
antitumour activity and macrophage release of Mycobacteria are destroyed by phenols, hypo-
chemotactic factors. chlorites or glutarldehyde. Formaldehyde is suitable for
disinfection of rooms or safety cabinets, but it has low
Another important class of lipid based on trehalose
penetration power and its effectiveness is diminished
is the sulfatides. In these molecules, trehalose is sulfated
when bacilli are embedded in sputum. Mycobacteria are
at 2 position and acylated with array of specialized fatty
also killed by acetone, propanol and 70% alcohol, which
acids. Its association with virulence has been demon-
are used for disinfection of clinical thermometers.
strated in guinea pigs. The biological activities of the
Mycobacteria are resistant to drying and survive for
sulfatides has been proposed as an antagonist of the
weeks to months on inanimate objects if protected from
fusion of the secondary lysosomes with phagosomes or
sunlight. It does not appear to replicate in the
phagosome activation, thus promoting intracellular
environment but it survives for several months in soil
survival of pathogen.24
and cow dung. Sensitivity of mycobacteria to sunlight
or ultraviolet light depends, to some extent on their
Cell Envelope Proteins
pigmentation. Scotochromogenic strains are more
Some of the proteins of mycobacteria are preferentially resistant than nonchromogens while uninduced photo-
associated with the cell wall and are powerful chromogens are the most sensitive to all. The pigment
immunogens. A 23 kiloDalton (kDA) protein appears to does not act as a filter for UV light but appears to
be tightly, although noncovalently, associated with neutralize photo excited substances like superoxides.
peptidoglycan. A 59 kDa protein has been identified as Mycobacteria are more sensitive to UV light than E.coli
the porin and the 65 kDa protein is the heat shock protein and this may in part be dependent upon genome size
which acts as the molecular chaperon. Bioinformatic and capacity for DNA repair.
analysis of the M. tuberculosis genome predicts >65
lipoproteins of ‘cell envelope’ origin, some of which were Genetics of Mycobacteria
identified previously as ‘secreted’ proteins, or enzymes
involved in cell wall biogenesis. Besides these, there are Ribosomal RNA sequence comparison demonstrates that
17 conserved MmpL and MmpS proteins, and >600 other mycobacteria are member of high Guanine + Cytosine
‘putative’ membrane proteins. (GC) content gram positive bacteria. GC content varies
49
from 58% for M. leprae to 69% for M. intracellulare, and On the basis of systematic sequence analysis of
65.6% for M. tuberculosis. 26 loci of several isolates, it is concluded that the genome
Focusing on specific operons by physical methods has of M. tuberculosis is either unusually inert or that the
revealed the organization of the rRNA locus in several organism is relatively young in evolutionary terms. The
species of mycobacteria. As is the case of all the other size of the mycobacterial genome is 2.5 × 109 daltons of
Eubacteria studies, the three rRNAs are organized into 4.4 million base pairs (bp). M. tuberculosis has the same
an operon with 16S RNA positioned first at the 5' end, re-association kinetics as E. coli K12. The past decade has
the 23S rRNA in the middle and and the 5S rRNA at the seen dramatic advances in the understanding of the
3' position. The slow growing mycobacteria such as M. metabolic and intracellular life style of M. tuberculosis
tuberculosis and M. leprae have only one copy of the rRNA culmination in the recent publication of the complete
operon and the fast growing mycobacteria like genomic DNA sequence of large number of strains.26 Of
M. smegmatis and M. phlei having two, this is radically the estimated 4000 encoded proteins, about 40% have
different from E.coli which has 7 copies of rRNA operon known biochemical functions, another 44% have
(rRNA-G).25 sequence homology but 16% are completely unknown
A truly remarkable feature of the pathogenic (the fun genes). 59% of the genes are transcribed in the
Mycobacteria is their extremely slow growth. The same direction as chromosomal replication.
Mycobacteria increase their glycogen storage which is
used during the unsuitable growth conditions. Mycobacterial Genome
Mycobacteria have a doubling time of approximately 17 A total of 45 different Mycobacterium species are being
hours under optimal conditions in vitro, and ~ 24 hours sequenced as listed in the Table. 5.3.
in animal models, which is by far the longest doubling The genomes of M. tuberculosis26 and M. bovis27 have
time for any free living bacterium. However, most of the been fully sequenced. The M. tuberculosis has 4,411,529
nonpathogenic soil mycobacteria have considerably base pairs, with a G + C content of 65.6%. The genome is
faster growth rates. rich in repetitive DNA, particularly insertion sequences
Table 5.3: Genomic sequence of mycobacterial species
Name of the strain Associated with Size of Sequencing center Status

the genome
Mycobacterium Environmental bacterium 5 Mb Genoscope complete

abscessus that causes lung, wound,
and skin infections
M. avium 104 Causative agent of 5 Mb TIGR complete
mycobacterial disease in
children, the aged, and in
immunocompromised
individuals
M. avium subsp. Causative agent of McGill University, in progress
avium ATCC mycobacterial disease in Canada/University of
25291 children, the aged, and in Minnesota
immunocompromised
individuals.
M. avium subsp. Causative agent of 4 Mb University of Minnesota complete
paratuberculosis Johne’s disease, or
K-10 paratuberculosis, a chronic
severe intestinal infection
M. bovis Causative agent of bovine 4 Mb Sanger Institute complete
AF2122/97 tuberculosis
M. bovis BCG Brazilian vaccine strain Fiocruz - FAP in progress
str. Moreau RDJ
M. bovis BCG The causal agent of bovine 4 Mb Mycobacterium bovis complete
str. Pasteur tuberculosis sequencing teams
1173P2
Contd....
50
Contd.... Table 5.3: Genomic sequence of mycobacterial species

the genome
M. bovis BCG This strain is being Japan BCG Laboratory/ in progress

str. Tokyo 172 sequenced for Agencourt Bioscience
comparative genome Corporation
analysis
M. chelonae Environmental bacterium Genoscope in progress
that causes wound,
cornea, and skin infections
M. gilvum PYR- Capable of degrading a 5 Mb DOE Joint Genome complete
GCK variety of polycyclic Institute
aromatic hydrocarbons
M. intracellulare Clinical isolate McGill University, draft assembly
ATCC 13950 Canada
M. kansasii ATCC Well-studied clinical strain McGill University, draft assembly
12478 Canada
M. leprae Br4923 Strain isolated from a Institut Pasteur/Institut in progress
human skin biopsy in Pasteur PF1
Brazil
M. leprae TN Causative agent of human 3 Mb Sanger Institute complete
leprosy
M. liflandii Causes a systemic disease Monash University in progress
128FXT in frogs
M. marinum Causes systemic infection Monash University in progress
DL240490 in fish and skin infections
in humans
M. marinum M Causes systemic infection 6 Mb Welcome Trust Sanger complete
in fish and skin infections Institute
in humans
M. microti Causes generalized Sanger Institute in progress
tuberculosis in rodent,
cattle, and humans
M. smegmatis str. Generally non-pathogenic 7 Mb TIGR complete
MC2 155 mycobacterium capable
of causing soft tissue
lesions
Mycobacterium sp. A pyrene-degrading 6 Mb DOE Joint Genome complete
JLS bacterium isolated from Institute
the Libby Montana
Groundwater Superfund
Site
KMS bacterium isolated from Institute
the Libby Montana
Site
MCS bacterium isolated from Institute
the Libby Montana
Site
Mycobacterium sp. Isolated from a creosote DOE Joint Genome in progress
Spyr1 contaminated site Institute
M. tuberculosis Strain for comparative Broad Institute in progress
’98-R604 INH- analysis
RIF-EM’
Contd....
51
Contd.... Table 5.3: Genomic sequence of mycobacterial species

the genome
M. tuberculosis Strain being sequenced for Broad Institute draft assembly

02_1987 comparative analysis
M. tuberculosis Causative agent of 4 Mb TIGR in progress
210 tuberculosis
M. tuberculosis Isolate from China Broad Institute draft assembly
94_M4241A
M. tuberculosis C Drugsusceptible strain draft assembly
M. tuberculosis Causative agent of 4 Mb TIGR complete
CDC1551 tuberculosis
M. tuberculosis Sequenced for comparative Broad Institute draft assembly
EAS054 analysis
M. tuberculosis F11 Predominant strain in 4 Mb Broad Institute complete
South African epidemic
Mycobacterium Strain used for Broad Institute draft assembly
tuberculosis GM 1503 comparative genome
analysis
Mycobacterium An attenuated strain used Beijing Genomics draft assembly
tuberculosis H37Ra in mycobacterial virulence Institute
research draft assembly
Mycobacterium An avirulent strain derived Chinese National HGC, complete
tuberculosis H37Ra from its virulent parent Shanghai/Fudan
strain H37 Bacteria University, PR China,
Shanghai/Johns Hopkins
University, Department
of Molecular
Microbiology and
Immunology, Bloomberg
School of Public Health,
USA, Baltimore
Mycobacterium Causative agent of 4 Mb Sanger Institute complete
tuberculosis H37Rv tuberculosis
Mycobacterium Multidrug-resistant clinical Broad Institute draft assembly
tuberculosis isolate
KZN 1435
Mycobacterium Drug-susceptible clinical Broad Institute draft assembly
tuberculosis isolate
KZN 4207
Mycobacterium Extensively drug-resistant Broad Institute draft assembly
tuberculosis KZN 605 clinical isolate
Mycobacterium Strain will be sequenced Broad Institute draft assembly
tuberculosis T17 for comparative genome
analysis
Mycobacterium Susceptible strain Broad Institute draft assembly
tuberculosis T85
Mycobacterium Clinical isolate Broad Institute draft assembly
tuberculosis T92
Mycobacterium A drug resistant strain Broad Institute draft assembly
tuberculosis str. found in crowded human
Haarlem populations
Mycobacterium Mycolactone-producing Monash University in progress
ulcerans 1615 strain
Mycobacterium The causal agent of Buruli 5 Mb Institut Pasteur complete
ulcerans Agy99 ulcer
Mycobacterium Capable of degrading a 6 Mb DOE Joint Genome complete
vanbaalenii PYR-1 variety of polycyclic Institute
aromatic hydrocarbons
Contd....
52
and in new multigene families and duplicated Precise function could be attributed to ~40% of
housekeeping genes. The G + C content is relatively predicted proteins while some information similarly
constant throughout the genome indicating that could be found for another 44%. The remaining 16%
horizontally transformed pathogenicity islands of a resemble no known proteins and may account for specific
typical base composition are probably absent. This mycobacterial function. Amino acid analysis of these
information has also led to development of multiplex problems revealed a significant preference for Ala, Gly,
PCR assay for simultaneous detection and differentiation Pro, Aug and Trp which are all encoded by G + C rich
of M. tuberculosis and M. avium complex (Fig. 5.5). codons and a comparative reduction in the use of amino
The rrn operon is situated unusually 1500 kb distant acid encoded by A + T rich codons such as Asn, Ile, Phe
from the putative oriC (origin of replication) and may in and Tyr. Circular representation of M. tuberculosis H37RV
part explain the slow growth of M. tuberculosis. The genes genome and M. avium subsp. paratuberculosis K-10 is
encoding tRNAs that recognize 43 to 61 possible sense given in Figure 5.6.
codons are distributed throughout the genome. 3,924 A summary of the complete genome of M. para-
open reading frames (ORF) have been identified in the tuberculosis K-10 and the comparison with other
Mycobacterial genome, accounting for ~ 91% of potential mycobacterium species is given in Table 5.4.
coding capacity.26
Fig. 5.5: Multiplex PCR Assay for Simultaneous Detection and Differentiation of Mycobacterium tuberculosis, M. avium Complexes, and other
mycobacterial species directly from clinical specimens: M–100 bp marker (MBI, Fermentas),1,4 – M. tuberculosis, 2, 5 – M. avium complex,
3, 6 – M. tuberculosis + M. avium complex, 7 – Negative control
Table 5.4: Summary of the complete genome of M. tuberculosis and the comparison with other
Mycobacterium species (http://www.ncbi.nlm.nih.gov/sites/entrez?db)
Property M. ap M. av M. tb M. bovis M. leprae M. smeg

• Genome size, bp 4,829,781 5,475,738 4,411,532 4,345,492 3,268,203 6,988,209
• GC content, % 69.30 68.99 65.61 65.63 57.79 67.40
• Protein coding, % 91.30 NA 90.80 90.59 49.50 92.42
• ORFs 4,350 NA 3,959 3,953 1,604 6,897
• Gene density, bp per gene 1,112 NA 1,114 1,099 2,037 1,013
• Average gene length, bp 1,015 NA 1,012 995 1,011 936
• tRNAs 45 45 45 45 45 47
• rRNA operon 1 1 1 1 1 2
• ABC transporters# 60 — 39 42 24 —
M. ap – M. avium subsp. paratuberculosis, M. av – M. avium subsp. avium 104, M. tb – M. tuberculosis H37Rv,
M. smeg – M. smegmatis
#
Gopinath K, Singh A, Singh Sarman, Unpublished data.
53
Fig 5.6: Circular Representation of M. tuberculosis H37Rv genome and M. avium subsp. paratuberculosis K-10
Comparative Mycobacterial Genomics as a Tool for Drug an additional group of 45 genes whose presence, and
Target and Antigen Discovery possibly function, is facultative. From the combined
findings, it can be concluded that >200 genes exist that
There is an evergrowing need for new drugs and vaccines are not essential for growth of M. tuberculosis complex
to treat and prevent mycobacterial diseases and for members in the host but may influence the degree of
improved diagnostic tools to detect infection more virulence.
reliably. The desired properties of new antitubercular The diagnosis of both the active and latent TB which
agents include reduction of the duration of treatment, as relies heavily on clinical expertise and detection of acid-
well as activity against latent TB infections and MDR- fast bacilli in sputum smears will also benefit from
TB. Several different approaches are available to comparative genomics. Latent infection is often
determine which genes of M. tuberculosis are essential diagnosed by monitoring the extent of delayed type
and thus worthy of further investigation as targets for hypersensitivity reactions following intradermal
drug development. These include gene knockouts, injection of tuberculin, an ill-defined mixture of antigens.
transcript analysis and definition of the proteome. Tuberculin reactivity is of limited value in communities
Comparative genomics is a powerful tool for where BCG vaccination is a component of National
exploring microbial evolution and identifying genes that Program of Immuni-sation as in India. Its interpretation
might encode new drug targets or protective antigens. may be confounded by infections involving other
Genomic diversity of the M. tuberculosis complex has been mycobacteria. The identification of 120 genes in the
studied by DNA array technology, facilitated by the fact tubercle bacillus, which are absent from BCG allows a
that all members share a >99.95 percent identity at the move towards the development of a more specific test
DNA level. Comparative genomics of the respective that can distinguish between infection and immuni-
members of the M. tuberculosis complex has revealed the zation. Microarray and proteomics will also find wide
existence of a gene gradient. The human tubercle bacillus, application in monitoring biodiversity with in the
M. tuberculosis, has more genes than M. africanum, M. tuberculosis complex and help to confirm the presence
M. microti, and M. bovis, as these have lost genetic material or absence of candidate diagnostic antigens. By utilizing
through deletion events. Gene loss occurs at a high these cutting-edge techniques like 2D gel electrophoresis
frequency within the species of M. tuberculosis as a result and Matrix—assisted laser desorption/ionization-Time
of homologous recombination events between copies of of Flight (MALDI-TOF), 54 proteins, which are unique
IS6110 that flank genes in the direct orientation. and expressed only in multidrug resistant strains have
Microarray and Affymetrix chip studies have uncovered been identified (Fig. 5.7).
54
Fig. 5.7: Comparative proteomic analysis of multidrug resistant and drug sensitive strain of M. tuberculosis. The whole cell proteins were extracted
from both sensitive and resistant M. tuberculosis strains and analyzed with two dimensional gel electrophoresis. The spots with difference on
comparison were identified by MALDI-TOF. The results showed that more than 20 proteins are expressed only in drug resistant and not in
sensitive strains (Singh A, Gopinath K, Singh Sarman. Unpublished Data)
The dilemma facing tuberculosis researchers and Mycobacteriophages consist of a head and a tail. The
funding agencies is whether to give priority to viral genome is enclosed within a protein shell (capsid).
operational research to determine the most effective ways Some phages are inactivated by organic solvents because
of using the available control measures or to focus on their capsids contain structural lipids. The double
basic research into new diagnostic tests, vaccines, and stranded genomes of mycobacteriophage TM 4 (lytic
phage), L1 (temperate phage) and L5 are approximately
treatment regimens. Effort is being devoted to both
50 kilobases in size, that of D29 phage is 48 kb and of 18
approaches, involving a multidisciplinary approach from
phage 43kb. Mycobacteriophage D29 was isolated from
diverse disciplines such as molecular biology, social soil29 and is a lytic phage which is able to infect and
anthropology and health economics. Nucleic acid replicate in the slow growing pathogenic strains such as
technology will provide rapid, specific, sensitive M. tuberculosis and M. ulcerans and fast growing
diagnostic tests and rapid detection of drug resistance. environmental strains such as M. smegmatis. Growth is
Vaccine which is able to prevent the emergence of post initiated when a phage particle absorbs to a specific cell
primary infectious tuberculosis will be one of the surface receptor by the tip of its tail and infects its double
principal means of controlling tuberculosis. An stranded DNA molecule into the host. Phage infection
immunotherapeutic agent used in conjunction with drug can result in death of the host by lysis (virulent phage) at
treatment will lead to a much lower failure rate, even in the end of the replicative cycle or in permanent
cases of drug resistant diseases, and new “designer” association between the temperate phage and the host
drugs with specific antitubercular activity will be used by integrating viral DNA into the bacterial chromosome
to treat resistant cases. as prophage and establishing lysogeny.
In the past, phage typing has been used as one of the
Metabolic Pathway methods of finger printing of M. tuberculosis.29,30 The
From the genome sequence, it is clear that the tubercle utility of D29 for testing susceptibility of Mycobacteria
bacilli has the potential to synthesize all the essential to anti-tuberculosis drugs was demonstrated in 1980 by
amino acids, vitamins and enzyme co-factors. David et al.31 Recently mycobacteriophages have been
M. tuberculosis can metabolize a variety of carbohydrates, used in the rapid identification and rifampicin drug
hydrocarbons, alcohol, ketones and carboxylic acids. susceptibility testing directly from the clinical samples
Approximately, 13 sigma factors govern the gene with encouraging results both in pulmonary and
expression at the level of transcription initiation and more
extrapulmonary clinical samples. Commercially, the
than 100 regulatory proteins are predicted.26
method is known as fast-plaque assay (Figs 5.8A to C).
Mycobacteriophages Animal Pathogenicity
Mycobacteriophages are viruses that infect Mycobacteria. Humans are the only natural reservoir for M. tuberculosis
First discovered 50 years ago, there are now over 250 although it can be grown in laboratory primates, guinea
known mycobacteriophages.28 pigs and mice.
55
Figs 5.8A to C: FASTPlaque-TBTM method for identification of the Mycobacterium tuberculosis. All culture plates are seeded with M. smegmatis
as substrate (sensor cells) for mycobacteriophage. A. FASTPlaque-TBTM. Negative control, showing no lysis (plaque formation) of the sensor
cells. B. FASTPlaque-TB.TM Positive control, showing more than 20 plaques (virucidal units). C. FASTPlaque-TB.TM showing heavy mycobacterial
load in the clinical samples, indicated by presence of confluent (4200) plaque formation (For color version see Plate 3)
The guinea pig is highly susceptible to experimental • Cell wall constituents

infection with both M. tuberculosis and M. bovis. An acute – Lipoarabidomannan
form of disease process is seen in guinea pigs exposed to – Trehalose based glycolipids
tuberculosis by aerosol.32 In these animals the infection – Cell envelope proteins
is initially contained by a granulomatous response, • Metabolic biosynthesis
but after 8 to 15 weeks the centers of certain lesions • Genetics of Mycobacteria
degenerate leading either to mineralization of the lesion • Mycobacteriophages
or extensive caseous necrosis or cavitation, eventually • Animal Pathogenicity
resulting in the death of the animal. This process appears • Mycobacterial Genome.
to mirror the course of events in untreated human Comparative mycobacterial genomics as a tool for
patients. Despite this closeness to the human condition drug target and antigen discovery.
animals larger than mice are rarely used to evaluate
antimycobacterial therapies.
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Nontuberculous Mycobacteria by Tetrazolium 22. Brennan PJ, Draper P. Ultrastructure of M. tuberculosis.
Microplate Assay. Ann Clin Microbiol Antimicrob In Bloom BR (Ed): Tuberculosis: Pathogenesis, Protection
2008;7:15. and Control. ASM Press, Washington DC 1994;271-84.
10. Good RC. Opportunistic pathogens in the genus 23. Misaki A, Azuma I, Yamamura Y. Structural and
Mycobacterium. Ann Rev Microbiol 1985;39: immunochemical studies on D-arabino-D-mannan of
347-69. M. tuberculosis and other Mycobacterial species. J Biochem
11. Grange JM, Yates MD. Infections caused by opportunist 1977,82:1759-70.
Mycobacteria: A review. J R Soc Med 1986;79:226-9. 24. Goren MB, Hart PD, Young MR. Prevention of
12. Singh S, Shahdad S, Kaur M, et al. Nontubercular phagosome – lysosome fusion in cultured macrophages
Mycobacterial infections in Indian AIDS patients by sulfatides of M. tuberculosis. Proc Natl Acad Sci USA
diagnosed by genus and species specific 16S rRNA and 1976,73:2510-4.
Novel ESAT-6 Polymerase Chain Reaction primers. Jpn 25. Mcfadden I. Molecular biology of the mycobacterial
J Infect Dis 2007;60:14-8. North Yorkshire, Surrey University Press, 1990.
13. Runyon EH. Anonymous Mycobacteria in pulmonary 26. Cole ST, Brosch R, Parkhill J, et al. Deciphering the
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14. Ratanasuwan W, Techasathit W, Chuenarom V, et al. genome sequence. Nature 1998; 393:537-44.
Infection due to nontuberculous Mycobacterium other than 27. Garnier T, Eiglmeier K, Camus JC, and 19 other authors.
MAC in AIDS patients at Siriraj hospital during 1998- The complete genome sequence of Mycobacterium bovis.
2000: saprophyte vs pathogen. J Med Assoc Thai Proc Natl Acad Sci USA 2003; 100:7877-82.
2002;85:886-93. 28. McNerney R. Tuberculosis. The return of the phage. A
15. Inderlied CB, Kemper CA, Bermudez LE. The review of fifty years of mycobacteriophage research. Int
Mycobacterium avium complex. Clin Microbiol Rev J Tuberc Lung Dis 1999;3: 178-84.
1993;6:266-310. 29. Froman S, Will SD, Bogen E. Bacteriophage active against
16. Smith MB, Schnadig VJ, Boyars MC, et al. Clinical and virulent Mycobacterium tuberculosis: isolation and activity.
pathologic features of Mycobacterium fortuitum infections. Am J Public Health 1954; 44:1326-33.
An emerging pathogen in patients with AIDS. Am J Clin 30. David HL. Genetics of the Mycobacteria. In: Bacteriology
Pathol 2001;116:225-32. of the Mycobacterioses. Centres for Disease Control,
17. Gopinath K, Singh S. Multiplex PCR Assay for Washington, DC: US Dept. of Health, Education and
simultaneous detection and differentiation of Welfare. DHEW publication no (CDC 76-8316) 1976;71-
Mycobacterium tuberculosis, M. avium Complexes, and 104.
Other Mycobacterial Species directly from clinical 31. David HL, Clavel S, Clamentand J, et al. Effects of tuber-
specimens. J Applied Microbiol 2009; 107:425-35. culosis and antileprosy drugs on mycobacteriophage D29
18. O’Brien RJ, Geiter L, Snider DE. The epidemiology of growth. Antimicrob Agents Chemother 1980;18:357-9.
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States. Am Rev Respir Dis 1987;135:1007-14. Bloom BR (Eds). Tuberculosis: Pathogenesis, Protection
19. Smith M, Zahuley J, Preifer D, et al. Growth and and Control, ASM Press, Washington, DC, 1994;135-47.
cholesterol oxidation by mycobacteria species in Tween 33. Laidlay M. Mycobacterium: tubercle bacilli. In Collee JG,
80 medium. Appl Environ Microbiol 1993; 59:1425-9. Duguid JP, Fraser AG, Marmion BP (Eds). Practical
20. Burback BJ, Perry JJ. Biodegradation and bio- Medical Microbiology, 13th edition, Edinburgh,
transformation of groundwater pollutant mixtures by Churchill Livingstone. 1989; 399-416.
6 Nontuberculous Mycobacteria
Sarman Singh, K Gopinath, Ashok Rattan
INTRODUCTION The Genus Mycobacterium consists of more than 121

species of which some species are conventionally
In 1882, Robert Koch identified Mycobacterium tuberculosis responsible for causing tuberculosis in humans or higher
as the cause of tuberculosis. Thus, by priority this bacillus animals (M. tuberculosis. M. bovis, M. africanum) are
became the “typical” mycobacterium. Other myco- grouped in the Mycobacterium tuberculosis complex and
bacteria, however, were soon observed that differed from leprosy in humans (M. leprae), while M. microti causes
M. tuberculosis, and these became known as “atypical” tuberculosis like condition in voles. While rest of the
mycobacteria. In 1954, Timpe and Runyon first classified species are known as Nontuberculous Mycobacteria
atypical mycobacteria into four groups on the basis of (NTM) and are further subdivided into slow and rapid
their growth characteristics. This system, known as the growers. Rapid growers require < 7 days to produce a
Runyon classification, has undergone so many visible colony in solid culture media on subculture, while
modifications that it has been more or less abandoned. colonies of slow growers appear only after more than 7
Members of the genus Mycobacterium are diverse in days of incubation and may require up to 8 weeks of
their pathogenicity, in vivo adaptation, virulence, in vitro incubation. The cell walls of mycobacterium have high
growth rate, pigment production and/or pathogenicity. lipid content with characteristic mycolic acids with long
The isolation of M. tuberculosis in pure culture by Robert branched chains. Nontuberculous Mycobacteria also
Koch (1882) was soon followed by isolation of resist decolorization by acid-alcohol like typical
M. smegmatis (1885), M. avium subsp. avium (1890), M. Mycobacteria, hence the term acid-fast bacteria (AFB)
avium subsp. paratuberculosis (1894) and others from applies to these also. The Table 6.1 shows the
different hosts and environments. These nontuberculous classification based on the growth rate of NTM.3,4
mycobacteria (NTM) have been referred as atypical,
environmental, unidentified, anonymous, opportunistic,
CLASSIFICATION OF NTM ON THE BASIS OF PIGMENT
or mycobacteria other than tuberculosis (MOTT). These
PRODUCTION
are commonly isolated from environmental sources such
as water and soil and were considered to be either of 1. Photochromogens: They are slow growing organisms
low virulence or commensal. However, these myco- and produce a yellow-orange pigment when exposed
bacteria attracted attention during the AIDS epidemic. to light, e.g. M. kansasii, M. marinum.
Interestingly, most of the reports are from TB non- 2. Scotochromogens: They are slow growing organisms
endemic western countries. Nontuberculous myco- and produce a yellow-orange pigment irrespective
bacterial diseases are being increasingly reported from of exposure to light, i.e. in the light or in dark, e.g. M.
HIV positive individuals from both TB non-endemic and scrofulaceum.
TB endemic countries like India, Brazil, and other 3. Nonphotochromogens: They are slow growing and
countries.1,2 may or may not produce pigment, e.g. M. avium
intracellulare complex (MAIC).
TAXONOMY 4. Rapid growers: They are rapid growing mycobacteria
and do not produce pigment.
All Mycobacteria belong to Kingdom Bacteria, Phylum
Actinobacteria, Order Actinomycetales, Suborder
Geographical Distribution of NTMs
Corynebacterineae and Family and Genus Mycobacterium
(Lehman and Neumann 1896). The minimal standards The first argument, to justify the highly variable
for including a species in the genus Mycobacterium are (i) incidence and distribution of NTM, put forward is
acid-alcohol fastness, (ii) the presence of mycolic acids global diversity in environmental and climatic
containing 60–90 carbon atoms which are cleaved to C22 conditions. However, the literature search does not
to C26 fatty acid methyl esters by pyrolysis, and (iii) a reveal significant difference among the most common
guanine + cytosine content of the DNA of 61 to 71 mol%. environmental and clinically relevant mycobacterial
58
Table 6.1: Classification of nontuberculous Pietermaritzburg and other small towns of South Africa9
mycobacteria based on growth rate and similar observation were reported from USA.14
These observations correlated the prevalence of MAC
S.No Slow growing NTMs Rapidly growing NTMs with high rate of hypersensitivity pneumonitis like
1. MAC M. abscessus reaction after the exposure to showers and hot tubs.
2. M. asiaticum M. aichiense Even though, life style of using hot water tubs is not
3. M. branderi M. aurum common in tropical countries like India, the swimming
4. M. celatum M. chelonae and consumption of unsafe water is quite common in
5. M. conspicuum M. chubuense rural India. In 1981, during the famous Chingleput BCG
6. M. flavescens M. fortuitum
trial different species of NTM were isolated from the
7. M. gastri M. gadium
ponds located near the trial area. 10 Based on these
8. M. genavense M. mageritense
9. M. gordonae M. mucogenicum findings some studies have suggested NTM infection
10. M. haemophilum M. phlei as occupational hazard. 15-18 Prashar et al 18a have
11. M. interjectum M. smegmatis emphasized the importance of several environmental
12. M. kansasii M. thermoresistible mycobacteria which have been shown to be important
13. M. lentiflavum M. vaccae human pathogens linked to immunomodulation,
14. M. malmoense M. neoaurum especially in relation to effect on vaccination. One
15. M. marinum hundred nineteen isolates of environmental
16. M. scrofulaceum mycobacteria were grown from 291 (116 soil and 175
17. M. shimoidei water) samples. These isolates were identified by
18. M. simiae
standard biochemical tests, a simple, rapid and cost
19. M. szulgai
effective in house developed gene amplification
20. M. terrae
21. M. triplex restriction analysis targeting 16S-23S rRNA spacer and
22. M. ulcerans flanking region and 16S-rRNA sequencing. Biochemical
23. M. xenopi tests could clearly identify only 68.1% (81/119) of
isolates to the species level. The in-house developed
gene amplification-restriction analysis methods could
species between the TB endemic and TB non-endemic confirm the identity of 102 of 119 (85.7%) isolates and
countries, though exception of a few species do exist, the remaining 17 isolates (14.3%) were confirmed by 16
where these species are confined to certain geographical SrRNA sequencing also. These 119 environmental
regions or habitats.5-10 M. avium complex was most mycobacterial isolates, included several potentially
frequently isolated species in a data gathered by pathogenic species such as M. fortuitum, M. chelonae, M.
International Union Against Tuberculosis and Lung avium, M. marinum, M. manitobense, M. kansasii and
Diseases (IUATLD) from 41 laboratories of 14 countries others belonged to nonpathogenic species such as M.
in five geographical areas.7 Similarly, M. avium complex terrae, M. smegmatis, and M. flavescens. M. chelonae was
was a predominant and potential pulmonary pathogen isolated from water samples only. Whereas M. fortuitum
in China,11 India,1,2,10 and Korea.12,13 M. fortuitum was was isolated from both water as well as soil samples.
isolated from soil and water samples collected from TB
endemic northern parts of Malawi. This population also
Clinical Manifestations
showed high cross reactivity in tuberculin test. 8
M. fortuitum was also found to be one of the most The number of known nontuberculous mycobacteria
frequently encountered species in the laboratories of (NTM) has increased steadily during the last decade,
Belgium (2.1%), Czech Republic (17.5%), Denmark with, on an average, three new species described per year
(5.3%), Finland (6.7%), France (6.5%), Germany (12.2%), since 1990. Recent developments in mycobacterial
Italy (2.5%), Portugal (16.5%), Spain (10.8%), taxonomy, however, are often disregarded by clinicians.
Switzerland (17.5%), Turkey (33.9%) and United Their prevalent opinions are that NTM are rarely
Kingdom (6.0%) during a multicountry study.7 clinically significant; that even when they are responsible
The environment is main reservoir of these for disease, their identification to species level is of little
mycobacteria. There is no evidence of human-to-human clinical relevance. It is useful only to distinguish the M.
or animal-to-human transmission.14 Most infections are tuberculosis complex from NTM. Tortoli et al19,20 have
acquired either from water, both treated and untreated, elaborated on the clinical features of infections caused
or from soil. M. kansasii, M. xenopi and M. simiae are by nontuberculous mycobacteria. Griffithe et al14 on
universally associated with water exposure. M. avium behalf of ATS/IDSA have detailed nontuberculous
complex (MAC) was isolated from the drinking mycobacterial diseases, their diagnosis, treatment and
water distribution systems of Pretoria and prevention.
59
Chapter 6 Nontuberculous Mycobacteria
Respiratory Disease and by fistula formation with prolonged drainage. No

changes in hematologic parameters are found.
The respiratory tract is the most frequent target of
Antimicrobial treatment is usually ineffective, but total
mycobacterial pathologies.21 NTM pulmonary infection
excision of the involved nodes assures definitive recovery
is usually not distinguishable from tuberculosis, with
in almost all cases. The route of entry is usually oral,
which it shares a wide spectrum of manifestations
including throat, gingivae, and lips. Tooth eruption has
ranging from lack of symptoms to cavitary disease.
been related to infection. Cases of adult infection and
Although not yet demonstrated for most of the newly
involvement of other nodes, such as inguinal, femoral,
described species, the environment is considered the
axillary, or epitrochlear, are rare.
natural reservoir of NTM. The main route of infection,
therefore, is by inhalation, although ingestion and direct
M. bohemicum
inoculation may have roles. Contaminated aerosolized
water is thought to be one of the most important sources M. bohemicum was responsible for disease in two cases,
of mycobacteria. NTM pulmonary disease is rare in one in an 11- year-old male and the second in a 2-year-
young subjects and in patients without predisposing old girl. In both cases, treatment, including
conditions. clarithromycin, was undertaken initially, and subsequent
resort to lymph node excision led to complete recovery.
Diagnostic Criteria of Nontuberculous Mycobacterial
Lung Disease M. celatum type I
A. If three sputum/bronchial wash results are available M. celatum type I was isolated from pus draining from
from the previous 12 months: the incised lymph node of a 15-month-old boy. Cure was
1. Three positive cultures with negative acid-fast obtained by complete surgical removal of the node.
bacillus smear results
or M. elephantis and M. genavense
2. Two positive cultures and one positive acid-fast
M. elephantis is the only mycobacterium species described
bacillus smear.
in the last 15 years that has been reported to be
B. If only one bronchial wash is available:
responsible for lymphadenitis localized to a region other
Positive culture with a 2+, 3+, or 4+ acid-fast bacillus
than the neck. This organism was isolated from the
smear or 2+, 3+, or 4+ growth on solid media.
excised axillary lymph node of a 27-year-old male.
C. If sputum/bronchial wash evaluations are
M. genavense was isolated from cheesy material in a
nondiagnostic or another disease cannot be excluded:
cervical lymph node removed from a 4-year-old girl with
1. Transbronchial or lung biopsy yielding a
normal immune function.
nontuberculous mycobacterium
or M. heidelbergense
2. Biopsy showing mycobacterial histopathologic
features (granulomatous inflammation and/or M. heidelbergense was isolated in a more complicated case
acid-fast bacilli) and one or more sputa or bronchial of a 2-year-old girl with cervical lymphadenitis. Despite
washings are positive for a nontuberculous removal of the nodes involved and subsequent treatment
mycobacterium, even in low numbers. with isoniazid, rifampicin, and pyrazinamide, a fistula
Criteria refer to symptomatic patients with infiltrate, developed. Surgery was found ineffective when a new
nodular or cavitary disease, or a high resolution fistula appeared. Subsequent involvement of the
computed tomography scan that shows multifocal contralateral lymph nodes required neck dissection with
bronchiectasis and/or multiple small nodules. removal of both tonsils and several lymph nodes.
Lymphadenitis M. interjectum
Lymphadenitis due to NTM is typically a childhood M. interjectum is one of the species most frequently
disease that involves upper cervical lymph nodes. involved in childhood cervical lymphadenitis. Five cases
Swelling, which develops in a few days, may vary from have been reported in three girls and two boys with ages
barely perceptible to very disfiguring. Pain, if present, is ranging from 18 months to 3 years. In four cases, one of
minimal. The infection remains unilateral and localized, which required two surgical procedures, total excision
without signs of thoracic involvement on X-ray. The of the infected lymph nodes was required for full
overlying skin tends to be adherent and erythematous, recovery. In the fifth case, satisfactory results were
without increased warmth. The evolution of disease may obtained with drainage of purulent material and
be characterized by softening of the lymph node mass thorough curettage of the cavity.
60
M. lentiflavum fistulization. Granulomatous lesions accom-panied by

bone necrosis characterize the osteitis.
Five cases of infection due to M. lentiflavum have also been
reported. Four boys, with ages between 19 months and 4
Disseminated Disease
years, were cured by means of lymph node excision. In a
3-year-old girl, suppurative cervical lymph nodes were Disseminated mycobacterial infections are limited to
treated with clarithromycin and ethambutol, without patients with impaired immune systems. The most
improvement in the subsequent 6 months. important risk factors are HIV infection, hematologic
disorders, organ transplantation, and protracted steroid
Cutaneous and Soft Tissue Infections treatment. Mycobacterial bone disease and endocarditis
may also be responsible for dissemination. Particularly
Traumas and surgical wounds are frequently the source in AIDS patients, the most frequent symptoms are
of soft tissue mycobacterial infections. The clinical longlasting, often high fever; weight loss; abdominal pain,
manifestation, a nodular granulomatous lesion, develops usually related to adenopathy; and splenomegaly.
in the skin or subcutaneous tissue on an average within Pulmonary manifestations are limited, and radiological
1 month. Underlying lymph nodes may be involved, often signs are lacking.
associated with suppuration, and dissemination of
infection is a frequent outcome. Other manifestations Mycobacterium Species Associated with Sepsis
include ulcer formation and cellulitis. Even though Several cases of catheter-related sepsis due to newly
mycobacteria are often visible in the stained smear of described mycobacteria have been reported. In three
clinical material, their failure to grow in culture is not cases, Mycobacterium immunogenum was isolated from a
exceptional. Iredell et al21a has reported by laboratory bone marrow transplant patient, a subject with acute
identification and in vitro susceptibility tests of 29 isolates leukemia, and a patient with pacemaker-related sepsis.
from Queensland Health Department Tuberculosis Five isolates of M. hackensackense were grown from
Reference Laboratory contacting referring practitioners catheter and peripheral blood specimens from a 6-year-
to obtain clinical details of patients. It was in 29 patients, old girl with relapsed acute lymphocytic leukemia and a
M. marium was isolated, 12 had evidence of involvement history of multiple infections. A change of treatment from
of deep tissues (including two cases of arthritis). Delay vancomycin to amikacin for 1 week and clarithromycin
between onset of symptoms and consultation with a for 4 weeks produced rapid and definitive improvement.
medical practitioner was five months (range two weeks The only strain of M. septicum isolated to date was from
to two years). Cure was obtained in 22 of 23 cases. three blood specimens and the tip of a central venous
Chemotherapy alone was adequate in 11 cases. catheter from a 2-year-old child with metastatic
Surgical intervention was required in three. A combination hepatoblastoma.
approach was required in eight cases. The drugs given
were trimethoprim/sulfamethoxazole which was
Role of Ethnicity and Genetic
successful in nine case, combination of rifampicin and Susceptibility to NTM Infections
ethambutol in six, tetracycline was employed as a single— Agriculture is the major occupation of habitants of rural
agent in nine patients and effective in seven. Synovitis South East Asian countries. In a recent study carried out
was a common presenting feature of M. marium infection at four Thailand hospitals,16 it was found that nearly half
in Queensland patients. Occupational or recreational (46%) of the disseminated NTM infections in HIV
exposure to salt or fresh water was common. It is negative cases could be associated with farming. In these
summarized in their experience, that chemotherapy alone patients, the commonest organ involved was lymph node
is often adequate even with deep tissue involvement. (89%) followed by skin and soft tissue (26%) and lungs
Combination of conventional antimycobacterial drugs (19%). The major occupation in countries of this region
may be the therapy of choice specially for serious infection including India, China and Bangladesh remains manual
although success was recorded with trimethoprim/ farming which leads to common physical injuries. These
sulfamethoxazole combination. injuries added with exposure to soil and water can result
into tissue invasion by NTMs.15 However, in spite of
having similarity in the occupation and safety norms, the
Bone and Joint Infections
trend of high prevalence of NTMs observed in the Thai
Mycobacterial infections of synovia, tendon sheaths, patients is yet to be endorsed from other countries of the
bursae, and bone tissue almost always have a traumatic region. Ethnicity seems to be the least likely reason for
or postsurgical origin and frequently evolve to this under reporting. Probably in other tropical countries,
osteomyelitis. Tenosynovitis involves the tendon sheaths NTMs are being missed out due to lack of awareness
and causes loss of function, swelling, and, at times, about these potential yet neglected pathogens.15,22-30
61
Nevertheless some studies demonstrate the genetic transducer and activator of transcription 1 [STAT1], and
susceptibility to disseminated NTM infections in the nuclear factor-κβ essential modulator [NEMO]).
children. This susceptibility has been associated with Association between bronchiectasis, nodular pulmonary
multiple mutations in the interferon-γ receptor 1 gene.31,32 NTM infections and a particular body habitus,
Huang et al31 investigated the polymorphisms in the predominantly in postmenopausal women have been
human natural resistance-associated macrophage protein reported by Griffith et al.14 Pulmonary diseases by NTM
and interferon-γ receptor 1 gene. They found no normally occurs in patients with structural lung disease,
correlation with Mycobacterium avium intracellulare such as chronic obstructive pulmonary disease (COPD),
(MAI) pulmonary disease. The susceptibility to MAI bronchiectasis, cystic fibrosis (CF), pneumoconiosis, prior
disease was due to subtle immune defect and physical TB, pulmonary alveolar proteinosis, and esophageal
phenotype of the patient may be merely a coincidental motility disorders. NTM lung disease also occurs in
marker.31 In addition, idiopathic disseminated infections women without clearly recognized predisposing
due to BCG or NTM are frequently observed with factors.14,21,40 Bronchiectasis and NTM infection, usually
parental consanguinity and familial forms. This Mycobacterium avium complex (MAC), often coexist,
syndrome was designated as Mendelian susceptibility making causality difficult to determine. These patients
to mycobacterial infection (Mendelian inheritance in man may carry multiple MAC strains.
number 209950). Therefore, this syndrome does not seem Mycobacteria including the Mycobacterium bovis
to be confined to any particular ethnic group or (M. bovis) bacillus Calmette-Guérin (BCG) are considered
geographic region. On the other hand, an Australian and as strong inducers of T-helper type 1 immune responses
two different New Zealand groups investigated the (Th1) and modulate the development of asthma both in
pediatric population with mycobacterial lymphadenitis animal models and human beings. It is shown that a new
and correlated the Caucasian ethnicity as a feature in subset of lymphocytes (Th17) are triggered by BCG and
children with NTM lymphadenitis and non-Caucasian this activation induces a proinflammatory cytokine IL-
as a risk factor for TB. Prior exposure to TB mounts an 17 production. This cytokine, is considered to be
responsible for several autoimmune diseases including
adaptive immunity which protects them from least
asthma, allergic airway inflammation, diabetes mellitus,
virulent NTM infection as is the case with non-
etc. 41 Such report are mostly published from
Caucasians.33-35 The prior exposure of environmental
industrialized world. However, hypersensitivity
mycobacteria leads to the poor efficacy of BCG vaccine
pneumonitis associated with NTM infections has not
as was found during the Indian36 and Malawi trials.37
been reported from India.
Nevertheless this exposure provides protection against
tuberculosis and leprosy.38 The most protective antigens
Beneficial Effects of NTM Infection
expressed by the anti-TB vaccine Mycobacterium bovis
(BCG) and M. tuberculosis are also conserved in M. avium39 The positive facet of NTM exposure is considered very
and other mycobacterial species. The prior exposure of beneficial to humans. This includes not only increased
tuberculosis in endemic countries may provide cross resistance to infections and prolonged survival of BCG
and/or adaptive immunity against NTM infections. vaccinated people37-39 but also an immune regulatory
action of another NTM, the Mycobacterium vaccae.14,41
Association of Nontuberculous Recently another nontuberculous Mycobacterium w has
Mycobacteria with other Diseases been found to be highly immunogenic against leprosy42
NTM can cause a variety of symptoms and may also and pulmonary tuberculosis.43 It is reported that this
result in asymptomatic infections. The rates of mycobacterium shares antigens with both M. leprae as
asymptomatic infections have been estimated using well as M. tuberculosis. The vaccine trials conducted in
antibody assays against common mycobacterial antigens India show that it provides protective immunity in both
such as lipoarabino-mannan (LAM) or skin tests using BCG responders as well as BCG non-responders.42,43
NTM specific purified protein such as PPD-B against Beside these well documented beneficial uses of NTMs
M. intracellulare.14 In AIDS patients, disseminated NTM there may be several other beneficial effects of NTM
infections typically occurred only when the CD4+ T exposures.
lymphocyte count fell below 50/µl, suggesting that specific
T-cell activities are required for protection against NTM Laboratory Facilities for Establishing the Diagnosis
infections like M. tuberculosis.14,22-25 However, in the HIV-
Immunology of NTM Infections
uninfected patients disseminated NTM infection have
been associated with specific genetic syndromes such as Mycobacterial tuberculosis DosR regulon-encoded antigens
mutations in interferon (IFN-γ) and interleukin (IL-12) are highly immunogenic in M. tuberculosis infected
synthesis and in response pathways of the signal humans and are associated with latent tuberculosis
62
infection. Lin et al43a documented T-cell immunity (IFN- less likely to demonstrate acid-fast bacilli on direct smear
γ responses) to M. tuberculosis DOSR regulon-encoded microscopy (95% 0.0-0.75). Children with NTM were
antigens in individuals infected with or exposed to older (p < 0.001) and demonstrated constitutional
nontuberculous mycobacteria (NTM), in the absence of symptoms (p = 0.001) including fever (p = 0.03) and loss
M. tuberculosis infection, M. tuberculosis exposure, or BCG of weight or failure to gain weight (p = 0.04). However,
vaccination. These results support the hypothesis that tuberculin test is less likely to be strongly positive (p <
M. tuberculosis DOSR regulon-encoded antigen-directed 0.001) and radiological features consistent with
responses can be the result of exposure to or infection pulmonary tuberculosis (p = 0.04) were absent. NTM may
with cross-reacting NTM. complicate the diagnosis of pulmonary TB in regions that
Kobashi et al43b evaluated the clinical usefulness of lack facilities for mycobacterial species identification.
the quantiFERON®-TB-2G (QFT-2G) test in patients with Inter-estingly, a reverse trend may also be observed while
nontuberculous mycobacterial (NTM) disease without a administering empirical anti-TB therapy, which is also
previous history of tuberculosis (TB). They concluded highly effective against M. kansasii and partially active
that QFT-2G may be a useful diagnostic method to against MAC.22-24 This makes the NTM incidence and
differentiate TB from M. avium-intracellulare complex prevalence data more difficult to interpret. Most of the
(MAIC) disease. However, its usefulness as a diagnostic TB laboratories in TB endemic countries still use egg-
method for other NTM diseases such as those associated based culture medium, which could be another limitation
with M. Kansaii and M. szulgai disease need further to recovery of NTM (in particular fastidious NTMs). Most
resolution of several problems such as positive cut-off of the laboratories which have reported maximum NTMs
level. have overcome the limitations of Runyon classification
In India, every day, under the Revised National system using more rapid culturing techniques, DNA
Tuberculosis Control Program (RNTCP), more than probes, and 16S rDNA sequencing methods. 2,46
65,000 new and old cases are diagnosed and administered According to the Seoul National University College of
antituberculosis therapy (ATT), which makes it humanly Medicine and Korean Institute of Tuberculosis, number
impossible for the laboratories to identify and speciate of isolation of NTM increased from 448 to 1,562 during
the Mycobacteria.30 With the implementation of directly the period 1992-2002. In comparison, the prevalence of
observed treatment short-course (DOTS), the diagnosis active TB over the same period decreased from 1.8 to
of pulmonary tuberculosis is mainly made on the basis 0.5%.27 This increase in NTMs was attributed to the
of sputum microscopy. Recently, retrospective analysis advances in methods of characterization.28 Similarly,
of four years data from South Korea has reported exact species diagnosis was made by identifying several
recovery of NTM from 8.1% (50/616) of sputum smear- potentially pathogenic and rare NTM species with the
positive patients. The most common organism found was application of molecular methods in China.11 In referral
Mycobacterium avium complex (MAC), followed by laboratories of TB endemic countries, single-species
M. abscessus.12,13 It was cautioned by these researchers specific PCR (M. tuberculosis specific) are commonly used
that a substantial proportion of patients with AFB smear- on clinical specimen which can miss the other infection(s)
positive sputum specimens may have NTM lung disease or coinfections with more than one species. The use of
rather than pulmonary tuberculosis (PTB).12 Further- multiplex PCR seems to be highly useful in detecting the
more, using only microscopic method of diagnosis some single and/or multiple infections caused by M. avium
cases of NTM infection may be missed.22,25,44 Alarming and M. tuberculosis.46 The recent guidelines of American
figures of 17.6% of the suspected MDR-PTB and 12.4% Thoracic Society 14 give useful information about
of the suspected extrapulmonary tuberculosis cases were establishing the diagnosis of NTM disease.
confirmed as nontubercular diseases with the application It is important to strengthen the laboratory
of molecular methods.2,44 Hatherill et al45 highlighted the infrastructure to address both species identification and
importance of isolation of nontuberculous mycobacteria drug susceptibility testing of mycobacterial species
in children investigated for pulmonary tuberculosis in a including the NTMs at referral laboratories.
rural South African community. These children were
investigated for pulmonary tuberculosis as part of a SUMMARY
tuberculosis vaccine surveillance program (2001-2005).
The comparative yield of positive NTM cultures from • The new mycobacteria described here are only
gastric lavage was 40% (95% Cl 31-50), compared to 67% occasionally responsible for human diseases, but
(95% CI 58-76) from induced sputum. Ninety-five percent include more than 50% of the species described since
of children with NTM isolates were symptomatic. In 1990. The number of cases reported in the literature
contrast M. tuberculosis was isolated in 187 children, a exceeds 200. Regardless of whether such numbers are
crude yield of 11% (95% Cl 9-12). As compared to culture important or not, the point should be kept in mind.
proved M. tuberculosis, children with NTM isolates were Many cases remain unpublished because the
63
mycobacterial agent has not been identified. Box 6.1: Possible factors for under-reporting of
Interestingly, several features seem to distinguish the NTM from TB endemic countries
infections due to recently described mycobacteria in • The NTM infections are not reportable
HIV-positive and HIV-negative patients. With few
• Lack of awareness in the treating physicians and
exceptions, disseminated infections, mostly due to M.
microbiology laboratories
genavense or M. celatum are reported in AIDS patients.
• Lack of proper laboratory infrastructure for culture and
Furthermore, the frequency of these infections has
identification of nontuberculous mycobacteria
decreased dramatically following the introduction of
highly active antiretroviral treatment. In contrast, in • High burden of TB and HIV, which attract major attention
of health care system and government’s fiscal inputs
HIV-negative patients, the spectrum of mycobacterial
diseases is broad, and many species are involved. • The lack of standardized or accepted criteria to define NTM
Slow growers are primarily involved in respiratory respiratory disease.
and lymph node infections, whereas sepsis and
infections of skin, soft tissues, bone, and joints are
Box 6.2: Facts regarding nontuberculous mycobacteria
frequently attributable to rapid growers.
• Very little information is available about the • AIDS patients are significantly more vulnerable to NTM
infections due to severe T-cell immunodeficiency
antimicrobial susceptibilities of nontuberculous
mycobacteria (NTM), in particular, of recently described • Solid organ transplant patients, even though
species. There is, however, a clear distinction immunocompromised, are not at high risk as their HIV
positive counterparts
characterizing the susceptibilities of rapidly and
slowly growing mycobacteria. Generally, speaking, • Though there are some genetic and anatomical
isoniazid and pyrazinamide are not effective against predisposing factors but there is no proven association
amongst the geographical, occupational or ethnicity and
the slow growers, a variable degree of activity is shown
NTM infections
by rifamycins (rifampicin and rifabutin), quinolones
(ciprofloxacin, moxifloxacin, ofloxacin, and • Anatomical abnormalities and other comorbidities such as
chronic obstructive pulmonary disease (COPD),
sparfloxacin), macrolides (clarithromycin),
bronchiectasis, cystic fibrosis (CF), pneumoconiosis, prior
aminoglycosides (streptomycin and amikacin), and
TB, pulmonary alveolar proteinosis, and esophageal
ethambutol. The resistance of M. celatum to rifamycins motility disorders are well established predisposing
is unquestioned, and the repeatedly reported conditions
multidrug resistance of the species genetically related
• Disseminated NTM infection have been associated with
to M. simiae, such as M. lentiflavum and M. triplex, specific genetic syndromes such as mutations in interferon
seems reliable. For rapid growers, the spectrum of (IFN)-γ, interleukin (IL)-12 synthesis and in response
effective antimycobacterial drugs is restricted to pathways and the nuclear factor-κβ essential modulator
ciprofloxacin, clarithromycin, tobramycin, and (NEMO).
amikacin, in addition to cefoxitin, doxycycline, • Conventional methods are not sufficiently sensitive to
imipenem, and sulfamethoxazole. estimate prevalence and incidence of the NTM infections.
• The identification of new and rarely encountered • Multiplex PCR systems on relevant blood and urine
mycobacteria is out of reach of most routine clinical samples should be set up at tertiary care reference
laboratories. The best choice is to submit strains not laboratories and unidentified strains should be sent to these
identifiable with commercial DNA probes to a for proper identification.
reference laboratory that uses genetic sequencing or,
at least, high-performance liquid chromato-graphic
analysis of cell wall mycolic acids.
2. Singh S, Gopinath K, Shahdad S, et al. Nontuberculous
mycobacterial infections in Indian AIDS patients detected
HIGHLIGHTS
by a novel set of ESAT-6 polymerase chain reaction
Boxes 6.1 and 6.2 highlight the factors for under primers. Jpn J Infect Dis 2007;60:14-8.
reporting of NTM from TB endemic countries and 3. Guidelines for the Control of Nontuberculous
important facts about nontuberculous mycobacteria. Mycobacteria in the Northern Territory. Centre for
Disease Control. Casuarina NT 2002:3-20.
4. Ferreira RM, Saad MH, Silva MG, et al. Non-tubercular
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Immunology of Tuberculosis:
7 Basic Aspects and Relevance for
Immunodiagnostic Tests
Heidi Syre, Harleen MS Grewal
INTRODUCTION compared to 10% of the healthy controls (P < 0.0001).10

Furthermore, the study showed that the plasma retinal
Tuberculosis (TB) poses a serious threat to humans.
2 concentration in TB patients was lower than that for
Mycobacterium tuberculosis, the causative agent of TB,
healthy individuals.10
infects 9.27 million and kills approximately 1.77 million
people annually.1 M. tuberculosis is a gram positive, rod- Vitamin A deficiency has been shown to be a risk
shaped bacterium with a cell wall that is able to retain factor for developing TB.11
acid-fast color during staining, thereby named acid-fast. Various mechanisms like poor dietary intake due to
M. tuberculosis is a member of the M. tuberculosis complex loss of appetite, poor absorption of nutrients from the
(MTC), which consists of the following species: intestine and increased uptake of nutrients by specific
M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, target tissue due to increased body metabolism, are
M. canettii, M. microti, M. caprae and M. pinnipedii. 2,3 associated with nutritional deficiency in TB patients.11
Members of the MTC have different host preferences with Since anti-TB treatment is given to malnourished TB
M. tuberculosis, M. africanum and M. canetti being human patients, there is a possibility that nutritional deficiency
pathogens. may impair treatment outcome. A study from Indonesia
Central to the success of M. tuberculosis as a pathogen by Karyadi et al. reported that micronutrient
is the ability to persist within humans for decades in a supplementation resulted in an earlier elimination of
clinically latent state, creating a potentially large reservoir M. tuberculosis from the sputum.12 The number of patients
for further transmission of the microbe by reactivation. with sputum smear negative for M. tuberculosis was
It is estimated that every third person in the world is higher in the micronutrient supplemented group
infected with M. tuberculosis and that 10 to 12% of immune than in the placebo group (23% vs 13%).12 However, a
competent individuals who acquire primary infection and recent study conducted in Tanzania on the effect of
are not given preventive therapy will develop active TB.4,5 micronutrient supplementation on treatment outcome in
The risk of active disease is highest in the first two years pulmonary TB patients showed that neither multi-
following infection, when half of the cases occur. The risk micronutrient nor zinc supplementation had a significant
of active TB is higher in immune compromised effect on sputum culture conversion, although multi-
individuals. Immune suppression can be caused by micronutrient supplementation was significantly
coexisting diseases such as HIV infection, use of immune associated with weight gain (0.78 kg; P = 0.02).13 Body
suppressive drugs, or by malnutrition. mass index (BMI) is an indicator of nutritional status. A
Other host factors influencing the development and study conducted in Tanzania on nutritional status and
severity of TB disease are age, genetic factors and BCG weight gain in patients with pulmonary TB showed that
immunization. Microbial factors that influence the disease 77% of males and 58% of females had a BMI below
are virulence, tissue specificity and number of bacilli 18.5 kg/m2 at the time of admission.9 Furthermore, a
inhaled. 6 Malnutrition has been associated with study from Malawi showed that there was a reduction of
increasing susceptibility to TB. Studies have shown that 20% in BMI (from 21.7 to 17.3) among pulmonary TB
TB patients suffer from wasting and micronutrient patients as compared with matched controls.8
deficiency.7
Concurrent macro- and micronutrient deficiency THE IMMUNE SYSTEM
compromises the immune system function which in turn The immune system comprises the outer defence (e.g.
increases the risk of TB reactivation.8 Interaction between skin, mucosa, sweat, proteolytic enzymes, acidic juices
malnutrition and TB is associated with complex of the stomach, and bacteria in the colon) and the inner
mechanisms.9 A study conducted to assess nutritional defence. The inner defence includes the innate and the
status between TB patients and healthy controls, showed adaptive immune systems (Table 7.1). The innate immune
that 66% of the TB patients were underweight as system provides immediate defence against potential
67
Chapter 7 Immunology of Tuberculosis: Basic Aspects and Relevance
Table 7.1: The inner defence of the immune system and they communicate via small signal molecules known
as cytokines. T lymphocytes include helper T-cells and
The innate immune system, the adaptive immune system cytotoxic T-cells, as well as unconventional T-cells (γδ T-
Phagocytes: T lymphocytes (cellular immune response): cells and CD-1 restricted T-cells) and regulatory T (Treg)
• Macrophages —helper T-cells (Th1, Th2, Th9 and Th17) cells. 17,18 The humoral immune response includes
• Monocytes—cytotoxic T-cells B lymphocytes and following activation, B lymphocytes
• Neutrophil granulocytes - γδ T-cells
produce antibodies specific to the antigen that caused
• Dendritic cells—CD1 restricted T-cells
the activation. The humoral immune response is induced
Natural killer cells mainly by extracellular microbes, most often bacteria.15
• Treg cells
M. tuberculosis enters the host through inhalation of
• Mast cells B lymphocytes (humoral immune response)
infectious droplets and crosses the mucosal surfaces of
• Eosinophil granulocytes
• Basophil granulocytes Molecules: the human lung. Macrophages and DCs are APCs that
• Cytokines are important in the surveillance of the mucosal surfaces
and ingest M. tuberculosis cells by binding via receptors
Molecules: antibodies
• Cytokines (interleukins, perforin and serine proteases, on their cell surface to M. tuberculosis specific antigens.19
chemokines, interferons) (granzyme A and B) Upon the microbe-receptor association, an inflammatory
• Eicosanoids (prostaglandins and leukotrienes) response is normally rapidly induced. The microbe is
• The complement system killed and digested inside the macrophage by the activity
• Acute phase proteins of digestive enzymes or following a respiratory burst that
releases free radicals. 17,19,20 The resulting antigens are
presented at the surface of the macrophage in association
with molecules known as major histocompatibility
dangers threatening the host, including microor- complex (MHC) class II antigens.19
ganisms,14,15 and comprises phagocytes (macrophages, If the immune system is not able to fully eliminate
monocytes, neutrophil granulocytes and dendritic cells the microbe, M. tuberculosis will remain in the host in a
[DCs]), mast cells, eosinophil granulocytes, basophil dormant state, and may later reactivate. Infected
granulocytes, natural killer (NK) cells, and immune macrophages and DCs migrate to adjacent lymph nodes
molecules (cytokines, eicosanoids, the complement where mycobacterial antigens are presented and specific
system and acute phase proteins). The innate immune immune responses are initiated (mainly Th1 type
system provides a nonspecific protection unaffected by immune response).21 Accumulation of immune cells at
repeated exposure to the microbe, i.e. no development of the site of infection will, in time, result in the formation
immunological memory.14,15 of a granuloma with central necrosis in which, the
The adaptive immune system provides an immune microbe actively multiplies. Antibodies against
response, including immunological memory by the M. tuberculosis are generated during the course of
proliferation of memory cells specific to the antigen.14 infection, but do not appear to be protective.22
Most often, antigen presentation is needed for activation,
and thus, the adaptive immune system needs time before Virulence Factors of M. tuberculosis
being fully activated. The main cells of the adaptive
immune system are T and B lymphocytes which belong M. tuberculosis is an extremely well-adapted microbe
to the cellular and humoral immune responses, which has coexisted with humans for millennia, and has
respectively.14,15 Both T and B lymphocytes carry specific learned to modulate protective host responses to ensure
receptors on their cell surfaces that recognize specific its own survival and dispersal. 23 The microbe has
targets. The B lymphocyte is able to recognize soluble evolved to invade and survive inside the macrophages,
antigens directly, whereas the T lymphocyte requires and affects many, if not all, processing steps inside the
antigens to be presented by antigen presenting cells professional APC.17,19 By adapting into an intracellular
(APCs), including macrophages, DCs and B microbe, the microbe is protected from attack by the
lymphocytes.15 Specific cell surface receptors enable the humoral immune system including antibodies.
lymphocytes to differentiate between self and nonself Clinical strains of M. tuberculosis both secrete and
antigens, and autoreactive T lymphocytes and B contain molecules on the cell surface that function as
lymphocytes are eliminated by apoptosis. One antigens eliciting an immune response in the host.
lymphocyte can recognize only one specific antigen.14,15 Secreted bacterial proteins generally generate a stronger
The cellular immune response is induced by immune response in the host than do cell surface
intracellular microbes like viruses and certain bacteria proteins.24 Although, the majority of these antigens seem
including mycobacteria.16 T lymphocytes and phagocytes to not be crucial to the viability of the microbe, they may
are the main effector cells in the cellular immune response function as virulence factors. 19 A number of
68
Table 7.2: Soluble molecules and cell wall components potent hydrolytic enzymes capable of degrading
of M. tuberculosis macromolecules. The pH optimum of the hydrolytic
enzymes is pH 4.5 to 5.0,28 and the acidic environment is
• Soluble molecules:
maintained inside the lysosome by ATP dependent proton
- Ag85
- CFP-10 pumps localized in the lysosome membrane. M. tuberculosis
- ESAT-6 inhibits fusion with lysosomes and arrests the acidification
• Cell wall components: of the phagosome, enabling growth and persistence inside
Lipids: the macrophage.19 The exact mechanism is not clearly
- muramyl dipeptides understood, but it is believed that M. tuberculosis interferes
- mycolic acids with putative transporters, iron-scavenging molecules and
- phospholipids lipid-synthesizing molecules to prevent normal
- trehalose dimycolate (cord factor) phagosome maturation. 19,20,23 By maintaining the
Proteins: phagosome in an immature state, the phagosome-lysosome
- 4 kDa
fusion is prevented.19
- 19 kDa
Some suggest that M. tuberculosis inhibits the
- 27 kDa
- 38 kDa maturation of the phagosome by the production of ESAT-
Polysaccharides: 6, CFP-10 and SecA1/2 which inhibit the ATPase
- arabinogalactan activity.23 M. tuberculosis thereby limits the acidification
- arabinomannan of the vacuole which is one of the key events in the
phagosome maturation in order to process and kill the
microbe.29,30 The process is moreover dependent, at least
M. tuberculosis antigens have been identified and to some extent, on blocking of a calmodulin-dependent
characterized (Table 7.2). Secreted mycobacterial proteins Ca2+ flux by multiple microbe derived molecules.31,32
include the Ag 85 family of mycolyl transferases, culture Another study has suggested that M. tuberculosis prevents
filtrate protein 10 (CFP-10), and early-secreted antigenic fusion between the phagosome and lysosomes by the
target 6 kDa protein (ESAT-6). Cell wall components production of ammonia via the urease enzyme.33 This
comprise lipids (muramyl dipeptides, mycolic acids, correlates well with the observation that ammonium
phospholipids, and trehalose dimycolate), proteins (14 chloride, a weak base, affects the saltatory movement of
kDa, 19 kDa, 27 kDa, and 38 kDa antigens) and lysosomes and alkalinizes the acidic environment inside
polysaccharides (arabinogalactan, and arabinomannan). the lysosome.33,34 Also the exclusion of Rab7, a GTP-
Some of the antigens are currently being assessed as binding protein located in late endosomes that facilitates
components in new vaccine candidates against TB, either
to replace or to boost the BCG vaccine. Table 7.3: Mechanisms that favor infection and survival
It has been hypothesized that cholesterol is necessary of M. tuberculosis in macrophages
for M. tuberculosis to enter the macrophages.25 A Entering the macrophage:
cholesterol-specific receptor, the Ck-like molecule on the • Cholesterol
cell surface of M. tuberculosis, interacts with cholesterol Prevention of phagosome maturation and phagosome-lysosome
in the macrophage cell membrane leading to entry of the fusion:
microbe into the APC. Furthermore, it is suggested that • TACO protein
cholesterol mediates the phagosomal association of • Inhibiting ATPase activity
tryptophan-aspartate containing coat (TACO) protein.25 • Blocking calmodulin-dependent Ca2+ flux
• Ammonia production
The TACO protein is a host protein which inhibits the
• Exclusion of Rab7
fusion between the M. tuberculosis containing phagosome
• Cord factor
and the lysosomes, and thus prevents degradation of Modulation of the immune response:
M. tuberculosis inside the macrophage.25,26 It has been • 9 kDa
reported that phagosomes containing less than five • ESAT-6
M. tuberculosis cells are unable to retain TACO, whereas • LAM
phagosomes containing more than five bacteria retain Inhibition of APC maturation:
TACO within their membrane. 27 An overview of • LAM
mechanisms that favor the infection and survival of Mycobacterial decoy antigens distracting the immune system:
M. tuberculosis in macrophages are provided in Table 7.3. • ESAT-6
M. tuberculosis is digested by the macrophage via • Ag 85 B
endocytosis and localized inside the cell in an early TACO– Tryptophan-aspartate containing coat, EAST-6– Early-
phagosome. Normally, a microbe containing phagosome secreted antigenic target 6 kDa protein, APC: Antigen presenting
will fuse with the lysosome, a complex vacuole containing cell, LAM– Lipoarabinomannan.
69
fusion of the endosome to lysosomes,35 may explain the LAM can induce the production and release of TNF by
inhibition of the fusion process. In addition, the macrophages43 which may be responsible for fever,
M. tuberculosis cell wall lipid trehalose dimycolate (cord weight loss, elevated acute phase reactants and necrosis
factor) affects the membrane trafficking, inhibits typically found in TB patients.
maturation of the phagosome and the expression of MHC M. tuberculosis produces specific antigens early in the
class II molecules and coreceptors on the cell surface of infection process which dominate the immune response.
the phagocyte. Thus, there is probably more than one It has been suggested that these antigens function as
mechanism that helps the microbe to block the maturation immunological “decoys” to distract the immune system
of the early phagosome and the fusion with lysosomes and prevent it from responding against antigens more
containing enzymes for microbe degradation. relevant to host protection.19,44 The decoy antigens bind
M. tuberculosis retains the access to early endosomal more strongly to MHC molecules than do the less
vesicles, through which the microbe can gain access to abundant but more important immunogenic antigens.
essential nutrients and cations, especially iron, which Potential decoy proteins are ESAT-6 and Ag85B.19 These
enables the cell to replicate and export its own proteins.23 are dominantly secreted in the initial stages of the
Once the microbe has entered the macrophage, long- infection and the production declines after approximately
chained fatty acids of the M. tuberculosis cell wall strongly 3 weeks.19 Activated T-cells specific to the decoy antigens
stimulate the immune response of the host, resulting in would soon fail to recognize macrophages infected by
increased antigen presentation and activation of the microbe since these would contain M. tuberculosis
T lymphocytes and NK cells to eliminate the invading which no longer produce the current antigen but instead
microbe. express other antigens that the activated T-cell clones
However, mycobacterial cell wall lipoproteins are able would not recognize. 19.44 Thus, it is possible that
to modulate immune responses to influence the M. tuberculosis through evolution has developed
elimination process. The 19 kDa lipoprotein of protective responses via decoy antigens.19,44
M. tuberculosis interacts with toll-like receptor (TLR) 1
and 2 of the APCs.36,37 The interaction inhibits cytokine Immune Cells of the Body
production from the APCs by reducing the expression of
The Macrophage
over a third of interferon (IFN)-γ activated genes.23
Moreover, the 19 kDa lipoprotein-TLR interaction Alveolar macrophages are the main cells infected by
reduces the antigen processing and MHC class II M. tuberculosis after the microbe has entered the alveoli.
expression of the APCs. Also ESAT-6 acts via the TLR-2 Macrophages are relatively large cells (15 to 25 µm in
and has a similar dampening effect on the immune diameter) and have a variable shape. Macrophages are
response.38 It is believed that ESAT-6 may contribute to professional APCs specialized for uptake, proteolytic
increase the virulence of the epidemic Beijing strain of cleavage, enzymatic processing, and intracellular
M. tuberculosis in humans by inducing high levels of IL-4 trafficking of antigens. Professional APCs activate the
and IL-13.23,39,40 naive Th0 cell (i.e. primary response).45 The processed
Lipoarabinomannan (LAM) is a highly immunogenic antigen is presented on the surface of the macrophage in
lipopolysaccharide specific to mycobacteria. LAM is association with MHC class II molecules specific to
associated with the mycobacterial cell wall and may professional APCs. M. tuberculosis can also survive and
function as a virulence factor.41 The molecule associates multiply in DCs, monocytes and neutrophils. 46
with DC-specific intercellular adhesion molecule- Macrophages and DCs are distributed in peripheral
grabbing non-integrin (DC-SIGN) molecules on the tissues in an inactivated state. Following the interaction
surface of APCs. The DC-SIGN molecule is important for with antigens, they undergo a maturation process,
maturation of APCs. By binding the DC-SIGN molecule, migrate to the draining lymph nodes and present the
LAM not only inhibits the maturation process, but also antigens to naive Th0 lymphocytes. Macrophages get help
reduces the IL-12 production by the induction of IL-10 to identify structures for ingestion by a process known
secretion by APCs.42 IL-10 suppresses the immune as opsonization. Opsonins are soluble factors of the
response by the inhibition of the following: Antigen immune system which mark or single out structures to
presentation, expression of MHC molecules, and be removed. The C3b fragment in the complement system
expression of costimulating receptors on the cells surface. and antibodies secreted by the B lymphocytes are
LAM can furthermore inhibit the activation of examples of opsonins.47 Furthermore, under the influence
macrophages by blocking the IFN-g induction of of IL-12, activated T lymphocytes secrete cytokines
important macrophage genes,41 by scavenging, the toxic (mainly IFN-γ and TNF-α) which activate and lead the
free radicals of macrophages, and by inhibition of the macrophage to the site of infection, resulting in a more
protein kinase C activity which plays a regulatory role efficient elimination of the microbe. Macrophages may
in macrophage activation. Lastly, it has been shown that also be activated by 1,25-dihydroxy vitamin D3 alone or
70
in combination with IFN-γ and TNF-α. By binding to the Table 7.4: Classes, phenotypic markers and main
vitamin D receptor of macrophages, the macrophages functions of lymphocytes
inhibit or kill M. tuberculosis in humans, probably by
Lymphocyte class Phenotypic markers Main function
inducing the expression of enzymes in the reactive
intermediate pathway.48-50 • Helper T-cell CD2, CD3, CD4, TCRαβ Regulates immune
The microbe-macrophage interaction starts cells via cytokine secretion
• Cytotoxic T-cell CD2, CD3, CD8, TCRαβ Lysis of cells
immediately following contact between the two cells. Cell
infected by virus or bacteria, cancer cells and allografts
surface antigens or antigens secreted by M. tuberculosis • γδ T-cell CD2, CD3, TCRγδ Lysis of cells infected by virus/
bind to pathogen associated molecular pattern (PAMP) bacteria/cancer cells, recognizes nonpeptide antigens
receptors localized on the surface of the macrophages and • CD-1 restricted T-cell CD2, CD3, mainly TCRαβ Recognizes
other host cells.23 The microbe-PAMP receptor association foreign lipid antigens presented by APCs, induces cytolysis
stimulates the macrophage to ingest M. tuberculosis, but • NK cell CD2, CD16, CD56 Lysis of cells infected by virus,
also initiates and shapes the immune system more specific bacteria or cancer cells
to the invading microbe. The TLR family is an example • Treg cell CD2, CD4/CD8, CD25, TCR Suppresses the
of a PAMP receptor, and in particular, TLR-2, TLR-4 and immune response, induces lysis
TLR-9 are essential in the creation of an effective immune • B cell CD19, CD21, MHC class II Antibody secretion
response against M. tuberculosis. 17 The binding of a CD– cluster of differentiation antigen, TCR- T-cell receptor,
microbial antigen to the corresponding TLR transmits a NK cell-natural killer cell.
signal to the host cell nucleus inducing the expression of
genes coding for the synthesis of cytokines. The cytokines,
in turn, bind to cytokine receptors of the cytokine helper T-cell and the cytotoxic T-cell. T lymphocytes are
producing cell or other immune cells for activation.23 activated by IL-1 secreted by activated macrophages and
Activated macrophages generate several effector by interaction between the T-cell receptor (TCR) localized
molecules with mycobactericidal effect. Reactive oxygen on the lymphocyte surface and a foreign antigen
and nitrogen intermediates are the main groups of presented by a MHC class II molecule of an APC.19 Helper
antimycobacterial molecules produced by macrophages T-cells are limited to associate with only one type of
by the use of the phagocyte oxidase enzyme and nitric antigen in their TCR. The TCR is coupled closely to the
oxide synthase 2 enzyme. In addition, sterilizing chloride CD3 antigen comprising a group of 5 transmembrane
compounds are produced inside the cell by the enzyme polypeptides. By binding a MHC class II associated
myeloperoxidase. IFN-γ and TNF-α synergistically antigen, the TCR/CD3 complex sends signals to the
stimulate the production of reactive intermediates via interior of the cell to proliferate and differentiate.52 The
induction of enzymes in the intermediate pathway.51 CD4 and CD8 coreceptors which exist each on the two
main groups of T lymphocytes; the helper T lymphocyte
T-lymphocytes and cytotoxic T lymphocyte, respectively, aid in the
T-cell activation together with the CD28 membrane
The main effector cells in the adaptive immune system molecule.52 The ligand of CD28 is B7 localized on the cell
are T and B lymphocytes, and their function is to surface of professional APCs. Thus, the helper T-cell
recognize and act against specific “non-self” antigens. The requires two signals for activation; one signal from the
B lymphocytes mainly survey the extracellular presented antigen through the TCR and one signal
compartments and the T lymphocytes control the through CD28. Without the CD28-B7 association, the
intracellular compartments.14 The T lymphocyte is able T-cell will not proliferate or develop effector mechanisms.
to identify cancer cells and cells of the host infected by Polarization into different T-cell sets is mostly dictated
microorganisms by the association with MHC molecules by cytokines, but also the microbe binding to the TCR
expressed on the host cell surface. Table 7.4 gives an and the genetic composition of the host contribute in the
overview of the existing classes of lymphocytes and their stimulation of appropriate effector cells providing the best
main function. possible immune response. Specific cytokines stimulate
The cells of the immune system have glyco-proteins the development of one T-cell type and suppress the
known as cluster of differentiation (CD) antigens on their development of another T-cell type.
surface. The CD antigens promote cell-cell interactions
and adhesion, and transduce signals that lead to
Helper T-lymphocytes
activation of the lymphocyte. The CD antigens are used
as phenotypic surface markers to subcategorize the Helper T-cells, also known as CD4+ T-cells, play a major
immunocompetent cells.52 All T-cells express the CD2 and role in the immune defence against M. tuberculosis. This
CD3 antigens in addition to other CD antigens (Table 7.4). is demonstrated in TB-HIV coinfected individuals who
There are two main groups of T lymphocytes; the have a considerable increased risk of progression to TB
71
after infection, when the number of helper T-cells is Table 7.5: Cytokine origins and function in response to
reduced. By cytokine production and by direct contact, M. tuberculosis
the helper T-cells regulate the immune response by Cytokine secreting cell function
directing immune cells; T helper 1 (Th1) cells regulate • IFN-γ Th1 cells*, NK cells, γδ T-cells activates
the activity of macrophages and cytotoxic T-cells, and T macrophages, NK cells and cytotoxic T-cells
helper 2 (Th2) cells regulate the activity of B cells. • IL-1 Macrophages Activates T-cells, ↑IL-6 production by
Helper T-cells express receptors including CD3, CD4, macrophages
CD28 and TCR on their surface.52 The TCR of the helper • IL-2 Th1 cells ↑ proliferation of helper T-cells, cytotoxic
T-cell recognizes antigens presented along with the MHC T-cells and NK cells
class II molecules which only exist on the surface of • IL-4 Th2 cells*, eosinophils, basophils, antagoniges the
TNF-α effect, suppresses the effect of mast cells, NK cells
professional APCs (macrophages, DCs and possibly also
and some APCs the Th1 response
B lymphocytes). One specific helper T-cell recognizes only • IL-6 Macrophages and Th2 cells mediates
one type of antigen and the cell is activated when (i) the hyperglobulinemia, ↑acute phase proteins
MHC class II associated antigen is coupled to the TCR • IL-10 Macrophages, Th1 and Th2 cells ↓ Th1 and Th2
and (ii) the B7 receptors of the macrophages interact with proliferation and cytokine production, inhibits antigen
the T lymphocyte DC28 receptor. presentation
Following activation, the T-cell increases in size, the • IL-12 Macrophages ‘↑IFN-γ secretion, activates
receptors on the cell surface change and they differentiate NK-cells
into a helper T-cell subtype. Classically, following • IL-17 M Th17 cells recruit neutrophils to infection site
activation helper T-cells differentiate into Th1 cells or Th2 • TNF-α Macrophages*, Th1 and Th2 cells protects against
cells. Recent data suggest that naive helper T-cells may active TB, induces apoptosis, granuloma formation
• Lymphotoxin Macrophages, Th1* and Th2 cells regulate
also develop upon activation into two novel T-cell lineages;
leukocyte movement and granuloma formation
T helper 9 (Th9) cells and T helper 17 (Th17) cells. The
subtypes express different cytokine profiles and thereby *The main secreting cell.
have different functions. Th1 cells secrete IFN-γ, IL-2, IL-
12, granulocyte-macrophage colony-stimulating factor
Th17 cells. Also IL-23 (produced by DCs and macrophages)
(GM-CSF), and lymphotoxin (previously known as
is required for the Th17 cells to become an established
TNF-β). Th1 cell binding to the antigen recruits cytokine
population. Th17 cells are associated with autoimmune
production and IL-2 induces clonal expansion of the Th1
diseases, but they also recruit neutrophils to the infection
cell by binding the IL-2 receptor (autocrine effect). Via the
sites, participate in the inflammatory responses in response
secretion of cytokines, Th1 cells activate the microbicidal
to an infectious microbe and thus, participate in the
function of macrophages (mainly by IFN-γ and TNF-α),
protection against TB.58 Th17 cells probably provide a first
NK cells and cytotoxic T-cells (mainly by IL-2) and are thus,
line of defence against the microbe and participate in the
important in the cellular immunity against intracellular
early steps of granuloma formation.59
microbes like virus and mycobacteria.16 Several studies
Recently, a second subpopulation of helper T-cells,
have shown that the IFN-γ production by Th1 cells is of
know as Th9 cells, has been presented. Th9 cell
major importance for protection against TB in mice17,53,54,
subpopulation develops under the influence of IL-4 and
and IFN-γ receptor deficiency on the immune cells is
TGF-β, typically in chronic diseases like asthma.60 Th9
associated with increased susceptibility to mycobacterial
cells secrete IL-9 and IL-10. IL-9 has an important role in
infections.55-57 The different cytokines and their function
airway remodeling, most notably with mucus production
in response to M. tuberculosis infection is summarised in
in the epithelium.61
Table 7.5.
The T-cell receptor (TCR) together with an up-
Cytotoxic T-lymphocytes
regulation of the CD40 ligand on the cell surfaces of
activated Th2 cells provides stimulatory signals for the The cytotoxic T-cells, also known as CD8+ T-cells, kill
activation of B lymphocytes. The cytokines secreted by cells infected by virus or bacteria, or otherwise damaged
the Th2 cells are IL-4, IL-5, IL-6, IL-10 and IL-13. Th2 cells or dysfunctional cells, by the secretion of cytotoxins. One
support the differentiation and proliferation of specific cytotoxic T-cell recognizes only one type of
B lymphocytes leading to production of antibodies, which antigen and the cell is activated only when the specific
are important in the fight against extracellular microbes antigen in association with a MHC class I molecule is
as well as in atopic and parasitic diseases.16 coupled to the TCR. The MHC class I molecule exists on
Tumour growth factor (TGF)-β is important in the the surface of all human cells. Recognition of the antigen-
development of helper T-cell lineages distinct from Th1 MHC complex is aided by a coreceptor named CD8,
and Th2. Under the influence of IL-6, the TGF-β is thereby the name CD8+ T lymphocytes.52 Like the helper
responsible for the development of the IL-17 producing T-cell, also the cytotoxic T-cells require a second signal
72
for activation, the association between CD28 localized phase of an infection. These cells have receptors distinct
on the surface of the cytotoxic T-cell and the B7 molecule from helper T-cells and cytotoxic T-cells and they target
of the macrophage. Activated cytotoxic T lymphocytes different molecules than the more conventional
express IL-2 receptors on the cell surface. IL-2 from T lymphocytes. Thus, the unconventional T lymphocytes
activated helper T lymphocytes binds the IL-2 receptor extend the number of epitopes the immune system is able
and induces proliferation of the cytotoxic T lymphocytes. to act against.
Activated cytotoxic T lymphocytes travel in the body CD1-restricted T-cells comprise two functional
searching for identical antigen-MHC complexes groups: cells that produce mainly Th1 cytokines and are
presented on the cell surfaces. Upon binding, cytotoxins often cytolytic in their function, and cells that produce
including perforin are secreted. Perforin contributes to both Th1 and Th2 cytokines, particularly important in
pore formation in the plasma membrane of the infected preventing autoimmunity.63 CD-1 restricted T-cells
target cell resulting in cell lysis, thereby limiting infection recognize mycobacterial glycolipids, such as LAM and
by elimination of the place where M. tuberculosis mycolic acids, presented by DC-1 molecules expressed
multiplies.19 Granlysin, another cytotoxin secreted by the mainly on the cell surface of professional APCs.63
cytotoxic T-cells, diffuses into the cell via the perforin- Upon binding the antigen, the CD-1 restricted T-cell
created pores and induces target cells to undergo induces cytolysis of the M. tuberculosis infected APC. γδ
apoptosis. Apoptosis can also be induced by association T-cells respond to small nonpeptide M. tuberculosis
between the Fas receptor (also known as CD95 or the antigens. 64 Activated γδ T-cells proliferate and
death receptor) on the surface of an infected cell and the differentiate into cytotoxic cells and secrete cytokines
Fas ligand on the cytotoxic T-cell surface.62 Fas ligand is typically associated with a Th1 response. The IFN-α
expressed on the surface of the cytotoxic T-cell following secretion results in increased expression of MHC and
activation. Thus, apoptosis of the target cell may be costimulating molecules on the macrophages surface, and
induced both by soluble molecules secreted by the increases the IL-12 and IL-18 production which again
cytotoxic T-cell and by direct cell-cell interaction. By have a positive feed-back effect on the IFN-γ production.
inducing cell lysis, M. tuberculosis is exposed to activated The importance of IL-12 has been demonstrated in human
macrophages with increased antimycobacterial activity. genotypes with mutations in the IL-12 receptor which
In addition, cytotoxic T-cells contribute to protect against are associated with an extreme susceptibility for
infection by the production of IFN-γ. Following activation, mycobacterial infections.
T memory cells specific to M. tuberculosis will develop.
A beneficial attribute of cytotoxic T-cells in Regulatory T-Cells
mycobacterial infection is their recognition of antigens
coupled to MHC class I molecules that are expressed by Treg cells are a subset of CD4+ T-cells that suppress
all cells in the host, whereas the helper T-cells only immune responses by the production of IL-10 and
recognize antigens coupled to MHC class II molecules TGF-β.18,65,66 The two cytokines reduce the inflammatory
limited to APCs. Thus, parenchymal cells of the lung responses by the inhibition of macrophages, DCs and
infected with M. tuberculosis would remain undetected lymphocytes resulting in reduced host tissue damage.65,67
by the helper T-cells. Such infected cells would be Treg cells also induce cytolysis via secretion of granlysin
detected only by the cytotoxic T-cells and probably by and perforin. Treg and Th17 cells appear to have opposing
the γδ functions in the regulation of protective immunity in TB.
T-cells. A recent study has shown that a population of purified
CD4+ T-cells from naive mice gave protection to Rag1
Unconventional T-lymphocytes knock out mice (mice without B and T-cells) against TB,
whereas the protection was reduced to that seen in wild
The unconventional subgroup of T lymphocytes includes type mice when Th and Treg cells were cotransferred into
γδ T-cells and CD-1 restricted T-cells. The membranes of Rag1 knock out mice.18 The results suggest that the
the unconventional T lymphocytes contain receptors presence of Treg cells could reduce an otherwise effective
which are less variable than those of B and T lymphocytes, T-cell response against M. tuberculosis and thereby
and γδ T-cells have an alternative TCR (γδ) as opposed to prevent efficient clearance of the microbe.
the TCR of helper T-cells and cytotoxic T-cells (αβ). The
unconventional T-cells do not need MHC molecules for
The B-lymphocytes
antigen recognition. The exact function of such cells is
not known, but it is believed that they are important in The B-lymphocytes identify microbes when antibodies
the early stages of the immune response, before the localized on their cell surface bind to a specific foreign
cytotoxic T-cells and helper T-cells have been fully antigen.14 The antigen-antibody complex is ingested by
activated. The γδ T-cells and the CD-1 restricted T-cells the B-lymphocyte and peptides are generated through
undergo considerable proliferation during the initial proteolysis. The peptides are presented together with
73
MHC class II molecules on the surface of the deficient and SCID mice (mice 15 with impaired ability
B-lymphocyte14, and attract a matching Th2 lymphocyte to make T or B lymphocytes) show that antibody
via cytokine secretion (mainly IL-2, IL-4 and IL-5) or via responses are essential to combat mycobacterial
direct association between cell surface molecules of the B infection.72,73
and T lymphocytes. More specifically, the antigen binding
induces the B lymphocyte to express the B7 and CD40 NK Cells
molecules on their cell surface. B7 and CD40 interact with
CD28 and CD40 ligand, respectively, on the cell surface NK cells are large lymphocytes specialized to identify
of the activated Th2 cell. Following activation, the B-cell and kill infected cells (e.g. cells infected with virus or
starts to proliferate and evolve into antibody producing intracellular bacteria as M. tuberculosis) or cancer cells in
plasma cells and memory cells responsible for the body. NK cells are cytotoxic and small granula in their
immunity.14 B lymphocytes can also be activated without cytoplasm contain proteins such as perforin and proteases
helper T-cell assistance. The T-cell independent activation known as granzymes which induce apoptosis of the target
of B lymphocytes occurs most often in the presence of cell. NK cells express CD16 (which includes the Fc
carbohydrate antigens with identical repetitive antigenic receptor for IgG) and CD56 molecules on their cell
determinants or in the presence of polyclonal activators, surfaces. In contrast to T lymphocytes, they do not express
exemplified by lipopolysaccarides localized in the outer CD3 or TCR. NK cells are activated in response to
membrane of gram negative bacilli. The T-cell dependent cytokines and have two kinds of receptors on
B lymphocyte activation occurs most often in the presence the cell surface to control cytotoxic activity; activating and
of protein antigens. inhibitory receptors. The inhibitory receptors recognize
Each B-cell line expresses a unique, antigen-specific MHC class I molecules present on all cell surfaces of the
antibody. The specific antibodies circulate in the lymph host. If the amount of MHC class I molecules is reduced,
and blood, and bind antigens identical to the original as by infection or by cancer cells, the NK-cells kill the cell
epitope. Antigen-antibody complexes activate the by inducing apoptosis. NK cells also kill cells coated by
complement system, macrophages and granulocytes. IgG antibodies by binding the antibodies to the Fc receptor
Macrophages bind the antigen-antibody complex via of CD16 (antibody dependent cell mediated cytotoxicity;
the Fc receptor and engulf the microbe. Macrophages also ADCC).
contain complement receptors on their cell surfaces, and
may by this receptor, engulf the complement-bound Cytokines
microbes. Finally, antibodies can neutralize antigens Cells of the immune system communicate in part via
directly. Examples of such antigens are toxins or receptors direct contact and in part via small soluble molecules.
located on the cell surface of the microbes. Signal molecules of the immune system are usually small
It has been generally accepted that B cells and their polypeptides or glycoproteins (MW 15-35 kDa) and are
antibodies play a limited role in the TB immune response, known as cytokines. They are produced mainly by helper
since M. tuberculosis is an intracellular microbe and T lymphocytes, but also by B lymphocytes, macrophages
antibodies are specialised for targeting extracellular and other immune cells. Cytokines function by association
microbes. However, new knowledge opens for the with specific receptor on the cell surface of the secreting
possibility that the humoral immune response contributes cell (autocrine effect) or a neighbour cell (paracrine effect).
in the defence against M. tuberculosis. The demarcation The most important cytokines in the fight against TB are
between humoral and cellular immune responses is IFN-γ, IL-4, IL-10, IL-12 and TNF-α. IFN-γ protects against
probably more synergetic than previously suggested, TB disease (Table 7.5)74 and is produced mainly by the
resulting in a mixed immune response. B cells secrete helper T-cells. IFN-γ is probably also produced by γδ T-
cytokines typically associated with a Th1 response (IFN- cells and NK cells in the initial phase of the infection, and
γ and IL-12) or cytokines associated with a Th2 response by cytotoxic T-cells in later stages of the disease. The
(IL-4). B cells also secrete IL-6 which stimulates the T-cell important role of IFN-γ in the fight against M. tuberculosis
response and IL-10 which inhibits the activity of DCs and can be demonstrated by testing monocytes from healthy
macrophages. IL-10 furthermore suppresses the DC individuals exposed to the microbe. The monocytes will
production of IL-6 and IL-12. Antibodies secreted by the by exposure to M. tuberculosis specific antigens produce
B-lymphocytes play an essential protective role against high levels of IFN-γ. Monocytes from patients with
mycobacterial infections via their opsonin effect, as pulmonary TB and TB-HIV coinfection have reduced INF-
previously mentioned. It has been shown that neutrophils γ production,75 indicating that the Th1 responses are
and macrophages increase the internalization and killing depressed in patients with TB. Moreover, IFN-γ knockout
of mycobacteria in the presence of antibodies68,69, and mice are highly susceptible to virulent M. tuberculosis53,76,
mycobacteria coated by specific antibodies are processed and individuals with defect in genes for IFN-γ or the IFN-
more efficiently by DCs. 70,71 Also studies in B-cell- γ receptor are susceptible to M tuberculosis infection.77 INF-
74
γ activates macrophages, NK cells and cytotoxic cell death by apoptosis. Cell death by necrosis, on the
T-cells. Furthermore, IFN-γ stimulates the development other hand, results in lysis of the infected cell and the
of T-cells towards a Th1 cell direction, and inhibits the release of viable M. tuberculosis into the adjacent
development of T-cells towards a Th2 cell or Th17 cell extracellular matrix. This in turn damages the
direction.78 The Th2 cell cytokines IL-4 and IL-10 have surrounding tissue 81 , leads to central necrosis of
similar inhibiting effect on the development of Th1 cells. unresolved granulomas, and extracellular M. tuberculosis
Secretion of IL-4 is induced by cell wall components of may spread to new hosts. M. tuberculosis has evolved to
M. tuberculosis (phosphoglycolipids and 19 kDa antigen) actively promote necrosis over apoptosis82-84 and to
and tends to increase in serious phases of TB disease inhibit apoptosis, and thereby avoid the death of its host
(miliary and meningeal TB). It has been suggested that cell.
progressive TB disease is due to the suppressive effect of
IL-4 on the Th1 response, and not due to the absence of a TB Pathogenesis
Th1 response, since IL-4 producing T-cells and IL-4
mRNA are increased in pulmonary TB patients and M. tuberculosis is spread through the air by droplet nuclei
correlates with the extent of lung cavitations.79 The IL-4 produced by a patient with active pulmonary TB. Droplet
hypothesis is supported by the observation that vaccine nuclei are 1-5 µm in diameter, contain two or three
candidates (a DNA vaccine based on heat shock protein M. tuberculosis cells, and are small enough to reach the
65 of M. leprae and a heat-killed M. vaccae vaccine alveoli within the lungs.85 Alveolar macrophages survey
candidate) that down-regulate the IL-4 effect have an the mucosal surfaces of the lungs and ingest the
immuno-therapeutic in murine TB models.79 It is also M. tuberculosis containing particles. Some of the infected
suggested that IL-4 antagonizes the apoptotic stimulation macrophages traffic to the draining lymph nodes and
effect of TNF-α.23 present the microbes to naive T lymphocytes. Other
IL-10 is an inhibitory cytokine. IL-10 inhibits antigen infected macrophages are trapped in the lung
presentation, expression of MHC molecules and parenchyma. Following antigen presentation, the
costimulating receptors on the cell surfaces of APCs. activated M. tuberculosis specific T lymphocytes
IL-10 furthermore inhibits the production and function proliferate and differentiate into effector cells. Cytokines
of IFN-γ, lymphocyte proliferation, cytokine production produced by immune cells located at the site of infection
by lymphocytes, and IL-12 production by macrophages.17 attract uninfected macrophages and leukocyte popu-
IL-10 increases in patients with active TB, whereas IL-12 lations, including T lymphocytes. Activated antigen-
induces IFN-γ production and thereby protects against specific T lymphocytes recognize M. tuberculosis-infected
TB disease. Mutations in the gene encoding the IL-12 macrophages and granuloma formation is induced. A
receptor make such individuals extremely susceptible to granuloma is characterized by a relatively small number
TB infection.80 of M. tuberculosis infected phagocytes, surrounded by
The important anti-mycobacterial effect of TNF-α is activated macrophages and lymphocytes. 86 In the
demonstrated by the high risk of reactivation of TB granuloma, M. tuberculosis has the capacity of staying
infection in patients with rheumatoid arthritis treated by viable for years. Whether or not the inhaled bacilli are
TNF-α receptor antagonists. However, together with high able to multiply inside the macrophage and establish an
levels of IL-4, the TNF-α has an opposite effect: induces infection in the lung depends on the degree of aerosol
necrosis and apoptosis, resulting in the formation of production, the bacterial load in the inoculum, the
granulomas. TNF-α is furthermore responsible for the bacterial virulence, and the microbicidal ability of the
weight loss and fever in TB patients. immune system of the host.85
No single immunological marker has so far alone In the majority (approximately 90%) of immune
shown to give full protection against TB. Instead, competent individuals, the immune response arrests and
combinations of certain pattern of cytokines released are limits M. tuberculosis to the primary site of infection; the
most likely to provide protective immunity. lung parenchyma and the local draining lymph nodes,
resulting in the primary complex (the “Ghon complex”).
This stage of TB infection is known as latent TB or
Cell Death
persistent TB. Individuals with latent TB have no
If the cell-mediated immune response fails to eliminate symptoms of TB disease. The majority of primary
the intracellular microbe, the host needs to eliminate the complexes are not visible on chest radiography and are
infected cell to remove the microbe. This may be done by clinically silent.85 A positive tuberculin skin test is the
two different processes; apoptosis and necrosis. By only indication of M. tuberculosis infection. Gradually, the
apoptosis the infected cell is eliminated without major granulomas heal and leave small, fibrous and calcified
effects on the neighboring, uninfected cells, resulting in lesions. The lesions can be identified on chest radiography
minimal tissue destruction.81 TNF is a potent inducer of for years. Individuals with latent TB are not infectious,
75
cannot transmit the microbe and can be asymptomatic include in theory all tests or markers that can tell if the
for the rest of their life-time. If the immune system of the person is infected with M. tuberculosis. Currently, the most
host is unable to control the initial TB infection or if the widely used biomarkers for TB infection and disease are
infected person later in life becomes immune compro- the chest radiography, the TST and the Ziehl-Neelsen
mised for example due to HIV infection, malnutrition, (ZN) staining of sputum smears. Another widely used
drugs or age, primary TB disease and post-primary biomarker for TB infection is IFN-γ secreted by antigen-
TB disease, respectively, may develop. The granulomas specific T-cells. Measurement of IFN-g is also used to
may increase, become liquefied and function as a rich monitor vaccine efficacy in clinical trials.
medium where M. tuberculosis can multiply uncontrolled. WHO recommends performing sputum-smear
Primary TB is defined as TB disease that develops during microscopy on all patients suspected to suffer from
the first five years following the primary infection.5 pulmonary TB.90 Limitations of ZN smear microscopy
Postprimary TB is defined as any TB diagnosed more than are low sensitivity (detection limit: 5,000-10,000 bacilli/
5 years after primary infection. Cell death in the ml sputum, and approximately half of the estimated TB
granuloma leads to necrosis. If the granuloma is close to cases worldwide are sputum smear negative) and low
the lung surface, tissue destruction caused by necrosis specificity in areas with a high prevalence of
can breach the mucosal surface and M. tuberculosis reach nontuberculosis mycobacteria since all mycobacteria are
the lung lumen, a process referred to as cavitation. At acid fast bacilli. Moreover, in areas with high prevalence
this point, the patient will have the prototypic symptoms of HIV-TB coinfection, the smear microscopy has become
of TB: persistent cough with hemoptysis and fever. The less useful since the suppression of cellular immune
person is highly infectious and spreads the microbe by responses results in reduced cavity formation and thus,
aerosols. greater proportion of both smear negative TB and
Viable M. tuberculosis may leave the granuloma and extrapulmonary TB.91 This has stimulated the search for
infect the surrounding lung parenchyma (active new biomarkers to replace smear microscopy.
pulmonary TB) or migrate to other organs through Cultivation and drug susceptibility testing are the
lymphatics and blood (miliary or extrapulmonary TB). gold standards of TB diagnostics, but these are limited
Certain organs and tissues are more susceptible to the in many areas with a high incidence of TB due to high
multiplication of M. tuberculosis than others. Examples of costs and/or long turn around time. Numerous novel
environments that favor the growth of M. tuberculosis are biomarkers have been developed and evaluated, but no
the upper lung zones, kidneys, bones and brain. test has been able to replace ZN smear microscopy. New
biomarkers of TB infection need high sensitivity and
Biomarkers specificity, should be easy to perform and interpret, have
Early identification of active TB is crucial to combat the low costs, provide rapid test results, and should be able
TB epidemic. Also identification of individuals with latent to be performed in small laboratories in resource-limited
TB, especially those with the highest risk of progression areas. Moreover, the patient should not need to return to
to active TB, assessment of disease activity, immune the TB diagnostic centre for a test result assessment as
responses, responses to treatment, and early indication currently needed for TST.
of relapse would be useful. It would further more be TB specific and host specific biomarkers may be useful
helpful to classify TB patients at diagnosis or early on as an adjunct to conventional tests for the diagnosis of
during therapy into risk groups and adjust the treatment pulmonary TB. The promising TB specific biomarkers
accordingly. malate synthase (MS) and MPT51 are most likely to be
Studies have shown that patients responding early expressed during active replication of M. tuberculosis. It
on anti-TB treatment may receive a shortened course of has been shown that MS and MPT51 elicit the production
treatment, 87,88 thereby improving compliance and of antibodies in patients at different TB stages (smear
treatment outcome. Finally, biomarkers could help to negative TB, smear positive TB, non-cavitary TB and
define a surrogate end-point for vaccine efficacy in Phase cavitary TB) in both HIV positive and HIV negative
II/III vaccine clinical trials. The vaccine end-point of individuals.92-95 Moreover, anti-MS and anti-MPT51 have
today is the diagnosis of clinical TB disease which due to been detected in sera from patients drawn before they
a usually long incubation time is inconvenient. The developed active TB92, but were absent in sera from
development of such tests has proven to be one of the persons with negative purified protein derivative (PPD)
greatest challenges in TB research and control. A test, healthy PPD test positive or HIV positive, TB
biomarker is defined as an objectively measured negative persons, thus, demonstrating their correlation
characteristic feature which is evaluated as an indicator with active TB. A recent study performed by Wanchu et
of a normal or a pathological process or as an indicator al. on 480 Indian subjects including HIV positive and HIV
of the response to an intervention.89 Biomarkers of TB negative TB patients showed that anti-MS and anti-
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MPT51 provided high sensitivity (~80%) and specificity most likely benefit from TB preventive therapy. More
(>97%) for the diagnosis of active TB, and the performance precise targeting of preventive treatment is a key element
was not compromised by concurrent HIV infection or the of TB control.
site of infection.96 The antibodies were also detected in In 2001, Lalvani et al. developed an enzyme-linked
sera from ~45% of HIV negative, smear negative TB immunospot (ELISpot) for the detection of IFN-γ
patients. To increase the sensitivity, the authors suggest producing T-cells in response to the M. tuberculosis specific
including one or two additional antigens together with antigens ESAT-6 and CFP-10.99 ESAT-6 and CFP-10 are
MS and MPT51. Thus, detection of antibodies to MS and encoded by the region of difference 1 (RD1), a region
MPT51 may serve as biomarkers for active TB and for of the mycobacterial genome present in all
incipient TB in HIV positive individuals at high risk of M. tuberculosis and pathogenic M. bovis strains, but absent
developing active TB.96 Table 7.6 gives an overview of in M. bovis BCG vaccine strains and most environmental
selected TB biomarkers. mycobacteria (with the exception of M. kansasii, M. szulgai,
M. flavescens and M. marinum).
Host Specific Biomarkers ESAT-6 and CFP-10 elicit secretion of high IFN-γ levels
from T-cells pre-sensitized with M. tuberculosis100 during
IGRAs early stages of TB infection. Moreover, it has been
The diagnosis of latent TB has for many decades relied questioned if a rise in IFN-γ represents bacilli replication
on the TST. Limitations of the TST are as follows: Inability and thus, the IFN-γ level could be used as a prognostic
to differentiate M. tuberculosis infection from BCG factor for development of active TB. Currently, two
vaccination or exposure to environmental mycobacteria, commercially available tests for the detection of T-cell
low sensitivity (< 75%) particularly in immune activation by M. tuberculosis, the IFN-γ release assays
compromised individuals, in persons of young age and/ (IGRAs), have the potential to replace the TST; the
or with severe malnutrition97, and false negative results QuantiFERON-TB In-Tube (Cellestis Limited, Victoria,
that may be associated with extensive disease. 98 Australia) and T-SPOT.TB (Oxford Immunotec, UK).
Moreover, the person tested has to return for test result Meta-analysis and systematic review undertaken by
assessment two days after the test has been administered Menzies et al.101 and Pai et al.102, respectively, have shown
which may be difficult for persons living far from TB that IGRAs have high specificity (QuantiFERON-TB Gold:
diagnostic centers. Efforts are being made to find a test 94-100% and T-SPOT. TB: 86-100%) unaffected by previous
to replace the TST, but it is difficult without a proper BCG vaccination. The specificity of TST is high in
reference test for TB latency. The goal is to develop a test unvaccinated persons (95-99%), but low and variable in
for identification of persons at high risk of progression BCG vaccinated individuals. The sensitivities of the IGRAs
from latency to active TB and therefore, those that would and TST were not consistent across tests and populations,
but on average the T-SPOT. TB was more sensitive than
the other tests evaluated (QuantiFERON-TB Gold 72-82%,
Table 7.6: Overview of immune-based TB biomarkers T-SPOT. TB 86-93% and TST 71-82%). Even though the
M. tuberculosis specific biomarkers-Host specific biomarkers IGRAs show a high specificity for TB infection, they have
Antigen 85 complex (sputum)-TST not proven to be able to distinguish between active and
Antigen 85B RNA (sputum) IFN-γ release assays: latent TB101, and data on populations with high risk of
38 kDa antigen (serum) - ESAT-6 developing active TB, including children and immune
LAM—CFP-10 compromised persons, are limited. Studies have shown
M. tuberculosis DNA (urine) IL-4/IL-4δ2 ratio that the sensitivity of IGRAs in children is reduced
Malate synthase—M. tuberculosis specific antibodies: compared to adults (83% vs 90%, respectively) and that
MPT51—anti-LAM
indeterminate results have been detected in patients on
MPT64—anti-38 kDa antigen
Antigen 60—anti-MS
immunosuppressive therapy.103 However, in a study in
PE and PPE antigens (serum)—anti-MPT51 South Africa where 293 children suspected to suffer from
HBHA—anti-antigen 85 TB were tested, it was found that the sensitivity of ELISpot
DosR regulon—encoded M. tuberculosis antigens - anti- (on which T-SPOT.TB is based) was higher and less affected
PPE55 by factors such as age under three years, HIV co-infection
Volatile M. tb markers-(breath) and malnutrition, than TST.97 Other studies conclude that
CFP-10–Culture filtrate protein 10, ESAT-6–Early-secreted the T-SPOT. TB test performs independently of HIV
antigenic target 6 kDa protein, HBHA–Heparin-binding associated immune suppression.104,105 The results suggest
hemagglutinin adhesion, IL–Interleukin, IFN–Interferon, a potential role for IGRAs in the diagnosis of M. tuberculosis
LAM–lipoarabinomannan, MS: Malate synthase, M. tb–M. infection and disease in immune compromised individuals.
tuberculosis, PE–proline-glutamine, PPE–Proline-proline- Since the IGRAs do not differentiate between latent and
glutamine, TST–Tuberculin skin test. active TB, the test may be useful for detection of latent TB
77
in contact tracing and screening of high-risk groups in low- obtain from the patient compared to induced sputum,
endemic areas. The test performance will be reduced in they are easy to perform, and test results may be available
high-endemic areas since a large proportion of the within one day. There are three main groups of
population is likely to be latently infected. Carrara et al.106 immunological tests for the detection of pulmonary TB:
have used the IFN-γ assay (ELISpot) to monitor treatment (i) detection of humoral immune responses (antibodies)
outcome in 18 microbiologically confirmed TB patients. to M. tuberculosis in serum, (ii) detection of T-cell based
They found a fall in the T-cell responses to ESAT-6 in the cellular immune responses (IFN-γ release assays: IGRAs)
blood of all 13 active TB patients with an adequate clinical in whole blood, and iii) detection of antigens in specimens
response during anti-TB therapy (measured by the time other than serum (e.g. lipoarabinomannan in urine).
of diagnosis and after 3 months of anti-TB treatment), but Most tests have focused on the detection of
remained elevated in the five patients where the treatment M. tuberculosis specific antibodies in serum, but the
failed. specificities have been low due to the use of crude,
Similarly, studies have shown a fall in specific IFN-γ nonspecific antigen mixtures.113 Development of purified,
production in patients recovering from TB disease.107,108 recombinant M. tuberculosis specific proteins has
If the IGRAs correlate with mycobacterial load, the tests increased the test proficiencies. Dozens of commercially
could be useful biomarkers for successful anti-TB available serological tests for active TB are available, but
treatment. no immunological test has as yet proven accurate enough
Nemeth et al. have recently demonstrated the ability to replace microscopy and culture.102,114,115 Recent reviews
to distinguish latent and active TB by flowcytometric and meta-analysis have shown that existing commercial
assessment of M. tuberculosis specific IFN-γ producing and in-house antibody based tests have poor accuracy
helper T-cells isolated from the infection focus compared and limited clinical utility in pulmonary TB.114,115 The
to the number of specific T-cells isolated from peripheral Anda-TB IgG ELISA kit for the detection of antibodies to
blood.109 Fifteen patients diagnosed with active TB were Antigen 60 was the most frequently evaluated test in the
examined and the test showed a sensitivity of 100% and review and showed limited sensitivity (range, 63-85%)
specificity of 90%. Flowcytometric measurements can and inconsistent specificity (range, 73-100%) in smear
provide the test results the same day. The study positive TB patients.114
demonstrates that the examination of T-cells from Commercially available antibody detection tests for
peripheral blood alone may not be sufficient for the the diagnosis of extrapulmonary TB provide highly
detection of active TB cases. Larger prospective clinical variable estimates of sensitivity (range, 0% to 100%) and
trials are needed to evaluate if responses assayed by IGRAs specificity range, 59 to 100%).116 Thus, today antibody
from local infection sites have the potential to distinguish detection tests have no role in case detection of
between active and latent TB. extrapulmonary TB116 and limited role in the detection
of pulmonary TB. Possible reasons for the low test
δ2 Ratio
IL-4/IL-4δ performances of immunological TB diagnostic tests could
be that a good TB test has to distinguish between
It has been shown that IL-4, IL-4δ2 and IL-13 are raised exposure, latency and active TB disease, as well as
in freshly isolated peripheral blood mononuclear cells distinguish between TB infection and infection caused
and in bronchoalveolar lavage cells from TB patients and by NTM or by BCG vaccination. It is likely that sera from
their levels correlate with the severity of disease.110,111 patients in different stages of TB infection and TB disease
Wassie et al.112 have evaluated the expression of IL-4, IL- show antibody reactions specific to the current TB stage.
4δ2 and IFN-γ over time in TB patients from Ethiopia and Thus, it has been recommended that panels of multiple
their contacts. They found that the IL-4/IL-4δ2 ratio was antigens have to be analysed to improve the test
higher in healthy contacts than in patients, the ratio performance.117,118 Combinations of absence or presence
increased after treatment, the ratio decreased in contacts of antibodies in the sera may indicate a specific infection/
who developed symptoms, and that the ratio tended to disease stage.
rise in patients with latent TB. Thus, the authors
concluded that the IL-4/IL-4δ2 ratio was a correlate of
Microbe Specific Biomarkers for TB
immunity.
Antigen 85 Complex Proteins
Antigen/Antibody Based Tests
The Antigen 85 (Ag85) complex proteins are major
The detection of antigens, antibodies or immune- secretory proteins produced by actively replicating
complexes associated with M. tuberculosis is an alternative mycobacteria and include Ag85A, Ag85B, and Ag85C.
to conventional diagnostic tests for TB. Immunological The proteins are mycolyl transferases important in the
diagnostic tests for TB are advantageous in areas with biosynthesis of trehalose-dimycolate (cord factor) in the
high TB incidence, since blood and urine are easy to final stages of the cell wall synthesis. Mycolyl-transferase
78
inhibitors inhibit the transfer and the deposition of detected in the urine and the bacterial load, thus, LAM
mycolates into the mycobacterial cell wall.119 The proteins based diagnostic tests do not show a sufficient test
share high sequence homology with each other and with performance to be used as the only TB test in a field
Ag85 from other mycobacterial species. They induce setting.126-128 Also tests for the detection of anti-LAM
delayed hypersensitivity, protective immune responses, antibodies in serum have been developed, but so far no
and the production of specific antibodies in infected mice test has shown a sufficient test performance.
and guinea pigs. The level of anti-Ag85 is often low in Theoretically, direct antigen detection in urine would
healthy PPD-positive individuals but high in patients be advantageous, especially in areas with a high incidence
with active TB.120,121 It has been shown that the median of TB-HIV coinfection, because of the following: no need
serum Ag85 level is 50 to 150-fold higher in patients with for an invasive procedure for specimen collection,
active TB than in healthy controls or in patients with non- independent of a well functioning immune system,
tuberculous pulmonary disease.122 Wallis et al. evaluated reflects more uniformly the total body bacillary burden,
the Ag85 complex expression in 42 patients with and HIV infected TB patients are more often likely to have
pulmonary TB and found that relapse after anti-TB extrapulmonary TB. The ideal test would be in a dip-stick
treatment could be predicted by an increase in Ag85 in format where the result could be read after minutes
sputum after two weeks of therapy.123 All subjects with allowing a high sample throughput. Potential biomarkers
Ag85 complex values of <60 pg/ml on day 14 after the for the detection of TB in the urine are LAM and
initiation of anti-TB treatment responded rapidly to mycobacterial DNA fragments. Disadvantages are low
treatment and were cured. Of those with values of > 60 test performance till date and the fact that the tests do
pg/ml, TB persisted at or after day 90 in 33% and not provide information on anti-mycobacterial drug
treatment failed in 17%. Ag85 is not detectable in urine susceptibilities.
since most serum Ag85 exists in complexes with plasma
fibronectin and IgG rather than in unbound form and Transrenal Mycobacterial DNA
thus, is too big for filtration in the kidneys.
Small extracellular DNA fragments from mycobacteria
38 kDa Antigen originating in the lungs or extrapulmonary foci may be
detected in the urine collected from TB patients in the
The 38 kDa antigen is a lipoprotein on the cell surface of form of 150 to 200 bp fragments.129 Metabolically active
mycobacteria and functions as a phosphate transport mycobacteria promote apoptosis of the infected host cell.
protein. Several kits for detection of the 38 kDa antigen Bacillary DNA released from the apoptotic cell into the
as a biomarker for M. tuberculosis infection are plasma is later cleared by the kidneys. Cannas et al.130
commercially available. The test performance varies with evaluated 43 pulmonary TB patients confirmed by culture
the sputum smear status of the patient, patient population for the detection of trans-renal M. tuberculosis complex
studied and disease manifes-tations.124 In sera from specific fragments (IS6110 DNA) by semi-nested PCR.
patients with culture positive specimens, the sensitivity M. tuberculosis complex specific sequences were found
ranged from 40 to 89% and the specificity from 44 to in the urine of 34 (79%) of the 43 TB patients studied,
100%.124 The test performance increased when the 38 kDa whereas all controls (10 patients with non-tuberculous
antigen was combined with other antigens to detect pulmonary diseases and 13 healthy controls) were
antibodies in TB patients. Furthermore, it has been shown negative. The M. tuberculosis complex specific DNA
that the severity of TB disease correlates with levels of fragments could not be detected in the patients 2 months
antibodies against the 38 kDa antigen and such antibodies after initiated anti-TB treatment. The method, although
are particularly found in patients with advanced TB promising, requires nested PCR and the sensitivity may
disease.125 not be sufficient for M. tuberculosis strains with a low
IS6110 copy numbers.
Lipoarabinomannan
One of the candidate antigens for the immunological MPT64
diagnosis of TB is LAM. LAM is released from The secreted protein MTP64 is a 23-kDa protein which
mycobacteria into the circulation and may be detected in elicits T-cell responses in individuals infected with TB.
serum or urine after filtration through the kidneys. MTP64 is specific to the members of the M. tuberculosis
Theoretically, the titre of LAM in the urine should reflect complex (MTC), but absent in some strains of BCG.131 It
the bacterial load, metabolic activity and/or rate of has been shown that MPT64 protects mice from
degradation of the bacteria, and hence permit developing TB following M. tuberculosis H37Rv challenge
differentiation between individuals with active TB, latent by prompting the Th1 response.132 Recently, using
TB and non-infected individuals. However, there is not a immunohistochemistry, MTP64 has been used as marker
consistent relationship between the levels of LAM of infection with MTC in biopsies from patients suspected
with TB.133
79
Antigen 60 encoded by this regulon are antigens with the potential

to be protective against TB. The proteins are produced
Antigen 60 (A60) is one of the most widely studied by M. tuberculosis in vitro under hypoxia and low-dose
mycobacterial antigens and is deployed in a commercially nitric oxide exposure,137 conditions thought to mimic the
available ELISA kit.114,124 As mentioned previously, the environment encountered by M. tuberculosis in vivo during
sensitivity and specificity of an anti-A60 based test in latency.138 Thus, these antigens are considered to be
patients with pulmonary TB varies considerably.114,124 The characteristic of latent infection139 and have been
sensitivity is lowest in children and in patients with associated with immunity against latent M. tuberculosis
extrapulmonary TB. infection. Black et al.140 have tested the immunogenicity
of the DosR regulon regulated antigens, measured by
PE and PPE antigens IFN-g responses of 51 DosR regulon regulated
The Proline-Glutamine (PE) and Proline-Proline- M. tuberculosis antigens in 131 TST positive and/or ESAT-
Glutamine (PPE) antigens are protein families named after 6/CFP10 fusion protein positive, HIV negative healthy
the amino acid sequences located near the N-terminus in household contacts of TB patients in South Africa, Gambia
the majority of these proteins. A protein in the PPE family, and Uganda. Rv1733c was the most frequently recognized
PPE55 which is specific to the M. tuberculosis complex, is DosR regulon regulated antigen, but also Rv1735c and
detected in sera from guinea pigs with incipient TB after Rv1737c were frequently recognized. The results may
being infected with virulent M. tuberculosis.134 In the same provide hope for the development of a rBCG vaccine with
study, anti-PPE55 was detected in sera from 29/30 (97%) some of the DosR regulon regulated antigens
HIV-negative and 17/24 (71%) HIV positive TB patients. incorporated (BCG alone fails to induce significant
Sera from PPD positive healthy controls were negative, responses to latency antigens) 141 that can provide
suggesting that the expression of PPE55 protein correlates protection against progression from latency to active TB
with active M. tuberculosis infection. Anti-PPE55 was disease.
furthermore detected in sera obtained prior to
manifestation of clinical TB from 17/21 (81%) HIV positive Volatile Mycobacterial Markers in Breath
patients, suggesting that the protein is expressed during Recently, suggestions have been made to use volatile
incipient TB in HIV-infected persons.134 metabolites from M. tuberculosis for the rapid diagnosis
Rv3872, a PE-related protein encoded in the RD1 of TB as well as for biomarkers of cure and relapse.142
region (which is absent in M. bovis BCG), has shown The hypothesis is based on the observations that
promising sensitivity and specificity when tested on sera mycobacteria and oxidative stress in patients resulting
from pulmon ary (n = 240) and extra-pulmonary (n = 179) from mycobacterial infection both produce distinctive
TB patients from India and compared to healthy BCG patterns of volatile metabolites that are liberated into the
vaccinated controls (n = 123). The sensitivity for breath. Several mycobacteria including M. tuberculosis
pulmonary TB patients was 92.5% and for extra- produce volatile metabolites that act as chemical
pulmonary TB patients 89%, the specificity was 95%.135 fingerprints, and 2 compounds specific to M. tuberculosis
Further studies are required to confirm these results. and M. bovis have been identified by solid phase
microextraction and gas chromatography/mass
HBHA spectrometry:143 methyl p-anisate and methyl nicotinate.
Heparin-binding hemagglutinin adhesin (HBHA) is a These compounds were detectable in culture before the
surface protein found in all MTC members and promotes visual appearance of colonies, and had characteristic
bacterial aggregation and adhesion to epithelial cells odors. Phillips et al. have studied volatile metabolites in
required for the extrapulmonary spread of the microbe.71 TB patients confirmed by culture and patients previously
HBHA identifies TB patients in an early stage of infection suspected to be suffering from TB, but where TB had been
and it has been suggested that the detection of antibody ruled out. The authors concluded that the volatile
specific to HBHA may be an alternative biomarker for biomarkers in breath were sensitive and specific for
TB infection. However, a pilot study performed in Finland pulmonary TB.142 Further evaluation of this approach for
showed that anti-HBHA can also be detected in healthy, TB diagnosis is underway.
BCG vaccinated individuals.136 Thus, HBHA detection
may not discriminate TB infection from immune reactivity New Trends in Search for Biomarkers in TB
caused by previous BCG vaccination.
New approaches for the identification of TB biomarkers
have been developed. The use of novel technological
DosR Regulon Regulated Proteins
platforms such as transcriptomics (analysis of gene
The 48-gene dormancy survival regulon (DosR) is expression), proteomics (analysis of protein expression)
believed to be associated with latency and proteins and metabolomics (analysis of small metabolites in body
80
fluids) where “fishing” for rather than targeted search to of a previous BCG vaccination, making BCG inapplicable
identify novel biomarkers involved in TB disease, as a booster vaccine.23 The variable efficacy of BCG may
pathogenesis and treatment response are exploited.88 The indicate that vaccines derived from M. tuberculosis strains
complex nature of the immune response makes it may provide better protection than BCG154, or that more
probable that a combination of biomarkers; a than one vaccine may be needed to provide protection
biosignature, rather than one single biomarker will be worldwide. Also strategies for combining BCG with a
required for a reliable correlate of protection.88 These new vaccine to improve the efficacy are attractive.
biomarker studies are ongoing and show promising Around 90% of HIV-negative individuals infected by
results. M. tuberculosis control the infection and will never
develop active TB. Thus, the immune system of the host
Vaccination and Vaccine Candidates has mechanisms to control the microbe although, the host
TB remains a major cause of morbidity and mortality rarely achieve eradication of M. tuberculosis. By studying
worldwide. In spite of effective anti-TB drugs and the the naturally induced host responses, it maybe possible
widespread use of BCG, TB is out of control globally. The to find potential biomarkers that indicate a protection
most effective tool for disease prevention is vaccination, against TB. These biomarkers could serve as a guideline
and a more effective vaccine has to be developed and for monitoring vaccine-induced immunity against TB,
distributed before the TB epidemic can be controlled.144 and could provide valuable information about vaccine
BCG has been distributed to >3 billion people and is the efficacy prior to the clinical end-point of TB disease.
most commonly used vaccine in the world. By vaccination New vaccines candidates include recombinant BCG
the person is able to mount an accelerated response to (rBCG) or other live vaccine vectors expressing immune
the microbe if re-exposed, by the generation of long-lived dominant mycobacterial antigens, attenuated strains of
memory T-cells. BCG provides a good protection against M. tuberculosis, DNA vaccines and subunit vaccines
miliary and severe forms of TB in infants, but the efficacy (protein, peptide or non-peptide vaccines in adjuvants).
against pulmonary TB in adults is highly variable (varies Table 7.7 provides an overview of some of the vaccine
from 0% to 80%). A meta-analysis has concluded that BCG candidates being evaluated in clinical trials. Currently,
immunization reduces the risk of pulmonary TB in adults at least 16 new TB vaccine candidates are under
by an average of 50%.145 BCG provides protection against development and the candidates are first extensively
TB in areas with high incidence of TB for a limited time tested in animal models before they can be tested in
period.146 The vaccine provides high protection against humans. Factors that influence the protective efficacy in
M. tuberculosis in low-epidemic areas (For examples: UK animal models are: the species of test animals used, the
and North America) but reduced protection in high- route of vaccination (respiratory, intranasal and oral), the
epidemic areas such as India and Africa.145,147,148 The interval between vaccination and challenge, the route and
highly variable efficacy of BCG may be explained by dose of challenge, and the interval between challenge
previous exposure to atypical mycobacteria which alters and termination of testing in the animal model.155 Prior
the immune response to BCG,149 by the use of genetically to Phase I clinical trials, preclinical evaluation of the
different BCG strains in different parts of the world150, vaccine candidate including safety and efficacy testing
phenotypic changes in the BCG strain during passage in mouse and guinea pig models, and if possible
from original cultures and during manufacturing
processes, variability in dose, route and age at
administration, deletion of protective antigens from Table 7.7: Overview of the vaccine candidates currently
BCG151, and by host variables which alter the ability of being evaluated
certain population groups to respond successfully. Vaccine candidate
Immunological responses elicited by BCG vaccination rBCG:
comprise a wide spectrum of T-cell phenotypes, including • rBCGΔUreC:Hly+
unconventional T lymphocytes, since BCG contains a • rBCG-pfo
• rBCG30
number of proteins, lipids and carbohydrates. In contrast,
Attenuated M. tb:
the response following subunit vaccination comprises • ΔlysA ΔpanCD mutant
mainly helper T-cells and cytotoxic T-cells that respond • ΔRD1 ΔpanCD mutant
to protein antigens. Sub-unit vaccines:
Studies have shown that BCG is ineffective in • Mtb72F
individuals pre-exposed to atypical mycobacteria.152,153 • Hybrid-1
A possible explanation is that the pre-existing Viral-vectored vaccine:
mycobacterial immune responses may cross-react with • MVA expressing Ag85A
BCG and neutralize the BCG immune responses. This may Ure—Urease, Hly—Listeriolysin, pfo—Perfringolysin, lys—Lysine,
explain why BCG fails to increase the immune response pan–pantothenic acid, MVA—Modified Vaccinia Ankara virus
81
evaluation of safety in non-human primates is required. Novel TB Vaccine Candidates

In animal models the vaccinated test animals are
challenged by a virulent strain of M. tuberculosis to Live Attenuated Vaccines
evaluate the degree of post-vaccine induced resistance. (modified BCG and M. tuberculosis)
Both bacteriological and immunological tests are BCG was generated in the early 20th century by continual
performed: by autopsy bacterial loads and passage of virulent M. bovis, the causative agent of bovine
histopathological changes in the organs are assessed, and TB. Live attenuated vaccines are safe, efficacious,
immunological signs of protection are looked for, i.e. stimulate both humoral and cell-mediated immune
increased IFN-γ, TNF-a and IL-2 production by activated responses, and are generally more potent than nonliving
T-cells. IFN-γ is not the perfect biomarker to identify vaccines in stimulating cell-mediated immune responses.
protective vaccines, since IFN-γ alone is insufficient The difficulty in live attenuated vaccines is safety; to
for the prevention of TB disease. However, IFN-γ is till achieve a satisfactory level of attenuation without
date the best biomarker for protection against severely compromising immunogenicity. The strength of
M. tuberculosis. Another approach for the measurement the immune response is a function of the amount of
of the immune protection level is to assess the increased antigens expressed. The goal is to develop an attenuated
numbers of activated helper T-cells and cytotoxic T-cells strain able to perform a limited replication in vivo, yet
in the lungs. If the vaccine candidate shows equal or safe with the potential to induce a robust and prolonged
superior protection compared to the conventional BCG, memory T-cell response. With the availability of the
it may be evaluated in clinical Phase I, II, III and IV trials. complete genome sequence of BCG and M. tuberculosis,
In Phase I clinical trials, the vaccine candidate is for it is possible to develop mutants with improved
the first time tested in a small group (usually 10 to 25 immunogenicity.
individuals) of healthy adults volunteers, and safety and Recombinant BCG (rBCG) expressing listeriolysin
side effects are measured. Phase II evaluates the effect of (rBCGΔUreC:Hly+) is a recombinant vaccine under
increasing dose of the vaccine candidate on safety and development. rBCG with listeriolysin uses BCG as vector
immunogenicity. Phase III evaluates the efficacy of the to improve the activation of cytotoxic T-cells. Listeriolysin
vaccine, and Phase IV clinical trials are normally the large is a cytolysin derived from Listeria monocytogenes that
scale surveillance of individuals who have received the forms pores in the membrane of the early phagosome in
vaccine with registration of adverse effects that occur with macrophages.151 By secretion of listeriolysin, the early
a low frequency. Optimal design for a Phase III efficacy endosomes are destroyed and BCG may leak into the
trial is a double blind, randomized, placebo controlled cytosol of the infected host cell. Since listeriolysin is most
trial. However, ethical norms prevent the withdrawal of active in an acidic environment and urease blocks the
BCG vaccination in a randomized control trial of a new acidification of early endosomes, the urease gene of BCG
TB vaccine in a TB endemic area since BCG has shown to (ureC) is deleted in the vaccine candidate. The presence
protect against serious childhood forms of TB. A of BCG in the cytoplasm increases the MHC presentation
randomized placebo controlled trial of a vaccine of BCG antigens to cytotoxic T-cells and induces a
candidate to boost a previous BCG vaccination is possible cytotoxic immune response. Apoptosis releases BCG
without the withdrawal of BCG. derived antigens into the extracellular environment and
Most TB vaccines candidates under development induces cellular immunity. A mouse model has shown
today attempt to induce cellular immune responses that the rBCGΔUreC:Hly+ provided better protection and
dominated by the IFN-γ secreting helper T-cells, essential was safer than BCG in immune compromised SCID
for control and elimination of intracellular microbes. mice.159 Phase I trials for this vaccine started in 2006. An
However, also IFN-γ secreting cytotoxic T-cells provide equivalent rBCG vaccine has been constructed to escape
protective immunity against TB especially important in from the endosome using the pH-independent
the absence of helper T-cells as in HIV infected perfringolysin (rBCGpfo), instead of listeriolysine. The
individuals156, and cytotoxic T-cells are important in the vaccine candidate overexpresses immunodominant
control of latent TB.157 Recent studies have shown that antigens, including Ag85A, Ag85B and TB10.4, thereby
M. tuberculosis elicits a mixed immune response involving combining two ways of immune activation.
both humoral and cellular immunity. 124 Vaccine Another rBCG vaccine candidate is the rBCG30 with
candidates consisting of a combination of subunits stimu- the overexpression of Ag85B. Ag85B is a highly
lating both humoral and cell-mediated parts of the immunogenic protein secreted by M. tuberculosis and BCG
immune system elicit a stronger immune response than with mycolyl-transferase activity required for
either of the subunits alone124,158 and are probably the mycobacterial cell-wall synthesis. Studies have shown
best candidates. There are two potential vaccine strategies that the vaccine candidate induces an increased level of
against TB: before (pre-exposure, prophylactic) or after protection compared to its parental BCG strain160,161 and
(postexposure, therapeutic) exposure to the microbe. there were no significant safety issues in the Phase I trial.
82
Problems associated with rBCG vaccines are the need to Ag85 family, MPT32, MPT53, MPT63, MPT64, GroES,
demonstrate a better efficacy than BCG before moving ESAT-6, CFP-10, the19-kDa lipoprotein, Rv3407, Mtb32
on to Phase I trials, and the possibility of inhibition by and Mtb39. Single proteins have so far not shown to elicit
prior sensitization by environmental mycobacteria.162 high enough protection, but hybrid protein vaccines,
Live, attenuated M. tuberculosis strains are attractive, consisting of two or more strongly immune stimulating
novel vaccine candidates. They have the ability to persist proteins, have shown promising results. The recombinant
in the host for a limited time, may have a greater fusion protein constructs Mtb72F (consists of Mtb32 and
protective efficacy than that of the BCG and have an Mtb39) and Hybrid-1 (constitute Ag85B and ESAT-6)
improved safety profile. An absolute criterion for have shown to be protective in mice and guinea pig
knockout mutants of M. tuberculosis as vaccine candidates models against TB.166-169 The protective effect of Hybrid-
is to eliminate the possibility to mutate back to the 1 has been shown not to be affected by previous
parental wild type genotype and thereby cause disease. sensitization with environmental mycobacteria162, and
At a minimum, live attenuated M. tuberculosis vaccine moreover, boosts the immune response provided by BCG,
candidates used in humans should have two independent with a resulting survival time doubled to over two years
and unlinked genomic deletions (double knockouts) as in guinea pigs.166 Mtb72F and Hybrid-1 are currently being
well as proven safety in immune compromised persons. evaluated in Phase I clinical trials.
This is particularly important in TB vaccines since TB Prime-boost vaccine strategy is a new approach in the
epidemic areas also have a high prevalence of HIV development of more effective TB vaccines. By boosting
infection. A way to evaluate safety is to test the vaccine the BCG effect with another antigen, the TB specific pre-
candidate in SCID mice. existing memory T-cells against antigenic epitopes shared
Current multiple knock-out mutants of M. tuberculosis by both the priming and booster vaccines expands. The
include the DlysA DpanCD mutant (known as mc26020) booster includes viral vectors such as recombinant
and the DRD1 DpanCD mutant (known as mc26030). The adenovirus or poxvirus engineered to express
panC and panD genes are involved in the pantothenic acid immunogenic and protective mycobacterial candidate
synthesis and both mutants have been shown to be highly antigens (for example, Ag85A, Ag85B and TB10.4) or
stable and conferring significant protection in mice or recombinant proteins (for example, HyVac-4, Hybrid-1
guinea pigs following aerosol challenge with virulent and Mtb72F) delivered with adjuvants (such as AS02A,
M. tuberculosis equivalent to that provided by BCG AS01B, IC31 and LipoVac). The prime-boost approach is
vaccination. The DlysA DpanCD mutant was completely of high interest since BCG has been distributed to > 3
cleared from the organs of SCID mice within the first 5 billion people worldwide.
weeks163 and > 50% of SCID mice vaccinated by the DRD1
DpanCD mutant survived for over 350 days.163 Larsen et Viral-vectored Vaccines
al. have shown that both mutants were safe and well
tolerated in monkeys, but the vaccine candidates did not Vaccines elicit the best immune responses when highly
provide an efficacy superior to that of BCG164 following active expression vectors are used. Plasmids with a strong
a high-dose intrabronchial challenge with virulent viral promoter that drives the in vivo transcription and
M. tuberculosis. Moreover, Waters et al have shown that translation of the gene of interest are good vectors. Non-
the DRD1 DpanCD mutant given in two weeks old calves replicating, recombinant poxviruses and adenoviruses
failed to protect them against low dose, aerosol M. bovis are able to efficiently boost a previously primed T-cell
challenge at 2.5 months of age. 165 In contrast, BCG response. Recently, the AERAS-402/Crucell Ad35 vaccine
vaccinated calves had reduced TB associated pathology candidate using a replication-deficient adenovirus as
as compared to nonvaccinated calves and calves vector has entered Phase IIb clinical trials in South Africa
vaccinated with the mutant.165 in 2008. The vaccine includes the 3 highly immunogenic
mycobacterial antigens Ag85A, Ag85B and Tb10.4, and
is designed to boost BCG or rBCG. The AERAS-402/
Sub-unit Vaccines
Crucell Ad35 vaccine induces high levels of cellular
To eliminate the risk of reactivation of attenuated whole immunity in mice.170
cell vaccines, sub-unit vaccines, consisting of one or two A leading booster vaccine is the recombinant Modified
defined protein antigens or recombinant protein Vaccinia Ankara virus (MVA) that expresses Ag85A from
components delivered with powerful adjuvants, have M. tuberculosis. Goonetilleke et al. have shown that
been developed. Most of the M. tuberculosis specific boosting a previous BCG primed immune response with
antigens tested have been derived from bacilli culture MVA85A induced increased levels of helper T-cells and
filtrates containing approximately 200 different proteins cytotoxic T-cells and enhanced protection in mice and
produced during different stages of incubation (early guinea pigs compared with a vaccination regimen using
versus mid-log phase). Antigens under evaluation are the either BCG or MVA85A alone.171,172 The safety and
83
immunogenicity of boosting a BCG vaccine with modulate protective host responses to ensure its own
MVA85A has been evaluated in a series of Phase 1 and survival and dispersal.
Phase 2 studies conducted in the United Kingdom, • TB specific and host specific biomarkers may be
Gambia and South Africa.173-175 MVA85A has been found useful as an adjunct to conventional tests (smear
to be safe, well tolerated, and highly immunogenic. The microscopy and culture in solid or liquid media) for
MVA85A vaccine candidate has entered Phase IIb clinical the diagnosis of pulmonary TB. TB biomarkers are
trials in South Africa in 2009, where the efficacy will be also useful to monitor vaccine efficacy in clinical
evaluated in 4-month-old BCG vaccinated infants in a trials. The complex nature of the immune response
randomized, placebo controlled study design. The Phase from M. tuberculosis makes it probable that a
III trial for this vaccine is anticipated in 2012. combination of biomarkers; a biosignature, rather
than one single biomarker will be required for a
DNA Vaccines reliable correlate of protection.
• BCG, the current TB vaccine, provides high
DNA vaccines consist of small, circular DNA fragments
protection against M. tuberculosis in low epidemic
known as plasmids that have been genetically engineered
areas, but reduced protection in high-epidemic
to produce one or two M. tuberculosis specific proteins.
areas.
The plasmids are injected into the host cell, following
• The most effective tool for disease prevention is
which the host cell machinery produces the bacilli
vaccination, and a more effective vaccine has to be
proteins. The M. tuberculosis specific proteins are foreign
developed and distributed before the TB epidemic
to the host and trigger an immune response. DNA
can be controlled. Promising novel vaccine
vaccine candidates have received increased attention and
candidates are under development.
many of these candidates have shown protection in
mouse models. These include both DNA vaccines
encoding native proteins, but also DNA encoding active ACKNOWLEDGMENT
fusion polyproteins. DNA vaccines function well in The authors thank Dr Mark Doherty for helpful
prime-boost strategies, can be delivered in multiple ways, suggestions and are grateful for support from the
and can be codelivered with genes encoding Research Council of Norway, NUFU and the Western
cytokines.171,176 Norway Regional Health Authority.
In the long-term, satisfactory control of the TB
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8 Clinicoimmunological Profile
Vimlesh Seth
INTRODUCTION types: (a) nodal, (b) parenchymal and (c) paren-

chymal plus nodal.
Clinical, morphological and immunological studies of iv. Tuberculous lymphadenitis (TBL) with or without
human tuberculosis have demonstrated the existence pulmonary lesion of the nature of nodal,
of a spectrum of immune response in tuberculosis. At parenchymal or nodal plus parenchymal lesion.
one extreme, the infection is subclinical and merely v. Progressive primary disease (PPD).
leads to tuberculin hypersensitivity and at the other vi. Miliary tuberculosis (MTB).
extreme is a progressive disseminated disease of the vii. Meningeal tuberculosis (TBM).
nature of miliary and meningeal tuberculosis. The
presence of an immune spectrum in tuberculosis was
Interaction between Immune
first suggested by Skinsness in 1968.1
An immune spectrum with two polar forms, reactive
Status and Clinical Manifestation
and unreactive tuberculosis (RR and UU) was described Immune status of patients can be tested by indirect
by Lenzini way back in 1977.2 The reactive form (RR) is indicators such as tuberculin test, leukocyte migration
characterized by localized lesions with lymphocytes and inhibition test (LMIT), T cell counts, and immunoglobulin
epitheloid cells and by a marked early response to profile.
antituberculosis drugs. Immunologically, this form
shows evidence of active cell mediated immunity with Tuberculin Test
little or no antibody response. In particular, the reaction
of PPD-tuberculin is that of a typical delayed Tuberculin test is an indirect indicator of T cell function.
hypersensitivity response and is also reflected in the It is also used for diagnosis of tuberculosis in children.
positive cellular response in vitro. The unreactive form Table 8.1 shows results of tuberculin test in children
(UU) is characterized by rapid dissemination of the diagnosed to have SMP, PPC and TBL.
lesions within the chest and to other organs and a An induration of >10 mm to PPD-tuberculin has been
poor response to treatment. This group shows taken as a positive tuberculin reaction and leukocyte
immunologically a very poor or an absent cell mediated migration inhibition test (LMIT) was considered as
immune response, resulting in both tuberculin test and positive if the index was less than 0.8.6,7 Analysis of the
leukocyte migration inhibition test (LMIT) being immunological aspects of the data from studies by Seth
negative with abundant antibody response. In between et al3-7 have been presented.
these two polar forms is an intermediate reactive group
(IR) showing characteristics of the two extreme polar
Table 8.1: Degree of positive tuberculin reaction in
groups RR and UU. various manifestations of tuberculosis
Clinical Profile TB group Size of tuberculin reaction (mm)
10-14 15-19 > 20
A number of studies were carried out by Seth
et al3-5 to study the immunological spectrum of tuberculosis a. SMP N = 25 3 (12) 11 (44) 11(44)
b. PPC N = 70 8 (11.4) 20 (28.5) 23 (32.8)
in children. The following profile has emerged using the
c. TBL N = 25 5 (20) 4 (16) 11(44)
above criteria.
i. Tuberculin positive, asymptomatic with no manifest P value a × b NS NS NS
tuberculous lesion: the asymptomatic Mantoux b×c NS NS NS
a×c <0.01 <0.01 NS
positive (ASMP) group.
ii. Tuberculin positive with symptoms of tuberculosis Figures in parentheses indicate percentages.
but without any manifest tuberculous lesion: the SMP = Symptomatic Mantoux positive, PPC– Pulmonary
symptomatic positive (SMP) group. primary complex, TBL– Tuberculous lymphadenitis,
NS– Not significant.
iii. Pulmonary primary complex (PPC) which is of three
91
Chapter 8 Clinicoimmunological Profile
Table 8.2: Tuberculin reaction positivity and leukocyte tuberculosis there is, on an average, a decreased
migration inhibition test (LMIT) positivity in various proportion of lymphocytes, competence for cellular
manifestations of tuberculosis immunity and the more extensive the tuberculous
TB group Positive tuberculin Positive process, the greater the decrease in T cell counts. In the
reaction LMIT study at AIIMS, total lymphocyte counts, absolute T-
lymphocyte counts and LMI index were comparable in
a. SMP N = 25 25 (100) 16 (64)
b. PPC N = 70 51 (72.8) 30 (42.8) SMP, PPC and TBL. However, there was slight variation
c. TBL N = 25 20 (80) 11 (44) in the percentage of T cells. It indicates that immune
competence in these types of TB manifestations is
P value
comparable (Table 8.3).
a×b <0.01 NS
a × c, b × c NS NS In severe cases of pulmonary tuberculosis in adults,
the T cell unresponsiveness has been attributed to antigen
Figures in parentheses indicate percentages.
load. Lenzini2 demonstrated that in the intermediate
forms of tuberculosis, the LMIT positivity could be
induced with a larger dose of antigen in the in vitro
Tuberculin reaction positivity was highest in TBL system. In the present study, the dose of antigen used
group after SMP. Distribution of cases according to the was 15 µg/ml standardized in a tuberculin positive child
size of tuberculin reaction was comparable in SMP and who had not received BCG vaccination and had no
TBL groups. A larger proportion (44%) of children in the evidence of active disease radiologically or
TBL group had induration more than 15 mm.5,6 bacteriologically. It is possible that PPC and TBL groups
are some what similar to the intermediate category of
Leukocyte Migration Inhibition Test (LMIT) immune spectrum of tuberculosis described by Lenzini.2
These may be requiring a large dose of antigen to have
LMIT was positive only in 64% of tuber-culin positive an optimum amount of secretion of specific migratory
children with no obvious tuberculous lesion (SMP). In inhibition factor (MIF) lymphokine necessary for LMIT
PPC group, 72.8% were tuberculin positive and 42.8% positivity. It is possible that in PPC and TBL groups, the
LMIT positive. In TBL group, the immune profile was lesion gets localized mostly by the formation of
somewhat similar to PPC showing 80% tuberculin nonimmune response. The direct activation of
positive and 44% LMIT positive children (Table 8.2). macrophages by bacterial cell wall prevents early
The extent of inhibition in LMIT positive cases in the dissemination of bacilli. This type of macrophage
three groups was also similar (Table 8.3). Percentage of activation of granuloma formation is induced by peptido-
T cells was significantly lower in TBL group in glycan layer of the bacterial cell wall and also by its
comparison to PPC and SMP groups. However, the total synthetic derivative muramyl dipeptide. This probably
lymphocyte and absolute T cell counts were comparable is the mechanism by which the local host response
in the three groups. In miliary and meningeal tuber- generated is sufficient to fight the infection (locally) in
culosis groups reported earlier,5 only 13.3% of children the lungs. The specific cell mediated immune response
were tuberculin positive as against 93.3% LMIT positive induced by thymus dependent lymphocytes activates the
children, the difference was highly significant (P < 0.001). macrophages for their antibacterial action through a
It is quite baffling that no correlation was found lymphokine called macrophage activating factor (MAF).
between the tuberculin and LMIT positivity in the three It is possible that in PPC and TBL groups this amount of
clinical presentations of SMP, PPC and TBL in childhood specific immune response by its action through
tuberculosis. Skvor and Trinka8 observed that in active macrophage activation factor (MAF) is sufficient to
Table 8.3: T cell percentage and LMI index (mean±SD) in various manifestations of tuberculosis
TB group T cell % Total lymphocyte count Absolute T-lymphocyte count LMI index
a. SMP N = 25 62.06± 2719.28± 2462.48± 0.65±

7.08 1053.09 1796.51 0.13
b. PPC N = 70 58.93± 4030.07± 2086.54± 0.64±
9.06 2103.29 1178.34 0.12
c. TBL N = 25 48.76± 3709.92± 1864.92± 0.70±
10.42 1838.24 912.37 0.08
P value a × b NS NS NS NS
a×c,b×c p < 0.001
92
localize the infection at the local site. The other Table 8.5: Cell mediated immune response after BCG
lymphokine MIF which is necessary for the LMIT vaccination in preschool children in relation to nutritional
positivity is probably secreted in lesser quantities as there status
may be lesser number of a subset of immune competent Nutritional status Tuberculin LMIT
T cells due to a low antigen load in well-localized lesions +ve No. + ve No.
of PPC and TBL. In SMP the host defense mechanisms
a. Normal N = 61 42 (68.8) 34 (55.7)
attempt to localize the infection by preventing the
b. Undernourished 43 (62.3) 51 (73.9)
migration of leukocytes by secreting differentially a larger N = 69
amount of MIF. Probably different stimuli or signals c. Severe PEM N =24 9 (37.5) 20 (83.3)
induce secretion of different lymphokines by different
P value a×b NS <0.05
subpopulations of T cells 9 . Gatner et al, 10 have
b×c <0.05 NS
demonstrated that the amount of leukocyte migratory- a×c <0.02 <0.01
inhibitor factor (LMIF) secreted in adults with pulmonary
Figures in parentheses indicate percentages
tuberculosis is comparable to the value among non-
tuberculous subjects. It substantiates our hypothesis that
there is differential secretion of various lymphokines by
different immune competent T cells and probably MAF after three months treatment. In our study most of the
has an upper hand in localizing the infection. Hence, in children had not received any antituberculosis drugs. A
few had received chemotherapy upto 2 weeks. It is
addition to the detailed studies of subpopulation of T
possible that mere presence of the drug in vivo
cells, assay of different lymphokines in vitro is needed to
differentially activates the macrophage system much
unravel the mechanisms of tubercular immunity in
more, both directly and through MAF and there is less
children. secretion of MIF.
Kramer et al11 demonstrated in animals that the T cells In conclusion, the comparison of immune
from malnourished guinea pigs secrete a larger amount mechanisms in some of the clinically encountered types
of MIF to low doses of antigen in comparison to the T of tuberculosis in children has raised many queries. There
cells of well-nourished animals. Keeping this in view, the is an urgent need for carrying out prospective studies on
nutritional status was also assessed in our studies. It is immunology of tuberculosis in children as per WHO
clear from Table 8.4 that the percentage of children having recom-mendations to provide some guidelines regard-
grade III malnutrition was very low in SMP, PPC and ing management of tuberculosis in children. Research in
TBL in comparison to miliary and meningeal tuberculosis. the areas of (i) determination of phenotype and function
This maybe responsible for lower response in LMIT of T cells, (suppressor or helper), lymphokine production,
positivity in these three clinical situations. In an earlier assessment of macrophage function, monocyte/
study by Seth et al12 where CMIR was measured by macrophage activation for killing of M. tuberculosis and
tuberculin reaction and LMIT after BCG in relation to the chemotaxis would be of immense help in the
nutritional status, it was demonstrated that LMIT understanding of a very wide clinical spectrum of
positivity had a direct relationship with the degree of tuberculosis in children. It is the interaction between
malnutrition. The more severe the malnutrition, the tubercle bacilli and the immune system of the body which
higher the positivity of LMIT (Table 8.5). determines the outcome of primary infection. The
Khumenku et al13 demonstrated lesser extent of relationship is shown in Figure 8.1.
inhibition in LMIT in pulmonary tuberculosis in adults It is mostly the cell mediated immunity which
determines the outcome of primary infection though
changes in the humoral immunity also occur. Seth et al5
Table 8.4: Nutritional status in various manifestations
of tuberculosis
investigated the cell mediated immune response (CMIR)
to assess the delayed cutaneous hypersensitivity (DTH)
TB group Nutritional status in children with tuberculosis under five years of age. The
Normal Under-nutrition Severe
clinical profile is shown in Table 8.6. A large proportion
kutrition Grade I and II PEM
(86.7%) of children were malnourished with severe
SMP N = 25 12 (48) 12 (48) 1 (4) malnutrition in 30% of them. Quantitatively there was
PPC N = 70 30 (42.9) 36 (51.4) 4 (5.7) no significant difference in the value of T cells in the
TBL N = 25 6 (24) 17 (68) 2 (8)
children with tuberculosis in comparison to the controls
Miliary and
TBM N = 15 2 (13.3) 8 (53.4) 5 (33.3)
(Table 8.7). Leukocyte migration inhibition test was
positive in 63.3% of cases; LMIT positivity was
Figures in parentheses indicate percentages, PEM = protein significantly higher (p < 0.001) in cases investigated
energy malnutrition
before initiation of therapy as compared to the group
93
Table 8.8: LMIT in relation to therapy and correlation

with positive tuberculin test (5TU)
Before During
therapy therapy
LMI index (N = 15) (N = 15)
LMI index +ve 15 (100)* 7 (46)*
Tuberculin +ve (5 TU) 8 (53) 5 (33)
Tuberculin –ve (LMI +ve) 7 (47) 2 (13)
Both tub and LMI – ve 0 8 (53)
Both tub and LMI +ve 7 (47) 5 (33)
*P < 0.001. Tub– Tuberculin, Figures in parentheses are
percentages
tested during therapy (Table 8.8). The value of leukocyte

migration inhibition index was much lower which was
statistically significant in before therapy group as
compared to the controls and during therapy group
(Table 8.8).
In the spectrum of tuberculosis it has been
demonstrated by Seth et al14 that in pulmonary primary
complex, the most common manifestation of tuberculosis
in children was an absolute T cell count which was more
in the nodal and nodal plus parenchymal groups in
comparison to the group with parenchymal lesion alone.
Fig. 8.1: Clinical profile of tuberculosis
CMIR judged by Mantoux test and LMIT was comparable
in the three groups who were normally nourished. But
in children who were malnourished CMIR was better in
Table 8.6: Clinical profile of tuberculosis
the nodal and nodal plus parenchymal groups.
Types of TB No.
Tuberculous meningitis 14 Immunology of Tuberculous Lymphadenitis
Miliary 1
The immunology of tuberculous lymphadenitis, the next
Spinal 2
Constrictive pericarditis with mediastinitis 1 common manifestation of the tuberculous disease in the
Peritoneal (with ascites) 3 outpatient department was investigated in children below
Cervical lymphadenitis 1 12 years by Seth et al. 15 Both cellular and humoral
Pulmonary tuberculosis: components were studied. The three groups investigated
Primary complex (PPC) 6 were histologically proved tuberculous lymphadenitis,
Collapse, consolidation (PPD) 2 reactive lymphadenitis group and controls. The status of
Total 30 severe malnutrition, and Mantoux test positivity was
highest (93.3%) in the histopathologically proved with
definitive diagnosis of TBL group (Table 8.9). Routine
Table 8.7: LMI index and T cells (mean ±SD) in childhood hemogram was comparable in the three groups (Table
tuberculosis 8.10).
CMIR Patients Controls
CMIR estimated quantitatively by T cell estimation
(N = 30) (N = 12) and qualitatively by LMIT (Tables 8.11 and 8.12)
demonstrated that absolute T cell counts were It is mostly
LMI index :
the cell mediated immunity which determines the
Before therapy 15 0.62 ± 0.16*
During therapy 15 0.87 ± 50 1.06 ± 0.22
outcome of primary infection though changes in the
Total 30 0.74 ± 0.38** humoral immunity also occur. Seth et al5 investigated the
cell mediated immune response (CMIR) to assess the
T cells:
Percentage 16 56 ± 9.29 57.6 ±11.2
delayed cutaneous hypersensitivity (DTH) in children
Absolute count 16 2222 ± 12 2193 ± 99 with tuberculosis under five years of age. The clinical
profile is shown in Table 8.6. A large proportion (86.7%)
*P < 0.001
**P = 0.05
of children were malnourished with severe malnutrition
in 30% of them. Quantitatively there was no significant
94
Table 8.9: Status of nutrition, BCG vaccination and Mantoux test in tuberculous lymphadenitis
Nutritional status
Group BCG Mantoux test
Normal nutrition Under PEM Severe PEM vaccination positivity
(I and II) (III and IV)
a. Control (N = 20) 9 (45) 10 (50) 1 (5) — 2 (10)
b. Reactive (N = 27) 14 (51.8) 11 (40.7) 2 ( 7.4) 8/24 (33.3) 4/27 (14.8)
c. TBL (N = 18) 4 (22.2) 12 (66.7) 2 (11.1) 4/16 (25 ) 14/15 (93.3)
P value*
a×b NS — NS
a×c NS — < 0.001
b×c NS NS < 0.001
Figures in parentheses are percentages, * Chi square test,
NS– Not significant,
TBL– Tuberculosis lymphadenitis
Table 8.10: Hemogram (mean ±SD) in chronic cervical lymphadenitis

Group Hemoglobin TLC DLC
(g/dl) (per cumm)
P L E B
(1) (2) (3) (4) (5) (6)
a. Control 10.96 ± 1.68 9246 ± 3790.33 57 ±18.09 36.68 ± 18.07 1.32 ± 2.54 2.64 ± 2.49
(N = 20)
b. Reactive 10.64 ± 1.11 10462 ± 4311.60 51.55 ±9.76 41.95 ± 10.37 1.95 ± 1.47 3.70 ± 3.18
(N = 20)
c. TBL 10.17 ± 1.51 10562.3 ± 4304.19 54.07 ± 8.96 39.60 ± 11.51 2.27 ± 2.12 4.47 ± 4.31
(N = 15)
P value* a × b, NS** NS NS
a × c, b × c
* For variables 1, 3 and 4 – One way analysis of variance test
**For variables 2, 5 and 6 – Wilcoxon’s nonparametric test
Table 8.11: T cells (I and 24 hours) in chronic cervical lymphadenitis

T cells
Group Percentage Absolute count Percentage Absolute count
(1) (2) (3) (4)
a. Control (N = 20) 39 1712.95 54.44 1840.50
±6.8 ± 748.6 ±10.50 ±1039.37
b. Reactive (N =27) 36.8 1658.6 48.89 2268.9
± 5.9 ± 645.5 ± 7.45 ±916.99
(N= 20) (N = 20)
c. TBL (N = 18) 33.2 1493 44.95 1951.62
± 5.5 ± 652.5 ±6.63 ± 836.69
P value*
a×b NS NS <0.05 NS
a×c <0.05 NS <0.01 NS
b×c NS NS NS NS
*For variables 1 and 3 one way analysis of variance followed by, Norman-Keul’s multiple range test,
For variables 2 and 4 Wilcoxon’s nonparametric tests were applied
95
Table 8.12: Leukocyte migration inhibition test (LMIT) in chronic cervical lymphadenitis
Group LMIT positivity Value of LMIT (mean % ± SD) P value*

Control (N=20) 0 0.98 ± 0.47
Reactive (N=15) 7 (46.6) 0.83 ± 0.25 <0.01
TBL (N=10) 6 ( 60 ) 0.77 ± 0.24 <0.01
*For variable (1) - Chi square test. For variable (2) one way analysis of variance test, P value between the reactive and TBL
groups were applied
Table 8.13: B cells and serum immunoglobulins (mean + SD) in chronic cervical lymphadenitis
Data are mean ± SD

B cells Immunoglobulin levels (IU)
Group Percentage Absolute count IgG IgM IgA
a. Control (N = 20) 19.84 662.71 147.26 220.02 107.37
± 4.71 ±346.71 ±53.18 ±108.10 ±44.49
b. Reactive (N = 24) 14.48 634.94 274.93 288.14 128.14
± 4.05 ±293.97 ±330.25 ±296.90 ±55.74
c. TBL (N=18) 13.94 465.08 191.83 255.67 156.50
± 2.71 ±179.41 ±37.88 ± 67.82 ±32.42
P value*
a×b < 0.001 NS 0.001 NS NS
a×c < 0.001 <0.05 <0.05 NS <001
b×c NS <0.05 <0.001 NS NS
*Wilcoxon’s nonparametric test
difference in the value of T cells in the children with Table 8.14: Total and differential serum proteins (mean ±
tuberculosis in comparison to the controls (Table 8.7). SD) in chronic cervical lymphadenitis
Leukocyte migration inhibition test was positive in 63.3%
Serum proteins (g/dl)
of cases; LMIT positivity was significantly higher
(p < 0.001) in cases investigated before initiation of Group Total Albumin Globulin
therapy as compared to the group tested comparable in a. Control (N = 20) 7.40 4.07 3.11
all the groups. LMI index value was significantly low (i.e. ±1.31 ±0.78 ±0.84
more positivity) in the TBL group. b. Reactive (N = 20) 7.02 3.31 3.71
Humoral immunity estimated by B cell counts and ±3.31 ±0.38 ±0.46
levels of IgG, IgM and IgA indicated that absolute B cell c. TBL (N = 15) 7.29 3.49 3.82
±0.60 ±0.48 ±0.28
counts were significantly low in TBL group. Levels of IgG
were significantly higher in this group (Table 8.13). The P value*
level of albumin was decreased in TBL with a correspon- a×b NS <0.001 <0.01
ding increase in the level of globulins (Table 8.14). a×c NS <0.05 <0.01
b×c NS NS NS
Immunology of Tuberculous Meningitis *One way analysis of variance test followed by Norman-Keul’s
multiple range test were applied
CMIR as well as humoral immune response (HIR) was
investigated by Seth et al16 in this most serious form of
tuberculosis in children. Absolute T cell counts were Table 8.15: T and B cell profile (mean ± SD) in tubercular
significantly increased though T cell percentages were meningitis (TBM)
comparable with the control group, LMIT positivity was T-cell B-cell
very high (93%) (Tables 8.15 and 8.16). In humoral
Group Percentage Absolute Percentage Absolute
response, there was no quantitative but qualitatively all
count count
the three types of immunoglobulins IgG, IgM and IgA
were statistically significantly low (Table 8.17). TBM 59.80 3126 18.95 679
(N = 30) ±8.44 ±1632 ±5.13 ±312
Hence investigation of both CMIR and HIR (humoral
Control 54.44 1840 19.84 662
immune response) indicated that there was an increase
(N = 20) ±10.50 ±1039 ± 4.71 ±342
in the absolute T cell counts, maximum being in TBM
and minimum in PPC. Mantoux test, an in vivo measures P value NS <0.01 NS NS
96
Table 8.16: Leukocyte migration inhibition test (LMIT), Mantoux test positivity, and LMI index in
tubercular meningitis (TBM)
Positive No. (%) LMI index
Group Mantoux LMIT (mean ± SD)
TBM
Before therapy (N = 15) 8 (53.3) 14 (93.3) 0.62 ± 0.16
During therapy (N = 28) 15(53.5) 16 (57.1) 0.77± 0.23
Control (N = 20) — — 1.20 ± 0.41
P value NS < 0.05 < 0.001*
*Level of significance in comparison to ‘before therapy and during therapy’ groups
Table 8.17: Serum immunoglobulin (mean ± SD) and IMMUNE RECONSTITUTION DISEASE ASSOCIATED
complement profile in tubercular meningitis (TBM) WITH MYCOBACTERIAL INFECTIONS
Group of Immunoglobulin Complement Tuberculosis (TB) occurs commonly in HIV-infected
cases levels (IU) levels
children especially in the absence of antiretroviral therapy
IgA IgG IgM (mg/ml) (ART).19 Clinical deterioration of TB can occur despite
TBM 79.48 115.01 148.50 0.651 appropriate anti-TB chemotherapy on start of ART.
(N = 30) ±33.78 ±32.56 ± 51.88 ±0.27 Occurrence of this deterioration is called paradoxical
Control 109.63 149.75 208.35 0.537 immune reconstitution inflammatory syndrome (IRIS).
(N = 20) ±43.22 ±52.13 ±107.81 ±0.27 The paradoxical reactions are due to inflammatory
P value <0.01 <0.01 <0.05 NS phenomena. 20 Paradoxical IRIS due to TB is well
recognized in adults but there are few clinical descriptions
in children. The immune reconstitution inflammatory
of CMIR indicated that there was maximum positivity in syndrome (IRIS) has emerged as a new clinical entity in
PPC followed by PPD disease group and least in the TBM. HIV infected children with tuberculosis associated with
However, leukocyte migration inhibition test positivity use of antiretroviral therapy.21 Immunereconstitution
was maximum in TBM followed by PPD and PPC disease associated with a range of mycobacteria including
especially in the malnourished group. Quantitative BCG constitutes a challenge to delivery of antiretroviral
measures of B-cell indicated an increase in the absolute treatment worldwide. Data concerning the pathogenesis
counts, maximum was in PPC, followed by PPD, it was and management of all forms of mycobacterial immune
least in TBM. Serum IgG levels were significantly reconstitution disease are lacking.20,22 It was more
increased in PPC and PPD but decreased in TBM. IgM commonly seen with advanced HIV infection and
levels were decreased in all the three, but were malnutrition.23,24 The clinical manifestations include
comparatively higher in TBM. IgA levels were decreased worsening of clinical features (fever, distress) and
only in TBM. The rise in complement was also more in radiological features after starting ART.25 Enlargement
PPC and PPD in comparison to TBM. The results indicate and suppuration of regional lymphnodes in BCG
that there is gradient of both humoral and cellular vaccinated children may occur following ART. 26
immunity, the best immunocompetence being in PPC, Lymphnode enlargement, chylothorax and chylous ascites
followed by PPD and the least in TBM. Humoral have been reported as IRIS in a child with HIV and TB.27
immunity is of significance as it indicates an attempt of
using these antibodies to coat the antigen before REFERENCES
processing by macrophages. The high positivity of LMIT
in patients, specially the malnourished, indicates that 1. Skinsness OK. Comparative pathogenesis of myco-
bacterioses. Ann N Y Acad Sci 1968;154: 19.
there is an increased secretion of migratory inhibition
2. Lenzini L, Rottali P, Rottali L. The spectrum of human
factor, a lymphokine attempting to produce CMIR which
tuberculosis. Clin Exp Immunol l 1977; 27: 230.
is the main protective immune mechanism in 3. Seth V, Nath N, Singh U. Immunological spectrum in
tuberculosis. tuberculous children. Indian J Tuberc 1985;32:29-39.
Seth et al17,18 have reviewed the subject of tuberculosis 4. Seth V, Seth SD. Cell mediated immune response in
in its complete immunological perspective and can be childhood tuberculosis. Proceedings of the International
referred to for details. Meeting of the Commonwealth Foundation 1984.
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5. Seth V, Malaviya AN, Sahai V, et al. Cell mediated 17. Seth V, Singh U. Immunopathogenesis in tuberculosis.
immune response in childhood tuberculosis. Indian J Med Part I. Cellular mechanisms of resistance. Indian J Pediatr
Res 1981;73:68-73. 1987; 54: 311-19.
6. Seth V, Kukreja N, Sundaram KR, et al. Leucocyte 18. Seth V, Singh U. Immunopathogenesis in tuberculosis,
migration inhibition test as an in vitro measure of cell Part II. Humoral mechanisms of resistance. Indian J
mediated immune response after BCG in preschool Pediatr 1987;54:830-40.
children in relation to their nutritional status. Indian J 19. Walters E, Cotton MF, Rabie H, et al. Clinical presentation
Med Res 1981;74: 554-8. and outcome of tuberculosis in human immunodeficiency
7. Seth V, Kukreja N, Sundaram KR, et al. Delayed virus infected children on antiretroviral therapy. BMC
hypersensitivity after BCG in preschool children in relation Pediatrics 2008; 8: 1.
to their nutritional status. Indian J Med Res 1981; 74: 392-8. 20. Boulware DR, Callens S, Pahwa S. Pediatric HIV immune
8. Skvor J, Trinka L. Immunological profile studies in reconstitution inflammatory syndrome. Curr Opin HIV
patients with pulmonary tuberculosis. Correlation of AIDS 2008; 3: 461-7.
pretherapy cellular tests with characteristics of the 21. Zar HJ. Global paediatric pulmonology: Out of Africa.
disease. Scand J Respir1979; 60: 161-8. Paediatr Respir Rev 2006; 7 Suppl 1: S226-8.
9. Grange JM. Some aspects of immunology relevant to 22. Lawn SD, Lipman MC, Easterbrook PJ. Immune
pediatric tuberculosis. Pediatr Clin India 1983; 18:50-60. reconstitution disease associated with mycobacterial
10. Gatner EMS, Anderson R. An in vitro assessment of infections. Curr Opin HIV AIDS 2008;3: 425-31.
cellular and humoral immune function in pulmonary 23. Wang ME, Castillo ME, Montano SM, et al. Immune
tuberculosis. Correction of defective neutrophil mobility reconstitution inflammatory syndrome in human
by ascorbate, levamisole, metoprolol and propranolol. immunodeficiency virus-infected children in Peru.
Clin Exp Immunol 1980; 40: 327-40. Pediatr Infect Dis J 2009; 28: 900-3.
11. Kramer TR. Ability of protein malnourished guinea pigs 24. Smith K, Kuhn L, Coovadia A, et al. Immune
to produce MIF to low doses of antigen. Fed Proc 1976; reconstitution inflammatory syndrome among HIV-
35: 588-94. infected South African infants initiating antiretroviral
12. Seth V, Kukreja N, Seth SD, et al. In vivo and in vitro therapy. AIDS 2009; 23: 1097-107.
correlation of cell mediated immune response in
25. Narendran G, Swaminathan S, Sathish S, et al. Immune
preschool children after BCG in relation to their
reconstitution syndrome in a child with TB and HIV.
nutritional status. Indian J Med Res 1982; 75: 360.
Indian J Pediatr 2006; 73: 627-9.
13. Khumenku AG, Auerbach MM. Chemotherapy and
26. Puthanakit T, Oberdorfer P, Punjaisee S, et al. Immune
antituberculous immunity. Bull Int Union Tubercle 1983;
reconstitution syndrome due to Bacillus Calmette-
58: 1236-42.
14. Seth V, Singh U. Immune basis or symptomatic Guérin after initiation of antiretroviral therapy in
pulmonary primary complex. Indian Pediatr 1986; 23: 830. children with HIV infection. Clin Infect Dis 2005; 41:
15. Seth V, Rohatagi M, Bhuyan UN et al. Tuberculous 1049-52.
cervical lymphadenitis in children as a relatively immune 27. Rabie H, Lomp A, Goussard P, et al. Paradoxical
competent state. Indian J Med Res 1985; 81:364-71. tuberculosis associated immune reconstitution
16. Seth V, Kabra SK, Beotra A, et al. Tuberculous meningitis inflammatory syndrome presenting with chylous ascites
in children manifestation of an immune compromised and chylothorax in a HIV-1 Infected Child. J Trop Pediatr
state. Indian Pediatr 1993; 30: 1181-6. 2010 Jan 25. [Epub ahead of print].
SECTION 4
CLINICAL SPECTRUM
• Pulmonary Tuberculosis
• Tuberculous Lymphadenitis
• Abdominal Tuberculosis
• Neurotuberculosis
– Pathology and Pathogenesis
– Clinical Manifestations, Diagnosis and
Management
– Case Studies
• Osteoarticular Tuberculosis
• Genitourinary Tuberculosis
• Tuberculosis and the HIV Infection
– TB in HIV Infected Children
– Tuberculosis and the HIV Infection
• Tuberculosis and Childhood Malignancy
• Unusual Manifestation of Tuberculosis
• Cutaneous Tuberculosis
• Adolescent Tuberculosis: Prelude to Future Infertility
• Endocrine Manifestations of Tuberculosis
• Congenital Tuberculosis
9 Pulmonary Tuberculosis
INTRODUCTION to treatment (AFB >2+; OR: 4.7, 95% CI: 1.7-12.3), and
living in ethnic minorities (OR: 5.4, 95% CI: 2.2-13.6).2
Lungs are the portal of entry of Mycobacterium tuberculosis
A study from Paris reported a total of eight
in the body. Majority of infections due to Mycobacterium
independent risk factors that determine the risk of latent
tuberculosis remain unrecog-nized and recover
TB infection: age, with three subgroups: 6-14 years (3.6;
spontaneously without treatment. Lungs are the
1.6-8.0); 15-29 years (3.7; 1.8-7.7); > or > 30 years (4.1; 2.0-
commonest site for tuberculous disease. The disease in
8.5); cavitation on the index case’s chest radiograph (1.6;
lungs varies from a small parenchymal lesion to dissemi-
1.1-2.2); an index case sputum smear with 100 or more
nated disease. The clinical manifestations depend on the
acid-fast bacilli per field (1.8; 1.2-2.8); household contact
underlying pulmonary lesions. This chapter deals with
natural history of tuberculous infection, clinical at night (2.1; 1.3-3.2); first-degree family relationship with
manifestations of various lesions and diagnosis of the index case (2.1; 1.3-3.3); active smoking by the contact
pulmonary tuberculosis. (1.6; 1.1-2.4); free health care (2.0; 1.2-3.2); and birth in a
country with TB incidence rate higher than 25 of 100,000
TRANSMISSION (2.2; 1.5-3.2).3
Transmission of M. tuberculosis generally is from person- PATHOPHYSIOLOGY

to-person and occurs via inhalation of mucous droplets
that become airborne when an individual with Primary infection with M. tuberculosis in children usually
pulmonary or laryngeal TB coughs, sneezes, speaks, occurs following inhalation of viable microorganisms.
laughs, or sings. After drying, the droplet nuclei can The usual sites of primary tuberculous implantation in
remain suspended in the air for hours. Only small lungs are the lower segments of middle lobe (lingula) and
droplets (<10 microns in diameter) can reach alveoli. upper segments of the lower lobe. Initially, there is
Droplet nuclei also can be produced by aerosol treat- polymorphonuclear response; this is later replaced
ments, by sputum induction, and through manipulation by macrophage/mononuclear cell response. In a
of lesions. previously nonexposed child, the mycobacteria multiply
Numerous factors are associated with the risk of intracellularly after being phagocytosed by the
acquiring M. tuberculosis infection.1 The risk of acquiring macrophages. Cell mediated immune response develops
infection has been associated consistently with the in about 2 to 4 weeks time. In the absence of cell-mediated
extent of contact with the index case, the burden of immunity the tissue damage is minimal and the
organisms in the sputum, and the frequency of cough in symptoms and signs are absent. Once cell mediated
the index case. Patients with smear-positive pulmonary immunity develops, lesions undergo caseous necrosis in
TB are more likely to transmit infection. Markers of close their centers and bacillary multiplication decreases. The
contact such as urban living, overcrowding, and lower area of necrosis is surrounded by macrophages,
socioeconomic status all are correlated with the acquisi- lymphocytes, giant cells and collagenous fibers—forming
tion of infection. An increased risk of developing infec- a granuloma, called tubercle. Some tubercle bacilli
tion has been demonstrated in multiple institutional set- traverse into the regional lymph nodes via the lymphatic
tings, including nursing homes, correctional institutions, vessels and cause an inflammatory response there. The
and homeless shelters. The risk of acquiring infection primary focus, the draining lymphatics and the involved
increases with age from infancy to early adult-hood, likely regional lymph node are collectively called the primary
attributable to increasing contact with other persons. complex. About 80% of the primary infections are initiated
In a recent report from Laos increased latent by one focus.4,5 These are more commonly present in the
tuberculosis infection was found in children below 15 mid zone of the lungs as the ventilation is maximum here.
years of age living with sputum positive adults (OR: 3.3, Lesions in right lung are more common than in the left
95% CI: 1.4 -7.7), patients highly positive sputum prior because of greater volume and the fact that the right
102
Section 4 Clinical Spectrum
bronchus is more vertical, short and wide. Some authors, in children under 5 years. However, adult-type disease
however, suggest that all parts of the lungs are apparently with delayed clinical onset can occur even after
at equal risk of being seeded.6 Sluggish air current in the calcification.
peripheral parts of the lung allow the bacilli to stay there
Phase 5: It occurs more than 3 years after primary
longer; this explains the predominant occurrence of
infection. This represents the period in which late
primary focus in the subpleural region. Ghon noted that
manifestations of TB including pulmonary reactivation
at least 70% of primary pulmonary foci are subpleural.4 disease develops.
A hallmark of primary tuberculosis infection is the Marais et al 11 pointed out that this time table describes
relatively large size and importance of the adenitis, common clinical patterns of disease and does not
compared with the relatively insignificant size of the represent dogmatic rules regarding the course of
initial focus in the lung. tuberculosis in children. The vast majority of disease
The lymphatic drainage of lungs predomi-nantly manifestations occur in the first 6 to 12 months following
occurs from left to right.7 This explains the frequent primary infection.
involvement of right paratracheal nodes, the There are varying immune mechanisms underlying
parenchymal lesion is left sided even when cervical nodes the different intrathoracic manifestations of tuberculosis
may be affected as they have communications with in childhood. The maturation of host immunity is an
paratracheal lymph node chains and also they drain the important variable that influences the ultimate TB disease
apical pleura.
manifestations in childhood. Dynamic host-pathogen
balance is affected by variation in both the pheno- and
RISK OF INFECTION TO DISEASE IN INFANTS AND genotypic pathogenicity of the organism. Pabst way back
YOUNG CHILDREN in 198012 emphasized the ontogeny of the host immune
Risk of developing tuberculosis disease is more in young response towards infection with M. tuberculosis. Seth13
children, specifically infants. This is contributed by described immune basis of clinicoradiological
multiple factors including: decreased monocyte presentation of pulmonary tuberculosis and tuberculosis
recruitment at site of infection, reduced microbial killing, in its entire spectrum. Childhood covers the age range
less effective major antigen presenting cells (APC) and from birth to 15 years of age. In this age period due to
poor response of naïve T cells.8-10 profound changes occurring in the immune system
development the natural response to infection is variable.
NATURAL HISTORY OF TUBERCULAR INFECTIONS It is a period of dynamic growth and maturation. Marais
et al14 described the diverse and changing spectrum of
Time Table of Clinical Disease After Pulmonary Infection pathology seen in childhood tuberculosis, and also
in Childhood described the diversity of disease in childhood pulmonary
tuberculosis. They have proposed radiological
Time table of clinical disease after pulmonary infection classification of childhood intrathoracic tuberculosis
in childhood has been described by Marais et al11 as which highlights the changing spectrum of pathology
follows: seen in childhood tuberculosis.15 On this depends, the
Phase 1: It occurs 3 to 8 weeks after primary infection. treatment and prognosis. Hence, the knowledge of age
The initial incubation period is usually asymptomatic but dependent differences in the immune response to
at times may have initial fever, erythema nodosum, a M. tuberculosis infection is crucial for not only directing
positive tuberculin skin test response due to future research but helps in improved case management.
hypersensitivity reaction. On chest radiograph there is
formation of primary complex.
PRINCIPLES OF DISEASE
Phase 2: It occurs 1 to 3 months after primary infection.
This period follows the occult hematogenous spread Dynamic Balance
occurring during incubation period. It represents the
period of highest risk for development of tuberculous Balance between the pathogenicity of the organism and
meningitis and miliary tuberculosis in young children. host’s immune competence determines the clinical
manifestations of an infectious disease. Persistence of
Phase 3: It occurs 3 to 7 months after primary infection. dormant bacilli inside sequestered foci (latent infection)
This is the period of pleural effusions in children over 5 provides an ever present risk of reactivation whenever
years and bronchial disease in those below 5 years. there is a shift of the balance in favor of the organism. In
Phase 4: It lasts 1 to 3 years after primary infection and addition to the risk of reactivation of a primary focus,
continues until the primary complex is calcified. This is high level of transmission implies a high-risk of
the period of development of osteoarticular tuberculosis reinfection in high burden settings.
103
Chapter 9 Pulmonary Tuberculosis
Pathogen dissemination occurs frequently during 1st 4 to 6 weeks

after primary infection. For prevention of uncontrolled
The number of organisms inhaled (size of the infecting disease progression and containment of organism,
inoculum), the virulence of the organisms and their ability acquired cellular immune response is of crucial
to resist eradication (persistence) are various variables importance. There is striking age-related risk of
related to pathogen which determine the spectrum of developing tuberculosis following primary infection and
disease presentation. Variation in the dose of infecting the age related difference in the disease manifestations.
organism Mycobacterium tuberculosis seems negligible. Immature immune response in very young children (2 to
Only the tiniest aerosol droplets containing <5 bacilli are 3 years of age) are at high risk of developing progressive
likely to reach the terminal airways and establish a
disease while children (3 to 10 years) are the least likely
pulmonary focus of infection. Larger droplets of
to progress to disease after primary infection. In India
organisms do not remain suspended in the air and are
even 3 to 5 years age is considered vulnerable but less as
deposited in the proximal airways where the infection is
compared to less than three years. After this golden
effectively resisted.
period there is a sudden increase in the risk of progressing
The intensity of exposure influences the risk of both
to disease following primary infection during
infection and disease.16,17 Duration of exposure and
adolescence. This is what leads to so called Adult type of
number of infectious particles in the ambient air influence
disease, i.e. development of adult type pulmonary
the risk of infection. In humans, multiple infections or
increased virulence of the infecting organisms rather than cavitation.20 In early childhood, disease is mostly limited
the variation in the infecting dose are responsible for to regional lymphadenopathy. The time since infection
increased tendency of infection progressing to disease. is another important variable that influences particular
High intensity exposure is to a sputum smear-positive disease manifestations by the time table of tuberculosis
case in the household. Primary infection is usually in children.
visualized as a single parenchymal (Ghon) focus. The course of the infection depends on the immune
Exposure to multiple infecting doses increases the response of the host. If the host resistance is good, the
likelihood of establishing infection and/or disease. The inflammatory exudate around the primary focus is
phenotypic virulence might differ according to the absorbed and the caseous area inspissated. Healing
sputum smear-status of the source case. Exposure to occurs by fibrosis and calcification. When the cell
ultraviolet irradiation or drying determine the influence mediated immune response is weak, the bacilli continue
of these environmental factors depending upon the to multiply and the inflammatory process extends to the
proximity of the source case. contiguous areas. Progressive primary disease (PPD) is
Genetic variation in the organism does not explain a serious complication of the primary pulmonary complex
the consistent epidemiological finding that household (PPC) in which the PPC, instead of resolving/calcifying,
contacts of sputum smear-positive source case are enlarges steadily and develops large caseous center. The
more likely to progress to disease following infection. center then liquifies; this may empty into an adjacent
Several mechanisms that enable M. tuberculosis to persist bronchus leading to formation of a cavity. This is
both intracellularly (inside macrophages) and associated with large numbers of tubercle bacilli.11 From
extracellularly (inside the caseous centers of granulomas)
this stage, the bacilli may spread to other parts of the
have been demonstated.18,19 Unless there are favorable
lobe or the entire lung. This may lead to consolidation of
circumstances, the reactivation of dormant bacilli does
area of lung or bronchopneumonia. Cavitary disease is
not occur. One of the important factor is compromization
of immune response which is responsible for activation uncommon in children before adolescence. It may be
of the disease. difficult to differentiate PPD from a simple tuberculous
focus with superimposed acute bacterial pneumonia.
Appearance of a segmental lesion is fan shaped on a
Host Immunity
roentgeno-gram, representing mainly atelectasis and
Local pulmonary defenses along with innate and acquired almost always involves that very segment occupied by
immune responses comprise host immunity. Decreased the primary pulmonary focus21,22 (Figs 9.1 and 9.2).
mucosal immunity, compromised clearance of the micro- Some of the events may occur because of involvement
organisms, and a favorable microenvironment at the of lymph nodes.4,23,24 The enlarged lymph nodes may
point of deposition of organism, all contribute to an compress the neighboring airway.25-27 Ball-valve effect
increased risk of infection and disease. due to incomplete obstruction may lead to trapping of
The protection provided by the innate immune air distal to obstruction (emphysema).28 Enlarged paratra-
response seems limited because bacilli grow unrestrained cheal nodes may cause stridor and respiratory distress.
in the naïve macrophages and occult hematological Subcarinal nodes may impinge on the esophagus and may
104
Complicated Ghon’s Focus and/or Disseminated Disease

(RIsk group: Children <2 to 3 years of age/all immune
compromised children)
Immune compromised children with suboptimal cellular
immune responses which results in poor disease
containment. They are usually very young (<2 to 3 years
of age). Eventual cavitation of the Ghon’s focus due to
unrestrained multiplication of bacilli at the point of
Fig. 9.1: Natural history of tubercular infections
Figs 9.2A to D: Pulmonary tuberculosis
cause dysphagia. If the obstruction of bronchus is deposition of organisms will cause progressive
complete, atelectasis occurs. parenchymal damage. Tuberculous meningitis can result
due to poor containment of bacilli with in the regional
Description of Specific Disease Entities lymph nodes. Disseminated disease rarely occurs in older
immune competent children.
Uncomplicated Ghon’s Focus and/or Lymph Node • Complicated lymph node disease
Disease (Risk group: Children <5 years of age) (Risk group children < 5 years of age)
A spectrum of air way complications are referred as
A localized pneumonic process develops at the site of lymphoproliferative tuberculosis due to lymph node
organism deposition with primary pulmonary infection. disease. This is due to the exuberant lymph node
Bacilli drain via local lymphatics to the regional lymph enlargement following primary infection along with
nodes from this Ghon’s focus. Together these constitute the anatomical characteristics of small size of their
the primary complex. It is often subclinical and is only airway which leads to lymphoproliferative disease in
detected if there is active surveillance after recent children < 5 years of age. Marais14 has emphasized
infection. It is considered a proof of recent primary that extraluminal com-pression results when an
infection but not necessarily disease when there are no airway is compressed by large lymph nodes and
clinical symptoms of disease or presence of radiological the associated inflammatory edema. Polyps,
complications. granulomatous tissue or caseous material within the
105
airway, partial airway obstruction can cause childhood, major changes relating to the effective
intraluminal obstruction. Ball-valve effect with distal containment of primary M. tuberculosis infection seems
hyperinflammation and total obstruction can lead to to occur around 2 years and around puberty (>10
distal atelectasis. years of age) when hormonal changes might be an
Intrabronchial spread can occur due to aspiration important factor in the altered pathogenesis. Immune
of caseous material from a diseased lymph node that response during adolescence is essential for disease
has herniated into the bronchial airway. Destructive containment and excessive tissue necrosis aids in the
caseous pneumonia can be a severe complication development of parenhymal cavities. This distinctive
depending on the dose and virulence of the aspirated immune response allows the organisms to take full
bacilli, the degree of airway obstruction and immune advantage of a favorable microenvironment. Oxygen
competence of the host. tension is highest in the lung apices owing to high
• Pleural effusion ventilation/perfusion (V/Q) ratios29 which allows
(Risk group: Children > 5 years of age) vigorous growth and multiplication of M. tuberculosis
A peripheral Ghon’s focus may have a limited pleural in these areas. A more favorable microenvironment
reaction which is considered as a part of primary results due to progressive parenchymal damage
complex but large effusions are less common. It occurs which raises the V/Q ratio and oxygen tension. Poor
mainly in children > 5 years of age and indicates recent blood flow and decreased lymph node formation also
primary infection. It occurs when a few organisms is responsible for the vulnerability of lung apices.29
from a subpleural focus spread to pleural cavity, These changes explain the occurrence of adult type
bilateral pleural effusions indicate either bilateral of TB at adolescence and its anatomical location.
pulmonary foci or hematogenous dissemination.
Pathology based disease classification of pulmonary
Accumulation of straw-colored fluid containing very
tuberculosis in children described by Marais11 et al is as
few bacilli is due to the hypersensitivity response.
follows:
Caseous tuberculous empyema can result rarely if the
bacilli are very virulent and immune competence of
the host is limited. Pulmonary Infection
• Adult type disease Tuberculosis infection uncomplicated by clinical
(Risk group: Children > 10 years of age) symptoms (there is only self-limiting viral like illness) or
Cavitation occurring in the lung apices is the disease radiological abnormalities (other than primary complex).
characteristic in this category and appears around Primary complex includes the Ghon’s focus with
puberty. Posterior segments of the upper lobes and associated tuberculous lymphangitis and affected
the superior segments of the lower lobes are also regional lymph nodes. When there is successful
frequently involved. The natural history of the disease containment of the organism, there is no progression of
indicates that this type might rapidly follow (within pulmonary infection to disease.
6 to 12 months) the primary infection. There is
associated positivity of tuberculin skin test (TST). This Pulmonary Disease
is due to poor containment of a recent primary
infection rather than reactivation of an old, well It is associated with marked clinical symptoms and
contained infection. Preferential organism deposition radiological abnormalities apart form primary complex.
and their growth explains the typical anatomical There are separate disease entities:
distribution. Ghon’s focus with or without cavitation: There is poor
• Preferential deposition: Air flow is directed towards containment of organism leading to progressive
the dependent lung zones on inhalation which favours parenchymal caseation surrounding Ghon focus. Cavity
deposition of the organisms in the lung bases. formation can result due to discharge of caseous material
Coughing can cause airdropping and the organisms into the bronchus with endobronchial spread.
get deposited in the apices or simon focus can occur
due to preferential hematogenous spread. However, Lymph node disease: The presence of marked clinical
radiologically in Ghon’s focus, dependent zones of symptoms due to enlargement of regional lymph nodes
the right lung (middle and lower lobes) are most differentiate lymph node disease from primary infection.
frequently involved. Bronchial disease: Affected regional lymph nodes attach
• Preferential growth: The occurrence of adult type of to the bronchus associated with primary infection. It can
disease around puberty is due to the changes that be accompanied with (i) airway obstruction (ii) collapse/
occur in the immune response around puberty rather hyperinflation. There can be allergic consolidation,
due to the preferential growth of M. tuberculosis. bronchopneumonic consolidation, or caseating
Although immune maturation occurs throughout consolidation.
106
Pleural disease: It can be due to pleural involvement after Hematogenous dissemination of M. tuberculosis occurs
direct spread of caseous material from a subpleural early in the course of the disease; this results when the
parenchymal or lymph node focus or from hematogenous bacilli find their way into bloodstream through lymph
spread. The degree of pathology depends upon the dose nodes. This may result in foci of infection in various
and virulence of bacilli entering the pleural space together organs. If the host immune system is good, then these
with the immune status of the host. It can be associated foci are contained and disease does not occur. Seeding of
with effusion, empyema or adult-type disease. apex of lungs leads to development of Simon’s focus.
Lowering of host immunity may lead to activation of
Hematogenous Spread these metastatic foci and development of disease. This is
especially seen in young infants, severely malnourished
This is a condition of infinite gradation depending upon children, and children with immunodeficiency (including
the frequency, dose and virulence of the bacilli as well as HIV infection). Massive seeding of bloodstream with M.
host immunity. During the occult spread bacilli are tuberculosis leads to miliary tuberculosis, where all lesions
seeded into susceptible organisms and the child remains are of similar size. This usually occurs within 3 to 6
asymptomatic. When it is associated with invasion of the months after initial infection.
bloodstream, tuberculous bacilli lodge in small capillaries, Pulmonary tuberculosis resulting from endogenous
where they may progress to form tubercles. These are reactivation of foci of infection is uncommon in children;
visible as typical, even sized miliary lesions on chest but may be seen in adolescents. The commonest site for
radiograph usually less than 2 mm. this type of disease is the apex of the lung (Puhl’s lesion),
because the blood flow is sluggish at apex. Regional
Outcome of Bronchial Obstruction lymph nodes are usually not involved in this type of
i. Complete expansion and resolution of chest X-ray tuberculosis. A summary of the pathological progression
findings. of disease without chemotherapy is given in Figure 9.3.
ii. Disappearance of the segmental lesions. In summary pulmonary tuberculosis in childhood is
iii. Scarring and progressive compression of the lobe often considered a benign condition with little risk to the
or segment leading to bronchiectasis. child and no contribution to the transmission of disease
A caseated lymph node may erode through the wall with in the community. Marais 11 emphasizes that
of the bronchus, leading to tuberculous bronchitis/ although this is true for the majority of infected children,
endobronchial tuberculosis. Fibrosis and bronchiectatic specific high-risk groups exist where disease poses a high-
changes may supervene. Discharge of M. tuberculosis into risk to fatality for the individual and or a high-risk of
the lumen may lead to bronchial dissemination of transmission to the community. It has been further
infection. described by him that major determinant of risk for
Fig. 9.3: Progression of pathology in intrathoracic TB following primary pulmonary infection in childhood—Marais et al15
107
disease development after primary infection is the host decreased air entry, and crepitations. Cavitating
immunity. Infants with immature immune systems are pulmonary tuberculosis though uncommon is well
at highest risk for development of pulmonary disease (30 documented in children.32,33 Cavities are better seen on
to 40%). Tuberculous meningitis or miliary disease can computerized tomographic scan than X-ray film of
occur in 10 to 20%. The risk decreased in the second year chest.34
reaching its lowest in the 5 to 10 years age group. It was Marais et al20 reported eight children (10 to 14 years
highlighted by Marais20 that primary infection during of age) who developed adult-type cavitating disease
adolescence was associated with a high risk of developing which could be diagnosed by sputum smear microscopy
adult-type disease. in contrast to younger children for whom smear
microscopy has very little diagnostic value. This
CLINICAL FEATURES emphasizes the importance of correct disease
classification in childhood tuberculosis both for prognosis
Childhood TB can be divided into two broad
and estimation of the transmission risk. It is well known
classifications: intra and extrathoracic TB. Most children
that adolescent girls are at higher risk to develop
with TB will develop pulmonary TB. Nonetheless, the
tuberculosis after primary infection than boys.
recognition of extrathoracic TB is equally important
Children with endobronchial tuberculosis may
because of its great potential for causing morbidity. There
present with fever, troublesome cough (with or without
is a trend that extrathoracic tuberculosis is increasing in
expectoration). Dyspnea, wheezing and cyanosis may be
children and constitutes up to half of total cases.30
present. Occasionally, the child may be misdiagnosed as
asthma. In a wheezing child less than 2 years of age,
Intrathoracic Tuberculosis possibility of endobronchial tuberculosis should always
Diagnosis of tuberculosis in a child is often difficult be considered, especially if there is poor response to anti-
because of absence of typical symptoms; signs and asthma medications. Partial compression of the airway
microbiologic evidence in the majority of children with can lead to emphy-sema. Features of collapse may be
pulmonary tuberculosis. The onset of symptoms is present if a large airway is completely compressed.
generally insidious, but may be relatively acute in miliary Miliary tuberculosis is an illness characterized by
tuberculosis. heavy hematogenous spread and progressive
Primary infection usually passes off unrecognized. development of innumerable small foci throughout the
Asymptomatic infection is defined as infection associated body. The disease is most common in infants and young
with tuberculin hypersensitivity and a positive tuberculin children. The onset of illness is often sudden. The clinical
test but with no striking clinical or radiologic manifestations depend on the numbers of disseminated
manifestations. Most symptoms in children with primary organisms and the involved organs. The child may have
complex are constitutional in the form of mild fever, high grade fever, which is quite unlike other forms of
anorexia, weight loss, decreased activity.31 Cough is an tuberculosis. The child may also have dyspnea and
inconsistent symptom and may be absent even in cyanosis. There are hardly any pulmonary findings but
advanced disease. Irritating dry cough can be a symptom fine crepitations and rhonchi may be present. These
of bronchial and tracheal compression due to enlarged findings may occasionally be confused with other acute
lymph nodes. In some children, the lymph nodes continue respiratory infections of childhood. The illness may be
to enlarge even after resolutions of parechymal infiltrate. severe, with the child having high fever, rigors and
This may lead to compression of neighboring regional alteration of sensorium. In addition, these children may
bronchus. Pulmonary primary complex is the most have lymphadenopathy and hepatosplenomegaly. The
commonly encountered presentation in the outpatient other presentation of miliary tuberculosis may be
setting. In a community setting, often primary infection insidious with the child appearing unwell, febrile and
occurs without sufficient constitutional symptoms to losing weight. Choroid tubercles may be seen in about
warrant medical advice. The PPC may be picked up 13 to 87% children. 35 Meningitis may occur due to
accidentally during evaluation of intercurrent bacillemia involving meninges and brain.36
infections.31 The pleura may also be infected by hematogenous
Progressive primary disease (PPD) is the result of spread from the primary focus. The effusion usually
progression of primary disease. Children with PPD may occurs because of hypersensitivity to tuberculoproteins.
present with moderate to high grade fever and cough. If the sensitivity is high, there is significant pleural
Expectoration of sputum and hemoptysis are usually effusion along with fever and chest pain on affected side.
associated with advanced disease and development of Minor effusions associated with the rupture of primary
cavity or ulceration of the bronchus. Physical findings of foci are usually not detected. Tuberculous effusion is
consolidation or cavitation depend on the extent of the uncommon in children younger than 5 years of age, is
disease. Abnormal chest signs consist mainly of dullness, more common in boys, and is rarely associated with
108
segmental lesion and miliary tuberculosis. The onset may CLINICAL FEATURES/SCORING SYSTEMS
be insidious or acute with rise in temperature, cough,
dyspnea and pleuritic pain on the affected side. There is It is important to make early diagnosis of tuberculosis in
usually no expectoration. Pain in chest may disappear children. Early intervention with antituberculosis drugs
once the fluid separates the inflamed pleural surfaces; in children may prevent dissemination of illness. Early
this may be replaced by some discomfort. Increase in diagnosis of tuberculosis in children based on clinical
effusion may make breathing shallow and difficult. The features is difficult. The common clinical features such
clinical findings depend on the amount of fluid in the as-fever, cough, loss of appetite, weight loss or poor
pleural sac. In early stages, a pleural rub may be present. weight gain may be present in other common childhood
Early signs include decreased chest wall movement, illnesses.
impairment of percussion note and diminished air entry To overcome the problem of diagnosis in children;
on the affected side. As the fluid collection increases, the combination of clinical features, history of exposure to
signs of pleural effusion become more definite. 37 an adult patient with tuberculosis, result of tuberculin
In some instances, acute secondary bacterial infection test and radiological finding have been evaluated by
occurs, presenting with high fever, cough and various workers. In these scoring system38,39 more
crepitations. The symptoms and signs respond to weightage is given to laboratory test, i.e. acid-fast bacilli,
antibiotics, but the chest X-ray findings persist due to tubercles in biopsy, suggestive radiology and tuberculin
underlying tuberculosis. Calcification of the primary test >10 mm induration. Various scoring systems have
complex results from caseation. This occurs more been developed after giving different weightage to these
commonly in children. variables (Table 9.1). Migliori et al40 proposed certain
criteria for diagnosis of pulmonary tuberculosis in
Extrathoracic Tuberculosis children for countries where culture for AFB are not
available (Table 9.2). These scoring systems need
A complete description of extrathoracic TB is beyond the validation in individual countries. To reduce the problem
scope of this chapter, but clinicians must consider this of under/over diagnosis Osborne has provided
possibility when evaluating children with a history of guidelines for suspecting TB in children (Table 9.3).41
persistent fever. The most common forms of extrathoracic
disease in children include TB of the superficial lymph
Laboratory Tests
nodes (scrofula) and the central nervous system. Other
rare forms of extrathoracic disease in children include The diagnostic tests for pulmonary tuberculosis can be
osteoarticular, abdominal, gastrointestinal, genitourinary, broadly divided into 2 categories:
cutaneous, and pericardial disease. a. Demonstration/isolation of Mycobacterium tuberculosis
or one of its components.
DIAGNOSIS b. Demonstration of host’s response to exposure to
Diagnosis of tuberculosis in children is usually based on M. tuberculosis, are described here with:
clinical signs and symptoms, chest roentgenogram,
tuberculin testing and history of contact with adult
patients. Clinical features may be nonspecific and chest Table 9.1: Scoring systems for diagnosis of tuberculosis
radiograph and Mantoux test are difficult to interpret. In
Parameters Stengen Nair Seth*
addition these do not give conclusive evidence of the et al38 et al39
disease. Though demonstration of mycobacte-rium in
Acid-fast bacilli +3 +5 +5
various clinical specimens remains gold standard, this is
often not possible in children due to the paucibacillary Tubercle in biopsy +3 +5 +5
nature of the illness. Tuberculin test >10 mm +3 +3 +3
Over last few decades many advances in Suggestive radiology +2 +3 +3
microbiologic methods, molecular techniques and Compatible physical
immunological investigation have taken place. Benefits examination +1 +3 +2
of these advances are not available to people in Contact with tuberculosis
developing countries due to cost, technical problems and in the family +2 +2 +3
limited resources. Even with availability of these tests in Scores 1-2 – TB unlikely; 3-4 tuberculosis possible; 5-6
developed countries they are not very useful in children tuberculosis probably; > 7 tuberculosis unequivocal,
suffering from tuberculosis due to paucibacillary nature * Unpublished data
of illness.
109
Table 9.2: Diagnostic criteria for pulmonary tuberculosis40 Gastric Lavage

Gastric washes positive for AFB The best specimen for demonstration of M. tuberculosis
or in children is the early morning gastric aspirate (GA)
Two or more of the following criteria: obtained by using a nasogastric tube before the child
• History of contact with a tuberculosis adult
wakes up and peristalsis empties the stomach of the
• Suggestive symptoms of PTB (cough for more than 2 weeks)
• 2 TU PPD reaction positive
respiratory secretions swallowed overnight.44 The yield
>10 mm in unvaccinated BCG patients of M. tuberculosis on ZN stain is less than 20% and
>15 mm in vaccinated BCG patients depends on extent of pulmonary disease and number of
• Radiological findings compatible with PTB specimen tested. 45 For better results 3 consecutive
• Response to treatment (body weight increase > 10% after specimen of gastric aspiration are recommended.46 If a
2 months of treatment, plus clinical improvement). delay in the processing of specimen is expected the GA
should be neutralized with sodium bicarbonate for higher
Table 9.3: Guidelines for the diagnosis of tuberculosis yield.47
Suspected tuberculosis
Any child with history of contact with confirmed case of Bronchoscopy and Bronchoalveolar Lavage
pulmonary TB
It has been documented that gastric aspirate (GA) is
• Is not gaining normal health after measles, pertussis
• Has loss of weight, cough and wheeze not responding to superior to bronchoalveolar lavage (BAL) fluid for the
antibiotic therapy for respiratory disease yield of AFB in childhood tuberculosis.44,48 A recent study
• Has painless swelling in superficial group of lymph nodes. on 58 children comparing GA and BAL showed that in
Probable tuberculosis 10 (17.2%) children M. tuberculosis was grown from gastric
A suspected case and any of the following: lavage whereas 12 children had their BAL positive for
• Positive mantoux test (induration > 10 mm) this bacteria. Overall, mycobacterial isolation was
• Suggestive radiological finding possible in 20 patients (34.4%) as two children had grown
• Suggestive histological appearance of biopsy M. tuberculosis in GA as well as BAL.49 Addition of BAL
• Favorable response to antituberculosis therapy to the diagnostic workup increased the mycobacteriolo-
Confirmed tuberculosis gical yield from 17.2% with gastric lavage alone to 34.4%
• Detection of tubercle bacilli by microscopy or culture when BAL was also performed. Results of this study
• Identification of tubercle bacilli as mycobacterium by suggest that there is no difference in mycobacterial
culture characteristics. isolation rates from gastric lavage and BAL when studied
in isolation. However, when both GA and BAL are used,
Demonstration of M. tuberculosis or its Components these procedures complement each other to increase the
diagnostic yield. Gastric lavage for isolation of M.
Specimens for demonstration of M. tuberculosis: The tuberculosis is a well-accepted method. It is suggested that
specimens used for demonstration of M. tuberculosis in one should try to obtain gastric aspirate for diagnosis of
pulmonary tuberculosis include: sputum, gastric lavage, tuberculosis in children as far as possible. Bronchoscopy
bronchoscopic lavage fluid, or pleural fluid. may be considered when diagnosis is doubtful or a
Sputum: Sputum is conventionally used for diagnosis of possibility of resistant tuberculosis is considered.
tuberculosis in adult patients. However, it is difficult to
collect sputum in young children. Therefore, gastric Methods for Identification of M. tuberculosis
aspirate is used for demonstration of M. tuberculosis in
A. Smear
children with suspected pulmonary tuberculosis. Recent
i. Ziehl-Neelsen (ZN) staining: ZN stain is positive if the
reports suggest good results of isolation of M. tuberculosis
number of M. tuberculosis is more than 104 /ml of
from induced sputum in young children.42,43
specimen. 50 It can be used on all the specimen
For sputum induction child is pretreated with 200 µg
including sputum, induced sputum, gastric aspirate
salbutamol given via metered dose inhaler with attached
and bronchoalveolar lavage. The yield of M.
spacer or nebulizer to prevent the occurrence of
tuberculosis on ZN stain is less than 20% and depends
bronchoconstriction. A jet nebuliser attached to oxygen
on extent of pulmonary disease and number of
at a flow rate of 5 liter/min or compressor can be used to
specimens tested.45
deliver 5 ml of 3% sterile saline for 15 minutes. Sputum
ii. Special staining for AFB: Fluorochrome stained smears
is obtained either by expectoration (in children able to
can be viewed more efficiently as they are viewed
cooperate) or by suctioning through the nasopharynx or
under high dry magnification rather than oil
oropharynx using a sterile, mucus extractor of catheter
immersion. The organisms are easier to detect
size 6. Specimens should be transported directly to the
against dark background and significantly larger
laboratory for processing.
110
area of the smear can be screened per unit of time.45 Septi-check AFB system requires about 3 weeks
These smears have a greater sensitivity than those incubation. Various studies carried out in adults have
of ZN stain51 Staining at 37° C enhances detection of suggested that Septi-check system is more sensitive than
mycobacterium by fluorochrome staining.52 More LJ Media/7H11 and BACTEC in percentage age of
recently immunomagnetic separation have been isolates recovered.58 Though, pediatric studies are not
used to improve the detection of mycobacterium.53 available, this system may be useful in children as well.
In a recent study, the sensitivity of ZN stain on Mycobacterial Growth Indicator Tube System (MGIT): It
GA in pulmonary primary complex (PPC) and uses a fluorescent compound embedded in silicone on
progressive primary disease (PPD) was 1.1% and the bottom of the tube containing modified 7H11 broth
31.8% respectively; it improved to 9.4 percent with antibiotic mixture and growth supplements for
and 50% respectively with auramine-O staining.54 mycobacteria. As this fluorescent compound is sensitive
Though auramine-O staining increases the yield of to oxygen, depletion of the latter by growth of
identification of M. tuberculosis, need for fluorescence mycobacteria, unmasks the fluorescence, which can be
microscopy limits its role in the diagnostic work up. detected by observing the tube under long wave
B. Culture: A variety of media are in use for cultivation ultraviolet light. Available literature suggests that this
of M. tuberculosis. These include Lowenstein Jensen (LJ), method is as sensitive as the BACTEC system.59 Nutrient
Middlebrook 7H10 and 7H11 media. broth growth supplementation of standard MGITs
LJ medium is most widely used. In this characteristic improved the mycobacterial yield and significantly
features of colony morphology, growth rate and pigment reduced the time to detection of mycobacteria in pediatric
production can be seen. Using culture technique it is samples. 60
possible to isolate mycobacteria from specimen
containing more than 10 mycobacteria/ml. Though the C. Polymerase chain reaction (PCR): Polymerase chain
culture technique is simple, 7 to 10 weeks of incubation reaction is the most commonly used technique of nucleic
may be necessary for detection of organisms. Microscopic acid amplification, used for diagnosis of tuberculosis. The
examination of thin layer culture plate may lead to PCR may be used to:
detection of microcolonies of M. tuberculosis as early as i. Diagnose tuberculosis rapidly by identifying DNA
7 days.55 However, recovery of M. tuberculosis from this from M. tuberculosis in clinical samples that are
is less efficient and labor intensive. The yield of culture negative by microscopic examination.
varies from 30 to 50%. Higher yield up to 70% have been ii. Determine rapidly whether acid-fast organisms
reported in infants with extensive disease.46 identified by microscopic examination in clinical
Excessively long period required for isolation of specimens are M. tuberculosis or atypical
M. tuberculosis by LJ medium has led to development of mycobacteria.
other techniques for culture: BACTEC Radiometric Assay, iii. Identify the presence of genetic modifications known
Septi-check AFB system and Mycobacterial growth indicator to be associated with resistance of some
tube system (MGIT). antimycobacterial agents.
The BACTEC system improves the yield of positive The results of the studies on utility of PCR in diagnosis
cultures from clinical specimen and lessens the time taken of childhood tuberculosis has been summarized in
to detect M. tuberculosis.56 The average time required for Table 9.4. In children, the results of PCR have been
detection of M. tuberculosis by BACTEC is 9 to 14 days. compared with clinical diagnosis and not culture. The
Venkatraman et al56 reported 87% of the positive cultures most commonly used target for detection of M.
by day 7 and 96% by day 14. The capability of performing tuberculosis is the insertion sequence IS6110. The
rapid mycobacterial drug sensitivity is an additional sensitivity ranges from 4 to 80% and the specificity 80 to
advantage of the BACTEC system.57 100%.54,61-65 These results are not very promising.
The limitation of BACTEC system include high cost A blinded study comparing results obtained on
of instruments, inability to observe colony morphology specially prepared standardized samples by 7 different
and detect mixed cultures, overgrown by contaminants, laboratories, demonstrated significant differences in the
need for disposal of radioactive and extensive use of results obtained.66 This demonstrates the variability in
needles. the pickup rates in different laboratories. In addition, the
The available studies have used sputum in BACTEC clinical laboratories may not obtain results similar to those
system. The experience with other body fluids including in research laboratories.
gastric lavage is limited. In a recent study using gastric It appears that PCR has a limited role in evaluating
aspirate in BACTEC, there was not even a single case children for tuberculosis. A negative PCR never
positive of Pulmonary Primary Complex (PPC).54 eliminates possibility of tuberculosis, and a positive result
111
Table 9.4: Utility of PCR in diagnosis of tuberculosis in children (in gastric aspirate)
Authors Subjects Test/ Fragment Standard Sensitivity Specificity
Delacourt 53 suspected TB, PCR/ IS6110 Clinical Active disease 83.3, 100
et al,61 (24 active disease diagnosis Infection without
1995 11 Exposure and disease 38.9
Mantoux +ve,
11 Suspected TB;
7 Exposure –ve
Mantoux +ve)
15 Controls
Smith et al62 35 Pulmonary TB PCR/ IS6110 Clinical 40 100
1996 diagnosis
Ninan SA54 40 (31- PPC, PCR/ IS6110 Clinicoradio- PPC 38.6 80
1997 9-PPD) logic diagnosis PPD 44
Neu et al63 27 Suspected TB PCR Clinicoradio- 4.1 (There was
1999 (Amplicor) logic diagnosis discordance
between culture
and PCR results)
Jatana et al64 80 children, IS6110 as target Clinical 100 with CSF, 93
2000 41 probable TB, for DNA criteria 20 with gastric
39 controls aspirate, 100
pleural fluid
samples
Montenegro 392 specimen Heminested Clinical 90 in culture 94
et al65 2003 from 222 children IS6110 PCR diagnosis and positive cases
culture 100 for smear
positive,
77 for smear
negative
PPD— Progressive primary disease
is not always confirmatory. In addition, the results of this In vivo and by Leukocyte Migration Inhibition Test (LMIT)
expensive technique may be less promising in routine and lymphoblast transformation in-vitro.
clinical laboratories. The PCR may be useful in evaluat-
ing children with significant pulmonary disease when Serodiagnosis
diagnosis is not readily established by other means, and
In absence of good diagnostic method for tuberculosis, a
in evaluating immunocom promised children (HIV
lot of interest has been generated in serodiagnosis. ELISA
infection) with pulmonary disease.67-69 has been used to detect antibodies to various purified or
D. Gas liquid chromatography (GLC) or High complex antigens of M. tuberculosis in children. Despite a
performance liquid chromatography (HPLC): These large number of studies71-76 published over the past
methods have been used to aid in characterization of several years (Table 9.5), serology has found little place
mycobacteria by analysis of cellular long chain fatty acids. in the routine diagnosis of tuberculosis in children, even
The fatty acid pattern is species specific. Though this though it is rapid and does not require specimen from
method is reliable, economical, it requires considerable the site of disease. Sensitivity and specificity depend on
expertise.70 the antigen used, gold standard for the diagnosis of
tuberculosis and the type of tubercular infection. Though
Demonstration of Host Response on Exposure to most of these tests have high specificity, their sensitivity
M. tuberculosis is poor.71-76 In addition, these tests may be influenced
The host response to infection with M. tuberculosis may by factors such as age, prior BCG vaccination and
be cell mediated or humoral. Humoral immune response exposure to environ-mental mycobacteria. At present,
may be assessed by measuring the immunoglobulins to serodiagnosis does not have any role in diagnosis of
various antigens (serodiagnosis). The cell-mediated childhood pulmonary tuberculosis. Most of the available
response can be demonstrated by skin tests (Mantoux test) tests lack acceptable sensitivity and specificity.
112
Table 9.5: Utility of serodiagnosis in diagnosis of childhood TB

Authors Subjects Antigen used Antibody Sensitivity (%) Specificity (%)
Delacourt 14 culture positive A 60 IgG 71 in culture positive TB 98
et al,71 (1993) 17 probable TB 65 in probable TB
16 infected but
healthy
198 healthy controls
Gupta et al72 58 definite A 60 IgG, IgM 55.2 IgM 92.6 (1997)

pulmonary TB IgA, IgG 32.7 IgG 95.7
161 controls IgM IgA 36.2 IgA 96.3
IgM+ IgA 72.4 IgM+A 92
Zheng et al73 122 children with Polymerized IgG OT 40.3 OT 96.3

(1994) clinical diagnosis old tuberculin PPD 50 PPD 96.8
of TB (OT) 30 kD 36.1 30 kD 97.3
187 controls PPD 30 kD
antigen
Turneer et al74 35 asymptomatic A 60 IgG, IgM IgG IgM IgG or IgM IgG 95
(1994) primary TB (ATB) ATB 6 23 26 IgM 95
29 symptomatic STB 14 17 31 IgG and IgM
TB (STB) Post 26 35 48 99
23 post TB TB
81 controls
Swaminathan 35 pulmonary TB, A 60 IgG, IgM IgM IgG IgM 50
et al75 (1999) 7 TB lymphaade- 38 kDa Pulm TB 74 17 IgG 86
nitis and 22 antigen TBL 57 86
healthy control IgG Culture + 80 30
Pulm TB 37
TBL 86
Culture + 50 IgG 73
Imaz et al76 74 active TB, 16-kDa IgG, IgM IgG IgM

IgA
(2001) 49 healthy contact antigen and IgA ATB 34 19
3
149 nonmyco-
bacterial infection
TBL – TB lymphadenitis, PPD – Purified protein derivative
PCR Based Cytokine Detection in Tuberculosis pulmonary diseases; whereas the levels of mRNA
transcription for TGF- beta was high, the levels of mRNA
Cytokine expression has not been studied in detail in transcription for IFN-gamma and TNF-alpha remain low.
children with TB. The relative amounts of the various All children had low levels of mRNA for IL-12. IL-4 was
cytokines released at the site of infection may be barely detectable in all cases. Children with miliary TB
important determinants of TB disease development and had high levels of IL-10 transcripts and low levels of
pathology. Aubert-Pivert et al77 determined cytokine mRNA encoding TGF-beta. The immunosuppressive
transcripts (IFN- gamma, IL-12, TNF- alpha, IL-10, IL-4, cytokines TGF-beta and IL-10 are overproduced in
TGF- beta 1) in bronchoalveolar cells (BACs) recovered children with non-miliary TB and miliary TB respectively
from 9 children presenting with TB and from 9 children and are probably involved in the progression of the
with pulmonary diseases other than TB. Expression of disease. Further studies are required to confirm these
mRNA encoding TGF-beta, TNF-alpha and IFN-gamma findings. Such information may lead to development of
was statistically significantly higher in BACs from tests to help differentiate tuberculosis from other
children with TB than in BACs from children with other respiratory conditions.
113
Circulating Immune Complex

Simonney et al78 performed ELISAs using the three
glycolipids LOS, DAT and PGLTb1 in whole serum and
immune complexes from 20 children with tuberculous
disease or infection, in seven child contacts, and in 26
children with nontuberculous disease. The contribution
of complexed IgG antibody to the diagnostic values was
established for each group. The antibody levels in free
serum were higher (P < 0.01) in children with tuberculous
disease or infection and in contacts than in controls. By
contrast, except for PGLTb1, the IgG antibody levels were
higher (P < 0.02) in children with tuberculous disease than
in the other groups. The detection of immune complexes
Fig. 9.4: X-ray film of PPC showing left hilar adenopathy with ill
and IgG antibodies against the three glycolipid antigens
defined parenchymal lesion
is useful as a complementary technique for the
serodiagnosis of children with a high probability of
pulmonary tuberculosis. As of now, this test does not consensus regarding the most common site of
seem to have significant contribution in diagnosis of involvement.80-83 In Tuberculosis clinic of AIIMS, New
tuberculosis in children. Srivastava et al79 measured Delhi, India 35% of children had only parenchymal lesion,
antigen and antibody in circulating immune complexes nodal component in 36%, whereas 29% had both
(CIC) in 52 children with pulmonary and extrapulmonary parenchymal as well as nodal lesions (Table 9.6).
TB. CIC antigen was present in 92.3% and CIC antibody Consolidation in progressive primary disease (PPD)
in 88.96% of children. Out of these 52 patients, 20 were is usually heterogeneous, poorly marginated with
proved cases and CIC antigen and antibody were present predilection of involvement of apical or posterior
in all 20 cases. More experience is required for use of CIC segments of upper lobe or superior segment of
in diagnosis of TB in children. lower lobe84 (Fig. 9.5). There may be features of collapse
Table 9.6: Distribution of parenchymal (P), nodal (N) and

Skin Test as a Measure of Cell Mediated
parenchymal plus nodal (P+N) lesions of pulmonary
Immune Response primary complex (PPC)
Tuberculin skin test is useful in evaluation of children Type of lesion N %
suspected of having tuberculosis in as much that a
PPC (P) 567 35
significant reaction supports the diagnosis, while absence PPC (N) 585 36
of the same does not rule out tuberculosis. The test should PPC (P + N) 444 29
be performed using 1 TU PPD with RT23 and tween 80;
Total 1596 100
as the cutoff values for induration are available for this
strength for Indian children. An induration of more than
10 mm in presence of clinical setting suggest active
tuberculosis. Isolated positive tuberculin test indicates
infection with M. tuberculosis. An induration of between
5 to 10 mm with a clinical setting in children with
immunocompromized state suggest presence of
tuberculosis disease.
Radiology
Chest radiograph has an important role in diagnosis of
childhood tuberculosis, especially pulmonary
tuberculosis. In extrapulmonary tuberculosis, presence
of lesions on chest radiograph supports diagnosis.
The typical chest X-ray appearance of a pulmonary
primary complex is that of an airspace consolidation of
variable size, usually unifocal, homogeneous (Fig. 9.4).
Enlarged lymph nodes are usually seen in the hila, right
paratracheal region. Adenopathy alone may be the sole
manifestation of primary tuberculosis. There is no Fig. 9.5: PPD showing consolidation
114
as well (Fig.9.6). Bronchiectasis may occur in PPD because

of (i) destruction and fibrosis of lung parenchyma
resulting in retraction and irreversible bronchial
dilatation, and (ii) cicatricial bronchostenosis secondary
to localized endobronchial infection resulting in
obstructive pneumonitis and distal bronchiectasis. In
children, cavitary disease is uncommon (Fig. 9.7).
Pleural effusion may occur with or without lung lesion
(Fig. 9.8).
In miliary tuberculosis, there are multiple lesions of
size 2 to 5 mm (Fig. 9.9). Associated lymphadenopathy is
seen in more than 90% children.85 Occasionally, the chest
radiograph may be normal and lymphadenopathy may
be detected on computed tomography (CT), which is not
evident radiographically.86 In addition, CT features such
as low attenuation lymph nodes with peripheral
enhancement, lymph node calcification, branching
centrilobular nodules and miliary nodules are helpful in Fig. 9.8: Massive pleural effusion on left side
Fig.9.6: Collapse consolidation of right upper lobe Fig. 9.9: Miliary shadows with right paratracheal adenopathy
suggesting the diagnosis in cases where the radiograph

is normal or equivocal. Other features such as segmental
or lobar consolidation and atelectasis are nonspecific.87
In a study by Kim et al,87 CT including high resolution
CT (HRCT) revealed lymphadenopathy, which was not
demonstrated in 21% of radiographs, and parenchymal
abnormalities, not seen on 35% of radiographs. HRCT is
more sensitive than chest radiography for the detection
of miliary TB. The HRCT findings are widespread
multiple small (< 2 mm diameter) nodules.88 The nodules
may be so numerous that they coalesce to form larger
nodules greater than 2 mm in diameter or even
consolidation with air bronchograms. Thickening of the
interlobular septa may also be a feature. Mediastinal and
hilar lymphadenopathy may also be present. Cavitation
is reported to be rare on chest radiography in children
with TB. However, children with both HIV and TB may
Fig. 9.7: Cavity have atypical radiographic features and cavitation has
115
been reported89,90 CT may show areas of cavitation that most often made by combination of a positive tuberculin
are not apparent on chest radiography, which may raise skin test, chest radiograph, physical examination and
the possibility of a previously unsuspected underlying history of contact with adult patient often in the family
immune disorder.91 HRCT can differentiate old fibrotic with tuberculosis. Newer diagnostic methods such
lesions from newly active tuberculous lesions. CT scan as PCR, chromatography have not given encouraging
may help in CT guided aspirations for diagnosis and results. Same is the case with serodiagnosis. Newer
drainage of cold abscess.92 Role of high-resolution and staining and culture methods have found their place in
color Doppler ultrasonography (US) in diagnosis of the better and early laboratory diagnosis. There is an
cervical lymphadenopathy has been reported. Central urgent need to develop better techniques for diagnosis
irregular hyperechogenic areas, blurred margins and of tuberculosis disease in children. The suggested
central necrosis were most frequent in bacterial, algorithm for diagnosis of pulmonary TB in children is
tuberculous and cat scratch disease.93 given in Figure 9.10.
METHODS TO DIAGNOSE LATENT TUBERCULOSIS Treatment

INFECTION The principles of therapy have been dealt with elsewhere.
Till date, tuberculin skin test (TST) was the only method One of the important biologic determinants of success of
to diagnose latent tuberculosis infection. Recently, new therapy is the size of the bacillary population in the child.
in vitro diagnostic aids that measure a component of cell- Most of children with pulmonary tuberculosis have
mediated immune reactivity to M. tuberculosis, and is paucibacillary disease. The approximate numbers of
based on the quantification of interferon-gamma (IFN- bacilli in different types of lesions are as follows: cavity
gamma) released from sensitized lymphocytes in whole 109, asymptomatic Mantoux positive 103 to 104, primary
blood incubated overnight with different antigens from complex 104 to 105. To some extent, the load can be judged
M. tuberculosis. Initially the interferon gamma release on a chest X-ray. Lack of cavitary lesions implies a lower
assays (IGRA) used purified protein derivatives (PPD) bacillary load. A child with positive Mantoux and a
as stimulating antigens. Now PPD is replaced with more normal chest X-ray has some bacilli in his macrophages,
specific antigens like, Early Secreted Antigenic Target-6 the bacillary load is less. It increases in primary complex
(ESAT-6), Culture Filtrate Protein 10 (CFP 10), TB 7.7 and progressive primary disease.
(Rv2654). Antigens; ESAT-6 and CFP 10 are not shared
with BCG and other species of atypical mycobacterium, Drug Regimens
making these tests more specific for infection with During the last few years, dramatic changes have
mycobacterium tuberculosis. There are two sets of occurred in the therapeutic approaches to childhood TB
commercially available tests based on interferon-gamma
(IFN- gamma) estimation (Quanti FERON-TB(R) Gold In-
Tube (QFT-IT) and T-SPOT.TB). Studies comparing
performance of both tests suggest variable results.94
However, on reviewing all the studies it can be concluded
that the sensitivity and specificity of IGRA methods
compares well with the TST. However, IGRA methods
are associated with single visit and as it is an in vitro test
there are no chances of complications associated with TST,
including exaggerated delayed type hypersensitivity
reactions causing necrosis and vesiculations. At present
the major limiting factor to replace TST with these tests
is their cost. In future when the cost is less they may be
used to replace TST.95
The sensitivity of IGRA based tests may be less in
younger age as compared to tuberculin skin test.96
DIAGNOSTIC ALGORITHM FOR PULMONARY

TUBERCULOSIS
The diagnosis of tuberculosis disease in children
continues to be extremely challenging throughout the
world. Even in the advanced nations, the diagnosis is Fig. 9.10: Proposed diagnostic algorithm for pediatric PTB
116
as a result of large number of treatment trials for children Indian Academy of Pediatrics and Revised National
and increased concern about the development of Tuberculosis Control Program (RNTCP) has also
resistance to antituberculosis drugs. Short-course chemo- proposed a classification of different types of tuberculosis
therapy, with the treatment duration as short as 6 months, in children into three categories.105
has become the standard practice. Thrice weekly
intermittent regimens have been documented to be as Drug Regimens for Pulmonary Tuberculosis
effective as daily regimen in the adult population.97 Table 9.7 gives standardized clinical categories given by
However, there are few studies comparing twice a week WHO. For all type of pulmonary tuberculosis except PPC
intermittent regimen in childhood tuberculosis.98-101 A and minimal pleural effusion the recommended
meta- analysis of all these studies revealed that daily treatment regimen is 2H3R3Z3E3 4 H3R3 if treated under
regimen is superior to twice a week intermittent DOTS and otherwise it may be a daily regimen of 2HRZE
regimen.102 4 HR at home. For PPC and minimal pleural effusion
Directly observed therapy short-course (DOTS) has under DOTS it may be 2 H3R3Z3, 4 H3R3 and otherwise a
been successfully used in children.103 The major problem daily regimen of 2 HRZ 4 HR is recommended. Here
in inclusion of children in DOTS is difficulty in minimal pleural effusion is defined as unilateral blunting
demonstration of AFB and classification of different of costophrenic angle but lung fields are visible and an
clinical manifestations according to categories described underlying lung parenchymal lesion has been ruled out.
for adults. There have been efforts to develop Children who have received antituberculosis drugs in
classification of different types of childhood TB into three past for more than 4 weeks should receive 2 S3H3R3Z3
categories similar to those for adults. A classification was E3/1 H3R3Z3E3/5 H3 R3 E3 under DOTS otherwise a daily
developed and evaluated in the tuberculosis clinic of a regimen of 2 SHRZE 1 HRZE 5 HRE should be given to
tertiary care hospital.104 In this study on 459 children with them.
TB, 365 (80%) children completed the treatment. Of these, Though DOT short-course chemotherapy regimens
302 (82.7%) were cured with the primary regimen have been found to be very effective in adults, it is not
assigned to them in the beginning, 54 (14.8%) required possible to have the kind of infrastructure needed under
extension of treatment for 3 months and 9 (2.5%) patients DOTS for all children across board. Hence along with
required change in the treatment regimen. The authors DOTS, the regimens suggested in Table 9.7 by the authors
concluded that it is feasible to classify and manage various should be evaluated further.
types of tuberculosis in children in different categories In HIV infected children with pulmonary tuberculosis,
similar to WHO guidelines for adult tuber-culosis.105 these regimens can be used, but the duration of therapy
Recently a consensus statement jointly prepared by is increased to 9 months.
Table 9.7: Standardized (clinical categories, clinical conditions and suggested drug
regimens by the authors in children)
Categories As suggested by Suggested conditions Suggested drug
WHO for adults in children regimens
• Category I New sputum positive PPD, TBL 2 HRZE
Pulmonary TB Pleural effusion 4 HR
Abdominal TB or
Osteoarticular TB 2 SHRZ
Genitourinary TB* 4 HR
CNS TB
• Category II • Relapse Relapse 2 SHRZE
• Treatment failure Treatment failure 1 HRZE
• Return after adult default Interrupted treatment 7 HRE
(Interrupted treatment)
• Category III • Sputum-negative pulmonary Single lymphnode 2 HRZ
with limited parenchymal Small effusion 4 HR
involvement Skin TB
• Extrapulmonary TB PPC
(less severe forms)
PPC— Pulmonary Primary Complex , PPD—Progressive Primary Disease, TBL— Tubercular Lymphadenitis, CNS TB—
Central Nervous System Tuberculosis
*In genitourinary tuberculosis, dose to be adjusted as per creatinine clearance.
117
Interrupted Treatment subjective well-being is assessed. The child is examined

for weight gain and improvement in chest findings.
Whenever the treatment is interrupted for more than
Compliance is assessed by talking to parents and checking
2 weeks, the child should be reassessed clinically and
medications on each visit. Majority of children show
radiologically. Wherever possible bacteriological
examination should be perfor-med. A suggested improvement in symptoms within a few weeks.
guideline for treatment after interruption of therapy is In the presence of poor response or worsening of
given in Table 9.8. symptoms or signs, the initial basis of diagnosis is
reviewed, especially, if there are no problems with
Corticosteroids compliance. Assessment for possibility of drug resistant
tuberculosis should be made. After the treatment is over,
Corticosteroids, in addition to antitubercular drugs, are follow-up every 3 to 6 months for next 2 years is desirable.
useful in treatment of children with CNS tuberculosis and
some children with pulmonary tuberculosis. These are Radiological Criteria
mainly useful in settings where the host inflammatory
Clinical improvement precedes radiological clearance of
reaction contributes significantly to tissue damage. Short-
lesion on chest X-ray films. The optimal frequency of
courses of corticosteroids are indicated in children with
radiological monitoring in children with pulmonary
endobronchial tuberculosis that causes localized
tuberculosis is unclear. One protocol suggests obtaining
emphysema, segmental pulmonary lesions or respiratory
X-ray films of the chest after 4 to 8 weeks of therapy. If it
distress. Some children with severe miliary tuberculosis shows improvement in combination with clinical
may show dramatic improvement with cortico-steroids response, 2nd X-ray should be done at the end of
if alveolo-capillary block is present. Significant therapy.107
improvement in symptoms can occur in children with In our opinion, the first chest X-ray during therapy
tuberculous pleural effusion with use of corticosteroids. should be done after 8 weeks, i.e. at the end of intensive
The most commonly used medication is prednisolone, in phase. In patients who show increase or little change in
dose of 1 to 2 mg/kg/day for 4 to 6 weeks. radiological features coupled with delayed clinical
response, prolongation of intensive phase by a month is
Monitoring of Therapy recommended. Further films are taken after 4 weeks. If
the child is better, should be shifted to continuation phase;
Response to treatment can be judged by using the
else the child is investigated for failure of treatment and
following criteria: clinical, radiological, bacteriological,
drug resistance. The degree of radiological clearance can
and laboratory test.106
be graded as (1) Complete clearance, (2) Moderate to
significant clearance(1/2-2/3 clearance), (3) Mild
Clinical Criteria clearance (1/3 decrease in size) or (4) No clearance or
Clinical improvement in a child on ATT is the mainstay appearance of new lesion.108
of judging response to therapy. The child should be seen One should not attempt to treat till complete
every 2 to 4 weeks initially, then every 4 to 8 weeks. On radiological clearance, improvement in the X-ray may
each visit, improve-ment in fever, cough, appetite and continue to occur even after stoppage of therapy.109
Microbiological Criteria
Table 9.8: Treatment after interruption
Most of the childhood pulmonary tuberculosis is
Duration Duration of Decision
therapy interruption paucibacillary. In children, where isolation of
M. tuberculosis was possible at the time of diagnosis, every
Up to 4 weeks < 2 weeks Resume original regimen effort should be made to document disappearance of
> 2 weeks Reassess and start appropriate bacilli during therapy.
regimen
4-7 weeks < 2 weeks Resume original regimen Nonspecific Test for Monitoring
> 2-8 weeks Extend intensive phase by
1 month, Category II regimen Although an elevated erythrocyte sedimentation rate
> 8 weeks Reassess and start appropriate (ESR) may be expected in children with tuberculosis, a
regimen recent study found that one-third of children with TB had
> 8 weeks < 2 weeks Resume the original regimen
a normal ESR at the time of diagnosis, suggesting little
> 2 weeks Resume therapy Category II
value in using ESR as a diagnostic and monitoring test
for childhood tuberculosis.110
118
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Short course chemotherapy for pulmonary tuberculosis Paediatr Today 1999;2:81-4.
in children. Indian J Tuberc 1998;45:83-7. 107. Seth Vimlesh, Kabra SK, Lodha R. Management
99. Kansoy S, Kurta N, A it S, et al. Superiority of intermittent tuberculosis in children. In: Seth V, Kabra SK (Eds).
short-course chemotherapy in childhood pulmonary Essentials of tuberculosis in children, (2nd edn). New
tuberculosis. Turkish J Med Sci 1996;26:41-3. Delhi: Jaypee Brothers Medical Publishers (P) Ltd.
100. Kumar L, Dhand R, Singhi PD, et al. A randomised trial 2001;349-54.
of fully intermittent and daily followed by intermittent 108. Mukhopadhyay S, Gupta AK. Imaging in childhood
short-course chemo-therapy for childhood tuberculosis. tuberculosis. In: Seth Vimlesh, Kabra SK (Eds). Essentials
Pediatr Infect Dis J 1990;9:802-6. of tuberculosis in children, (2nd edn). New Delhi: Jaypee
101. Te Water Naude JM, Donald PR, Hussey GD, et al. Twice- Brothers Medical Publishers (P) Ltd. 2001;262-85.
weekly vs daily chemotherapy for childhood TB. Pediatr 109. Starke JR. Current concepts of epidemiology, diagnosis
Infect Dis J 2000;19:405-10. and treatment of childhood tuberculosis in the United
102. Menon P R, Lodha R, Sivanandan S, et al. Intermittent or States. Indian Pediatr 1991;28:335-55.
daily short-course chemotherapy for tuberculosis in 110. l-Marri MR, Kirkpatrick MB. Erythrocyte sedimentation
children: A systematic review and meta-analysis of rate in childhood tuberculosis: Is it still worthwhile? Int J
randomized controlled trials. Indian Pediatr 2010;47: Tuberc Lung Dis 2000; 4:237-9.
67-73. 111. Sivanandan S, Walia M, Lodha R, et al. Factors associated
103. Sharma S, Sarin R, Khalid UK, et al. The DOTS strategy with treatment failure in childhood tuberculosis.Indian
for treatment of pediatric pulmonary tuberculosis in Pediatr 2008;45:769-71.
10 Tuberculous Lymphadenitis
Ben J Marais, PR Donald
INTRODUCTION protection against disease caused by these organisms.10 A

similar protective effect provided by natural infection with
Tuberculosis lymphadenitis (historically referred to as M. tuberculosis, which may also enhance the protection
scrofula) is the most common form of extrapulmonary provided by universal BCG vaccination, probably explains
TB recorded in children from TB endemic areas, being why lymphadenitis due to M. avium complex and other
present in 8-10% of children diagnosed with TB in India environmental mycobacteria are rare in countries with a
and South Africa. 1,2 The cervical lymph nodes are high-burden of TB, despite the fact that 10% of rural
predominantly affected. Lymph nodes become infected children react to avian PPD-tuberculin.11
with Mycobacterium tuberculosis following lymphatic
drainage from a local disease site or after hematogenous
dissemination. In highly endemic areas TB lymphadenitis
is a common cause of persistent cervical adenopathy in
children. In South Africa, 22% of children who presented
to a primary health center with persistent cervical
adenopathy (>1 × 1 cm, not responding to a course of
oral antibiotics) were diagnosed with TB lymphadenitis
and this increased to 64% once a visible local cause was
excluded. Figure 10.1 presents a flow diagram of all 167
children referred with persistent cervical adenopathy.
Table 10.1 demonstrates the demographics and etiology
of persistent cervical adenopathy in the 158 children who
were evaluated.
EPIDEMIOLOGY
The mycobacteria that cause cervical lymphadenitis are
highly variable depending on the setting. In areas where
the control of bovine tuberculosis is poor and milk is not
routinely pasteurized, M. bovis may be a frequent cause.3-5
In areas where TB is endemic and bovine TB is well
controlled, M. tuberculosis would be the most common
cause.3,6-7 In developed countries with low rates of TB Fig. 10.1: Children who presented to primary health care facilities with
transmission, non-tuberculous mycobacteria (NTM), persistent cervical adenopathy in a TB endemic area
particularly M. avium complex (MAC), are mainly Not TB—symptom resolution in the absence of antituberculosis
responsible.8 The etiologic agent may be determined by chemotherapy
TB—bacteriologic confirmation; isolation of M. tuberculosis from a lymph
different environmental conditions. For example, the node, or microscopically visible acid-fast or autofluorescent bacilli
decrease in M. scrofulaceum (historically associated with associated with caseating necrosis on cytology, or clinical diagnosis;
significant therapeutic response (lymph node size decreased from ≥2 ×
scrofula) and the concurrent increase in M. avium complex 2 cm to <1 x 1 cm after 3 months of standard antituberculosis treatment)
as a cause of chronic cervical lymphadenopathy has been Not evaluated—did not return to the clinic for evaluation by the
attributed to the chlorination of potable water supplies.9 investigator
Rx response—significant therapeutic response as for clinical diagnosis
In the context of these shifting epidemiological #
One chronic inflammatory process diagnosed after excision biopsy,
patterns, it is interesting to note that the stoppage of BCG one nonacute bacterial abscess diagnosed after incision and drainage
immunization in certain developed countries has led to a Adapted from Marais BJ et al—tuberculous lymphadenitis as a cause
of persistent cervical lymphadenopathy in children from a tuberculosis-
marked increase in the incidence of lymphadenitis caused endemic area3
by NTM, suggesting that BCG immunization provides
123
Chapter 10 Tuberculous Lymphadenitis
Table 10.1: Demographics and etiology of persistent PATHOGENESIS

cervical adenopathy in children presenting to primary In the vast majority of cases, TB lymphadenitis represents
health facilities in a TB endemic area (n = 158) the glandular component of a primary complex, which
Demographics Number (%) consists of the Ghon’s focus (or site of primary infection)
and the regional lymph nodes. This was concluded from
Gender
clinical experience during the prechemotherapy era.
Male 69 (43.7)
Female 89 (56.3)
Peripheral lymphadenitis frequently occurred in
Age groups complete isolation, but in a substantial number of cases
<5 years 93 (58.9) traces of a primary focus could be found after careful
5-9 years 51 (32.2) scrutiny.15 These cases suggested that the lymph nodes
>10 years 14 (8.9) involved also reflect the most likely site of the Ghon’s
Etiology focus. The submandibular group of nodes was most
Visible local cause 105 (66.5) frequently affected and was associated with visible
Bacterial infection (crusted impetigo) 26 (16.5) calcification of the intrathoracic lymph nodes, suggesting
Tinea capitis (with secondary infection) 34 (21.5) a primary focus in the lung. Similarly, involvement of
Traction folliculitis 44 (27.8)
Otitis externa 1 ( 0.6)
the supraclavicular nodes was associated with a primary
No visible local cause 53 (33.5) focus in the apex of the lung.15 However, in a minority
Tuberculous lymphadenitis 35 (22.2) of cases cervical lymph node involvement may originate
Reactive nodes 13 ( 8.2) from a Ghon’s focus in the tonsils, oropharynx or tissues
Nonspecific inflammation 4 ( 2.5) of the head and neck.15 TB lymphadenitis involving
Nonacute bacterial abscess 1 ( 0.6) axillary or inguinal nodes is uncommon but if present, it
Malignancy 0 is usually associated with a local Ghon’s focus and a
Reactive nodes—cervical mass <2 × 2 cm, tuberculin skin test negative diligent search may be rewarded by finding a tuberculous
and natural symptom resolution
skin lesion at some distal point.15-17 TB lymphadenitis
Adapted from Marais BJ et al—tuberculous lymphadenitis as a cause
usually develops within the first 6-12 months after
of persistent cervical lymphadenopathy in children from a tuberculosis-
endemic area.3 primary infection with M. tuberculosis. In rare cases,
generalized TB lymphadenitis may be associated with
hematogenous dissemination and this may occur in the
BCG itself may cause regional lymphadenitis and absence of overt miliary disease.18
even disseminated disease in severely immune Disease pathology within the lymph node is similar to
compromised children. The simultaneous change of the that seen in other organs, with initial tubercle formation
M. bovis BCG strain (from Japanese to Danish) and the and lymphoid hyperplasia that may progress to caseation
application route (from transcutaneous to intradermal) and necrosis. Isolated involvement of a single node is rare
used for neonatal BCG vaccination in South Africa and nodes are usually matted due to considerable
resulted in a marked increase in the number of infants periadenitis, although one node is frequently more
who developed right sided axillary lymphadenitis.12 This prominent than others within a matted group of nodes.19
sudden increase in regional BCG-related complications A cold abscess results when the caseous material liquefies
was partly explained by previous inadequate delivery
and this is signified by a soft fluctuant node with
methods and initial unfamiliarity with the new
violaceous discoloration of the overlying skin;
intradermal technique.12 However, of particular concern
spontaneous drainage and sinus formation may follow.16
was a number of HIV-infected infants who developed
Untreated, the natural course of TB lymphadenitis in an
both regional, defined as axillary lymphadenitis on the
immune competent host follows a prolonged and
side of the BCG vaccination scar, and/or disseminated
relapsing course often interrupted by transient lymph
BCG disease following neonatal vaccination.13 Axillary
node enlargement, fluctuation and/or sinus formation
BCG lymph adenitis may also be a manifestation of the
immune reconstitution inflammatory syndrome (IRIS), before ultimately healing with associated scarring and/
mostly seen in severely immunocompromised or calcification.16
HIV-infected children within the first 3 months of starting
anti-retroviral therapy (ART).13 In a Thai study, IRIS was
CLINICAL FINDINGS AND DIAGNOSIS
documented in 19% of children with low CD4 The various conditions that should be considered in the
percentages (<15%) newly started on ART; the majority differential diagnosis of a child with chronic cervical
of cases (9) were caused by MOTT’s, 3 by M. tuberculosis adenopathy are listed in Table 10.2. The clinical findings
and 2 by M. bovis BCG.14 in 35 children with confirmed TB cervical lymphadenitis
124
Table 10.2: Differential diagnosis of peripheral lymphadenitis
Infections
Acute suppurative
Bacterial Gram-positive organisms—Staphylococcus aureus, Group A streptococci and
peptostreptococci Gram-negative organisms
Chronic granulomatous
Mycobacteria M. tuberculosis, M. bovis, M. bovis BCG, nontuberculous mycobacteria (NTM), especially M.
avium complex (MAC)
Fungi Histoplasmosis, Coccidioidomycosis, Actinomycosis
Other Brucellosis, Tuleraemia, Toxoplasmosis, Cat scratch disease, Sarcoidosis
Reactive hyperplasia
Viral Infectious mononucleosis (EBV), Human Immuno-deficiency Virus (HIV), Mumps,
Cytomegalovirus (CMV)
Malignancy Non-Hodgkins lymphomata, particularly Burkitt’s lymphoma
Hodgkin’s disease, Neuroblastoma, Rhabdomyosarcoma, Histiocytosis X
Congenital malformations Branchial, Thyroglossal and/or Dermoid cysts
Deep cavernous hemangioma
Unknown Reactive hyperplasia of undetermined etiology
when they presented to the primary health care facility response to chemotherapy is frequently suboptimal.8
are described in Table 10.3. A history of close contact Incision biopsy should be discouraged at all times as this
with an adult index case remains important and is may result in sinus formation, a complication not seen
documented in approximately 50% of children with TB with FNA.3,26 Material obtained should be submitted for
lymphadenitis.3,19 The condition seems to occur with histology and/or cytology (rapid cytological diagnosis
equal frequency in all age groups, except infancy where reduces diagnostic delay); performing a mycobacterial
it is rarely seen.3 TB lymphadenitis is characteristically culture is also advised as it increases the diagnostic
painless and not tender to palpation; nodes are large accuracy, allows identification of mycobacterial species
(>2 × 2 cm) and frequently matted.3,19 The lymph nodes and drug susceptibility testing if required.
are initially firm but may become fluctuant and sinus HIV infection complicates the diagnosis of TB
formation may be present.19,20 If secondary infection lymphadenitis because the TST is more likely to be
complicates the picture the affected nodes become red, negative than in HIV-uninfected children, 27 which
warm and painful. Superficial lesions on the scalp such increases the importance of establishing a bacteriological
as infected tinea capitis may cause persistent cervical diagnosis. Studies in Zambia indicate that TB lymph-
adenopathy that disappears only when the local lesions adenitis is less common in HIV-infected (3%) children
are adequately treated. compared to HIV-uninfected children (5%).28 In contrast,
The most important clinical clues that may assist the axillary M. bovis BCG adenitis is more common in HIV-
diagnosis of TB lymphadenitis are summarized in Table infected children and usually develops within
10.4. A strongly positive tuberculin skin test (TST) and/ 3-6 months after BCG immunization, or as a manifestation
or radiographic signs suggestive of TB support a of IRIS when it presents within 3-6 months of ART
diagnosis of TB lymphadenitis. 3,21 In non-endemic initiation.13,14
settings, a positive TST is more indicative of NTM disease
and provides a fairly accurate diagnosis in the absence Tubercular Lymphadenitis—Indian Experience
of known TB exposure and/or BCG vaccination. 8
Radiographic signs of TB are present in less than 50% of Tubercular lymphadenitis is the commonest form of
children with TB lymphadenitis and few report extrapulmonary tuberculosis in India, may be at a
pulmonary symptoms.3,20,22 practitioners clinic, children surgical and medical
Culture from a discharging sinus may provide outpatient departments (Pediatric tuberculosis clinic at
bacteriological confirmation. If there is no sinus, fine a tertiary care center) like All India Institute of Medical
needle aspiration (FNA) is the diagnostic procedure of Sciences. The reasons are many, in reality the incidence
choice. FNA provides an excellent bacteriologic yield and of peripheral lymphadenitis has increased depending
is a minimally invasive procedure,3,23-26 especially when upon the center, e.g. in a TB hospital like Lala Ram Sarup
a fine 22G needle is used. In some cases, an excision Institute of Tuberculosis and Allied Sciences, the major
biopsy may be considered and this a treatment option as presentation in the Pediatric ward is pulmonary
well, particularly in NTM disease where the therapeutic tuberculosis of the adult type because their criteria for
125
Table 10.3: Clinical characteristics of children diagnosed with TB lymphadenitis in a TB endemic area (n = 35)
Lymph node characteristics Number (%)

Persistence (present for >4 weeks, no response to antibiotics) 35 (100)
Size
< 2 × 2 cm 4 (11.4)
(2-4) × (2-4) cm 25 (71.5)
> 4 × 4 cm 6 (17.1)
Character
Single 5 (14.3)
Multiple - discreet 14 (40.0)
- matted 16 (45.7)
Solid 28 (80.0)
Fluctuant - without secondary bacterial infection 5 (14.3)
- with secondary bacterial infection (red and warm) 2 ( 5.7)
Associated findings
Tuberculin skin test
0 mm 2 ( 5.7)
1-9 mm 0
>10 mm 33 (94.3)
>15 mm 32 (91.4)
Mean response 19.1 mm (standard deviation 2.9 mm)
Constitutional symptoms
Any symptom 21 (60.0)
Fever 7 (20.0)
Cough 9 (25.7)
Night sweats 8 (22.8)
Fatigue 19 (54.3)
Failure to thrive 10 (28.6)
Chest radiograph
Suggestive of tuberculosis 13 (37.1)
Lymph node disease - uncomplicated 8 (22.8)
- with airway compression 1 (2.9)
- with parenchymal consolidation 4. (11.4)
Size—transverse diameter of the largest cervical mass
Fatigue—less playful and active since the mass was first noted
Failure to thrive—crossing at least one centile line in the preceding 3 months or having lost more than 10% of bodyweight (minimum 1 kg) over
any time interval
Adapted from Marais BJ et al—tuberculous lymphadenitis as a cause of persistent cervical lymphadenopathy in children from a tuberculosis-
endemic area3
Table 10.4: Clues to the diagnosis of TB lymphadenitis

History Contact with an adult index case with pulmonary tuberculosis
Lymph node characteristics Cervical, rarely inguinal or axillary
• Location (If axillary nodes ipsilateral to the site of BCG vaccination, consider
BCG adenitis)
• Size and character Visible, >2 × 2 cm
Non-tender and/or matted
Usually solid, but may be fluctuant (may also be secondarily infected)
Duration Persistent for > 1 month
Despite excluding/treating potential local causes
Reactive tuberculin skin test (TST) >10 mm in all children, >5 mm if HIV-infected children
Chest radiograph Suggestive of TB
Fine needle aspiration (FNA) offers a relatively easy noninvasive means of establishing a definitive tissue and/or
bacteriological diagnosis
126
treating tuberculosis is like adults based on primarily the initial 2 months.31 Short-course chemotherapy with
sputum examination. The other major chunk is tubercular intermittent drug administration during the con-
lymphadenitis with a chronic discharging sinus not solidation phase gave satisfactory results in 110 children
responded to usual category three treatment. The reason with TB lymphadenitis in Papua New Guinea.32 These
is partial treatment with antituberculosis drugs before children received 2 months of daily INH, RMP, PZA and
the patient presents to the TB Hospital or children streptomycin followed by 4 months of twice weekly INH
surgical outpatient department. The diagnosis is often and RMP, but there is no convincing reason to add
made by aspiration cytology which usually shows streptomycin during the intensive phase. Good results
reactive hyperplasia due to partial treatment and poor have been reported in smaller groups of children
adherence to treatment. In the TB Hospital, usually receiving the same standard TB treatment regimen as
excision biopsy is done which is examined for used in children with uncomplicated intrathoracic
histopathology by detailed microscopic examination disease.3,33,34 In fact, the organism load in children with
and specimen is processed for all microbiological isolated peripheral TB lymphadenitis is low and an even
investigations. shorter courses of chemotherapy may suffice in
Same is the routine at a tertiary care center like All uncomplicated cases, but no randomized studies have
India Institute of Medical Sciences (AIIMS). In addition been performed to support this. Despite successful
at AIIMS, specimen is also examined for drug sensitivity treatment, nodal enlargement during or following
testing to rule out resistant tuberculosis. In such cases, treatment may occur in a minority of patients, which
family history of TB is often positive. probably represents an immune reaction as cultures from
such lesions are usually negative. Surgery is advised only
Mantoux Test for exceptionally tense fluctuant nodes or in the presence
of severe discomfort. Full excision is advised and not
In a project on the complete clinical, histopatholegical, incision and drainage.
microbiological and immunological studies done by The treatment of M. bovis and M. bovis BCG adenitis
Rohatgi and Seth29 revealed the following interesting is more problematic. Isolated axillary adenitis in an
finding: immune competent child may warrant a conservative
1. Clinical: Cervical nodes were the most commonly approach, with surgical excision only if no spontaneous
involved site. Size was bigger than 1 cm. The glands resolution occurs or in the presence of severe discomfort.
were often matted due to perilymphadenitis. In HIV-infected children, there is a real risk of developing
2. Histopathology: This was changed if the patient has disseminated BCG disease,13 and local excision is often
been put on antituberculosis therapy. It showed impossible due to poor anatomical localization and
infiltration of the tissues surrounding the lymph node.
reactive adenitis and not typical granulomatous
M. bovis is inherently resistant to PZA and in addition
lymphadenitis.
M. bovis BCG may show intermediate resistance to INH.35
3. Mantoux test: The positivity of Mantoux test was
Thus, treatment with ordinary anti-tuberculosis therapy
highest in comparison to any other type of
seems inadequate and should include INH in a dose of at
tuberculosis in children.
least 10-15 mg/kg together with a third and probably
4. Immunological: Cell-mediated immune response as
even fourth drug to replace PZA. No guidelines exist
measured quantitatively by absolute T-cell counts and
currently, but it seems prudent to medically treat HIV-
qualitatively by lymphoblast transformation and
infected or immune compromised children with M. bovis
leukocyte migration inhibition test was better
BCG adenitis in order to prevent disseminated disease.13
preserved as compared to the TB of other organs such
Lymphadenitis caused by NTM is more resistant to
as pulmonary, neurotuberculosis.
chemotherapy. Apart from rifampicin, ethambutol the
5. Resistant TB: Case reports.
newer macrolides have shown some efficacy, but surgical
excision is frequently required.8,36
TREATMENT
Randomized controlled trials have demonstrated REFERENCES
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12. 28. Chintu C, Bhat G, Luo C, et. al. Seroprevalence of human
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11 Abdominal Tuberculosis
BR Thapa, Pawan Rawal, Ravi Angara
INTRODUCTION TB and most cases are constituted by immigrant

population. In contrast in low and middle income
Tuberculosis (TB) is still a rampant disease in children countries, childhood TB constitutes about 15 to 40% of
with varying presentation in developing countries. Recent all TB, and risk factors being poverty, crowding and
upsurge has been noted in developed countries also. Main malnutrition.17 Furthermore, susceptibility to TB is
organs affected with tuberculosis are lungs, central enhanced by HIV infection. Studies have suggested that
nervous system and lymph nodes whereas abdominal HIV-infected children are more likely than HIV-
involvement is less common. There is paucity of literature uninfected children to be exposed to parents with smear
from medical centers regarding gastrointestinal positive TB.18 The increased risk of TB among HIV-
tuberculosis in the pediatric age group1,2 and it is mostly positive children is attributable to immunosuppression
reported from pediatric surgical centers.3-6 Pediatricians which makes the HIV-infected children more likely to
might be missing tuberculosis of gastrointestinal tract be exposed to TB within their families. Other factors that
(GIT) due to unawareness and lack of facilities to confirm are associated with an excess risk of TB infection in
the diagnosis. However, abdominal tuberculosis of adult children include malignancy, peritoneal dialysis and
population has been well published with large series and passive smoking.19 BCG plays an important but narrow
reviews.7-12 role in the prevention of TB, particularly childhood TB.
Abdominal TB is defined as TB infection of abdomen Efficacy of BCG has varied from 0 to 80% in the
including gastrointestinal tract, peritoneum, omentum, prevention of adult pulmonary TB. A meta-analysis
mesentery, lymph nodes and other solid organs like liver, estimated that the overall protective effect of BCG was
spleen and pancreas. Abdominal tuberculosis (ATB) may 50%.20 Its protective effect is in the serious forms of TB
be isolated or associated with extra intestinal tuberculosis as TB meningitis, miliary, disseminated or abdominal TB.
lesion. 1,13 Abdominal TB complicates untreated Hospital data shows that abdominal TB forms 0.8 to
pulmonary disease in 6 to 38% of cases.14 M. tuberculosis 3.6% of total admissions and intestinal TB contributes to
is the principle causative agent and rarely M. bovis and 15% of all intestinal obstructions and 5 to 7% of all
nontuberculous Mycobacterium are encountered. gastrointestinal perforations.
Epidemiology Causative Organisms

Exact epidemiology of abdominal tuberculosis is not In the early 19th century, TB was recognized as a disease
known. Majority of patients with TB live in the most believed to be caused by an infectious organism. In 1882,
populous countries of Asia: Bangladesh, China, India, Koch, identified M. tuberculosis as the causative
Indonesia and Pakistan and account for half (48%) of the microorganism. Despite routine use of BCG vaccine in
new cases that arise every year.15 Incidence of disease most parts of world, TB has not been fully controlled by
and the prevalence and death rates are almost stable in vaccination. M. tuberculosis has been the predominant
majority of regions of world with exception being parts mycobacterial infection in most developed countries. M.
of Africa.16 Present and past transmission and incidence tuberculosis has unusual tenacity and viability. It has the
rates and peak age have varied in different parts of world. ability to infect humans and then persist in a dormant
Incidence rate is highest among young adults, and most state in the host in lymphoid tissue especially in GIT for
cases are due to recent infection in Africa and South East many years. Four closely related mycobacteria are there:
Asia. By contrast, in Western Europe and North America, M. tuberculosis, M. bovis, M. africanum, and M. microti. M.
which now have low incidence rates, the most cases have microti does not cause disease in humans.21 Mycobacteria
shifted to older adults, and a higher proportion of cases other than those in the TB complex are referred to as
are attributable to a reactivation of latent infection. nontuberculous mycobacteria. These other mycobacteria
Similarly the risk factors and disease vary between can cause localized disease, such as regional
developed and developing countries. In developed lymphadenitis, in healthy individuals or disseminated
countries, childhood TB constitutes about 2 to 7% of all disease in immunocompromised patients.
129
Chapter 11 Abdominal Tuberculosis
Recognition of cattle as a potential reservoir of bovine Table 11.1: Predisposing factors for intestinal TB
TB lead to testing and destruction of infected animals,
universal pasteurization and the practice of boiling of • Rich in lymphoid tissue: Peyer’s patches and lymph
milk. This markedly reduced the spread of the disease. nodes
• AFB affinity for lymphoid tissue
Infected cattle remain a source of the disease in
• Number of bacilli ingested
developing countries. The major route of transmission
• Virulence of bacilli
of M. bovis is the ingestion of infected milk or milk • Nutritional and immunological status
products, and the intestinal tract and associated lymph • Alkaline pH in small and large intestine
nodes become the primary complex. Overall most bacilli • Stasis in ileocecal area (Ileal break)
isolated in patients with abdominal tuberculosis are M. • More of water absorption and no digestive activity
tuberculosis and not M. bovis though reports from San
Diego, California have shown that Mycobacterium bovis
is a significant cause of tuberculosis in children residing Table 11.2: Site of involvement in abdominal
along the United States—Mexico border in the Baja tuberculosis (n = 78)
California Region. In earlier reports from India, TB due Site Number Percent
to M. bovis infection constituted 5% but these days it is Intestinal 52 67
very rare. Duodenum 2 2.5
Nontuberculous mycobacteria usually do not cause Jejunum 3 3.8
disease but can affect immunocompromised hosts as in Ileum 34 43.6
HIV, immunosuppression treatment and malignancies. Ileocecal 5 6.5
Colon and rectum 8 10.2
The important nontuberculous mycobacteria include
Peritoneal 21 27.0
M. intracellulare and M. avium. High index of suspicion Nodal 3 3.8
and no response to routine antitubercular treatment Hepatic 2 2.5
should give clue to the presence of these nontuberculous
mycobacteria.
ileocecal region, colon, jejunum, rectum, duodenum,
Pathogenesis stomach and esophagus.23 The frequency of involvement
of various abdominal organs as seen by Thapa et al24 is
The major route for transmission of TB is respiratory.
shown in (Table 11.2). In another study of gastrointestinal
Most of the children become infected after contact with
tuberculosis, which included large number of pediatric
an adult living in their household. An adult with active
patients also, most common site of involvement was
cavitary/bronchiectatic pulmonary TB with a productive
ileocecal region followed by small bowel and colonic
cough is the classic source of infection. The abdominal
tuberculosis.25 7.3% of patients had evidence of perfo-
tuberculosis may involve the gastrointestinal tract (GIT),
ration and fistulae which included esophagocutaneous,
peritoneum, lymph nodes or solid viscera. Tuberculous
rectovesical, choledochoduodenal, rectoileal, jejuno-
involvement of abdomen can be due to primary
jejunal, rectoileouterine, ileoileal, rectouterine,
involvement of the intestines and other abdominal
enterocutaneous and coloduodenal. Secondary
viscera; however, this is very rare nowadays. In pre-
reactivation of old healed focus, common in adults, may
chemotherapeutic era it was calculated to be about 5%.22
occur in older children and adolescents. Contiguous
Boiling of milk, pasteurization, eradication of infected
extension from adjacent organs is commonly reported
cattle and lack of infected material may be responsible
in adolescent girls with tuberculous salpingitis and
for this. Ingestion of tubercle bacilli along with the
tuberculosis of the spine.22 The pathogenesis of ATB is
sputum can also lead to intestinal tuberculosis as evident
summarized in (Fig. 11.1).
from well established association with pulmonary
tuberculosis. Involvement of intestine might be related
Immunopathogenesis
to number of bacilli ingested, virulence of organism,
nutritional status and immunological state of the child. Macrophage cells found in the follicle-associated
The site of involvement also varies. Factors that lead to epithelium of intestinal Peyer’s patches of gut-associated
development of intestinal TB are given in (Table 11.1). lymphoid tissue, provide a route of entry for pathogens
The post primary complex elsewhere in the body may into the mucosa and can phagocytose tubercle bacilli.
spread via hematogenous route. Mostly, it is intermittent Cytokines have been implicated in the protective
silent bacteremia occurring at low rate and leads to the immunity, pathophysiology and development of tuber-
disseminated TB involving intra-abdominal organs. But culosis. Most people who become infected with M.
there can be rupture of infected focus into the blood vessel tuberculosis mount an effective protective immune
and this can lead to miliary tuberculosis involving GIT. response, but 5-10% develop disease. Patients with active
The order of involvement of various sites is ileum, disease show depressed interferon gamma responses to
130
• Peritoneal TB
– Peritonitis
- Ascitic
a. Generalized
b. Localized
– Dry plastic type
- Adhesions interloop
- Fibroplastic
• Miliary TB peritoneum
– Granular peritoneal surface
• Omental TB
– Rolled up
Fig. 11.1: Pathogenesis of abdominal tuberculosis in children – Miliary
• TB of lymph nodes
mycobacterial antigens in vitro, a state dened as anergy. – Tabes mesenterica
Systemic features are due to cell mediated immune – Retroperitoneal
response. Fever develops due to IL-1 and hyper- – Peripancreatic
globinemia due to IL-6. Interleukins-12 and -18 might – Porta hepatis
play an important role in the initial host responses to • Other organ TB—hepatobiliary, splenic, pancreas.
infection. The proinflammatory cytokine, TNF-α, may In majority of children the tuberculosis of intestine
play a critical immunomodulatory role in the defense presents pathologically in two major forms.
mechanisms of the disease, maintaining a balance
between protective immunity and pathophysiology. Ulcerative Type
Positive Mantoux test develops because of delayed Patients with ulcerative type have induration and edema
hypersensitivity. Development of endarteritis leads to of diseased segment with ulcers which can be solitary or
deep ulceration and hemorrhage. multiple. Ulcers are usually transverse to the long axis
of the bowel “Girdle ulcers.” Areas of normal mucosa
Pathology may be found amidst diseased segments and are called
as “skip lesions”. Depth of the ulcers varies from
The ileocecal region is the most common site of submucosa to muscularis propria or even serosa. Healing
involvement in older children and adults, although ATB and fibrosis lead to “napkin ring” strictures causing
can have a focus at any site in the gastrointestinal tract, obstructive symptoms. Adhesions between bowel loops
associated lymph nodes and/or peritoneum. Intestinal prevent free perforation but promote fistula formation.
Tuberculosis (ITB) usually has one of the three forms: Related mesenteric lymph nodes may caseate to form
ulcerative, hypertrophic or ulcerohypertrophic, or mesenteric abscesses.
fibrous. Tuberculous granulomas initially form in the
mucosa or Peyer’s patches, whereas ulcers are relatively Stricturous/Hypertrophic type
superficial, with a different appearance from those in
Crohn’s disease. Intestinal TB progresses slowly and In contrast to the ulcerative form, stricturous/
presents late with complications, especially acute or hypertrophic form may occur in young well nourished
subacute obstruction due to the mass (tuberculoma), patients. Cecum is the commonest site affected. Usually
stricture formation in the ileocecal region or perforation the clinical setting is of low volume infection by less
leading to peritonitis. Peritoneal TB (PTB) is rare in the virulent organisms in a relatively healthy host. Extensive
absence of any other debilitating disease. In PTB, the inflammation and fibrosis occurs in this form causing
peritoneum is studded with multiple yellow–white adhesion of bowel, mesentery and lymph nodes into a
tubercles. mass. Caseation is common in mesenteric lymph nodes.
Types of abdominal tuberculosis in children
• Tuberculosis of the intestine Clinical Features
– Ulcerative Abdominal tuberculosis has protean manifestations and
– Hypertrophic most of symptoms are nonspecific. In children, the
– Ulcerohypertrophic peritoneal and nodal form of tuberculosis is much more
– Stricture formation common than intestinal tuberculosis. The clinical
– Fistula presentation of abdominal tuberculosis can be acute,
– Miliary (granular) chronic or acute on chronic. Clinical presentation
131
Table 11.3: Clinical profile of abdominal TB
Symptoms No. Percent Signs No. Percent

Pain abdomen 63 81 Distention 54 69
Anorexia 60 77 Visible peristalsis 21 27
Fever 53 68 Lump abdomen 15 19
Weight loss 66 84 Doughy abdomen 30 39
Chronic diarrhea 50 64 Ascites 12 15
Vomiting 24 31 Hepatomegaly 41 52
Diarrhea 14 18 Splenomegaly 16 21
Enterocutaneous Fistula 3 4
Constipation 4 5 Peripheral lymphadenopathy 26 33
Cough 29 37 Lung signs 13 17
depends upon the site of disease and the type of fistula causing massive hematemesis are rare
pathological involvement. Analysis of symptoms and complications. Endoscopy, fine needle aspiration
signs of patients of abdominal tuberculosis by Thapa et cytology (FNAC) and biopsy are mandatory for
al have been shown in (Table 11.3).24 confirmation of the diagnosis.
Gastric: Involvement of stomach is rare due to paucity of
Presentation According to Site of Involvement
lymphoid tissue and presence of acid in stomach.
Peritoneal Tuberculosis Ulcerative form is the commonest form seen in stomach
in 80% with ulcers usually on the lesser curvature.30
Tuberculous peritonitis often exhibits female
Symptoms are nonspecific and include abdominal pain,
predominance. Individuals with HIV infection, cirrhosis,
nausea, vomiting, GI bleed, fever and weight loss.
diabetes, malignancy, and those receiving continuous
Sometimes patients may present with features of gastric
ambulatory peritoneal dialysis are at high risk for
outlet obstruction. Antrum is more often involved and
tuberculous peritonitis. 26,27 This type presents as
simulates Crohn’s disease, lymphoma or carcinoma.
abdominal distention and ascites or as soft cystic lump
secondary to loculated ascites. Constitutional symptoms Duodenal: This is also a rare site of tuberculosis.
of fever and night sweats may be present. Diffuse Symptoms include non specific dyspeptic symptoms,
abdominal tenderness, doughy abdomen, hepatomegaly, fever and weight loss. Patients can present with
and ascites may be noted on physical examination. obstruction which is more common due to extrinsic
Mesenteric lymph nodes may present as vague compression than luminal obstruction.31 Strictures and
abdominal pain. There may be associated systemic duodeno- colic fistula also have been reported.
manifestations seen in up to 33% of cases like low grade
Small intestinal and ileocecal: The involvement of ileocecal
fever, malaise, night sweats, anemia or weight loss. The
area is more commonly encountered in older children
extra-abdominal tuberculous lesion may give additional
and adults. It can present as ulcerative, hypertrophic or
clues towards the diagnosis of abdominal tuberculosis
both.7-11
especially when associated with GI symptoms.
Conversely, there may not be any evidence of tuber-
Ulcerative Type
culosis elsewhere in the presence of abdominal tuber-
culosis. Concomitant positive radiologic evidence of Ulcerative form has been found more often in
pulmonary tuberculosis has been seen in variable malnourished children. This type presents with chronic
percentages. It was 20% in a study by Narasimharao diarrhea and features of malabsorption. This has been
et al.28 Thapa et al reported 68.2% of patients having reported in 16-30% of patients.24 The cause of mal-
pulmonary lesions.24 absorption in intestinal tuberculosis is thought to be
In GIT, all parts from the esophagus to the rectum bacterial overgrowth in a stagnant loop, bile salt
may be involved in isolation or in combination. deconjugation, decreased absorptive surface due to
ulceration, and involvement of lymphatics and lymph
Esophagus: Esophagus is very rarely involved because of nodes. Rarely hemorrhage can be the manifestation of
its tubular structure. Involvement occurs mainly by this form of tuberculosis.
extension of disease from adjacent lymph nodes in
mediastinum. The patient usually presents with low
Stricturous/Hypertrophic Type
grade fever, dysphagia, odynophagia and an ulcer.29
Most commonly it involves mid or upper esophagus. Stricturous/hypertrophic type presents with features of
Tracheoesophageal fistula and rarely, aorto esophageal subacute intestinal obstruction in the form of
132
constipation, obstipation, vomiting, diarrhea, abdominal 3. Histological evidence of caseating granuloma.

distention and colicky abdominal pain. Subacute 4. Operative evidence of ATB.
intestinal obstruction is characterized by attacks of 5. Good therapeutic response to chemotherapy, which
incomplete obstruction that resolve spontaneously. This there is no evidence of any other disease.
may be associated with gurgling, feeling of ball of wind Granulomas have been reported in only 40% of ATB
moving in the abdomen and visible intestinal loops. It patients and may be present only in lymph nodes. They
may also present as enterocutaneous or enteroenteric are absent in enteric lesions. In a host with good defense
fistula, which may be single or multiple. In fact the response or low virulence of the organism noncaseating
intestinal tuberculosis has been a great mimicker of granulomas may be seen. Caseation is a histological
Crohn’s disease and resembles it in many ways. marker for ATB and helps in differentiating it from
Colorectal: It can present with nonspecific symptom or Crohn’s disease.39-41 ATB is a paucibacillary disease;
with weight loss, anemia and lower GI bleed. There can therefore the working diagnosis is mainly based on
be diffuse or segmental colitis.32-35 This can simulate history, clinical findings and histology. Most of the times
Crohn’s colitis and ulcerative colitis. the demonstration of AFB in tissue or culture is not possible
in children.
Anal tuberculosis: Anal tuberculosis is also uncommon
and has a distinct clinical presentation in form of anal Techniques for Definitive Diagnosis
discharge, perianal swelling, pain or fistulae. Tubercular
fistulae are usually multiple, hence should be Demonstration of AFB
differentiated from Crohn’s disease.36-37 Demonstration of bacilli can be done by direct staining
Hepatobiliary tuberculosis: Hepatobiliary tuberculosis may or culture of tissue or various body fluids which can be
occur as primary hepatic tuberculosis or as part of obtained by various techniques described below.
disseminated or miliary tuberculosis. Tuberculoma if Demonstration can be done by direct staining of the
found can be single or multiple. Other findings can be material or cultured by various methods. Zeihl-Neelsen
tubercular abscess, involvement of biliary tract, fatty staining, Cold staining methods like Kinyoun, Gabett
change, amyloidosis and granulomatous hepatitis. methods and fluorescence microscopy with auramine,
Presentation can be in the form of pain (usually localized rhodamine are the various staining method used.
to right hypochondrium), fever, jaundice, hepatomegaly, Conventional culture with LJ medium takes 6 to 8 weeks
tenderness, splenomegaly, anemia or ascites. for the result. Rapid culture methods like BACTEC, MGIT
(Mycobacterial growth indicator tube), Septicheck and
Pancreatic tuberculosis: Pancreatic tuberculosis occurs in
micobacteriophage based assays can be used to get early
2 to 4% in miliary tuberculosis. Focal tuberculosis of
results within 2 to 4 weeks.
pancreas is very uncommon. It may result in common
1. Fine needle aspiration cytology (FNAC): FNAC from
bile duct (CBD) obstruction. Untreated cases may develop
intra-abdominal mass is a well established mode of
changes of chronic pancreatitis.38 More often peripancreatic
quick diagnosis. This is less invasive if a mass is
lymph nodes are involved and lead to the mass formation
palpable. A mass could be due to lymph nodes, rolled-
engulfing pancreas.
up omentum, and hypertrophied lesion of intestine.
Splenic tuberculosis: Spleen usually gets enlarged as a Aspiration can be guided by ultrasound or CT if a
part of disseminated tuberculosis. Occasionally there can mass is deep seated or directly from enlarged lymph
be massive splenomegaly also. Spleen can show multiple nodes. US/CT guided FNAC is possible from
hypodense discrete or conglomerate granulomas of retroperitoneal, peripancreatic, mesenteric, and porta
variable size. There may be formation of abscesses also. lymphnodes. Endoscopic (upper and lower GI)
Sometimes the clinical and radiological picture may guided FNAC can be done from submucosal lesions.
mimic lymphoma. FNAC can pick up a background necrotic tissue. A
recently published Indian study reported 92 cases
Investigative Approach to Abdominal Tuberculosis diagnosed by FNAC from 1996 to 2006. It is a simple,
Abdominal tuberculosis is a paucibacillary disease. It is fast accurate and inexpensive diagnostic procedure.42
not possible always to obtain microbiological proof. A 2. Ascitic fluid for AFB and culture: The yield of
high degree of suspicion in endemic areas should guide organisms from ascitic fluid either by AFB staining
the investigative approach. Diagnosis of ATB is based or by culture is very low. AFB can be demonstrated
on any of the following positive criteria in the presence from the ascitic fluid in < 3% cases and tubercle bacilli
of strong clinical suspicion: can be cultured in < 20% cases. The yield of culture
1. Demonstration of acid fast bacillus (AFB) in the lesion can increase upto 80 to 83% if at least one liter of ascitic
or ascitic fluid. fluid is concentrated by centrifugation.43
2. Growth of M. tuberculosis on culture of tissue or ascitic 3. AFB in the biopsy tissue: Demonstration of AFB in
fluid. the biopsy material obtained by endoscopy confirms
133
the diagnosis. M. tuberculosis can also be cultured

from biopsied tissue/material or the specimen
obtained and can be subjected to PCR for detection.
In various studies sensitivity of endoscopic biopsy is
reported; varying from 30 to 80%, but 8 to 10 biopsies
for histology from same site by dug well technique
and 3 to 4 specimens for culture should be obtained
for better yield. The crushed smear made out of biopsy
can demonstrate necrotic tissue, epitheloid cells, giant
cells and AFB.44
Histopathology of the Tissue

Various ways to obtain biopsy material are:
1. Upper GI endoscopy: In children, pediatric size
endoscope can be used to have direct visual
impression of lesions in esophagus, stomach and
Fig. 11.2: Tubercular ulcer in duodenum (For color version see Plate 3)
duodenum (Fig. 11.2, see color verions, Plate 00). With
the help of flexible endoscopic biopsy forceps, biopsy
can be obtained. At the same time FNAC can be
obtained. Other endoscopic techniques like
enteroscopy, double balloon enteroscopy and capsule
endoscopy can be used to visualize the bowel to
greater extent and help in diagnosis.
2. Lower GI endoscopy: Pediatric size sigmoidoscope or
colonoscope is used to see the colon for any lesion
and the material can be directly obtained for
confirmation of diagnosis. Granulomas have been
reported in 8 to 48% patients and 33 to 38% of positive
cases showed caseation.34 In a study of 8 patients by
Thapa et al45 with colonic symptoms, biopsy material
revealed submucosal granuloma in all. Endoscopic
FNAC can be used for quick diagnosis. Ulcers ranging
from few mm to 2 cm long and nodular friable mucosa
are the most common findings at colonoscopy. Cecum
is the most commonly affected site. Ascending and Fig. 11.3: Ulceration, nodularity and gaping of ileocecal valve
transverse colon are more commonly involved than (For color version see Plate 3)
sigmoid colon. Endoscopic appearances in
tuberculosis include hyperemic nodular friable
mucosa, pseudopolyps, edematous folds and
deformed, edematous or hypertrophied and gaping
of ileocecal valve (Figs 11.3 and 11.4, see color verions,
Plate 00). Usually lesions are circumferential in
contrast to Crohn’s disease (Figs 11.5A and B, see color
verions, Plate 00). Areas of strictures with nodular or
ulcerated mucosa also may be seen and are usually
but not invariably <3 cm in size. Endoscopic biopsy
may not reveal granulomas in all cases as the lesions
are submucosal and deeper and segmental. At least 8
to 10 biopsies are taken from the edge of the ulcer
and deep biopsies from hypertrophied lesions are to
be taken. Entire colon may be involved in 4% cases10 and
segmental involvement of the disease up to 26% cases.46
Colonoscopic biopsies yielded 40% culture positivity and
combination of histopathology and cultures could
Fig. 11.4: Girdle shape ulcers with exudates in transverse colon
establish diagnosis in upto 60% cases. Demonstration of (For color version see Plate 3)
134
Figs 11.5A and B: (A) Transverse ulcers of tuberculosis in colon, (B) compared to longitudinal ulcers in Crohn’s disease
(For color version see Plate 4)
Fig. 11.6: Histopathology (For color version see Plate 4)
typical tuberculous granulomas with caseating necrosis histopathology and culture under direct vision which
and AFB confirms the diagnosis (Fig. 11.6, see color gives pick up rate of about 85%.45,46 The role of
verions, Plate 00). laparoscopy can be further extended to therapeutic
3. Peritoneal biopsy: Peritoneal biopsy can be done with purposes, i.e. stricturoplasty/adhesiolysis.
Vim-Silverman needle and Cope needle. It should be 5. Laparotomy: Rarely laparotomy may be needed when
carried out when enough ascitic fluid is there. Pick other parameters are not contributory and diagnosis
up rate varies from 30 to 50%, more so reported in of tuberculosis is strongly considered. Two patients
adult literature. were diagnosed on laparotomy only by Thapa et al.24
4. Laparoscopy/peritoneoscopy: These are very helpful to 6. Liver biopsy: Liver biopsy reveals varied changes such
diagnose peritoneal and omental tuberculosis as as granulomatous hepatitis, miliary tubercles,
tissue can be obtained for AFB detection, conglomerate tubercles and nonspecific hepatitis,
135
Figs 11.7A and B: Plain X-ray abdomen showing (A) Multiple dilated small bowel loops with air fluid levels,
(B) Calcified tubercular lymph nodes
fatty infiltration, inflammatory cell infiltrate portal concomitant pleural effusion as reported by Dinler
inflam-mation, portal fibrosis, Kupffer cell hyper- et al.48 Hilar adenopathy was seen in 32% and hilar
plasia, tuberculomas, abscesses and cholangitis in adenopathy with parenchymal lesions were present
abdominal tuberculosis.47 The yield is <30% on liver in 37% patients.24 In contrast to adults, cavitary lesions
biopsy, but on postmortem this goes upto 70%. and bronchiectasis ware rarely encountered in
7. Splenic aspirate: FNAC is very useful to pick up TB children.24,51 Signs of old tuberculosis was present in
lesions in the spleen in case of conglomerate 20% of patients, like obliterated costophrenic angle,
hypodense area on ultrasonography/computerized calcified lymphnodes or a fibrocalcific parenchymal
tomography (USG/CT). lesion by Kapoor et al.53 Chest X-rays are more likely
to be abnormal in patients who present with acute
Investigations to Support ATB complications.
b. Family screening: A definite history of contact is not
Mantoux Test always present but various case series reported
Mantoux positivity in ATB has been reported from18 to had a positive family history in 37 to 66% cases of
66% in different case series.48 In Indian children it ranged ATB.24, 48, 50 X-ray chest of all family members and
from 33 to 58%.49-52 Because of low sensitivity and speci- Mantoux test of preschool age children should be
ficity, its positivity alone is not reliable for diagnosis. done when there is history of contact.
Negative Mantoux test does not exclude tuberculosis. c. Plain X-ray abdomen: A mottled calcification in the
Utility of this test is doubtful especially in areas where mesenteric lymph nodes or calcified granulomas in
TB is highly endemic as positive test does not differentiate retroperitoneal lymph nodes and liver are well
between active or inactive disease. However if the defined on plain X-ray abdomen. Otherwise, the
Mantoux test is positive >15 mm usually indicates active plain film is invaluable in acute presentations like
TB in the child. acute/subacute obstructive features which show
dilated jejunal and ileal loops with multiple air fluid
levels (Fig. 11.7A) and relative paucity of gas in the
Radiology
colon, perforation and intussusception. Multiple
a. X-ray chest: Incidence of pulmonary tuberculosis fluid levels are seen in 13 to 20.5% suggesting
varies from 19 to 58% in abdominal tuberculosis.13 subacute intestinal obstruction (SAIO) and intra-
Abnormal chest X-ray is seen in 50 to 75% cases of abdominal mesenteric calcification 2.6 to 2.8% as in
tuberculous peritonitis.48 12 to 63% patients also had (Fig. 11.7 B).24,50
136
d. Barium studies: Sharp and Goldman reported Barium

meal follow through (BMFT) examination as the best
diagnostic test demonstrating bowel lesions, their
extent and site in upto 84% of cases.54
Barium swallow and meal: Barium examination can show
lesions in esophagus, stomach and duodenum (Fig. 11.8).
Barium meal follow-through

The features seen in a small bowel are, accelerated
intestinal transit, hypersegmentation of the barium
column (chicken intestine), precipitation, flocculation
and dilution of the contrast material, stiffened and
thickened folds; luminal stenosis with smooth but stiff
contours (“hour glass stenosis”), ulcerations, fistulae,
multiple strictures with segmental dilatation of bowel
loops and fixity and matting of bowel loops (Figs 11.9
and 11.10). Double contrast study can be used in which
barium and air form the contrast for study of small Fig. 11.8: Barium swallow study showing extrinsic impression
bowel and colon. In contrast to conventional barium (By mediastinal lymph nodes) in mid esophagus
study, this gives better delineation of the lesion and

pick up rate is very good.55,56 Enteroclysis (small bowel iv. Loss of normal ileocecal angle and dilated terminal
enema) is preferred when subacute intestinal ileum, appearing suspended from a retracted,
obstruction or stricture is suspected. It delineates the fibrosed cecum (“Goose neck deformity”) (Fig. 11.13).
single or multiple strictures in the jejunum and ileum v. Purse string stenosis: Localized stenosis opposite the
clearly (Fig. 11.11). Even bowel wall thickening and ileocecal valve with a rounded off smooth cecum
ulceration can be picked-up. Similarly double contrast and a dilated terminal ileum.
can pick colonic and cecal lesions. vi. “Stierlin’s sign” is a manifestation of acute
inflammation superimposed on a chronically
Barium enema involved segment and is characterized by lack of
barium retention in the inflammed segments of the
Barium enema is indicated when colonic/ileocecal lesion ileum, cecum and variable length of the ascending
is suspected. Barium enema helps to find out ulcerated colon, with a normal configured column of barium
and hypertrophic lesions causing obstruction in the colon on either side. It appears as a narrowing of the
(Fig. 11.12). This can also pick-up fistulous communi- terminal ileum with rapid emptying into a
cations.55,56 shortened, rigid or obliterated cecum.
The following features53 are very classical to suggest vii. String sign: There is persistant narrow stream of
tuberculous pathology. These radiological signs develop barium indicating stenosis. Both Stierlin and String
following burnt-out fibrosed lesions due to long standing signs can also be seen in Crohn’s disease and hence,
tuberculosis of the intestine. are not specific for tuberculosis. Enteroclysis
i. Early involvement of the ileocecal region can followed by a barium enema may be the best
manifest as spasm and edema of the ileocecal valve. protocol for evaluation of intestinal tuberculosis.
Thickening of the lips of the ileocecal valve and/or
wide gaping of the valve with narrowing of the Percutaneous fistulogram
terminal ileum (“Fleischner” or “inverted umbrella
sign”) are characteristic. Contrast can be injected through the fistulous tract to
ii. Thickened folds and irregular contour of the delineate the enteric communication as shown in Figure
terminal ileum, better appreciated on double 11.14.
contrast study as compared to conventional barium Double-contrast barium examination shows typically
enema. linear or stellate shallow ulcers with characteristic
iii. Conical cecum: Cecum is shrunken in size and pulled elevated margins. The ulcers in tuberculosis tend to be
out of the iliac fossa due to contraction and fibrosis larger than those in Crohn’s disease and oval rather than
of the mesocolon (Fig. 11.10D). The hepatic flexure round, and produces greater thickening of the bowel
may also be pulled down. wall. Fistulae and sinus tracts are rare. Characteristic
137
Figs 11.9A to D: Barium meal follow through (BMFT) study showing (A) Ulceration in terminal ileum with narrowing, (B) Multiple adhesive and
stricturous small bowel loops, (C) Multiple strictures, ulcers and ileocolic fistula and (D) Multiple strictures with segmental dilatation of bowel
deformities in advanced disease include symmetric iii. Motility disturbances (increased/decreased transit
annular “napkin ring” stenosis and obstruction, time).
shortening, retraction, and pouch formation and iv. Hypersegmentation or thickened mucosal folds.
amputated cecum. Amputation of the cecum may be seen
in amebiasis, but this disease rarely involves the small Abdominal Ultrasound
intestine to the same degree as in tuberculosis. Characteristic sonographic features of early ATB are
The signs suggestive of ATB are: mesenteric thickness of 15 mm or more, increased
i. Ulceration or filling defects in the cecum which may mesenteric echogenicity due to fat deposition and
be contracted or pulled up making the ileocecal lymphatic obstruction and mesenteric lymphadenopathy.57
angle obtuse and resulting in a gaping or stenotic Portal hypertension and lymphomas are the other two
ileocecal valve. conditions which can present with mesenteric thickening.
ii. Strictures or ulcers in the small bowel. Intra-abdominal fluid can be seen which may be free or
138
Figs 11.10A to D: Barium meal follow through (BMFT) study showing, (A) Clumped small bowel with peritoneal involvement, (B) Clumped
bowel loops with free perforation, (C) Terminal ileal strictures with enteroliths and (D) Pulled up, conical and contracted cecum
loculated and clear or complex with debris and septae. directly via cysterna chili. This feature can help ATB to
USG is superior to CT in detecting ascites. Local be differentiated from lymphomas. Lymph nodes in
exudation from the inflammed bowel forms interloop lymphoma have uniform echogenicity whereas in TB
ascites lead to localized fluid between radially oriented different lymphnodes have different echogenecities.
bowel loops (“Club sandwich” or “sliced bread” sign). Regression of these changes can also be noted on follow-
Presence of other sonographic findings like ascites, up after therapy. Lymphadenopathy regresses early and
dilated small bowel loops, matted fixed bowel loops, mesenteric thickening and echogenicity are last abnor-
omental inflammation and thickening of bowel wall malities to regress completely. These features can be
further substantiate the diagnosis.58 Tuberculosis has a followed up in patients who do not have other objective
predilection of involvement of periportal, peripancreatic evidence of disease like abnormal barium studies or
and mesenteric lymphnodes more commonly as colonoscopic evidence.58 Malik and Saxena59 evaluated
compared to retroperitoneal adenopathy. This is because the role of ultrasound and ultrasound guided biopsy. By
mesenteric lymphnodes drain from small bowel and ultrasound, findings can be evaluated with regard to the
other intra-abdominal viscera drain into thoracic duct involvement of lymphnodes, intestines, peritoneum,
139
Figs 11.11A to D: Barium enteroclysis showing (A) Enteroenteric fistula, (B) Small segment stricture with proximal dilatation which was missed
on BMFT, (C) Multiple small segment strictures in jejunum and (D) Terminal ileal stricture with ulceration
solid viscera and abdominal abscess. Peritonitis of the evaluated on CT. In earlier stages symmetric circum-
“wet” ascitic type is the most common. Ultrasound ferential thickening of cecum and terminal ileum is seen
guided FNAC can be directly taken from masses, (Fig. 11.17A). In later stages asymmetric thickening of
lymphnodes or hypertrophied bowel. Ultrasonography the ileocecal valve and adjacent medial wall of the cecum
can pick-up lesions in form of large conglomerate granu- is seen. In more advanced disease gross wall thickening,
lomas and abscesses in liver and spleen. The classical adherent loops, large regional nodes and mesenteric
thickening together form a soft tissue mass centered
sonographic findings in mesenteric lymph nodes and
around the ileocecal junction.60 Ulceration or nodularity
peritoneal tuberculosis (clumped loops and ascites) are
of the terminal ileum, narrowing and proximal dilatation
shown in (Fig. 11.15).
can be picked up on CT scan. Circumferential wall
thickening, narrowing of the lumen and ulceration are
CT Abdomen
the features of bowel involvement. Involvement of the
CT demonstrates lymphadenopathy, organ lesions, ascending colon is common. Complications like
conglomerate masses and omental ‘cakes’ (Fig. 11.16). perforation, abscess, and obstruction are also seen on CT
Hyperplastic ileocecal tuberculosis is usually well scan. Typically lymphadenopathy is in the porta hepatis
140
Figs 11.12A to D: Barium enema showing (A) Segmental colonic TB in transverse and descending colon,
(B) Multiple ulcers in large bowel seen as diffuse colitis, (C) Colonic perforation (D) Stricture and ulceration in rectum
and in the para-aortic region, but can also involve the determining the density of the ascitic fluid which is
mesenteric nodes with typical fanning out of the vessels reported to be having high attenuation (25 to 45 HU);
and marginalization of the bowel loops.61 The nodes are presumably due to the complex nature of the fluid. The
usually matted together with hypodense centers which high density nature of the fluid is reported by some
probably are due to caseation and many occasionally authors64,65 as specific for TB whereas others66 suggest
contain calcification.60,62 that it is not a reliable factor and can overlap with
Lymph nodes may be calcified or show calcification peritoneal carcinomatosis.63
over the time, but the most characteristic appearance is Mesenteric disease on CT scan is seen as a patchy or
that of ring-enhancing nodes with low-density centers. diffuse increase in density, strands within the mesentery,
Central necrosis with rim enhancement, though not and a stellate appearance. Lymph nodes may be
pathognomonic, is a useful sign and readily seen in the interspersed. Omental thickening is well seen often as
current generation CT scanners.63 an omental cake with stranding. A fibrous wall can cover
Unlike USG the complex nature of the ascites is the omentum, developing from long standing
difficult to demonstrate by CT, however CT is useful in inflammation and is called omental line.67 Lesions in solid
141
Fig. 11.13: Goose neck deformity with stricture Fig. 11.14: Fistulogram showing enterocutaneous fistula
in colon
Figs 11.15A and B: High frequency ultrasound abdomen showing (A) Multiple lymph nodes with hypoechoic centers and
(B) Multiple clumped small bowel loops with free fluid in abdomen
organs are seen as low-density multifocal areas, most lymphadenopathy (N = 17) followed by solid organ
commonly in the liver and spleen, and rarely in the involvement (Fig. 11.17B) (N = 12) ascites (N = 5), bowel
pancreas. Over time these lesions may show calcification. wall thickening (N = 5) inflammatory masses (N = 2),
Inflammatory masses composed of bowel loops with and omental thickening in one.61
adherent omentum and lymphadenopathy are best
demonstrated on CT, as are omental ‘cakes’, seen
Ascitic Fluid Analysis
immediately deep to the abdominal wall. A combination
of the above CT features, especially when lympha- The peritoneal fluid if present in ATB is either straw colored
denopathy is rim enhancing or calcified, is highly or clear and is exudative in nature with proteins more than
suggestive of the disease. CT scan can help in 3 g/dl, cells more than 1000/cumm (mostly lymphocytes),
differentiating intra-abdominal M. tuberculosis infections ascitic/ blood glucose ratio less than 0.96 and serum
from M. intracellulare infections in patients with AIDS.68 albumin ascitic gradient (SAAG) level less than 1.1 g/dl.
Andronikous et al evaluated the CT of 22 children Adenosine deaminase (ADA) in ascitic fluid has been
who had ATB. Commonest CT findings were considered to be a useful screening test in children with
142
Figs 11.16A and B: Computed tomography (CT) abdomen showing (A) and (B) Formation of omental cake
Figs 11.17A and B: Computed tomography (CT) abdomen showing (A) Thickened bowel loops with multiple enlarged lymph nodes with
hypodense necrotic centers and (B) Multiple hypodense lesions in spleen (Splenic tuberculosis)
ATB. A level of more than 33U/L has a sensitivity and Histopathology of Peripheral Lymph Node
specificity of 93% and 96% respectively with positive
predictive value of 93%.69 In presence of abdominal symptoms, lymph node biopsy,
FNAC is helpful in diagnosis. Presence of caseating
Malabsorption Studies granuloma is the histological marker of tuberculosis.
Abnormal malabsorption tests seen in these children are Hematological and Biochemical Tests
not diagnostic. Abnormal parameters were seen in 30.8% They may indicate the extent of dysfunction of GIT but
of cases in pediatric series.24 It has been 17 to 33.7% in are not specific for diagnosis of abdominal tuberculosis.
different series in adults.4,23 Malabsorption is due to Anemia, hypoalbuminemia and raised ESR are the usual
decreased small intestinal mucosal surface, lymphatic findings. TLC is raised with predominantly lympho-
obstruction, fistula formation between the small and large cytosis in upto 50% cases.24
intestine, deconjugation of bile salts secondary to
bacterial overgrowth and decreased bile salt pool because Newer Modalities
of impaired active absorption in the terminal ileum.
Virtual CT Enteroclysis and virtual CT Colonoscopy
Demonstration of AFB
This is performed to define the site of hypertrophic and
AFB can be demonstrated in gastric aspirate, stool, stricturous lesions non invasively and in cases where the
sputum, urine and secretions from the fistulous tract. routine endoscopy is not possible. This is done after good
However, their presence does not confirm abdominal preparation of the bowel and images are reconstructed
tuberculosis. to define the nature and exact location of pathology. The
143
limitation of this technique is that the biopsy specimen iii. Antigens: To detect the presence of mycobacterial
is not possible. antigen in the blood, very sensitive methods like RIA
and ELISA have been used. ELISA is highly sensitive
Sonoenteroclysis for detection of antigen in CSF.75 A simple dot-ELISA
for detection of M. tuberculosis in sputum samples has
Sonoenteroclysis is another modality with which bowel
been developed. The sensitivity of antigen detection
can be examined for mural thickening and intra mural
pathologies. was 61 % in AFB positive compared to 40% in AFB
negative samples.76
Ascitic Fluid Adenosine Deaminase iv. Polymerase chain reaction (PCR): Nowadays PCR is
used to diagnose tuberculosis rapidly by identifying
Adenosine deaminase (ADA) is an aminohydrolase DNA of M tuberculosis in clinical samples. Most
involved in the catabolism of purine bases that converts commonly used target is insertion sequence IS6110
adenosine to inosine. T lymphocytes have more activity which is present in 60% of specimens.77 Even though
of ADA than B-lymphocytes. ADA activity depends studies showed high sensitivity and specificity of PCR
upon the degree of T-cell activation. Because of in pulmonary TB whereas in ATB it has low sensitivity
stimulation of T-cells by mycobacterial antigens ADA
and specificity. This is attributed to large size of
levels are increased in tuberculous ascitic fluid. ADA in
specimens and uneven distribution of disease. But
ascitic fluid has been considered to be a useful screening
some studies showed that M. tuberculosis strains
test in children with ATB. A level of more than 33U/L
has a sensitivity and specificity of 93% and 96% originating from India do not contain IS6110. An
respectively with positive predictive value of 93%.69 Indian study of PCR in ATB using 340 bp nucleotide
sequence located within 38 kDa protein gene of M.
Serodiagnosis of Tuberculosis tuberculosis showed 77% sensitivity and 66%
specificity.78 PCR amplification of IS6110 in fecal
i. Antibodies: There are various serological methods to samples of intestinal tuberculosis showed high
detect antibodies such as complement fixation,
sensitivity (88.8%) and specificity (100%).79
hemagglutination precipitation and gel diffusion,
v. Interferon gamma release assays (IGRA): Recently
soluble antigen fluorescent antibody (SAFA), radio-
IFN-gamma responses to M. tuberculosis specific
immunoassay (RIA), enzyme linked immunosorbent
antigens (ESAT-6, CFP-10, TB 7.7) are being used
assay (ELISA), circulating immune complex and
agglutination tests such as Kaolin Agglutination Test in the in vitro diagnostic tests for tuberculosis.
(KAT). ELISA and SAFA have been reported to be Commercial version of these tests includes
more sensitive and specific.70-72 KAT in a recent study QuantiFERON-TB Gold (QFT-G), QuantiFERON-TB
was positive in 94.1% of abdominal tuberculosis.73 Gold in Tube (QFT-GIT) and ELISPOT. These tests
Various authors have shown rise of IgG and IgE have high specificity of 97.7% and 92.2% for QFT and
classes of antibodies but out of these IgG (IgG2) has a Elispot respectively.80
better correlation.70 In a study comparing efficacy of vi. Other newer serological markers: Most recently
ELISA for IgG anti-bodies against specific glycolipid chemokine IP-10 (CXCL 10) has been introduced as a
antigen(PGL Tb1, Study I) and AST 6 antigen of M. specific diagnostic marker for infection with M.
tuberculosis (Study II) with ZN staining and culture tuberculosis.81 Thakur et al has proposed high serum
on LJ media, ELISA tests showed a significantly CA-125 as a pointer towards tuberculous infection.82
higher sensitivity (49% study I; 53%, study II) as Purohit et al in their recent study concluded that
compared with LJ medium culture method (15.4%, immunohistochemistry using anti-MPT64 is simple
study I; 28.9% study II) and ZN staining (27.7%, study and sensitive technique for establishing an early
I; 20.5%, study II) in all patients (p < 0.05). The results diagnosis of M. tuberculosis with sensitivity and
were comparable with PCR (40%, study I; 42.2% study specificity of 92% and 97% respectively.83
II). Specificity of ELISA test was 100% in all the Various criteria have been suggested for the diagnosis
patients.74 of abdominal tuberculosis and are given in (Table 11.4).13
ii. Monoclonal antibodies: Monoclonal antibodies have Any one of these criteria has to be positive to label the
been developed against M. tuberculosis. Monoclonal diagnosis of abdominal tuberculosis.
antibodies (IgG type) also called TB 72, are raised in
74% of pulmonary tuberculosis but very high titres
Differentiating ATB from Inflammatory Bowel Disease
have been reported in patients with peritoneal, (IBD)
pleural, pericardial and bone tuberculosis. In the same Intestinal tuberculosis and inflammatory bowel disease
way, synthetic peptides have been developed to are great mimickers. Both intestinal tuberculosis and
detect M. tuberculosis antibodies.70 Crohn’s disease are chronic inflammatory disorders of
144
Table 11.4: Criteria for diagnosis of abdominal Table 11.5: Difference between intestinal
tuberculosis TB and Crohn’s disease
Definitive Intestinal TB Crohn’s disease

• Histological evidence of tubercles with caseation necrosis Fever ++ Fever +
• A good typical gross description of operative findings with Circumferential/ Deep linear ulcers and
biopsy of mesenteric nodes showing histologic evidence transverse and patulous normal IC valve
of tuberculosis IC valve
• Animal inoculation or culture of suspected tissue resulting Hypertrophic lesions/ Cobblestone appearance
in growth of M. tuberculosis Nodularity/ and Aphthous ulcers
• Histological demonstration of acid fast bacilli in a lesion. Pseudopolyps
Caseating conglomerate Noncaseating compact
Modified
granulomas, AFB +ve granulomas AFB –ve
• Histological evidence of caseating granulomas or AFB Anorectal lesions and More often
• Presence of M. tuberculosis in sputum or tissue or ascitic fistula less often
fluid Excellent response No response to ATT,
• Clinical/radiological/operative evidence of proven to ATT require immunosu-
tuberculosis elsewhere with good therapeutic response ppression therapy
• Good therapeutic response to antituberculosis
chemotherapy
in the lamina propria in Crohn’s colitis shows variation
in the density of the infiltrate in different parts of the
bowel that pose difficulties in differentiating from one biopsy. 80 AFB positivity establishes diagnosis of
another. Distinguishing intestinal tuberculosis from tuberculosis.
Crohn’s disease may be extremely difficult, even when Colitis type of lesions in tuberculosis is very difficult
the results of endoscopy, surgical, and histologic to differentiate from ulcerative colitis. The differentiating
evaluation are available.84 Although both have similar features are given in Table 11.5. No single endoscopic
clinical manifestations, their ultimate course and finding is absolutely specific to either disease. Combining
treatment are quite different. Intestinal tuberculosis can endoscopic findings can predict the correct diagnosis in
be completely cured if diagnosed early and treated nearly 90% of cases.84
appropriately. In contrast, Crohn’s disease is not curable Anorectal lesions, longitudinal ulcers, aphthous
and treatment modalities are completely different. ulcers, and cobblestone appearance were significantly
Steroids and other immunosuppressive agents are useful more common in patients with Crohn’s disease.
in the treatment of Crohn’s disease but, can be deleterious Involvement of fewer than four segments, a patulous
if used in intestinal tuberculosis. The differentiation of ileocecal valve, transverse ulcers, and scars or pseudo-
intestinal tuberculosis from Crohn’s disease is therefore polyps were observed more frequently in patients with
very important (Table 11.5). intestinal tuberculosis. The direction of ulcers is
It has been reported that 40 to 65% of patients with longitudinal in patients with Crohn’s disease and
Crohn’s disease either received a trial of ATT or were transverse in those with intestinal tuberculosis.84
misdiagnosed as having intestinal tuberculosis before Presence of extraintestinal manifestations such as
they were finally diagnosed as Crohn’s disease.85,86 uveitis, arthritis and fistulae strongly suggests Crohn’s
Confluent granulomas are strongly suggestive of disease. The correct diagnosis of either disease can be
tuberculosis and in Crohn’s granulomas are not confluent made in most patients, if the results of clinical, endoscopic
even though two or three may lie in close proximity.87 In (both conventional and capsule), pathologic, bacterio-
Crohn’s granulomas are typically comprised of closely logic, and PCR evaluations are combined.
packed aggregates of epitheloid cells and macrophages Colorectal tuberculosis can mimic ulcerative colitis
and multinucleated giant cells are usually more abundant when it presents in the form of colitis. The colitis in
in tuberculosis.39 The presence of central caseation is a tuberculosis is usually segmental though it can be diffuse
hallmark of granulomas caused by tuberculosis, but small at times, whereas ulcerative colitis usually involves
areas of central necrosis can occasionally be seen in a rectum and left colon and may present as pancolitis. The
granuloma caused by Crohn’s disease.39 The granulomas differentiating points between TB colitis and ulcerative
of tuberculosis are always surrounded by inflammatory colitis are given in (Table 11.6).
cells, whereas those of Crohn’s disease can occur in an
otherwise normal biopsy, particularly in the rectum.88
Complications
The ulcers of tuberculosis almost always show a
granulomatous response whereas in Crohn’s disease the The most common complication of ATB that requires
ulcers and fissures may not always show granulomas.39 surgical intervention is intestinal obstruction. Obstruction
In tuberculosis the inflammatory infiltrate is usually seen can be due to adhesions, enlarged lymphnodes causing
145
Table 11.6: Difference between colorectal TB and obstruction.94 ‘Abdominal cocoon’ is described primarily
ulcerative colitis in adolescent girls and tuberculosis is also described as
infrequent cause of cocoon leading intestinal obstruction.
Colorectal TB Ulcerative colitis
Rare case of cocoon due to tuberculosis is described in
Segmental lesions Left colon disease often children also.95,96
Rectal disease uncommon Commonly involved Although few nonspecific radiological signs on plain
Diffuse colitis rare Common in children
X-ray, barium series and computerized tomogram scan
Disease could be
are described but diagnosis is usually made at
elsewhere in small bowel Backwash ileitis at times
TB granuloma, AFB+ No granuloma, Chronic laparotomy, which shows the encasement of the small
colitis No AFB bowel within the sac-like cocoon. Although the disease
Response to ATT Response to 5-ASA and primarily involves small bowel, it can also involve other
steroids organs like the large intestine, liver and stomach. The
treatment is by lysis of this covering membrane, and
rarely, further procedure such as resection, is required.97
extrinsic compression or due to stricture formation.
Intestinal obstruction was the indication for explorative Treatment
laparotomy in 40 to 65% cases in various surgical series.52,89
Antituberculous chemotherapy is the mainstay in the
Fistula formation and confined perforation with abscess
management of abdominal tuberculosis. Surgical options
are also common. The most important fistulae are entero-
are reserved for tissue diagnosis or treatment of
enteric, entero-cutaneous and perineal which could be
complications. Chemotherapy consists of 4 drugs and for
single or multiple. Free perforations are rare because of
duration of 6 months. Short-course chemotherapy is well
thickened peritoneum and adhesions with adjacent tissues.
studied in adults. Even though initial responses are good,
Incidence of free perforation ranged from 0 to 11% in
it is associated with frequent relapses. So many physicians
different studies and terminal ileum is most common
tend to extend therapy upto 12 months. Short-course
site. Multiple perforations are reported in 10 to 40%
cases.90,91 Hemorrhage, enterolithiasis, cocoon formation, chemotherapy and role of pyrazinamide have not been
traction diverticula and malabsorption are uncommon evaluated in children with abdominal tuberculosis. There
consequences. is a report of short-term chemotherapy in adults with
Intestinal hemorrhage due to enteric tuberculosis is 3 drug regimen of INH, rifampicin and pyrazinamide for
uncommon and usually is mild. It is usually due to 2 months followed by INH and rifampicin for 4 months.
bleeding from ulcers. Massive GI bleed due to Favorable response was seen in 97% in short-course
tuberculosis is very rare. In case of massive GI bleed most therapy versus 92% in standard treatment group. However
common site is terminal ileum followed by large bowel.92 toxicity was 26% in short-course group and 13% in the
Intraperitoneal hemorrhage can also occur and it can be standard therapy group.98 Short-course chemotherapy
massive rarely due to erosion of major vessels. Ulceration regimen consists of INH (4-6 mg/kg per day), rifampicin
with thinned bowel wall, and adhesions can lead to (10 mg/kg/day), ethambutol (15 mg/kg/day) and
traction diverticulae. Malabsorption is also an uncommon pyrazinamide (25 mg/kg/day) for initial 2 months. After
complication. This can be due to strictures causing stasis, 2 months ethambutol and pyrazinamide are stopped but
bacterial overgrowth and deconjugation of bile acids. INH and rifampicin in same dose are continued for 7
Mesenteric adenopathy at times may cause lymphatic months. If the nodal tuberculosis is dominating then
obstruction and can cause fatty acid malabsorption. antituberculosis therapy (ATT) is continued for 9 to 12
Enteroliths also can occur in intestinal TB, stricture and months. In ATB nodal tuberculosis is always there,
stasis being the predisposing factors. Subacute intestinal therefore consensus is to continue ATT for 9 months to
obstruction is causative factor rather than a consequence avoid relapse. If M. bovis is isolated pyrazinamide can be
of enteroliths. They occur mostly in small intestine. They discontinued because of its innate resistance to the drug.
can be radiolucent or radio-opaque and can occur in But it usually takes 2 to 3 months to make this
various shapes. Radiolucent center with dense rim is the differentiation. Ninety percent patients with enteric
characteristic radiographic feature. Usually in duodenum tuberculosis and even higher percentage of patients with
and jejunum with acidic pH enteroliths are radiolucent peritoneal tuberculosis will respond to medical therapy
and in ileum with alkaline pH due to precipitation of alone if it is started early enough.99-101
calcium they are radio-opaque.93 Hepatic transaminases are monitored periodically till
‘Abdominal cocoon’, also known as ‘sclerosing completion of therapy. When hepatotoxicity is present,
encapsulating peritonitis’ (SEP), which is a rare condition both the drugs INH and rifampicin are stopped and
that is characterized by the encasement of the small bowel alternate therapy is given till the time there is recovery
by a fibrocollagenic cocoon like sac that causes intestinal of hepatic injury.
146
It is believed that ATT reduces fibrosis along with dissection and thus reduces chances of injury to the
healing and also causes some regression in fibrosis duodenum and ureter.101,110,111 Bypass procedures like
thereby reducing predisposition to adhesions and ileotransverse anastomosis are avoided and limited right
stricture formation. The role of corticosteroids in the hemicolectomy with a 5 cm margin from grossly
management of ATB to decrease the formation of abnormal bowel is the procedure of choice in ileocecal
adhesions and stricture is not proven.101,102 Two large TB.112
studies did not show any beneficial effect with use of In cases of perforation, resection rather than simple
steroids in ATB. 103,104 Clinical and radiological resolution closure is safer.113,114 Freshening of the bowel edges and
of tuberculous strictures may occur with treatment with transverse closure is an option if the bowel is healthy.
ATT even in patients presenting with features of subacute All patients of perforation and peritonitis should have
intestinal obstruction.101 Therapy can also increase the peritoneal toilet and drainage as well. Simple strictures
incidence of perforation. Drugs are usually well tolerated are best treated with stricturoplasty, which involves a
in children and adverse reactions occur in only 1.1% longitudinal enterotomy along the anti-mesenteric
cases, all of which are reversible.105 Compliance however, border which is then sutured transversely. 25, 52,101
still remains a significant hurdle, is seen in only 62%. Resection is advocated for multiple strictures or if there
Prolongation of treatment and motivation is needed in is significant edema of the bowel wall. Recurrent
such cases. The second cause of failure is the development adhesive obstruction may require intestinal stenting.
of drug resistance. Culture sensitivity studies and appro- Fistulizing disease like enteroenteric and entero-
priate modification of the regimen is required. cutaneous fistulae are initially treated with ATT for 3
In peritoneal tuberculosis, effective anti-tuberculosis to 4 months then can be taken up for surgical correction
therapy is the mainstay of treatment. In enteric in case of persistence.
tuberculosis which is commonly associated with Surgery in ATB is hazardous, requires great care and
complications, surgery may be required. Antituberculosis restrains to minimize bowel handling and dissection.
therapy should be given preferably for 6 to 8 weeks prior Enterocutaneous fistula formation is not uncommon after
to surgery and continued for at least 6 to 9 months after surgery. These high output fistulas require aggressive
surgery. management, which entails adequate drainage, TPN,
antibiotics and ATT.
Role of Surgery in Abdominal Tuberculosis
The role of surgery is now largely limited to tissue
diagnosis in case of peritoneal and lymphnodal ATB and
for the management of complications which include HIGHLIGHTS
obstruction, perforation, fistula formation or rarely • Abdominal TB is the uncommon form of
significant bleeding.2,101,106,107 The indications for surgical tuberculosis in pediatric age group.
treatment are: • The diagnosis is made on high index of suspicion
with detailed clinical history and examination of the
Diagnostic patient.
• Often the disease is either missed or over diagnosed
• Minilaparotomy and biopsy
due to lack of investigative tools in the peripheral
• Laparoscopic biopsy in ascitic type
centers.
• Extra-abdominal lymph node biopsy.
• Definitive diagnosis is made by demonstration of
– Exploratory laparotomy in acute abdomen
caseating granulomas with AFB positivity in the
– Management of complications like strictures,
tissue, however majority of times this is not possible.
adhesive obstruction, fistulae or bleeding.
• Endoscopic descriptions of lesions, FNAC,
Before the advent of effective antituberculous drugs,
histopathology of biopsy specimen, crush smears
surgical management consisted of bypassing the stenosed
for cytology, culture and PCR from the tissue give
segment with enterostomy and ileo transverse colostomy
the definite diagnosis in majority of cases of
procedures, because any resectional surgery is hazardous
intestinal TB.
in presence of active disease. These led to the
• Barium studies, USG and CT scan are the other
complications like short gut and blind loop syndrome,
modalities which have specific signs and add to the
fistulae and recurrent obstructions in the remaining
diagnostic armamentarium.
segments. However, with the realization that tuberculous
• In case of peritoneal, wet type of TB, estimation of
pathology heals well with ATT, conservative surgical
ADA is very sensitive and specific method.
resection and stricturoplasty became popular.42,108-110 For
• The diagnosis of nodal tuberculosis is made by
ileocecal lesions, limited resection of the ileocecal area
ultrasound, CT and FNAC of lymph nodes.
rather than a formal right hemicolectomy, involves lesser
147
20. Colditz GA, Brewer TF, Berkey CS, et al. Efficacy of BCG
• Surgical treatment is only required in cases of
vaccine efficacy in the prevention of tuberculosis. Meta-
complications otherwise ATT is very effective to analysis of the published literature. JAMA 1994;271:698-
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disease. 21. Centers of Disease Control and Prevention. Core
• The treatment has to be well controlled and curriculum on tuberculosis: What a clinician should
monitored and to be given for 9 months to avoid know. 4th edn. Atlanta (GA): US Dept of Health and
relapse. The outcome is excellent with adequate Human Services; 2000.
ATT. 22. Achar ST, Viswanathan Abdominal tuberculosis in
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New Delhi, Vikas Publishing House Pvt Ltd 1981;387-8.
23. Bhansali SK. Abdominal tuberculosis. Experience with
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12 Neurotuberculosis
12.1 PATHOLOGY AND PATHOGENESIS

PM Udani
MAGNITUDE, CHANGING CLINICAL PATTERNS AND also to understand its pathogenesis. Here early diagnosis
SYNDROMES SPECIALLY IN BCG-VACCINATED CHILDREN and adequate management is of vital importance.
In early 50s the mortality was high with low rate of
Tuberculosis in children is a major health hazard and
recovery. With improvement in treatment the recovery
neurotuberculosis especially tuberculous meningitis
rate has improved with an increase in serious sequelae
(TBM) is the main cause of death amongst the various
as the diagnosis and treatment are often delayed. Hence,
complications of primary infection. TBM has varied
the most important aspect is prevention of serious
pathological changes in the nervous system. Various
brain damaging mechanisms have been described and complications of primary infection by the use of three
some illustrated by neuropathological findings seen in drug combinations in the intensive phase followed by
children at autopsy. The classification of tuberculosis of two drugs in the continuation phase as labeled category
the nervous system has been described more than two decades III under DOTS in Revised National Tuberculosis Control
ago, but newer clinical pictures and syndromes have emerged Program (RNTCP) of the Government of India. This is
mainly over the last two decades because of extensive coverage particularly important in high risk cases.
of children with BCG vaccination. Misuse of powerful As long as tuberculosis in adults remains a major
antituberculous drugs has been in practice in recent years problem, the same will be reflected in children and
and these drugs are abused or inadequately used in many various changing manifestations of neurotuberculosis
types of pediatric tuberculosis resulting in poor control will continue to challenge the diagnostic and therapeutic
ability of the pediatricians.
of primary infection or disease. As a result, newer clinical
Neurotuberculosis is one of the serious complications
pictures of neurotuberculosis are emerging.
of primary tuberculous infection. TBM is the main cause
BCG vaccination imparts partial immunity. It
of death and disability in children with tubercular
prevents the hematogenous spread of infection.
disease. In a study by Dhariwal and Udani,1 of the 246
However, it cannot prevent the lodgment of tubercle
children who died at the Institute of Child Health,
bacilli in the lung and thus development of primary
Bombay, 16.5% died of tuberculosis. In another series by
infection and its local complications. Similarly partial or
them over a period of 2 years (1981-83) tuberculosis was
inadequate antituberculous drug therapy improves the
responsible for 9.6% of admissions and 10% of the
T lymphocyte functions in the child so that neurological
mortality.2 In an autopsy series of cases in adults and
complications of primary infections have emerged with protean
children under 15 years of age studied over a period of
clinical manifestations.
10 years from 1976 to 1987, deaths due to tuberculosis
The localized form of neurotuberculosis involving
were 11.6% in 7676 adults and 10.8% in 4080 children.3
brain and meninges are being commonly seen now. The
CNS tuberculosis accounted for 65.5% of the total deaths,
various neurological signs which develop during the i.e. neurotuberculosis was responsible for two-third of
treatment of TBM like convulsions due to tuberculoma, the deaths. This data represent the picture about two
are being seen under these situations and they have been decades ago. In the current scenario due to vigorous
described with cliniconeuropathological correlation. attempts of Government of India to cover adults and to
Thus, neurotuberculosis presentations pose a diagnostic some extent children with DOTS under RNTCP picture
challenge, though awareness of clinical features and the might have changed. However, even in the present
availability of CT scan and Magnetic Resonance Imaging scenario of availability of imaging technology (CT and
(MRI) have helped not only to suspect the disease but MRI), the high index of clinical suspicion is very
151
Chapter 12 Neurotuberculosis
important. (Some of these pathological changes can be

correlated with CT and MRI findings as illustrated in the
chapters 12.3 of clinical case studies and 26 on imaging
in children).
PATHOLOGICAL ASPECTS
General Considerations
The nervous system is damaged by a number of
pathological mechanisms in neurotuberculosis4-6 (Figs
12.1.1 to 12.1.10). The following description of
pathological aspects found on classical autopsy studies
need correlation with CT and MRI findings. Some of these
have been described in the imaging chapter.
Meningeal Exudate
These occur mainly at the base of the brain. Exudate per
se can involve a number of structures at the base of the
brain with resultant clinical manifestations (Figs 12.1.1 Fig. 12.1.2: Histological section study of narrowed third ventricle (see
to 12.1.6). Fig. 12.1.1) by medial border of the right thalamic tuberculoma (curved
arrows). On the left, there is basal exudate with a number of blood
vessels in it including a large artery (long arrow) showing marked
Obstruction of CSF Pathway narrowing of the lumen by subintimal fibrosis and exudate lining the
ependyma of the third ventricle, and periependymal congestion (paraffin
Hydrocephalus is mostly due to obstruction of the CSF section, hematoxylin and eosin X 15). Multiple brain damaging
pathway of the basal cisterns but can occur at the level of mechanisms in the region of the thalamus and hypothalamus can be
interventricular foramina, aqueduct of Sylvius or appreciated, viz. tuberculoma, basal exudate, ependymitis and its para-
foramina of Lushka and Magendie. At times the ventricular extension to the brain structures, (see Fig. 12.1.3) partial
arterial occlusion with ischemic brain damage, etc. (Dastur and Udani,
obstruction occurs at multiple levels. Hydrocephalus is 1983)4
one of the most common mechanisms of brain damage
by causing myelin depletion, axonal degeneration and
neuronal fall out initially in cerebral white matter and
later in the cortex (Figs 12.1.5 and 12.1.7).
Fig. 12.1.3: A microscopic view of the ependymal exudate seen in Figure

12.1.1, showing mass of small mononuclear cells on the ventricular
side of the destroyed ependyma, with some border-zone encephalitis
Fig. 12.1.1: Coronal slice through cerebral hemisphere showing large (in the form of perivascular inflammation) and edematous white matter
tuberculoma in the right thalamic and subthalamic region, asymmetrical at the lower border of the picture (hematoxylin and eosin X 110) (Dastur
dilatation of the lateral ventricles, virtual absence of left basal ganglia and Udani, 1983) 4
(due to infarction) with a small remaining scar (curved arrow) basal
exudate enveloping and causing narrowing of left middle cerebral artery
(short thin arrow), marked narrowing (almost like a slit) of the third
Large Vessels
ventricle (split arrow), which is displaced to the left by the tuberculoma
Varying degrees of involvement and occlusion of large
on the right. In the cerebral hemispheres bulkiness of white matter due
to edema and thinning of the gray matter can be seen (Dastur and vessels in the Circle of Willis and that of middle cerebral
Udani 1983)4 artery in the sylvian fissure by the exudate leads to
152
Fig. 12.1.6: Coronal slice of the brain in an advanced case of TBM

(Dastur and Udani, 1983).4 It shows proliferative type of basal exudate
surrounding the two optic nerves adhering to the base of the brain and
extending into the sylvian fissures especially on the right where the
middle cerebral artery is compressed and the upper lip of the fissure is
softened. Such dense basal exudate surrounding the two optic nerves
can produce: (i) optic neuritis per se, (ii) and/or direct compression of
Fig. 12.1.4: Microscopic view showing choroid plexitis. Histology of the the optic nerve by the exudate with primary optic atrophy, (iii) damage
third ventricle (Fig. 12.1.2) showing predominantly small mononuclear to the small arteries, (iv) compression of the middle cerebral artery on
cell reaction amidst thickened and obliterated papillae of choroid plexus right side with infarction in its territory, (v) necrosis and softening of
(Dastur and Udani, 1983)4 upper lip of the sylvian fissure, and (vi) hydrocephalus
Fig. 12.1.5: Coronal section of the brain in a child who died of advanced
TBM (Udani and Dastur, 1971).21 Figure shows destruction of the
subthalamic and subputaminar areas by the basal exudate which has
penetrated the region of the nucleus subthalamicus on both sides,
especially the right. Also note the hydrocephalus of both the lateral
ventricles caused by obstruction (gluing) of the basal cisterns. Edematous
bulky matter can also be seen on both sides. Such dense exudate at the
base of the brain can produce: (i) brain damage (infarction) by the occlu-
sion of vessels, (ii) damage to the nerves which are engulfed in the
exudate, and (iii) direct damage by the exudate by tracking up to the Fig. 12.1.7: Coronal slice through highly edematous right frontal lobe
basal ganglia, and (iv) obstructive hydrocephalus due to gluing of the (Dastur and Udani, 1983).4 Note pale bulky white matter due to myelin
basal cisterns loss and consequent thinning of the gray matter especially of the frontal
lobe constituting an edematous encephalopathy, the patient presenting
ischemic foci in the brain. With complete occlusion of with drowsiness progressing to coma
the artery, there is infarction with severe brain edema
around it (Fig. 12.1.6).
can be detected in CT scan as hypodense areas. They are
Small Arteries better appreciated in MRI of the brain.
Small arteries particularly lenticulostriate vessels have
small areas of infarction in the region supplied by them. Nerves
These small lesions lead to focal lacunar infarcts with Engulfment and/or destruction of the cranial nerves,
edema around them which clinically may present with particularly II, III, IV, VI, VII result in multiple cranial
localized encephalopathy (Figs 12.1.9 and 12.1.10) and nerve palsies.
153
Fig. 12.1.8: Histology of the edematous frontal lobe with pale bulky Fig. 12.1.9: Histological section of the brain with perivascular and
white matter (Fig. 12.1.7), that part of the edematous frontal white matter paravascular cellular reaction as well as diapedesis of red blood cells
showing marked pallor (due to loss of myelin) and a relatively darker gray into the brain. There are three small arterioles seen in the picture. Such
matter of the gyri included especially at the top left, outside which is some a peri-or paravascular microscopic hemorrhage is one of the
vascular reaction in the leptomeninges. The white subcortical line characteristic features of tuberculous encephalopathy. Though such
represents actual spongy degeneration (Heidenhain’s myelin stain, X lesions are seen in diffuse tuberculous encephalopathy localized
15) lesions/cerebral edema leading to cerebral damage might develop in
children who are vaccinated. Severe edema may lead to necrosis of
Other Structures the brain
Extension of the basal meningeal exudate into the brain

with damage to various structures, for example
involvement of nucleus subthalamicus and its pathways
results in ballismic movements (Fig. 12.1.5). Less
commonly damage to hypothalamic nuclei in the floor
of the third ventricle results in leukotomy or frontal lobe
syndrome.
Border-zone Encephalitis
This may coexist with meningitis.
Ventriculitis
This may occur with subpial or subependymal necrosis.
Choroid Plexitis
Large and small tuberculomas with varying degrees of
brain edema. Fig. 12.1.10: A case of hemorrhagic encephalopathy. Coronal slice of
one hemisphere shows confluent and discrete hemorrhages in the white
matter of the cerebrum and cerebellum. Such gross hemorrhages in
Generalized Edema due to Microangiopathy the cerebrum and cerebellum are rare, though microscopic
hemorrhages along with exudation of edema fluid due to damage to
Generalized edema can produce severe damage to the capillaries (microangiopathy) are characteristic features of tuberculous
brain without any infarction, tuberculoma or other naked encephalopathy. This girl took adequate treatment. Six months later
eye lesions. Edema and microscopic hemorrhages due she presented with high fever, meningeal signs and pin-point pupils. A
to capillary damage are the most important mechanisms posterior fossa tuberculoma was suspected. However, before the opera-
tion could be done she died. Autopsy revealed gross hemorrhages in
in tuberculous encephalopathy (Figs 12.1.9 and 12.1.10). the cerebrum and cerebellum
BCG-vaccinated Children
Venous Involvement
Those who have some immunity may get localized lesions
due to focal microangiopathy with clinical features Less commonly, involvement of the veins with
depending upon the area involved. Such localized hemorrhagic infarction and rarely thrombosis of superior
edematous area can be detected in CT scan and MRI of the longitudinal sinus are seen.
brain. When the edema is severe, it causes necrosis of the Extension of TBM to brainstem and around the spinal
brain tissue. cord constitute spinal TBM.
154
Fig. 12.1.11: Clinical classification of neurotuberculosis6,20 (does not include various neurological and other related syndromes)
HYD-Hydrocephalus, ENC-Encephalopathy, MULT.CR.N-Multiple cranial nerve
Damage to the Motor Roots neuropathy, and established that it is due to direct
destruction by immunocompetent T cells which migrate
By exudates or immunological mechanism which leads from blood of the neural tissues and produce myelin
to polyneuritis or localized motor neuropathy. damage. The same findings have been seen both in their
human as well as animals studies.
Peripheral Nerve Damage
By immunological mechanism. Brain Edema and Hemorrhage
Figure 12.1.11 gives the various types of These are due to severe damage to the capillaries. Nor-
neurotuberculosis encountered in day-to-day practice. mally, intact capillaries provide a strong blood-brain
barrier. With damage to the capillaries (usually immuno-
SPECIFIC CONDITINS mediated) there is greater migration of fluid into the brain
tissue, mainly in the white matter. Severe edema leads
Pathogenesis of Neurotuberculosis and its Implication to myelin loss, while capillary damage may produce
on the Detection of AFB in CSF and Highlighting the small microscopic hemorrhages in brain which are peri-
Clinical Spectrum of the Disease vascular and rarely, gross petechial hemorrhages.10-12
It is now well recognized that hypersensitivity plays a great

Immunological Study
role in the pathogenesis of neurotuberculosis in children.
Various studies have revealed that symptoms of TBM The immunological study of CSF by ELISA in children of
can be produced by injection of “tuberculoprotein” subacute meningitis, Chandramukhi and Nayak13 found
intrathecally or intracisternally in sensitized experimental that tubercle bacilli were not found in CSF of 105 children
animals while none can be seen in control animals.7 with tuberculous meningitis, while Tandon in an
Moreover, the symptoms and pathology are dose related. exhaustive study of tuberculous meningitis in adults
A large dose (with evidence of basal exudate) will isolated bacilli only in 2.5% of cases.14 The maximum
produce convulsions, coma and death in animals. Studies incidence of finding tubercle bacilli was 20% in children
by Tandon et al8 in Indian monkeys have confirmed the by Joishy and Sant.15 This shows that the yield of tubercle
production of localized meningitis or localized bacilli is very low in CSF in spite of repeated cultures even
encephalomalacia in BCG-vaccinated or drug protected at the advanced and sophisticated centers in India.
animals and meningitis with edematous and However, researchers in National Institute of Mental
hemorrhagic encephalopathy in animals who were Health and Neurosciences (NIMHANS), Bengaluru found
hypersensitized by tuberculoprotein and Freud’s that there was a high yield of TB antigen particularly LAM
adjuvant. When live bacilli were injected in nonsensitized (Lipoarabinomannan) antigen in 81.7% of cases and fairly
or tuberculin negative animals, they developed high yield of specifically delineated epitopes 14, 19, 38 and
generalized meningitis and died. A similar pathogenesis 50 kilodalton (kD) with defined levels of monoclonal
was postulated in children with varying types and antibodies. Also, there was fairly high yield of TB
severity of clinical features on meningeal involvement. monoclonal antibody to the epitopes mentioned above;
Wisniewski and Bloom9 studied the pathogenesis of though per se the yield is not high (35.41%) and is poor
myelin loss not only in TBM, but also in tuberculous under the age of two years.
155
Immune complex was found in a fair number of TBM Isolated Spinal Tuberculous Meningitis
patients indicating that antigen antibody reaction or
hypersensitivity plays a very important role in the Localized Lesions
causation of various symptoms. This has been the reason Localized lesions in various parts of the brain which may
why bacillary yield from CSF is very low as opposed to be isolated or present with different combinations of
the findings of workers in developed countries like UK. pathological and clinical features are:
It appears that depending upon whether tubercle bacilli, • Internal capsule.5
TB antigen, antibody, or immune complex are present in • Thalamic nuclei with or without involvement of
a patient and from time-to-time, there will be failure of adjacent structures.
detection of tubercle bacilli in CSF in children, as • Basal ganglia, viz caudate nucleus, putamen and
hypersensitivity plays a predominant role in the globus pallidus.
pathogenesis of TBM in them.7-9,12,15,16 • Subthalamic nucleus with development of
In this connection, the spectrum of tuberculous hemiballismic movements on the contralateral side
disease can be compared to leprosy where in a case of often with associated hemiplegia on the opposite
lepromatous leprosy there are huge number of bacilli, in side.21
tuberculoid leprosy there are fewer number of bacilli • Involvement of optic nerve by the exudate or
while in intermediate cases bacilli would be variable. tuberculoma causing primary or secondary optic
Hence, in children in India who are vaccinated and those
atrophy. The latter may require urgent surgical
who have received prior drug therapy the yield of
decompression.22
tubercle bacilli is very poor.
• Localized involvement of aqueduct with dilatation
of third and lateral ventricles.6
Atypical or Modified Clinical
• Localized involvement of geniculate bodies and/or
Pictures in BCG-vaccinated Children
superior and inferior colliculi with impairment of
A large number of atypical clinical pictures have been hearing and vision, particularly with involvement of
described by Udani et al17-20 in vaccinated children. eye movements like upward gaze.
Following are some of the localized lesions in the • Localized involvement of brainstem with
meninges or different parts of the brain. development of locked-in syndrome (Table 12.1.1).
Meningeal Tuberculoma • Localized involvement of midbrain with upper
cranial nerve palsy, III, IV, VI and red nucleus and
Serous tuberculous meningitis—It is at the base of the brain
other areas in the midbrain (Table 12.1.2).5
which may result in mild hydrocephalus and hemiparesis
• Localized involvement of lower part of pons and
on one side with or without cranial nerve palsies.19,20
medulla with involvement of VII to XII nerve nuclei
Localized meningitis on the or nerves.5
superiolateral surface of the brain • Some of the above mentioned clinical entities either
isolated or with various complications are examples
Localized meningitis in the posterior fossa—mentioned in the
of clinical manifestations of neurotuberculosis.
classification with unilateral or bilateral cerebellar
Table 12.1.1 gives the various brainstem syndromes
hemispheric signs or signs of involvement of vermis with
described by Rowland 23 some of which have been
disturbance of equilibrium.
recorded by Udani et al.17,18,21 Table 12.1.2 provides the
Table 12.1.1: Various brainstem syndromes likely to occur in localized TBM with involvement of vessels
Syndrome Artery Structure Manifestation

affected involved
• Medial syndromes Paramedian branches Emerging fibers of the Ipsilateral
medulla XII nerve hemiparalysis
• Inferior pons Paramedian branches Pontine gaze center, near or Paralysis of gaze
in the nucleus of to side of lesion
the VI nerve
Anterior inferior cerebellar Emerging fibers of the Ipsilateral facial
VII nerve paralysis
• Superior pons Paramedian branches Medial longitudinal Internuclear
fasciculus ophthalmoplegia
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Table 12.1.2: Clinicopathological correlation of extrapyramidal neurological syndromes in

tuberculous meningitis (Udani, 1965—unpublished data)
Clinical features Frequency Principal location of
morbid anatomy
• Unilateral plastic rigidity Rare Contralateral substantia
with static tremor (Parkinson’s syndrome) nigra plus(?) other structures
• Unilateral hemiballismus Very Contralateral subthalamic nucleus
common of Luys, prerubral areas and
Forel’s fields
• Choreic movements Rare Caudate nucleus and putamen
• Athetosis and dystonia Common Contralateral striatum and connec-
tions with thalamus
• Cerebellar incoordination, Not common Homolateral cerebellar hemisphere
intention tremor and hypotonia or middle and inferior cerebellar
peduncles, superior brachium
conjunctivum (ipsilateral if below
the decussation, contralateral if above)
• Decerebrate rigidity Usually present in Usually bilateral in tegmentum,
advanced stage involving upper brainstem parti-
cularly red nucleus or structures
between red and vestibular nuclei
• Facial myoclonus Rare Contralateral dentate nucleus or
(rhythmic) superior cerebellar peduncle or
ipsilateral central tegmental tract
(dentato-olivary pathway)
• Diffuse myoclonus Very rare Neuronal degeneration, usually
diffuse or predominating in cerebral
cortex and dentate nuclei
clinicopathological correlations of extrapyramidal ventricular structures are likely to be affected because of

neurological syndromes. ventriculitis affecting the adjacent grey matter of
With improvement and recovery in children with thalamus. The hypothalamus is much more likely to be
various types of neurotuberculosis especially TBM, there affected because of the basal exudate which is often dense
have been a number of new clinical features and at the base of the brain in the middle cranial fossa.
syndromes emerging either at the onset but more Exudate itself can spread to the adjacent areas of hypo-
commonly during the course of the disease and some thalamus or the dilated third ventricle may compress
even months and years after the child has recovered from upon various parts of the hypothalamus and hypo-
meningitis. Some of the syndromes have been described thalamic pituitary axis and rarely the red nucleus.
by Udani et al.10,1719,21,24,25 The various syndromes which The thalamus and hypothalamus, especially the latter,
were seen are detailed in the Tables 12.1.1 and 12.1.2. can also be damaged by ischemia produced by the exudate
However, after this description of the syndromes in 1974 compressing the various branches of the circle of Willis
Udani et al saw many more syndromes with increasing particularly their small branches. The various syndromes
recovery rate of TBM. They opined that the varieties of can present as isolated manifestation of a focal lesion. If
clinical features are likely to be encountered in children there are multiple focal lesions, the clinical presentation
with TBM at various stages.21,24,25 may change but when there is generalized meningitis and
involvement of brain, the syndromes are masked. However,
PATHOLOGICAL BASIS OF they may manifest during or after improvement of TBM
with treatment and at times at the onset from a focal
VARIOUS SYNDROMES21,26-28
lesion.
The structures at the base of the brain and around the Tables 12.1.3 to 12.1.5 mention some of the clinical
lateral and third ventricles particularly the latter, are syndromes observed in the past21,24,25 but are being seen
commonly affected and hence their damage is expressed in recent years particularly because of the detection of
with development of different syndromes. Peri- the lesions in the neuro CT scan and MRI with better
157
Table 12.1.3: Classification and incidence of various Table 12.1.4: Classification and incidence of various
syndromes at onset syndromes after the disease is well-established
Syndrome No. % Syndrome No. %
• Paralyses • Cranial nerve palsies
Hemiplegia 98 31.5 Optic nerve 71 18.3
Quadriplegia 96 30.9 Motor nerves 226 58.2
Monoplegia 13 4.2 • Motor
Paraplegia (cerebral) 3 0.9 Decorticate spasm/rigidity 16 4.2
• Abnormal movements Decerebrate spasm/rigidity 63 16.2
Hemiballismus 57 18.3 Flexor spasm 2 0.5
Tremors: Generalized 32 10.4 • Acute increase of intracranial pressure 5 1.3
Parkinsonian 1 0.3 • Cerebellar hemispheric syndrome 5 1.3
Myoclonic jerks 1 0.4 • Involvement of brainstem and – –
Posterior fossa meningitis with 2 0.6 locked-in syndrome*
midline cerebellar syndrome • Reappearance of neonatal reflexes* – –
• Therapeutic paradox 6 1.8 Total 388 100.0
• Spinal leptomeningitis 2 0.6
*These syndromes have been described in literature, but not
Total 311 100.0 documented in our series by Udani et al10,17-19,21,24,25
understanding of probable pathogenetic mechanisms. Table 12.1.5: Classification and incidence of various
These can be classified as: syndromes during the recovery
• Syndromes at onset (Table 12.1.3)
Syndrome No.
• After the disease is well established (Table 12.1.4)
• Those occurring during the recovery phase (Table • Hypothalamic-pituitary syndromes
12.1.5). Cushing’s disease 6
At the onset of the disease almost one-third of the Obesity* –
cases develop either hemiplegia or quadriplegia. When Diabetes insipidus* –
the disease is well established 58.2% of the cases develop Excessive sleeping (somnolence) 1
Syndrome of SIADH 1
paralysis of motor nerves. The rare syndromes occurring
Clinical pictures like Barter's syndrome* –
after the recovery from the disease.
• Syndrome of persistent pyrexia* –
• Recurrent attacks of serous meningitis* –
Korsakoff’s Syndrome • Postmeningitic encephalopathy* –
Udani et al saw this syndrome in a child when he was • Postlumbar puncture (postmeningitic)
recovering from TBM. The likely lesion is damage to the spinal “epidermoid” 2
mammillary body and Ammon’s horns of the * These syndromes have been described in literature, but not
hippocampus. documented in our series
Fever, Psychiatric Aberrations and Diabetes Insipidus21 Unilateral Contralateral Hemiballismus

This is due to damage of supraoptic nuclei of the This is commonly seen in children with TBM when they
hypothalamus and damage may be transient or long have hemiplegia on one side and hemiballismus on the
lasting. opposite side. With the improvement in hemiplegia often
the ballismic movements become bilateral. This is due to
Precocious Puberty damage to the subthalamic nucleus by the exudate
tracking up from the base of the brain.
Udani et al21 described precocious puberty in 1971. This
is probably due to involvement or damage to the pineal
Syndrome of Inappropriate Secretion of
gland, which has inhibiting influence on sexual
Antidiuretic Hormone (SIADH)
maturity. The destruction of the parenchyma of the
pineal gland abolishes this influence. It is also possible The supraoptic nucleus of the hypothalamus probably
that irritation of the tuber cinereum of hypothalamus produces antidiuretic hormone (ADH) which stimulates
by the enlarging third ventricle provides the stimulus absorption of water from distal portion of renal tubules
for early sexual development.5,21,27,28 independent of solids. Neurons of supraoptic nucleus have
158
osmoreceptors, which are very sensitive to changes in the Table 12.1.6: Hypothalamic and other syndromes
osmolality of the surrounding tissues and regulate the water described in neurotuberculosis24
metabolism of the body. Damage to these nuclei causes
Syndrome No.
diabetes insipidus and patient develops polyuria and
polydypsia. Polyuria occurs only if cortisol is present. • Massive hematemesis (acute gastric ulcers) 3
Operative removal of neurohypophysis does not prevent • Acute intestinal colic simulating acute
diabetes insipidus because ADH producing nuclei promote abdomen (appendix removed) 2
• Abdominal pain and hyperperistalsis –
the hormone to enter the circulating blood directly. SIADH
(common in advanced TBM)*
is common in TBM and some authors have found its
incidence to be as high as 67%. However, unless it is severe * Described in literature, but not documented in the series by
it can be easily missed.29 Udani et al.24
Persistent Pyrexia increased parasympathomimetic activity which may

result in increased intestinal peristalsis. Udani et al24 have
Often children with TBM improve with treatment but described severe abdominal pain simulating appen-
later start getting persistent high fever. This is probably dicitis. Laparotomy was done in these children and the
due to damage to the rostral hypothalamus particularly appendix was found to be normal. However, soon they
preoptic area which regulates body temperature. Such developed the characteristic picture of TBM and died
cases were seen in whom temperature is lowered with steroid (Table 12.1.6).
therapy. However, prognosis is poor in such cases.5
Acute Gastrointestinal Bleeding
Obesity/Emaciation
Hypothalamus also controls the regulation of food intake. Three children presented with massive hematemesis.
The lateral area of tubercinerium acts as a center for However, within one week of the bleeding episode the
hunger or appetite, while the ventromedial nucleus of children had characteristic evolution of signs and
the thalamus is concerned with satiety. Damage to the symptoms of TBM and died. Autopsy revealed acute
latter affects satiety with the result that child develops gastric ulcers. Such stress ulcers with bleeding from
voracious appetite and obesity. This is seen long after gastrointestinal tract are probably due to stomatostatin
the stoppage of steroid therapy is omitted in a child with depletion. Wright described acute gastric ulcers in
TBM and may appear even after months. On the other experimental animals caused by damage to the
hand, lesions in the lateral nucleus of the hypothalamus hypothalamus.30
produce total loss of appetite leading to emaciation.
Cushing Disease
Abnormal Sexual Development Four cases of cushing disease during the course of TBM
Both hypogenitalism as well as precocious puberty with have been described by Udani et al.24 These children had
involvement of hypothalamus have been described by hypertension, flushed facies, tachycardia, tachypnea and
Udani et al.24 If the child recovers there will be an effect striae-symptoms which are due to increased sympatho-
on the sexual behavior in future. The gonadotrophic mimetic activity caused by stimulation of caudal
center is located in the infundibular or ventromedial hypothalamus particularly the posterior nucleus and area
nucleus which releases gonadotrophic pituitary lateralis. Usually, the syndrome is caused by pituitary
hormone. Sexual behavior inhibitory center is located tumor (basophilic adenoma). However, hypothalamic
rostral to the ventromedial nucleus. As mentioned earlier, neurons being surrounded by dense capillary network,
precocious puberty has been observed in children in control neural as well as neurosecretory and humoral
whom tuberculous granulomatous reaction with mechanisms.26 It also occurs due to involvement of cells
vasculitis has produced damage to the hypothalamus of neurohypophysis.21
rostral to the infundibulum and ventromedial nucleus.
Loss of inhibitory center is considered as the cause of Hyperglycemia
precocious puberty.
Hyperglycemia and a picture of diabetes mellitus can be
seen rarely in a child during the course of disease.24 It
Serious Autonomic Nervous System Dysfunction
responds to insulin, is often transient, and is due to
Acute Abdomen damage to the caudal hypothalamus.
This usually occurs at the onset of the disease. The
hypothalamus represents the cerebral center for all
Behavior
autonomic functions of the body. Stimulation of the rostral There are various types of behavioral changes in children
hypothalamus particularly the supraoptic area produces during or after recovery. Irritability can occur at the onset
159
of meningitis but is often seen during course of the be caused by damage to the caudal portion of
disease or after recovery. A child may also develop hypothalamus and increased sympathomimetic activity
aggressive, destructive behavior which is due to damage which may also produce hypertension, increase blood
to the ventromedial portion of the hypothalamus. sugar, etc.
Leukotomy or Frontal Lobe Syndrome Focal Cerebral Lesions

This is due to involvement of the medial nucleus of the Focal cerebral lesions with focal neurological deficits
thalamus which sends fibers to the associated areas of resembling transient ischemic attacks which may or may
the prefrontal lobe. These children, who are usually not progress to TBM can also occur.
obese, develop personality changes like those seen after
leukotomy. The visceral impulses coming from hypo- Episodes of Sensory Disturbances
thalamus probably influence mood, leading to feeling of
happiness or of depression.26 Like numbness and weakness rarely the patients may
present with recurrent and reversible neurological
deficits resembling transient ischemic attacks and
Psychomotor Seizures
without progression to fixed neurologic deficits. The
When hippocampus particularly cells of Ammon’s pathogenesis of these episodes is unclear. Tuberculous
horns are irritated by inflammation or by the adjacent vasculitis is a strong possibility and tuberculoma with
tuberculous process, either an exudate, scar or a large edema is less likely. CT scan shows hypodense lesions
third ventricle it may produce seizure like conditions which are due to ischemia secondary to a vascular lesion
referred to as psychomotor attacks or twilight states. or may show frank tuberculoma. Diagnosis is evident if
EEG shows synchronized discharges. Ammon’s horn the patient progresses to frank TBM.26 A young adult
is the most epileptogenic part of the entire brain. had focal sensory signs on the right side and CT scan
showed hypodense area in the sensory area of the left
Bilateral Loss cerebral cortex. Later he developed right hemiparesis and
characteristic picture of TBM.
Bilateral loss of Ammon’s horns as well as damage to the
mammillary bodies produce Korsakoff’s syndrome
Alternating Hemiplegia
described earlier, in which the child has disorientation of
time and space. Child is conscious, replies well but has lost This finding has been described during the course of
ability to memorize and has no idea of time and space. TBM. Probable pathogenesis was suspected to be focal
Hessler27 considered the activity of Ammon’s horns to be a vasculitis with spasm.19
mechanism for the chronological registration and marking
of perceptions and experiences. Loss of Vision
Loss of vision occurring during treatment of TBM is well
Amnestic Syndrome documented. 24 A child of 8 years who was under
treatment for TBM developed blindness within a period
Bilateral inhibition of fornix can produce acute amnestic
of 4 days. CT scan revealed moderate hydrocephalus.
syndrome in which there is loss of memory of recent
Child was otherwise conscious and alert. However, after
events. In amnestic syndrome old memories are retained
shunt surgery and with three bactericidal drugs and
but there is loss of recent memory caused by damage to
steroids, he recovered fully in 4 months. Rapid deterio-
mammillary bodies and Ammon’s horns (which can also
ration of vision in a case was described by Teoh et al.31 A
produce Korsakoff’s syndrome). However, severe
cranial CT scan revealed visual failure due to tuber-
cerebral edema which can occur in a child with tuber-
culoma compressing both optic nerves and chiasma.
culous encephalopathy with or without meningitis can
Although continued antituberculous chemotherapy is the
produce transient compression of the arteries supplying
treatment of choice in intracranial tuberculoma, rapid
Ammon’s horns and may lead to amnestic syndrome.
deterioration in vision in this case necessitated immediate
surgical decompression with resultant complete recovery
Abdominal Symptoms
of vision. In children with TBM and optic atrophy caused
Abdominal colicky pain simulating appendicular pain by optochiasmatic arachnoiditis, scraping of the exudates
has been described earlier. Usually children with TBM vision improved in 2 out of 6 cases.32,33 However, with
have scaphoid abdomen. However, cases with abdominal better chemotherapeutic drugs and massive use of
distention simulating paralytic ileus and severe steroids and hylase, surgical intervention is usually not
constipation have been reported. Such a condition can indicated particularly in children in stage II of TBM.
160
Appearance of Tuberculoma during Treatment of TBM adhesions. Some of these patients who had paraplegia
at the onset of TBM, deteriorated neurologically for years
Udani and Dastur5 have described five cases of multiple
after the complication of syringomyelia. One patient
tuberculomas appearing during treatment of TBM as seen developed paraplegia 8 months after treatment of TBM
in serial CT scans. Depending upon the site of develop- was started. The authors suggest that syringomyelia
ment of tuberculoma, the child develops. Newer clinical following TBM is not communicating in type
signs, which should be kept in mind during the course and postulate that stagnation of perimedullary fluid and
of disease when antituberculous therapy is being subarachnoid blockage is a crucial pathogenetic mecha-
continued. Though paradoxical enlargement of nism in the causation of syringomyelia following TBM.
intracranial tuberculoma is well recognized, its
pathogenesis is not clear.31,3436 Perhaps the most likely Internuclear Ophthalmoplegia (INO)
explanation is a complex host-organism interaction.
Chemotherapy of any tuberculous focus causes destruc- It is not easy to diagnose this condition in infancy and
tion of acid fast bacilli and liberation of tuberculoprotein. early childhood but if kept in mind it can be detected in
This probably invokes the inflammatory response with older children and adolescents particularly when the
resulting edema and swelling of the focus. It is well child presents or develops focal signs during apparent
recognized that new cervical nodes may appear and improvement with treatment. In internuclear ophthalmo-
enlarge during treatment of tuberculous lymphadenitis. plegia the patient cannot adduct the eye on the side of
This is reported to occur in up to 25% of patients and has lesion, while there is nystagmus in the abducting eye.
been attributed to trapping of the antigen-reactive Internuclear ophthalmoplegia is caused by dysfunction
lymphocytes within the lymph node.37 of the medial longitudinal bundle in the brainstem
(Table 12.1.1). When signs are present in horizontal gaze
in both directions it is bilateral internuclear
Vertical Gaze Palsy
ophthalmoplegia and is usually seen in adults with
Vertical gaze palsy in a 14 years old boy with TBM has multiple sclerosis. Unilateral ophthalmoplegia is usually
been reported by Udani et al24 and Schlernitzauer et al.32 vascular in origin40 but has also been reported in TBM
It appears to be due to a lesion in the region of the dorsal by Teoh et al.40 As occlusive vascular disease causes INO,
midbrain. The syndrome occurred some years after it is usually due to tuberculous vasculitis causing intrinsic
recovery from TBM and the child recovered with steroids, ischemic brainstem damage and hence indicates poor
antituberculous drugs and shunt revision. prognosis as it can damage vital centers in the brainstem.
If INO presents at the onset or is detected early, aggres-
Horizontal Gaze Palsy sive treatment with massive steroid therapy for vasculitis
alongwith bactericidal drugs may help the child.
It is rare but occurs due to a lesion in the contralateral
However, two adult patients of Teoh et al40 were not
frontal or ipsilateral pontine gaze center. An irritative
lesion in the pontine gaze center causes the eye to deviate benefitted by steroids because of aggressive vasculitis.
in a direction opposite to the side of lesion. Deviation of This has happened in some of the cases of encephalo-
head and eyes to one side like in epileptic seizure, is often pathy probably because of hypersensitized T cell
seen in TBM particularly when the child has seizures.38,39 reactivity.
Syringomyelia following Tuberculous Meningitis Subacute or Chronic Encephalopathy following

Sudden Withdrawal of Steroids in TBM5
Patients recovering from TBM may develop intraspinal
cavities as a late complication. Chronic arachnoiditis at Udani et al6 have described a child of 1-year-age who
the foramen magnum probably leads to cavity formation developed this complication had intrathoracic
by interfering with CSF outflow from the 4th ventricle tuberculosis with parenchymal lesions, mediastinal
provided the central canal is patent. Circumstantial nodes, positive tuberculin test, history of contact within
evidence pointing to postmeningeal syringomyelia as the family. He developed TBM with characteristic CSF
being of communicating type came when contrast picture. CT scan showed small ventricles. The child was
material injected intraventricularly was seen filling the kept for 6 weeks in hospital with improvement in clinical
intraspinal cavity. In 3 out of 4 cases studied by Mateo et condition. Parents were advised to continue treatment
al39 by MRI of the brain and spinal cord, the cavity with three bactericidal antitubercular drugs.
extended through multiple segments of the spinal cord, Steroid therapy was tapered slowly over 6 weeks. In
usually in coexistence with marked arachnoidal such a case if a second CT scan alone is seen diagnosis of
161
Alexander’s disease; could have been made, but because Bobble-head Doll Syndrome
of overall data there was no doubt about the diagnosis
It is due to trapped 4th ventricle and aqueduct. Children
of TBM. It appears that sudden withdrawal of steroid with bobble-head doll syndrome have head tremors
therapy leads to severe hypersensitivity of T lymphocytes resembling movements of head suspension dolls.41 These
which particularly affects the white matter as per the movements disappear in supine position and during
second CT scan picture resembling leucodystrophy, sleep. Usually enlargement of third ventricle due to
Alexander’s disease and other white matter disease. This arachnoiditis or aqueductal stenosis has been found in
shows that massive dosage of steroids could control brain
these cases. With surgical decompression of the ventricle
damage by immune mechanism as sudden withdrawal
the tremors usually disappear. The syndrome is caused
of steroids showed a marked edema of the white matter.
by compression of the dorsal median nucleus of the thala-
It indicated that there was probably vasogenic edema
mus by the third ventricle. However, the same syndrome
which later did not respond to steroids, glycerol and
mannitol. Wisnieski and Bloom9 have demonstrated the has been described even with trapped and dilated fourth
mechanism of myelin damage both in experimental ventricle. It is postulated that dilated third ventricle and/
animals and humans which could be due to direct or aqueductal dilatation compress the red nucleus which
destruction of myelin by immune competent sensitized extends from the caudal margin of superior colliculus in
lymphocytes and secondly by macrophages activated by the central diencephalon. It is known that the lesions of
T lymphocytes. red nucleus can produce postural tremors.
12.2 CLINICAL MANIFESTATIONS, DIAGNOSIS AND MANAGEMENT

S Aneja, Vimlesh Seth, A Maheshwari
INTRODUCTION Table 12.2.1: Classification of Neurological Tuberculosis

Central Nervous System (CNS) disease caused by Intracranial TBM1
Mycobacterium tuberculosis is a devastating manifestation • Tubercular Meningitis
of tuberculosis. CNS tuberculosis accounts for • Space occupying lesions (tuberculomas, tubercular
abscess)
approximately 1% of all cases of tuberculosis, carries a
• Tubercular encephalopathy
high mortality and neurological morbidity, and
• Tubercular vasculopathy
disproportionately afflicts children. It is the most
common type of chronic CNS infection in developing Spinal TB1
countries. Due to the protean nature of the clinical • Pott’s spine and paraplegia
manifestations, tuberculosis of the CNS remains a • Tubercular arachnoiditis
• Nonosseous spinal tuberculoma
formidable diagnostic challenge. Because the burden of
• Spinal meningitis
CNS tuberculosis lies largely in resource-poor regions
of the world, additional challenges in implementing
practical and usable methods to diagnose and treat this Incidence of TBM varies from 1-4% of total inpatient
disease remain largely unmet. Increase in cases of multi- admissions in different parts of India. The developing
drug resistant TB and co-infection with HIV have added world has 1.3 million cases of TB and 40,000 TB-related
to the challenge especially in pediatric age group. deaths annually among children younger than 15 years.1
Neurological tuberculosis may be classified as shown in The rate of incidence of TB in developed world is stable
Table 12.2.1. at around 11 cases per 100,000 population since 1997. The
proportion of tuberculous meningitis (TBM), the most
Epidemiology severe form of TB, reported through the French
mandatory notification system is low, at around 1.5% of
Tubercular Meningitis (TBM) is the commonest type of all TB cases.2 Because of diagnostic difficulty and the lack
CNS tuberculosis encountered in children of our country. of a standardized definition for culture-negative cases,
The frequency of TB meningitis is closely related with the surveillance of TBM and comparison of its incidence
the incidence of primary infection with tubercle bacilli. across countries is difficult. In a high disease burden area
162
of Cape Town, the TB incidence rate in children aged 0- system. The two important glycolipids are lipo-
5 years was 338/100000, corresponding to a cumulative arabinomannans and lipomannans. Lipoarabinomannan
incidence of 1.7%. The proportion of TBM cases among is involved in the inhibition of phagosome maturation,
TB cases aged <1 year was 35% and proportion of miliary apoptosis, interferon-gamma signaling in macrophages
TB cases was 32%.3 and interleukin-12 cytokine secretion of dendritic cells.
The virulence of mycobacteria are dependent on their
Pathogenesis ability to induce macrophages to secrete large amounts
The pathogenesis of TB meningitis is the two-step model of tumor necrosis factor alpha (TNF-α) and interleukin-
10 (IL-10), but downregulate toll-like receptor-2, toll-like
of CNS tuberculosis, as described by Arnold Rich and
receptor- 4 and major histocompatibility complex class
Howard McCordock, more than 75 years ago. It remains
II expression.
central to our current understanding of pathogenesis of
Several genetic abnormalities are implicated in
CNS tuberculosis. Infection usually occurs after inhalation
increasing the host’s susceptibility to M. tuberculosis and
of the bacilli in infected respiratory secretions.
its severe forms particularly CNS and miliary forms. P2X7
Mycobacteria, inhaled as small aerosol particles, reach the receptor is an ATP gated calcium channel, which upon
alveoli where dendritic and macrophage cells process the activation leads to the induction of apoptosis and death
bacteria. Dendritic cells are particularly efficient at antigen of infecting mycobacteria. Polymorphisms of this
presentation due to their robust surface expression of receptor is associated with impaired killing of
major histocompatibility complex molecules, which mycobacteria, thereby increasing host vulnerability to
provide costimulatory signals for T-cell activation Antigen tubercular infection. 6 Polymorphism in interferon-
presentation mostly occurs in regional lymph nodes to gamma gene are also associated with increased host
CD4+ T-cells. 4 In the lungs, M. tuberculosis bacteria susceptibility to tubercular infection.7 Single nucleotide
multiply in alveolar macrophages. Within 2 to 4 weeks, polymorphisms (SNP) toll-interleukin-1 receptor and
through blood circulation, bacilli spread to presence of toll-like receptor-2 gene polymorphisms has
extrapulmonary sites and produce small granulomas in been shown to increase the susceptibility of host to severe
the meninges and adjacent brain parenchyma. These small forms of tuberculosis like miliary tuberculosis and
granulomas are known as ‘Rich focus’. Meningitis tuberculous meningitis. 8,9 Single nucleotide poly-
occurred once mycobacteria contained within these lesions morphisms, located at these genes, are thought to
are released into the subarachnoid space, an event that influence cytokine levels and regulate resistance and
might happen months or years after the initial bacteremia. susceptibility of an individual to tuberculosis.10 Recently
Decreased immunity is believed to play a role in rupture from an epidemiological study in Colombia, three M.
of Rich foci. Miliary tuberculosis is directly involved in tuberculosis clinical strains were isolated from the
the pathogenesis of tuberculous meningitis. The bacilli cerebrospinal fluid (CSF) of patients with meningeal
enter the central nervous system by traversing the blood– tuberculosis, and used to infect experimental mice
brain barrier (BBB). The bacteremia that accompanies through the intratracheal route. These strains showed a
miliary TB increases the likelihood that a meningeal or distinctive spoligotype pattern. The course of infection
subcortical tuberculous focus will be formed. in terms of strain virulence (mice survival, bacillary loads
The mechanism by which M. tuberculosis crosses the in lungs), bacilli dissemination and extrapulmonary
BBB into the CNS is not well characterized. Some have infection (bacilli loads in blood, brain, liver, kidney and
postulated that free bacilli traverse across the endothelial spleen), and immune responses (cytokine expression
barrier, while others suggested that bacilli enter via the determined by real time PCR in brain and lung) were
passage of infected macrophages. Using an in vitro studied and compared with that induced by the
monolayer of human brain microvascular endothelial laboratory strains of M. tuberculosis and other five clinical
cells and infecting them with several strains of strains isolated from patients with pulmonary TB. All
mycobacteria, Jain et al reported that extra cellular the clinical isolates from meningeal TB patients
mycobacteria are capable of traversing the endothelial disseminated extensively through the hematogenous
cells.5 route infecting the brain, producing inflammation in the
Apoptosis of infected macrophages is an effective cerebral parenchyma and meninges, whereas H37Rv and
host’s mechanism against tubercle bacilli. Virulent strains clinical isolates from pulmonary TB patients showed very
of M. tuberculosis have evolved several genetic limited efficacy to infect the brain. Thus, it seems that
mechanisms to escape host immune responses leading mycobacterial strains with a distinctive genotype are able
to prolonged survival. The cell wall glycoproteins of to disseminate extensively after the respiratory infection
virulent mycobacteria manipulate the host immune and infect the brain.11
163
Immunopathogenesis infarction, diffuse edema and tuberculoma. Diffuse

tubercular encephalopathy is characterized by diffuse
The entry of mycobacteria in the CNS triggers host edema of the brain, perivascular myelin loss and
immune responses leading to a surge in various cytokines hemorrhagic leuko-encephalopathy. The exact cause of
like TNF-α that result in breech of the blood-brain barrier tuberculous encephalopathy is unclear. Hypersensitivity to
with consequent cerebral edema and increased proteins liberated by lysed tubercle bacilli, isoimmunization
intracranial pressure.12 Microglial cells (the resident to host myelin proteins or cerebral microangiopathy play
macrophages of the brain) are the principal cells variable role.
producing cytokines against tubercle bacilli. Several Infarction is caused by inflammation of the vessels
studies have shown that microglia produce a variety of involved in the basal exudate. Frequently the exudate
chemokines that act to initiate or promote inflammatory causes external compression and occlusion of large
responses in the central nervous system through arteries at the base of the brain. The vessels of the circle
facilitating the recruitment of peripheral immune cells of Willis are more frequently involved than the vessels
into the brain parenchyma.13,14 The elevated levels of of the basilar system. There is arterial narrowing with or
serum and cerebrospinal fluid TNF-α and interferon- without total occlusion causing infarction in the zone
gamma have a positive correlation with the severity of supplied by the artery, mostly the middle cerebral artery.
the tuberculous meningitis.15 Human immunodeficiency The vascular changes occur in the form of periarteritis
virus co-infection with tuberculous meningitis attenuate and endarteritis, vascular edema, necrosis and
these inflammatory changes. The greater level of immune thrombosis. The changes depend on the caliber of the
suppression with advanced HIV disease leads to very vessels involved, severity, duration, stage of the disease,
low level of cerebrospinal fluid interferon-gamma and treatment status of the patient. In cases of long
concentration, which is independently associated with duration, subintimal fibrosis and changes in internal
death. Thus the host immune response is pivotal for elastica are seen in medium sized vessels.
host’s immunity and survival.16 Hydrocephalus is due to obstruction to the flow of
the CSF in the subarachnoid spaces by dense basal
Pathology leptomeninges and interference in the absorption of CSF
The characteristic pathologic features of TBM are by the arachnoid granulations. Excessive production of
meningeal inflammation, dense basal exudates, vasculitis CSF does not occur since the ependymal lining of the
and hydrocephalus. The tubercle bacilli are lodged choroid plexus is damaged by the exudate.
principally at two sites, leptomeninges and brain
parenchyma. The miliary tubercles in the leptomeninges Clinical Features
are most frequently on the lateral aspect of parietal and The majority of the cases (75-85 %) are below the age of
temporal lobes on either side of the sylvian fissure and five years. The disease can occur in any age group but is
along the blood vessels at these sites. The parenchymatous uncommon before 6 months and rare before 3 months.
lesions in the brain are commonly located at superficial The peak incidence is in 3-5 years age group. Only 2.55%
part of the brain (Rich focus), base of the brain (subthalamic of total TBM cases were younger than 6 months.19 There
and subputaminal region) and along the supero-lateral is preponderance of the disease in boys. The onset of the
surfaces. The exudate is usually copious, thick and disease is usually subacute or chronic, taking more than
adhesive in nature. The exudate has a predilection for the three weeks to develop.
interpeduncular fossa, over the floor of 3rd ventricle,
The clinical manifestations may be grouped into three
around the optic chiasm, distal ends of the internal carotid
stages (Table 12.2.2).20 Often the symptoms in the first
artery and proximal portion of the middle meningeal
stage are non specific and only when the child fails to
artery. The middle meningeal arteries are often throttled
improve and develops convulsions, meningeal irritation
by the exudate. The exudate extends backwards over the
or cranial nerve palsies, is referred to a hospital.
pons and cerebellum and occupies cisterna ambiens and
In prodromal stage (stage 1), the symptoms are
cisternapontis, forming a collar which compresses the
nonspecific and diagnosis is difficult to establish. The
brain stem and emerging third cranial nerve, and blocks
the medullocerebellar angles where the foramina of disease may follow any condition which lowers the
luschka open. Exudates may be seen surrounding the general resistance such as pertussis or measles, or any
lower part of the spinal cord and cauda equina resulting bacterial infection.
in tuberculous radiculomyelopathy. Occasionally head injury has been observed to initiate
The brain tissue underlying the tuberculous exudates the disease. The prodromal stage usually spans 2 to
shows varied degree of edema, perivascular cuffing, and a 3 weeks and often the symptoms are nonspecific such as
microglia reaction collectively termed as “border-zone low grade fever, anorexia and sleep disturbances. General
encephalitis”.17 Other parenchymal changes seen are apathy, lack of interest in play, irritability, lassitude,
164
Table 12.2.2: Medical Research Council, Staging of Hemiplegia and quadriplegia occur in about 20% of
tuberculous meningitis (TBM) cases of TBM, monoplegia and cerebral paraplegia are
uncommon. Paraplegia is either caused by tuberculous
Stage Clinical Manifestations radiculomyelitis or intramedullary tuberculomas.
Stage I The symptoms are nonspecific with few or no Tuberculous radiculomyelopathy is characterized by the
clinical signs of meningitis. The patient is fully subacute paraparesis. Several types of movement
conscious and alert disorders like chorea, hemiballismus, athetosis,
Stage II Signs of meningitis, drowsiness or lethargy, generalized tremors, myoclonic jerks and ataxia have been
cranial nerve palsies
described at onset or during the course of the disease.
Stage III Severe clouding of consciousness, stupor or coma,
These are more common in children than in adults.
convulsions, gross paresis or paralysis
Cranial nerve palsies are seen in approximately 25%
of cases. The sixth cranial nerve is most commonly
listlessness, altered behavior, headache and vomiting are affected cranial nerve. Third and fourth cranial nerves
usually present. While the older child can complain of may also be involved. They are affected either because
headache, those under 3 years of age can not localize their of nerve entrapment in adhesive basal exudates or raised
symptoms. In these children fatigue and altered behavior intracranial tension. Vision loss is a devastating
are subtle signs of TBM. In infants and children less than complication of tuberculous meningitis secondary to
three years, a high index of suspicion is required to optic nerve involvement. The possible reasons for optic
diagnose. In these children the presentation may be acute nerve involvement are optochiasmatic arachnoiditis and
and simulate pyogenic meningitis. In older children with granuloma, third ventricular compression of optic
subacute onset, there are behavioral disturbances and chiasma in patients with a large hydrocephalus, optic
they are sometimes referred to psychiatrist. nerve granulomas.25
Stage 2 is characterized by appearance of signs of
meningeal irritation and definite neurological signs. The
child may present with convulsions and develop Complications of Tuberculous Meningitis
neurological deficits involving cranial nerves such as
squint, visual disturbances, facial asymmetry, ptosis and Acute Complications
dilated irregular pupils. The child may develop motor
The acute phase of TBM is characterized by marked
deficit such as hemiplegia or monoplegia. Extrapyra-
features of raised intracranial tension. Seizures may be
midal signs are frequent accompaniment to the other
present in the initial part of the illness. The frequency of
presenting features. Meningeal signs are present along
acute symptomatic seizure in TBM ranges from 16.3 to
with symptoms of raised intracranial tension. The child
31.5%.23 They may also occur due to various electrolyte
develops loss of consciousness in the second stage. The
abnormalities like hyponatremia (repeated vomiting,
child who was apathetic, dull or drowsy in the first stage
SIADH or cerebral salt wasting), hypernatremia
now becomes semi comatose and can be aroused with only
(secondary to diabetes insipidus to diffuse cerebral
painful stimuli.
damage), hypoglycemia or hypocalcemia. Hematemesis
In the 3rd stage, there is deep coma, and child may
may occur at the onset of tuberculous meningitis. Acute
have progressive neurological deficits with dilated
gastric ulcers resulting from hypothalamic lesions have
pupils. As the child progresses in this stage, signs of brain
been documented. Autonomic dysfunction like excessive
stem compression with well marked neck retraction,
perspiration, abdominal pain and hyperperistalsis occur
opisthotonic posturing, decorticate followed by
occasionally.
decerebrate spasms appear. Irregular breathing pattern,
Biot’s breathing appears in 2nd stage and continue into
the 3rd stage. In the terminal stages, pupils are dilated
Hydrocephalus
and severe hyperpyrexia of central origin appears. The A recent report on a large cohort of children who had
advanced stages of tuberculous meningitis are marked tuberculous meningitis demonstrated hydrocephalus in
by deep coma, hemiplegia, decerebrate posturing, 70% of cases.22 Communicating hydrocephalus is the
deterioration in vital signs, and, eventually, death. commonest type. Obstruction of the fourth ventricular
The presenting symptoms reported in various series outlet foramina resulting in non-communicating
are fever in 80-90% cases, convulsions in 50-60%, vomi- hydrocephalus, occurs much less commonly (about 20%
ting in 40-45% and altered sensorium in 20-45%.20-23 of cases). Proximal CSF obstruction (at the level of
Generalized tonic and clonic seizures are the commonest foramen of Munro or aqueduct of Sylvius) is a rare cause
type of seizures followed by focal seizures and tonic of non-communicating hydrocephalus in tuberculous
spasms. In children with advanced central nervous meningitis. Progressive hydrocephalus if not appro-
disease even after the age of one year there may be priately treated may have devastating consequences of
reappearance of neonatal reflexes. irreversible optic atrophy and loss of vision.
165
The clinical features that suggest the presence of primarily arising in the spinal meninges, downward
hydrocephalus are nonspecific. In any patient with TBM extension of intracranial tuberculous meningitis; and
with altered sensorium, hydrocephalus should be extension of tuberculous spondylitis. Among these,
suspected irrespective of the presence or absence of involvement of the spinal arachnoid lining secondary to
papilledema. Hydrocephalus is also likely to be present intracranial tuberculous meningitis is the most common
in patients who are alert and who complain of increasing pathogenesis. The thoracic region is the most frequently
headache with or without vomiting and blurring of affected site, followed by the lumbar and cervical regions.
vision. Macroscopically, exudate can be seen surrounding the
spinal cord and nerve roots. Microscopically, granulo-
Tubercular Cerbrovascular Disease matous inflammation, areas of caseation, tubercles, and
fibrous tissue are noted. In chronic cases, the subarachnoid
TB has a significant impact on the global stroke burden. space may be irregularly obstructed, with the formation
Eight percent of strokes in the young in India have been of pockets of CSF. Spinal cord parenchymal changes
attributed to TB vasculopathy. The incidence of vasculitis include border-zone rarefaction and vacuolization of the
in TBM is variably reported. In autopsy study on TBM, cord, extensive atrophy and circumscribed central necrosis,
vasculitis was reported in 41%.18 On angiographic studies severe gliosis with no recognizable parenchymal tissue,
in TBM, irregular beaded narrowing in supra-clinoid and intramedullary tuberculoma, which can result in
portion of internal carotid artery, widely sweeping multicystic myelomalacia and syringomyelia.
pericallosal artery, and thalamostriate vein and delayed
circulation of middle cerebral vein with scanty collateral
circulation were reported. Computed tomography (CT) Diagnosis of Tubercular Meningitis
scan studies show infarctions in 17 to 63% of patients.22,24 Tuberculous meningitis is a serious illness which, if not
In TBM, the basal ganglionic infarcts are the commonest diagnosed timely and managed, leads to a high rate of
because of involvement of perforating vessels. In a CT scan mortality and permanent disabilities. Tubercular
study, the infarctions were located at head of caudate, meningitis poses a diagnostic problem. The reason is that
anteromedial thalami, anterior limb and genu of internal it presents in a similar manner to other meningoencepha-
capsule due to involvement of medial striate, thalamo- litides particularly partially treated pyogenic meningitis.
tuberal, and thalamoperforate arteries in 75%.26 On Definitive diagnosis of tuberculous meningitis can be
magnetic resonance imaging (MRI), infarctions were made by demonstration of mycobacteria in cerebrospinal
reported in 10 of 20 patients with TBM and confirmed the fluid (CSF), by direct staining or culture. These tests are
reported distribution of vascular involvement.27 Infarct has time consuming and seldom positive. Recognizing this
been reported as a poor prognostic predictor in children problem of diagnosis, many newer serological tests have
with TBM.28,29 been developed to diagnose tuberculous meningitis and
differentiate it from pyogenic meningitis. However, none
Ocular Lesions of these have a high specificity to be of any clinical utility.
A high index of suspicion is required for early diagnosis
The common ocular lesions in order of frequency are
of TBM. Global encephalopathy with focal deficit is
papillitis, optic atrophy and papilledema. Choroidal
hallmark of TBM. CSF must be examined in every such
tubercles may be associated with miliary tuberculosis.24
case. In case of inconclusive results, it should be repeated
Choroid tubercles are rarely seen but if present are
48-72 hours after antibiotic therapy and if it shows no
pathognomic of CNS tuberculosis. Optic atrophy may
change in clinical status and CSF results, then it may favor
sometimes be the primary manifestation of TBM. It may
diagnosis of TBM. CSF glucose must be interpreted in
revert back with early institution of antitubercular
conjunction with simultaneous blood glucose level. CSF
treatment. Involvement of visual area of cortex may lead
smear and culture are negative in 90% of cases. CSF antibody
to cortical blindness.
tests are not recommended due to poor sensitivity,
specificity and predictive value. CSF PCR is also variable.
Spinal Tuberculous Arachnoiditis
Mantoux test is negative in 70% of patients. CECT (contrast
It is a rare complication of CNS tuberculosis. It is an enhanced computed tomography) scan is useful and should
inflammatory condition that involves the arachnoid lining be considered if possible. Hydrocephalus and basal
along the spinal tract. This condition was previously termed exudates are seen in 80-100% patients. Normal CT scan does
adhesive spinal arachnoiditis or chronic adhesive not rule out TBM. Towards this end a set of criteria for the
arachnoiditis. This clinical entity is uncommon in developed diagnosis of TBM at admission was designed by Ahuja30 et
countries, but is still commonly reported in South-East Asia, al and its validity was tested against polymerase chain
the Indian subcontinent, South America, and Africa. Three reaction (PCR), bacterial isolation and autopsy when
different pathogeneses are suggested for the occurrence of available. Modified Ahuja Criteria were used by Seth and
spinal tuberculous arachnoiditis i.e. a tuberculous lesion Sharma31 for diagnosis of TBM in children is as documented
166
Table 12.2.3: Modified Ahuja31 Criteria for diagnosis of Table 12.2.4: Diagnosis of TBM
TBM in children
Demonstration of acid fast bacilli in the CSF or fulfillment
A. Mandatory features of the following criteria:
• Fever lasting for more than 14 days
Essential
• Abnormal CSF findings (pleocytosis with more than
20 cells and more than 60% lymphocytes, protein >100 CSF showing:
mg/dl, sugar <60% of corresponding blood sugar • Predominant lymphocyte pleocytosis > 50/mm3
values) • Protein > 60 mg percent
• Sugar < 2/3 of blood sugar
In addition to the above, any 2 of the following features
• Evidence of extra neural tuberculosis Supportive
• Positive family history of exposure to a case of Along with the essential ones, two or more of the following
tuberculosis clinicoinvestigational criteria:
• Positive mantoux reaction (1 TU) >10 mm
• History of fever of two weeks or more
• Abnormal CT scan findings (2 or more of following):
• Positive family history of tuberculosis
Exudate in the basal cistern or in the sylvian fissure
• Generalized lymphadenopathy
Hydrocephalus
• Mantoux test (5 TU) > 10 mm*
Infarcts
• Positive radiological evidence of tuberculosis
Gyral enhancement
elsewhere in the body
• CT scan evidence of basal exudates or CNS
in Table 12.2.3. In practice, treatment is generally started tuberculosis
on the basis of clinical features and CSF picture. Certain • Isolation of AFB from gastric lavage or other sites
clinical features like prodromal stage >7 days, optic atrophy • Histologically proven tubercular lymphadenitis
on fundal examination, focal deficit, abnormal movements,
and CSF leukocytes <50% polymorphs may give a clue to
the diagnosis.32
delayed type of hypersensitivity is better elicited with
Clinicoinvestigational Features of higher strength of PPD. Hence, Seth recommends based
TBM in Children at AIIMS on her various studies on immunology, tuberculin test
Diagnosis of TBM at AIIMS, a tertiary care hospital in positivity elicitation is more with 5TU PPD. For details
India is followed as per the following criteria (Table see chapter clinicoradioimmunological profile, i.e.
12.2.4). Chapter 8 and tuberculin test Chapter 19.23 The profile
In TBM higher strength of PPD, i.e. 5 TU is recom- of patients of TBM over a period of twenty years is given
mended for Mantoux test by Vimlesh Seth, because in Table 12.2.5.
Table 12.2.5: Clinicoinvestigational features in TBM (AIIMS Data), (1984-2004)
Parameter assessed 1984-1986 1991- 2000 2000-2004

N* = 52 N = 136 N = 23
• History of fever > 2 weeks 100 71.2 95.6
• Positive family history 40.6** 38.4 30.4
• Positive Mantoux 61.5 28.8 9.1
• Radiological evidence of pulmonary tuberculosis 69.2 45.6 21.7
• Isolation of AFB from any site – 4 –
• CT scan 100*** 84 100
• Histologically proven tubercular lymphadenitis – 1.6 –
• Generalized lymphadenopathy 44.2 5.6 –
Stages of TBM
Stage I 3.9 3.2 4.3
Stage II 59.6 38.4 39.1
Stage III 36.5 58.4 56.6
*N= Number of patients ***CT done in 45/52 patients
**N=Contacts surveyed by CXR All figures are in percentage
+ = Percent
167
Diagnostic Modalities bacilli have been reported in up to 87% of patients

with repeated sequential CSF examination in
Evidence of extraneural TB laboratory settings under ideal situations. But in
• Chest radiography: Posteroanterior and lateral views clinical practice the yield is not high. A recent study
may reveal hilar lymphadenopathy, simple established that both CSF volume and duration of the
pneumonia, infiltrate, fibronodular infiltrate/ microscopic evaluation are independently associated
cavitation, and/or pleural effusion/pleural scar. with bacteriological confirmation of CNS
Abnormal chest finding are seen in 87% of patients. tuberculosis, suggesting that a minimum of 6 ml of
CSF fluid should be examined microscopically for a
• Ultrasound: abdomen revealing retroperitoneal
period of 30 minutes. Using this simple method AFB
lymphadenopathy or matted bowel loops.
were demonstrated on microscopy in 58% of adults
• Tuberculin Skin Test (Mantoux test): In childhood
with TBM.34
tuberculosis (TB), 10 mm (induration) cutoff is taken
• CSF culture for M. tuberculosis is not usually
as positive reaction. It is applicable to use for strengths
positive. Rates of positivity range from 25-70%.
of PPD only up to 5TU. Efforts should be made to use Isolation of M. tuberculosis on solid media often takes
only 1 TU PPD to decrease the false positives. Negative 3 to 6 weeks, followed by another 2 to 4 weeks for
results from the purified protein derivative test do not drug susceptibility testing. Improvements in
rule out TB. It is non reactive in 50- 70% of cases with laboratory methods now permit more rapid culture,
TBM. identification, and drug susceptibility testing of
• IFN-γγ-Releasing Assays (IGRAs): A new generation mycobacterial by automatic radiometric methods,
of immune-based rapid blood tests for the diagnosis such as BACTEC, in which a decontaminated,
of latent tubercular infection, called IGRAs, offers concentrated specimen is inoculated into a bottle of
particular advantages over the conventional Mantoux medium containing carbon 14-labeled palmitic acid
test. These tests rely on the host response to M. as the substrate. As mycobacteria metabolize the
tuberculosis infection by measuring the IFN-γ labeled acid, carbon dioxide–14 accumulates in the
produced by T-cell responses to M. tuberculosis- bottle, where radioactivity can be measured. The
specific antigens called early secreted antigenic target addition of appropriate dilutions of antituberculosis
6 (ESAT-6) and culture filtrate protein 10. However, drugs permits the evaluation of drug susceptibility.
IGRAs do not distinguish between latent and active The time for isolation and drug susceptibility testing
disease. It has been suggested that very high or rising of mycobacteria can be reduced to 1 to 3 weeks if the
levels of IFN-γ in IGRAs may be able to predict the radiometric system is used. The use of high-pressure
asymptomatic individual with latent tuberculosis that liquid chromatography allows for rapid identification
is at highest risk of progressing to disease 33,34 but of isolated organisms, usually within 24 hours.
long-term prospective studies are needed to • Polymerase chain reaction (PCR): Amplification of
investigate this interesting finding. the mycobacterium tuberculosis-specific DNA
sequences by polymerase chain reaction (PCR) or
CSF Analysis (nucleic acid amplification) (NAA) has been
evaluated as a means of rapid diagnosis of TBM. One
• The CSF is under pressure and with the help of a step amplification used in conventional methods has
manometer pressure is estimated to be 30- 40 cm H2O. a low sensitivity which is attributed to the low copy
It may be opaque or clear on gross examination. There numbers of DNA template that could be extracted
may be pellicle or cobweb formation on standing. Cell from CSF of patients with TBM. In comparison two-
counts are increased with predominant lymphocytic step nested amplification can improve the sensitivity.
pleocytosis. Early on in the disease there is Using this technique, Liu et al detected the
polymorphonuclear response. Proteins are M. tuberculosis genome in 90.5% of patients with
moderately elevated often >100 mg/dl. Glucose levels clinically suspected TBM.35
with a simultaneous blood glucose level are less than The PCR has the advantage of being the only
2/3 of blood levels. technique besides AFB smear which can confirm the
• CSF smear for AFB: Definitive diagnosis of TBM can diagnosis within 24 hours. Kox et al observed a
be made only if acid-fast bacilli are isolated. Various sensitivity of 48% for PCR compared to 9% by
techniques can be used to improve the sensitivity of microscopy in their patients with TBM.36 PCR can be
AFB staining in the CSF. These include using multiple applied to CSF even after initiation of antitubercular
samples of CSF, staining the clot that forms in treatment. It is not affected by presence of other
standing CSF and spinning down the CSF sediment infecting bacteria as may occur in
onto a slide for microscopic examination. Tubercle immunocompromised patients.
168
False negative PCR results are attributed to several analysis the sensitivity and specificity and diagnostic
factors like treatment effect on CSF, presence of PCR odds ratios (DOR) were calculated based on arbitrary
inhibitory factors in CSF, extremely low bacterial ADA cut-off values from 1 to 10 U/l. The cut-off values
numbers, small amount of CSF tested and the method of 8 U/l (sensitivity 59% and specificity 96%)
of extraction of DNA. Even with PCR positive cases, improved the diagnosis of TBM (p <0.001).41 However
culture must be done for drug susceptibility testing ADA is also increased in pyogenic meningitis and it
especially for emergence of MDR strains. cannot be used to discriminate between TBM and
Nucleic acid amplification (NAA) tests are bacterial meningitis. The increased levels of ADA can
categorized as commercial and in-house (“home- be used as an adjunct to improve TBM diagnosis,
brew”). Most laboratories use commercial kits such particularly after bacterial meningitis has been ruled
as the Amplicor M. tuberculosis tests (Roche Molecular out.41
Systems, Branchburg, NJ, USA), and the Amplified • Tuberculostearic acid: Tuberculostearic acid is a fatty
M. tuberculosis Direct Test (MTD; Gen-Probe Inc, San acid component of the M. tuberculosis cell wall, which
Diego, CA, USA).37 Overall sensitivity of PCR for the has been detected in CSF of patients with TBM via
diagnosis of TBM ranges from 33 to 90.5%, with various forms of gas chromatography.42-44 Although
specificities ranging from 88.2 to 100%.38 An in- this method has good sensitivity (89-95%) and
house (“home brew”) PCR technique has been specificity (91-99%) in limited studies, the
requirement for expensive equipment and
developed for the detection of M. tuberculosis DNA,
considerable expertise has limited the clinical use of
which targets a 340 bp nucleotide sequence located
this technique. The biomarkers for the diagnosis of
within the 38 kDa protein gene, for amplification.
TBM are summarized in Table 12.2.6.
This was developed in Mumbai, India. This test can
detect as small an amount of DNA as 10 fg, which
is equivalent to two to three organisms, and is Serological Testing in CSF
highly specific. The sensitivity of this PCR was 90%
During an infection of CNS with M. tuberculosis many
and specificity, 100%.39 In the 35 studies with in- secretory or degradative products of the bacilli are
house tests, the summary accuracy could not be present in the CSF. Since the manifestations of TBM are
established with confidence because of wide due to immunologically directed inflammatory reaction
variability in test accuracy.38,39 Though the in-house to M. tuberculosis, it is logical to look for specific antigen,
PCR testing may be cheaper but they have antibody and immune complexes in the CSF. The use of
unreliable sensitivities. A systematic review and serological tests as a diagnostic tool appears attractive
meta-analysis of 49 studies was performed to but caution must be exercised in interpreting the results
establish the accuracy of nucleic acid amplification in relation to the stage of the disease. LAM antigen,
(NAA) tests for tuberculous meningitis. It estimated 17KDa antigen and antigen85 complex of M. tuberculosis
that in 14 studies with commercial NAA tests, the are strong candidate antigens useful in TBM.45 It must
sensitivity and specificity range were 0-56% and 0- be recognized that presence of concurrent immune-
98% respectively.40 The use of PCR to monitor complexes, and specific antigen selected affect the
successful treatment in TBM is not yet defined. PCR sensitivity of these tests. The antigen based tests would
can detect M. tuberculosis up to 6 weeks after starting be helpful early in the disease process. As the disease
treatment. Thus to conclude negative PCR does not progresses, increasing levels of antibodies form immune
rule out the possibility of TBM. The commercial NAA complexes which result in a phase where the detection
tests show a potential role in confirming tuberculous of both antigen and antibody becomes difficult.
meningitis diagnosis, although their overall low Subsequently the levels of antibody increases. The
sensitivity and comparative high cost precludes the changes in relation to temporal phase of the disease make
use of these tests in routine practice in resource poor interpretation difficult and limit the applicability of these
settings. tests in clinical practice.
• CSF adenosine deaminase (ADA) levels: Adenosine
deaminase is produced by lymphocytes and Antibody detection: Antibodies against glycolipids and
monocytes. The adenosine deaminase (ADA) activity proteins isolated from M. tuberculosis, BCG, PPD, antigen
test is a rapid test that has been used for the diagnosis 5 and lipoarabinomannan in the CSF have all been used
of the pleural, peritoneal and pericardial forms of as rapid test to diagnose TBM. ELISA, radioimmunoassay
tuberculosis. However, the usefulness of ADA in TBM and immunoblot techniques have been used to detect
is uncertain. Recently a systematic review was these antibodies. Various authors have reported
conducted to evaluate ADA as a diagnostic test for sensitivity ranging from 61-90% and specificity of 58-
TBM. Of 380 patients with TBM included in the 100%.46-48
169
Table 12.2.6: Performance of various diagnostic tests for TBM
Test Sensitivity Specificity Remarks

(%) (%)
Commercially available NAA assays 60 100 Positive PCR is specific for diagnosis;
Roche Amplicor MTB38 83 100 but negative PCR does not rule out
Modified Gen-Probe MTD51 56 98 TBM
Meta-analysis 14 studies with
commercial NAA assays40
In house PCR (Indian)39 31-98 88-100 In-house (so-called home-brew) PCR
produce highly inconsistent results
compared with commercial NAATs
Adenosine deaminase (ADA levels)41 59 96 ( 8 IU/L cut off) cannot differentiate
reliably between pyogenic meningitis
and TBM
Tuberculostearic acid assays 89 99 Requirement for expensive equipment
Gas chromatography and mass and considerable expertise has limited
Spectrometry42 the clinical use of this technique
Gas-liquid chromatography43 95 91
Antibody assays Commercial antibody testing has no
ELISA50 72 92 role in clinical care of pediatric cases
ELISA53 61 100
ELISA (immunoglobulin G complexes)54 64 91
ELISA and Western blotting57 93 96
Passive hemagglutination assay and 81 93
Western blotting58
Antigen assays
Reverse passive hemagglutination59 88 95 Not relevant for routine management
Radioimmunoassay56 79 100 and diagnosis of tuberculosis
Dot immunobinding assay60 63 100
While the detection of antibodies in the CSF to Antigen detection: In addition to measuring M.
diagnose TBM is rapid, earlier studies evaluating the tuberculosis-specific antibodies or antibody-secreting cells,
utility of measuring M. tuberculosis-specific antibodies assays to measure M. tuberculosis-specific antigens
in the CSF have shown that these techniques are limited directly in the CSF have also been evaluated.57-59 A
by the inability to differentiate acute infection from theoretical advantage of antigen detection over antibody
previous infection and problems with cross-reacti- detection would be that they indicate active infection . In
vity49,50 in addition to variable and often poor sensiti- a study among patients with a clinical diagnosis of TBM
vity and specificity.51-53 An example of a more recent that compared a dot immunobinding assay for an M.
study shows that measuring antibodies against a 30 kDa tuberculosis-specific 14-kDa protein antigen with PCR to
protein that is a specific antigen of M. tuberculosis 54 detect IS6110, specific for M. tuberculosis in the CSF, the
yielded a more promising sensitivity of 92%.55 In a study immunobinding assay was more sensitive than the PCR
of patients with a clinical diagnosis of TBM that method (75% versus 40.5%, respectively).60
compared the utility of detecting anti-M. bovis BCG Despite the obvious advantage of low cost and ease
antibody-secreting cells in the CSF by enzyme-linked of performing these antigen antibody tests as compared
immunospot (ELISPOT) assay, PCR to detect an to complicated and costly PCR based methods the utility
insertion sequence (IS6110) specific for M. tuberculosis of these tests in clinical situation is uncertain and are
in the CSF, and an enzyme-linked immunosorbent assay therefore not recommended in routine practice.
(ELISA) to detect anti-BCG antibodies, the ELISPOT Currently these tests also have limited utility in
method was more sensitive (84% versus 75% and 52.3%, clinical practice.
respectively) and as specific as (91.8% versus 93.7% and
91.6%, respectively) the other methods tested.56 Those
Neuroimaging
authors also emphasized that the sensitivity of the
ELISPOT method was better earlier in the clinical course CT (Computed Tomography)
of TBM and that the sensitivity improved to 100%
among those tested within 4 weeks of onset of TBM Neuroimaging studies can be useful for the diagnosis of
symptoms.56 TBM. The characteristic computed tomographic (CT)
170
changes include basal enhancement, presence of Table 12.2.7: Advantages of Godolinium enhanced MRI
exudates, hydrocephalus and periventricular infarcts. CT vs CECT for diagnosis of TBM
shows obliteration by iso-attenuating to marginally
• Detection of basal meningeal enhancement and small
hyperattenuating exudate at the basal cistern and plaque tuberculomas
like dural thickening. On intravenous contrast, there is • Detect diffuse or focal meningeal granulomatous change
enhancement of basal cisterns which may extend to the • Delineate focal infarcts of basal ganglia and diencephalons
convexities, ventricles and sylvian fissure. A review of • Can reveal hemorrhagic nature of infarcts?
computed tomographic findings of 289 patients revealed
that in 35 patients computed tomography was normal.
Table 12.2.8: The recommended doses of antitubercular
Remaining 254 patients had some abnormality. Common
drugs by Indian Academy of Pediatrics67
abnormalities were hydrocephalus (80.3%), parenchymal
enhancement (24.4%), contrast enhancement of basal Drug * Daily dose Intermittent
cisterns (19.2%), cerebral infarct and focal or diffuse brain (mg/kg) dose (mg/kg)
edema (15.3%), and tuberculoma (5.5%).61 Presence of Isoniazid ** 5-10 15
hydrocephalus was shown to be associated with a higher Rifampicin 10 15
risk of stroke and poor prognosis.62,63 Follow-up imaging Pyrazinamide 30-35 35
may be valuable as it may demonstrate some new feature Ethambutol 20 30
that is not initially present (like hydrocephalus and Strepyomycin 15-20 20
infarcts).62 The degree of hydrocephalus correlates with * All the drugs should be administered in a single daily dose
the duration of the disease. on an empty stomach.
** Vitamin B6 is not necessary in children taking INH.
Hepatotoxicity may be seen in vulnerable patients,
Magnetic Resonance Imaging (MRI) (malnutrition/disseminated disease)
Nonenhanced MRI may be normal in the early stages of
TBM. However gadolinium enhanced MRI is superior Antitubercular treatment: It is the cornerstone of effective
to conventional CECT for detection of basal meningeal treatment of TBM. The main objectives of anti-TB treatment
enhancement and small Tuberculomas. Advantages of are to: cure the patient; prevent death from active TB or
contrast MRI are summarized in Table 12.2.7. Post-gad its late effects; prevent relapse of TB (by eliminating the
MRI has been shown to be superior to computed dormant bacilli); prevent the development of drug
tomography in demonstrating ischemia in TBM, resistance (by using a combination of drugs) and decrease
especially of the brainstem.64 It is also superior to detect TB transmission to others. In TBM the drug should be able
diffuse or focal meningeal granulomatous change and
to penetrate the blood brain barrier (BBB) and achieve
delineate focal infarcts of basal ganglia and diencephalon.
effective concentration in CNS. The Consensus Statement
Cranial nerves may appear thickened on both T1 and T2
of IAP (Indian Academy of Pediatrics) recommends the
weighted images and may show hyperintensity on T2
doses of antitubercular drugs as listed in Table 12.2.8.67
weighted images. Proximal part of the cranial nerve may
show enhancement with gadolinium. MRI when The drug regimens used are summarized in Table 12.2.9.
combined with MRS (magnetic resonance spectroscopy) In 1993, RNTCP (Revised National Tuberculosis Control
is useful in differentiating tuberculomas from other Program) incorporating the internationally recommended
infective lesions such as brain abscess or neurocysticercosis DOTS strategy, was developed. The RNTCP recommends
and neoplastic lesions as it demonstrates the biochemical intermittent short-course chemotherapy (ISSC) under
fingerprints of the tubercle bacilli in a granuloma.65,66 Directly Observed Treatment-Short-course (DOTS)
For neuroimaging refer to chapter on imaging strategy and the Indian Academy of Pediatrics endorses
the same for all forms of childhood tuberculosis.68
Treatment of TBM Antitubercular therapy (ATT) regimens are divided
in two, an initial intensive phase and a continuation
The primary aim of treatment of TBM is to ensure the
recovery of the child without neurological deficit and phase. In intensive phase, a regimen of INH, rifampicin,
cognitive disabilities. In addition, it should prevent pyrazinamide along with streptomycin/ethambutol is
transmission and halt the evolution of resistant strains. recommended. In continuation phase, two drug regimens
In cases of doubt as to whether the patient has partially is given for four months or longer or optimal length
treated meningitis or TBM (a very important differential therapy is not yet established but most experts give ATT
diagnosis in our setting), it is prudent to start dual for at least 9 months.
therapy with antibiotics and antitubercular therapy and Due to different degrees of drug penetration into the
reassess the patient in 7-10 days. central nervous system, some experts recommend
171
Table 12.2.9: Drug regimens used in TBM

Protocol Intensive phase** Continuation phase** Total duration (months)
IAP consensus 2 HRZE 10 HRE 12

DOTS, RNTCP* 2H3R3Z3E3 7H3R3 Cat I of DOTS; 9 months
* intermittent therapy
** H (INH), R (Rifampicin), Z (Pyrazinamide), E (Ethambutol)
modifying the standard anti-TB treatment regimen for treatment. A randomized control trial done by Te Water
children. As ethambutol and streptomycin have poor et al73 concluded that fully intermittent twice weekly
penetration in CSF, some experts recommend chemotherapy is an acceptable treatment option for the
ethionamide as the fourth drug because it crosses both management of uncomplicated pulmonary childhood
healthy and inflamed meninges. Furthermore, because tuberculosis. There are no RCTs to conclude whether this
rifampicin does not penetrate uninflamed meninges well is applicable to cases of CNS tuberculosis. In fact a meta-
and pyrazinamide dose, some experts recommend analysis was done to compare the effectiveness of
continuing pyrazinamide for the full 6-months intermittent with daily chemotherapy (both containing
treatment.69 While optimal duration of therapy is not well rifampicin) in childhood tuberculosis (age < 16 years) to
established, it is prudent to use the upper end of the doses achieve cure or significant improvement. Four
range and longer continuation phase (up to 7 months) in randomized controlled trials comparing twice weekly
treatment of TBM. and daily therapy included 466 children (pulmonary 439;
Efficacy of ISSC (Intermittent Short-Course Chemo- extrapulmonary 27). It was concluded that twice weekly
therapy) in children with pulmonary tuberculosis (PTB) intermittent short-course therapy is less likely to cure
and other non-serious forms is well established.68-74 There tuberculosis in children as compared to daily therapy.80
is limited published data on its efficacy of ISSC in serious The studies included, however, did not have CNS
extra pulmonary tuberculosis (EPTB) particularly TBM.75- tuberculosis. Hence, for neurotuberculosis it is safer to
77
Regarding the efficacy of ISSC in tubercular meningitis use daily regimen.
(TBM), the published evidence is almost nonexistent in
children, and scarce in adults.78 WHO Guidelines for Corticosteroids
management of tuberculosis in children recommends the
treatment regimens for TBM as described in Table Corticosteroids are routinely recommended in TBM. The
12.2.10.69 There are no randomized controlled trials evidence of its utility to significantly reduce death and
(RCTs) available to definitely conclude the optimum disabling residual neurological deficit amongst patient
duration of treatment to prevent relapses and long term has recently been confirmed by Cochrane review.85 A
sequel. Multiple reports have confirmed the efficacy of study from Vietnam showed that patients who received
shorter courses of drugs with similar cure rates and better dexamethasone, on follow-up had significantly impro-
compliance with fewer drop out rates.79-84 ved survival. However, treatment with corticosteroids
did not alter the combined outcome of death and severe
disability. However, subgroup analysis revealed that
Daily versus intermittent?
for the patients in stage-I there was a slight statistically
Ideally daily DOTS would be desirable pending RCTs to significant benefit for the combined outcome. This
unequivocally establish the efficacy of intermittent observation suggested that early treatment is
therapy in pediatric tuberculosis especially severe important.86 The mechanism by which corticosteroids
extrapulmonary TB. Under the umbrella of RNTCP, fully
intermittent thrice weekly therapy is being used. The
overall response rate for treatment of pediatric TB is 95%, Table 12.2.10: Selected regimens for treatment of TB
meningitis in children69
which is comparable to 90-100% response reported with
daily therapy.68,71,72 The cure rates in neurotuberculosis Intensive phase Continuation phase
is 86%.79 The thrice weekly regimens under RNTCP has 2HRZE 4HR
good patient compliance, fewer dropouts in addition to
being cost effective and preventing emergence of resistant 2HRZ(S or Eth) 7-10HR
strains. 6HRZEth (regimen for 6 months
in total)
Relatively few studies have evaluated the
effectiveness of fully intermittent chemotherapy for Eth, ethionamide; H, isoniazid; R, rifampicin; S,
childhood tuberculosis or its effect on adherence to streptomycin; Z, pyrazinamide.
172
exert survival benefit is currently unclear. Two broad a pre-existing site, or the development of new tuber-
mechanisms have been proposed: (i) the immune culous lesions in a patient who initially improved on anti-
modulating effect of dexamethasone in the CNS and tubercular therapy. This phenomenon is more commonly
(ii) the ability of steroids to prevent hydrocephalus. associated with extra pulmonary tuberculosis. It most
Besides, steroids reduce the spinal block, decrease CSF frequently occurs in the first 2 weeks after starting treat-
protein and pleocytosis besides depressing the ment, but may occur anytime even up to 1 year during
tuberculin hypersensitivity. chemotherapy despite a regular standard antitubercular
Corticosteroids should be added to the therapeutic treatment. New granuloma(s) or abscess(es) may appear
regimen in patients of tuberculous meningitis. The in children receiving chemotherapy for TBM during the
treatment of cerebral edema has improved survival and follow-up. Hydrocephalus may also appear despite a
thus administration of corticosteroids in high dosage is regular chemotherapy in treated TBM cases. Immature
clearly indicated in the management of cerebral edema. faintly enhancing tuberculomas have a more likely
Oral prednisolone (2 mg/kg/day for 3 weeks then chance of resolution with antituberculous chemotherapy
tapered over next 3 weeks) can be used. Alternatively and glucocorticoids, while a well-formed and probably
dexamethasone (0.4 mg/kg/day) followed by oral large sized (>3 cm) granulomas may have a risk of
prednisolone can be used. The total duration of steroids paradoxical enlargement.88 Paradoxical reaction are more
is 6-8 weeks. common in HIV positive patient. It is as high as 30% in
HIV positive patients as compared to 10% in immuno-
Antiepileptic Drugs competent patients.
In acute phase of TBM, seizures may occur due to
electrolyte imbalance such as hyponatremia, raised Surgical Management of Hydrocephalus
intracranial pressure. They mainly require the treatment Modern imaging techniques, such as CT and MRI, have
of underlying cause. Seizures occurring later than the clearly shown that hydrocephalus is very common and
first week or associated with tuberculoma and infarct plays an important role in increasing the raised ICT with
require initiation of antiepileptic drugs (AED). Seizure subsequent brain damage.
in TBM are mainly acute symptomatic and may not There is no consensus in the literature regarding the
necessitate the use of long term AED. In the absence of most appropriate treatment for tuberculous
detailed investigatory work up for finding out the cause hydrocephalus, mainly because of lack of well-designed,
of convulsions, clinical presentation of seizures like focal prospective controlled trials. There are 2 options for
seizures and cases with generalized tonic clonic seizures treatment of hydrocephalus—ventriculoperitoneal shunt
(GTCS) and tonic seizures which are recurrent and those (VP shunt) and endoscopic third ventriculostomy (ETV).
manifesting after first week may be reasonable Palur staging is mainly used for determining the
indications for starting long-term AED.87 severity of the disease.89 Tuberculous meningitis with
Phenobarbitone should not be used for treatment as hydrocephalus was graded as follows: grade 1, normal
it has cerebral depressant effect and induces hepatic sensorium and no neurologic deficit; grade 2, normal
microsomal enzymes which lead to production of sensorium with neurologic deficit; grade 3, altered
acetylating agents of INH which causes increased sensorium with/without dense neurologic deficit; and
hepatotoxicity. grade 4, deeply comatose with/without decerebrate or
decorticate posturing.
Medical Management of Cerebral Edema The usual approach to the management of acute
Mannitol: Mannitol is most frequently used in the hydrocephalus and raised ICP in tuberculous meningitis
emergency treatment of cerebral edema. The dose of is that of selective shunting. Noncommunicating hydro-
mannitol (20 %) is 5 ml/kg stat followed by 2 ml/kg 6 cephalus, which carries the risk of herniation, is treated
hourly for 8 doses. Repeated administration of the by immediate ventriculoperitoneal shunt, whereas
mannitol may cause fluid and electrolyte imbalance with communicating hydrocephalus, which carries no
a secondary increase in intracranial pressure (the rebound immediate risk, is first given a trial of medical treatment.
phenomenon). Hence, these drugs should be used for Medical and surgical treatment was compared in
the first 48-72 hours of therapy only. Besides mannitol, children who had stage 2 and 3 tuberculous meningitis
glycerol and acetazolamide can be used for treatment of by means of a controlled clinical trial. The medical and
chronic raised intracranial pressure (ICP). surgical treatment groups did not differ in clinical
outcome or resolution of hydrocephalus (ventricular
size on CT) after completing 6 months of anti-
Paradoxical Response to Antitubercular Treatment
tuberculosis therapy.85 A large follow-up study recently
A paradoxical deterioration during antitubercular confirmed that approximately 70% of cases of communi-
therapy is defined as a transient worsening of disease, at cating hydrocephalus will respond to medical therapy
173
(antitubercular treatment and diuretics), which reduces Table 12.2.11: Indications of surgical intervention in
the need for shunt surgery significantly.89 The benefits hydrocephalus
of this, especially in resource limited countries where
tuberculous meningitis occurs most commonly, are Noncommunicating hydrocephalus
many. The risk of shunt dysfunction (obstruction or Communicating hydrocephalus not responding to medical
infection) in tuberculous meningitis has been reported treatment.
to be as high as 30%. 90 This percentage has been Grade II and III hydrocephalus
attributed to the high CSF protein content and also the
high incidence of shunt infection. Late shunt
dysfunction in a patient who has become shunt-
dependent may have serious consequences if left
undiagnosed or untreated because of unavailability of Prognosis
neurosurgical services. The mortality rate associated with treated TBM is 20 to
Some studies report good outcome after surgical 50% in several series.85,95-98 In a large series from Egypt,
intervention by VP Shunt.91 The potential for better the initial stage of disease at presentation was reported
outcome needs to be weighed against the risk of to be a major prognostic indicator for mortality.95 In their
complications of VP Shunt. series, the mortality rate was 18% for stage I TBM, 34%
Endoscopic third ventriculostomy (ETV) is another
for stage II, and 72% for stage III. The importance of the
surgical option. It creates a communication between third
stage of disease in predicting outcome has been well
ventricle and subarachnoid space bypassing cerebral
documented in other series as well.99-101 Even the large
aqueduct. It is now considered as a safe and long-lasting
dexamethasone trial by Thwaites et al had 31.8%
treatment option for hydrocephalus in patient with
mortality in the steroid-treated arm, with mortality rates
tuberculous meningitis. This procedure was most
frequently reserved for patients who experienced multiple diverging depending on the presenting stage of disease
episodes of shunt dysfunction. Endoscopic third (stage I, 16.7%; stage II, 31.1%; stage III, 54.8%).85 Among
ventriculostomy is likely to fail in the presence of advanced the survivors of TBM, some form of neurological
clinical grade, dense adhesions in prepontine cisterns and impairment afflicts approximately 20 to 30%. These
an unidentifiable third ventricular floor anatomy.91 impairments range from cranial nerve palsies,
Though various authors have had a success rate of 65- ophthalmoplegia, seizures, psychiatric disorders, and
68% for treatment of tubercular hydrocephalus, failure ataxia to hemiparesis, blindness, deafness, and mental
rates have been quite high in acute cases due to thickening retardation.
of the floor of third ventricle and distorted anatomy. Researchers seeking additional predictors of poor
However, success rate is higher in chronic and burnt out outcome in CNS tuberculosis, specifically in children,
cases. identified advanced stage of the disease at
To conclude the type of surgical management, and presentation,100,101 age, and the presence of any infarction
time of intervention depend upon the type of other than a purely hemispheric infarction as important
hydrocephalus and the grading of the patient. Initially, predictors. Studies that included primarily adults
medical management should be tried for a week or so in identified the stage of disease, HIV coinfection, the
patients in grades I and II. The patient should be combination of isoniazid and rifampicin resistance and
monitored closely during this period to detect any CSF parameters such as high CSF lactate, CSF leucopenia,
worsening or lack of improvement and a shunt should and low CSF glucose as being poor prognostic
be promptly offered in case of failure of medical indicators.102 Misra et al studied both children and adults
management. Prolonging medical therapy in patients in and identified stage, age, focal weakness, cranial nerve
good grades could be harmful and may lead to palsies, and hydrocephalus as predictors of mortality at
irreversible brain damage.92 3 months.103 Interestingly, features such as presenting
As children with grade IV disease usually have poor intracranial pressure, cytokines in the CSF,104 isoniazid
outcome, aggressive surgical management will have little or streptomycin resistance, 105 and M. tuberculosis
effect on outcome. Such children should have external genotype106 have been shown not to be predictive of a
ventricular drainage, followed by shunting only if poor outcome. Presence of brain stem lesion, as visualized
improvement is seen. on MRI, also portends poorer outcome. Prompt diagnosis
As expertise with ETV increases across various and timely initiation of antitubercular treatment and
centers its role in acute and subacute cases of TBM with corticosteroids is a major determinant to favorable
hydrocephalus may increase93,94 (Table 12.2.11). outcome.85,100-102
174
Mortality and Sequelae SPECIAL SCENARIOS

Motor disability and intellectual handicap are common When to Suspect MDR-TB
long-term complications in survivors. Adverse sequelae
The multidrug-resistant (MDR) TB has, increasingly been
occur in 10 to 85% of cases. 95-98 These are mental recognized in children commensurate with the rising
retardation, epilepsy, neurological deficit in the form of number of adults with HIV/AIDS. Tuberculosis is the
hemiplegia, quadriplegia, cranial nerve palsy (commonly most common opportunistic infection noted in these
7th, 3rd and 6th cranial nerves), blindness, deafness, adults, many of whom may be MDR. Close proximity to
behavioral problems, hydrocephalus, hypothalamic adult patients with multidrug-resistant TB makes
disturbances in the form of precocious puberty and children prone to developing primary multidrug- resis-
diabetes insipidus. Behavioral abnormalities have also tant TB, a vulnerability documented in a South African
been reported in patients with TBM. These children have study.108
disruptive behavior, attention problems, hyperactivity,
aggressive behavior, rule-breaking behavior. There is
Tubercular Meningitis in HIV Infected Children
high incidence of ADHD or conduct disorder amongst
stage III TBM patients.107 Confection with human immunodeficiency virus (HIV)
In a prospective study at AIIMS (2000-2004) by Seth and Mycobacterium tuberculosis poses major diagnostic
et al,100 90 patients with TBM were followed for 2 to 11 and management challenges. HIV-infected children are
months with a mean duration of follow-up of 6.5 months. more likely to develop disseminated forms of TB and
The neurological outcome was assessed as follows: may develop immune reconstitution phenomena and
complex drug interactions.
The clinical picture of TBM in children is often
Classification of Neurological Outcomes
insidious, resulting in delayed diagnosis. HIV infected
• Attention deficit children with TBM may manifest signs of HIV disease,
• Well—Child appears well, minor physical such as generalized lymphadenopathy, splenomegaly,
abnormality not interfering with normal routine. hepatomegaly, and clubbing, but are frequently
• Minor disability—Mild mental retardation, epilepsy, tuberculin skin test negative. Cerebrospinal fluid (CSF)
deafness, hyperactivity, behavioral problems findings are comparable in HIV-infected and HIV-
• Major disability—Severe mental retardation with uninfected patients with TBM.108,109
physical abnormalities such as hemiparesis or In the absence of a definitive microbiological diag-
blindness. nosis, computed tomography (CT) can provide
The neurological outcome depended upon the stage diagnostic certainty in most HIV-uninfected children.
of presentation (Table 12.2.12). However, HIV-infected children are less likely to display
In Stage I and II, the percentage of children who were the classic signs associated with TBM on CT: obstructive
well, ranged from 86-67% and there was no death. In hydrocephalus (72% vs 98%), basilar enhancement (38%
comparison in the children who presented in stage III, vs 71%), and parenchymal granulomas (0% vs 15%).109
61% had major disability and 27% died. The optimal time to begin antiretroviral (ARV)
therapy in the ARV-naive, HIV-infected child with TBM
Relationship with BCG is unclear because of the risk of immune reconstitution
inflammatory syndrome (IRIS). IRIS represents the
Children with TBM who are vaccinated with BCG appear paradoxical worsening of symptoms after an initial
to maintain better mentation and have a superior period (2 weeks to 3 months) of improvement. IRIS is
outcome. This may in part be explained by the better generally a self-limiting phenomenon and should not be
immune response to infection as reflected in the higher mistaken for ATT treatment failure. Most management
CSF cell counts.101
Table 12.2.12: Clinical outcomes of TBM in relation to stage of presentation.
Clinical outcome
Clinical stage No. of cases Well Minor disability Major disability Mortality
I 7 6(86)* 1(14) 0 0
II 43 29(67) 9(2) 5(12) 0
III 44 3(7) 2(5) 27(61) 12(27)
* Figures in parentheses are percentages.

175
guidelines suggest delaying ARV therapy for 4 or more epithelioid cells derived from altered mononuclear
weeks after ATT initiation. phagocytes and surrounded by lymphocytes. Tubercles
For children diagnosed with TBM while on ARV originate during initial bacteremia which is known to occur
therapy, the specific ARV drug regimen may need to be in chronic tuberculous infections. The extent and rate of
altered to minimize interactions with the ATT local progression of these initial foci into tuberculomas is
medications.110 Coadministration of antitubercular and extremely variable and depend upon complex and
antiretroviral therapy is common in high-burden incompletely understood mechanisms. Often,
countries where tuberculosis is the commonest polymorphonuclear leukocytes may infiltrate into these
opportunistic infection. Concomitant use of rifampicin lesions. The center of the tuberculoma becomes necrotic,
and many antiretroviral drugs is complicated by drug- forming caseous debris, while the periphery tends to
interactions caused by the potent induction by rifampicin encapsulate with fibrous tissue. There may be liquefaction
of genes involved in drug metabolism and transport, of the caseous material, resulting in a “tuberculous abscess”
which could result in subtherapeutic antiretroviral drug in extreme cases. Apparently this is due to the presence of
concentrations. The major interactions involve polymorphonuclear leukocytes.4 The size of cerebral
antiretrovirals used in resource-limited settings: the non- tuberculomas is quite variable. In most cases, their
nucleoside reverse transcriptase inhibitors (NNRTIs) diameter ranges from a few millimeters to 3 or 4
efavirenz or nevirapine, and ritonavir-boosted protease centimeters in size.
inhibitors. The reduction of nevirapine concentrations Intracranial tuberculomas in patients under the age
with concomitant rifampicin is greater than with of 20 years are usually infratentorial, but supratentorial
efavirenz, particularly during the lead-in dose period lesions predominate in adults.114 Most frequent site of
when subtherapeutic concentrations occur in the majority involvement in children was considered to be the
of patients. There is reassuring data on the effectiveness cerebellum. However, with the advent of neuroimaging,
of standard doses of efavirenz with concomitant supratentorial lesions are increasingly being recognized
rifampicin, but the largest cohort study found a higher in children. In spite of hematogenous origin of
risk of virological failure with nevirapine. The drug-drug tuberculomas due to initial bacillemia, solitary
interaction between rifampicin and ritonavir-boosted tuberculomas are more frequently seen than multiple
protease inhibitors is more marked than with the lesions.114
NNRTIs, and therapeutic concentrations have only been On gross examination, a cerebral tuberculoma is
achieved with adjusted doses of lopinavir/ritonavir or usually found to be hard, nodular, comparatively
with saquinavir/ritonavir. The major barrier to using avascular and easy to shell out. There may be a
adjusted dose protease inhibitors with rifampicin is the connection to the adjacent dura and occasionally there
high rates of hepatotoxicity seen in healthy volunteers. may be a gross resemblance to meningioma. Edema
The alternative strategy that can be followed in resource- forms the integral feature of tuberculoma. Indeed it is
rich settings is to replace rifampicin with rifabutin, but occasionally so extensive and out of proportion to the
even if the price of rifabutin were to be dramatically size of the tuberculoma itself that it has been considered
reduced it would be difficult to implement in high- to constitute a tuberculous edematous encephalopathy.
burden countries where standardized antitubercular In addition, there are many atypical forms of tuberculoma
regimens with fixed-dose combinations are used.111 including cysts and abscesses.
TUBERCULOMA OF BRAIN Clinical Features

Tuberculoma is a manifestation of tuberculosis which occurs Clinical features of intracranial tuberculoma are
in solid organs. A tuberculoma usually begins in an area of dependent on size and site of the lesion as well as
TB cerebritis as a cluster of microgranulomas, which presence of concurrent meningitis. Intracranial
coalesce into a mature noncaseating granuloma. The relative tuberculomas usually present with seizures without
frequency of CNS tuberculomas varies from country to associated meningeal signs or evidence of tuberculosis
country. The proportion of tuberculomas of the brain among elsewhere in the body. Neurological symptoms
the space occupying lesions ranges from 1.4-15.9%.112,113 Its consequent to the mass effect of a tuberculoma may
incidence is higher in the developing countries as compared occasionally precipitate symptoms of raised intracranial
to the developed world.111 With the availability of effective tension. Depending on the location of the lesion, various
antitubercular treatment, a correct diagnosis and early cerebellar or brain stem syndromes occur. Infratentorial
institution of specific treatment is warranted. tuberculoma may present with raised ICT. In a British
tertiary care set-up, a retrospective case survey revealed
Pathogenesis 38 children with CNS tuberculosis. TB meningitis was
A tuberculoma is a conglomerate mass of tissue made up apparent in 23 children and 10 cases had TBM with
of small tubercles which consist of a central core of associated tuberculomas and five had tuberculomas
176
alone. In five patients with TBM, new tuberculoma The imaging features of caseating granulomas or
developed during treatment as a result of paradoxical granulomatous abscess are not specific for TB and are
response to ATT.109 not distinguishable from cysticercus granuloma or, when
large, from fungal and pyogenic lesions. In areas where
Diagnosis both TB and cysticercosis are prevalent (as in India), a
The diagnosis of intracranial tuberculoma often rests on single ring-enhancing lesion detected on CT in a patient
clinical assessment, imaging findings and response to investigated for a focal or generalized seizure remains a
therapy. Bacteriological diagnosis is hardly ever made diagnostic dilemma. The morphological characterization
and surgical biopsy to confirm the diagnosis of TB is of intracranial mass lesions using conventional MRI
risky. A high clinical index of suspicion is required for alone, even after contrast administration may sometimes
timely diagnosis. Evidence of extra cranial TB and a close be difficult without the histopathological examination of
family contact with active TB are common pointers to the suspected tissue. Hence, other noninvasive
the diagnosis in pediatric age group. When the signs and
techniques are utilized to overcome this shortcoming and
symptoms of concomitant TBM are present, the diagnosis
provide more diagnostic specificity.109 Proton Magnetic
is relatively easy. The differential diagnoses that need to
Resonance Spectroscopy (1H-MRS) is helpful in diffe-
be considered are neurocysticercosis (NCC), brain
abscess, fungal infection and malignancy. rential diagnosis of untreated intracranial space-occu-
The advent of modern imaging techniques has pying lesions (SOLs).115,116 MRS provides a detailed bio-
revolutionized the diagnosis of intracranial granulomas. chemical analysis (metabolites) of the tissue, 117,118
Contrast enhanced computed tomography (CECT) is allowing direct insight into in vivo human brain
utilized as initial imaging modality. Focal parenchymal metabolism.118 Magnetic resonance spectroscopy of brain
tuberculomas measure 5-30 mm but are occasionally tuberculomas commonly detects a peak of lipids
larger, up to 60 mm and 15-20% present with multiple, attributable to the large lipid fraction in the tuberculous
separate lesions although grape-like clusters of bacillus.119,120 The MRS reveals increased choline/crea-
granulomas occur.112 Tuberculomas may occur anywhere tine ratio in tuberculoma which is the result of damage
in the parenchyma. A typical symptomatic tuberculoma
to the brain tissue and is minimal in NCC. MRS analyzing
has surrounding vasogenic edema and central necrosis.
viable cyst contents (cystic fluid) find other amino acid
The increased interstitial space fluid of vasogenic edema
peaks, including lactate, alanine, and succinate.121-125
is hypodense on CT and T2 hyperintense on MRI with
no contrast enhancement. The granuloma is iso- to Rajshekhar et al made an attempt to differentiate
hyperdense on CT and on MRI is slightly T1 hyperintense between these two entities on the basis of clinical and
with marked T2 hypointensity. Small granulomas, up to CT features of histologically confirmed tuberculoma and
10 mm, will enhance diffusely following IV contrast on NCC.126 They noted that cysticerci are usually round or
CT and on T1 post-gadolinium images. This is consistent oval with smooth margins, 20 mm or less in size with
with the vasogenic component of the inflammatory ring enhancement or visible scolex, and cerebral edema
process and the absence of (macroscopic) necrosis. severe enough to produce midline shift or focal
Necrosis, usually central, is associated with loss of neurological deficit is not seen.126
enhancement and results in ring-enhancing lesions. MRI Another technique to differentiate two common
changes are summarized in Table 12.2.13. etiologies of “ring lesions,” tuberculomas and cysticercal
Table 12.2.13: MRI changes in tuberculoma
Stage of tubercoloma MRI (Magnetic Resonance Imaging)

Non- caseating granulomas Hypointense compared to the brain tissue on T1 weighted images and are seen
hypointense on T2 weighted and fluid-attenuated inversion recovery (FLAIR)
images. They generally exhibit homogeneous nodular contrast enhancement and
a peripheral hypointensity.
Caseating granulomas with solid center Either hypointense or isointense on T1 weighted images with ring enhancement
on contrast administration.
Variable degree of perilesional edema is present. Most tuberculomas are further
outlined by a collar of high signal intensity due to edema.
Caseating granulomas with liquid center Central hypointensity on T1 and hyperintensity on T2 weighted images with a
peripheral hypointense ring which represents the capsule of tuberculoma.
177
Table 12.2.14: Differences between neurocysticercosis and tuberculoma
Tuberculoma Neurocysticercosis
May present at any age Rare before the age of 3 years
Present with progressive neurological deficit Generally no neurological deficit may have postictal
focal deficits of varying severity, and all deficits
resolve within a matter of days to weeks
On size > 20 mm, irregular outline with marked Usually smaller, regular rounded outline with less
cerebral edema cerebral edema
May be supratentorial or infratentorial Usually supratentorial
Likely to cause midline shift Midline shift usually not seen
MRS has lipid peak No lipid peak
Relaxation time on T2 relaxometry images to be T2 relaxation time is longer
shorter than NCC (above)
cysts, is to use T2 relaxometry. It is a simple, reliable and care of cerebral edema. A repeat scan should be done to
valuable non-invasive magnetic resonance imaging look for changes in radiological picture.
(MRI) technique to differentiate between intracranial The majority of tuberculomas respond to
cysticercal cysts and tuberculomas, and may be antituberculosis drugs, showing a radiological response
incorporated in routine diagnostic protocols. The mean in 6 to 8 weeks. Paradoxical increase in tuberculomas,
T2 relaxation times of cysticercal cysts is 617 ms (range although uncommon, can occasionally occur and requires
305-1365 ms; SD 272.2) and that of tuberculomas is 161 continued ATT and may at times need surgical decom-
ms (range 83-290 ms; SD 60.3; 95% confidence). 127 pression. Surgical decompression or excision is rarely
Differences between NCC and tuberculoma are required in large masses which cause significant
summarized in Table 12.2.14. increased intracranial pressure or impending loss of
Dynamic contrast-enhanced (DCE) MRI is a technique vision. A CSF diversion procedure may be performed in
that derives perfusion indices with immuno- cases of obstructive hydrocephalus caused by
histochemically obtained vascular endothelial growth tuberculomas.
factor (VEGF) and matrix metalloproteinase-9 (MMP-9)
in a cellular fraction of brain tuberculomas. Perfusion Outcome
indices include (cerebral blood volume [CBV], transfer Tuberculomas usually resolve over 3-6 months on TB
coefficient and leakage) and thereby maps are generated treatment, however, larger lesions may take considerably
for the quantitative analysis. Using this technique, it is longer. Occasionally paradoxical appearance of
possible to assess therapeutic response to ATT by granulomas and increase in size of granulomas may occur
evaluating the changes in k(trans) and edema volume in patients on anti-TB therapy. Occasionally calcification
even when there is a paradoxical increase in the lesion is noted and rarely a tuberculoma will resolve to a small
volume.124 calcified focus.
Stereotactic biopsy is the last resort if diagnosis is
uncertain. Previously published series have shown the SPINAL TUBERCULOSIS IN CHILDREN
efficacy of stereotactic biopsies using smear techniques
for pathology to be 28%. 128 In the rest, a chronic Tuberculosis of the vertebral column (Pott’s spine)
inflammation with gliosis was the histopathological Introduction
picture which was inconclusive. Invasive diagnostic
procedures are reserved for few atypical cases and Spinal TB can involve the bones of vertebral column (Pott’s
sometimes required for aspiration of TB abscess.129 disease), the cord (myelitis, abscess, or granuloma), and
its dura (arachnoiditis or extradural abscess). Pott’s disease
Treatment is the most common form of skeletal involvement by
tuberculosis (about half the cases of skeletal
The treatment protocol for intracranial tuberculomas tuberculosis).130 It is estimated that spinal involvement
includes antitubercular treatment as described in section occurs in less than 1% of patients with TB, but it still remains
with TBM. It is essential that in addition to antitubercular a leading cause of paraplegia in developing nations.130-132
treatment, adequate measures should be instituted for The other forms of spinal involvement like intramedullary
symptomatic management of raised intracranial tension tuberculomas, epidural abscess and spinal arachnoiditis are
and seizures. Steroids should also be instituted to take rare in pediatric age group.
178
Clinical Features appearance called the aneurysmal phenomenon. Wedging

of vertebral bodies leads to a kyphotic deformity. Less
Presentation depends upon the stage of the disease, site common radiological presentations of spinal tuberculosis
of the disease (bone or spinal cord), and presence of are central type, anterior type, and appendiceal type.
complications. Constitutional symptoms such as Central disease presents as destruction, ballooning of
weakness, loss of appetite and weight, evening rise of vertebral bodies, and concentric collapse. Anterior type is
temperature and night sweats generally occur before the more common in the pediatric dorsal spine and appears
symptoms related to the spine manifest. There may be as erosion of anterior margin of vertebral bodies. CT scan
evidences of associated extraskeletal tuberculosis like and MRI are increasingly being used to diagnose various
cough, expectoration, lymphadenopathy, diarrhea, and types of bony and soft tissue involvement and presence
abdominal distension. Back pain (spinal or radicular) is of associated abscess and granulation tissue.
the earliest and most common symptom. This pain may
worsen with activity. Relaxation of muscles during sleep
CT scanning and MRI
permits movements which are very painful and wake-
up the patient. As the infection progresses, pain increases, For a radiolucent lesion to be seen on a plain radiograph,
and paraspinal muscle spasm occurs. Muscle spasm 30% of mineral loss must be there. CT and MRI detect
obliterates the normal spinal curves, and all spinal lesions at an earlier stage. CT scanning provides much
movements become restricted and painful. better bony detail of irregular lytic lesions, sclerosis, disc
Physical examination of the spine reveals localized collapse, and disruption of bone circumference. Low-
tenderness and paravertebral muscle spasm. A kyphotic contrast resolution provides a better soft tissue
deformity due to prominence of spinous process may be assessment, particularly in epidural and paraspinal areas.
evident due to collapse and anterior wedging of vertebral CT is more effective for defining the shape and
bodies. Tuberculous necrotic material from the calcification of soft tissue abscesses. CT is useful in
dorsolumbar spine may lead to cold abscess in the rectus assessing bone destruction, but is less accurate in defining
sheath and lower abdominal wall along the intercostal, the epidural extension of the disease. MRI is the gold
ilioinguinal, and iliohypogastric nerves; in the thigh standard for evaluating disc space infection and
along the psoas sheath; in the back along the posterior osteomyelitis of the spine, and is most effective for
spinal nerves; in the buttock along the superior gluteal demonstrating the extension of disease into soft tissues
nerve; in the Petit’s triangle along the flat muscles of and the spread of tuberculous debris under the anterior
abdominal wall, or, in the ischiorectal fossa along the and posterior longitudinal ligaments. MRI is most
internal pudendal nerve. Upper cervical spine effective for demonstrating neural compression. MRI
involvement though less common, can cause dangerous with contrast is helpful in differentiating TB from
and rapidly progressive symptoms. In the case of noninfectious causes and delineating the extent of
retropharyngeal abscesses, the abscess may track down disease. Serial MRI can be used to assess the response to
the mediastinum to enter trachea, esophagus, or pleura; treatment and regression of the disease. MRI is the
may spread to sternomastoid muscle. Segmental signs imaging modality of choice for spinal arachnoiditis,
depending on the level of lesion and upper motor neuron intramedullary tuberculoma and epidural abscesses.
signs may be present on examination giving a clue to
underlying compressive myelopathy. Bone scan with Tc-99m
Bone scan with Tc-99m is considered to be highly
Imaging Modalities for Diagnosis of Spinal Tuberculosis
sensitive, but nonspecific. It may only aid to localize the
Plain radiographs site of active disease and to detect multilevel
involvement. Patients with active disease have an
Plain radiographs are the first line of investigations in our increased uptake. Bone scan however is not diagnostic
country. Earliest radiological features are narrowing of the of tubercular involvement because it shows increased
joint space and indistinct paradiscal margin of vertebral uptake in any inflammatory process.
bodies. Gradually, the disk space narrows due to either
atrophy or prolapse into the vertebral body of the disc Intramedullary Tuberculoma
tissue. The collection of tubercular granulation tissue and
necrotic material leads to formation of paravertebral Intramedullary tuberculomas may present like any other
abscess. In the region of thoracic spine it is visible on plain intraspinal mass with segmental signs and paraparesis distal
radiographs as a fusiform or globular radiodense shadow to the lesions. Intramedullary spinal tuberculomas are
called the bird nest appearance. Long standing abscesses extremely rare lesions, even in areas where TB is endemic.133
may produce concave erosions around the anterior Reviewing 74 cases of TB paraplegia without bony
margins of the vertebral bodies producing a scalloped involvement, Dastur134 found intramedullary lesions in 8%
179
of the patients. MacDonnell et al135 reviewed the literature circumscribed central necrosis, severe gliosis and
and found a total of 43 cases (mean age, 28 years) reported intramedullary tuberculoma, resulting in multicystic
between 1960 and 1990. The lesions most commonly myelomalacia and syringomyelia.
occurred in the thoracic cord.135 These patients mostly
present with progressive weakness, paresthesias, and loss Complications of Spinal Tuberculosis
of bladder and bowel control.136
Due to the destruction of the anterior part of vertebral
MRI is the imaging modality of choice for spinal
body, the cartilage plates that are responsible for the
involvement and can localize the tuberculoma in the
growth are destroyed. The growth of the vertebral
extradural, intradural extramedullary, and intramedullary
compartments.137 The lesions have hypo- to low intensity column in the child is thereby stopped and leads to major
on T1-weighted images, low intensity with or without growth discrepancy and progressive spinal deformity.
central hyperintensity (depending on the amount of The posterior part of the vertebral bodies is usually
caseous necrosis) on T2-weighted images, and ring unaffected and continues to grow. With the passage of
enhancement with a hypointense center on post-contrast time this can produce a significant kyphotic deformity.
images. The degree of damage to the anterior vertebra determines
the extent of growth alteration. Moreover, younger the
TB Extradural/Epidural Abscess child, greater is the final growth discrepancy. This can
lead to serious neurological complications.
Spinal epidural abscess is seen mostly in patients over
The neurological problems can arise due to physical
30 years of age and are rare in children. MRI demonstrates
compression of the neural tissues like spinal cord and
a sensitivity of 91% for the diagnosis of spinal epidural
nerves, inflammation of these structures and their
abscess,138 thus, being the investigation of choice.139
coverings by the disease (meningitis/arachnoiditis/neuritis),
Epidural TB lesions are usually iso-intense to the spinal
edema and vascular thrombosis. The functional deficit can
cord on T1 weighted images. Mixed signal intensity is
be as insignificant as tingling numbness and mild
seen on T2 weighted images, with peripheral
weakness (paraparesis, quadriparesis) or as catastrophic as
enhancement post-gadolinium in TB epidural abscess.140
complete loss of sensations, power and bladder-bowel
(paraplegia, quadriplegia) control.
Spinal Tuberculous Arachnoiditis
Spinal tuberculous arachnoiditis is a rare complication Treatment for Spinal Tuberculosis
of CNS tuberculosis. It is an inflammatory condition that In addition to institution of antitubercular treatment
involves the arachnoid lining along the spinal tract. This (with steroids) surgery may be required if features of
condition was previously termed adhesive spinal spinal cord compression are present. Usual indications
arachnoiditis or chronic adhesive arachnoiditis. This for surgical decompression are:
clinical entity is uncommon in developed countries, but • Neurological complications that worsen after a fair
is still commonly reported in South-East Asia, the Indian trial of conservative therapy (ATT + spinal
subcontinent, South America and Africa. Three different immobilization) for 3-4 weeks
pathogeneses are suggested for the occurrence of spinal • Patients with Pott’s spine in whom neurological deficits
develop during conservative treatment
tuberculous arachnoiditis, i.e. a tuberculous lesion
• Recurrence of neurological complications
primarily arising in the spinal meninges, downward
• Prevertebral cervical abscesses, neurological signs,
extension of intracranial tuberculous meningitis; and
and difficulty in deglutition and respiration
extension of tuberculous spondylitis. Among these, • Advanced cases of neurological involvement such as
involvement of the spinal arachnoid lining secondary to marked sensory or sphincter disturbances or flaccid
intracranial tuberculous meningitis is the most common paralysis.
pathogenesis. The thoracic region is the most frequently
affected site, followed by the lumbar and cervical regions. Prognosis
Macroscopically, exudate can be seen surrounding the Prognosis depends on many factors. The site and stage of
spinal cord and nerve roots. Microscopically, disease are important variables that affect the ultimate
granulomatous inflammation, areas of caseation, outcome. Severe malnutrition, delay in starting ATT,
tubercles, and fibrous tissue are noted. In chronic cases, degree of compression and neurological deficit also
the subarachnoid space may be irregularly obstructed, determines the prognosis. Prognosis is poor if cord
with the formation of pockets of CSF. Spinal cord involvement is complete, if there is longer duration of
parenchymal changes include border-zone rarefaction neural complications, late onset cord involvement, neural
and vacuolization of the cord, extensive atrophy and complications that developed rapidly.
180
HIGHLIGHTS and the emergence of drug resistant strains in HIV

• The incidence of CNS tuberculosis is directly positive patients.
• On analyzing our data, there was no difference in
proportional to the prevalence of tuberculous
the clinical spectrum of neurotuberculosis when
infection in general.
analyzed year-wise from 1991 to 2004 (p = 0.82)
• Neurotuberculosis is represented by different and
though the severity of the disease was lesser in later
possibly concomitant forms:
years.
– Intracranial TBM, TBM with miliary tuberculosis
• Various immunoassays are available such as
– Space occupying lesions (Tuberculoma, multiple
hemagglutination, enzyme linked immunosorbant
small tuberculomas with miliary tuberculosis,
assay (ELISA), immunofluorescent assay (IFA),
tuberculous abscess)
radioimmunoassay (RIA), immunoblot assays and
– Tuberculous encephalopathy, tuberculous T cell-based gamma interferon release assay. The
vasculopathy. variations in sensitivity and specificity of many
• Spinal–Pott’s spine and Pott’s paraplegia, immunoassays have resulted in lack of faith among
tuberculous arachnoiditis (myeloradiculopathy) clinicians in the use of immunodiagnostics of
nonosseous spinal tuberculoma, spinal meningitis. neurotuberculosis.
The most frequent are tuberculous meningitis • Differentiating cysticercus granuloma from
(TBM) and tuberculoma. tuberculoma is of paramount importance, both of
• In great majority of patients with neurotuberculosis, which are common in our country and have different
the diagnosis is based on characteristic clinical, treatment.
cerebrospinal (CSF) and imaging findings. • Early diagnosis and prompt treatment with all
• Because of partial immunity achieved by BCG, there regimens is recommended.
are a large number of localized lesions in different • Clinical response with antituberculosis therapy in
parts of brain and/or meninges with protean clinical all forms of neurotuberculosis is excellent if the
manifestations depending upon the site of the diagnosis is made early before irreversible
lesions (see for details Chapter 12.3 of case studies). neurological deficit is established. As the emergence
• There is increased incidence of tuberculosis with of neurological deficit has been seen in some of these
HIV. Of concern is the reported development of new studies, a minimum of 9-12 months of treatment
clinico-radiological findings of TBM despite therapy would be worth while.
12.3 CASE STUDIES

PM Udani, S Gulati, Rachna Seth, V Kalra, Vimlesh Seth
PROFILE OF TBM IN CHILDREN MODIFIED BY BCG— examination showed findings suggestive of suspicious
DR PM UDANI’S EXPERIENCE pyogenic meningitis. He was treated as a case of probably
mixed meningitis of both pyogenic and tubercular
Case 1 etiology. A second tuberculin test done after two months
Advanced TBM with hydrocephalus, multiple cranial of treatment was strongly positive. He was rehospitalized
nerve palsies, hemiplegia on right side and three months after tuberculin test and had well marked
hemiballismus on the left but the child had complete meningeal signs, evidence of increased intracranial
recovery on treatment pressure, right sided hemiplegia, hemiballismus on left
A one-year-old boy, had history of fever for a period side, multiple cranial nerve palsies, strongly positive
of one month. The child had convulsions after 22 days tuberculin and BCG tests. A lymph node biopsy revealed
which became more severe by the next day. The initial tubercular lymphadenitis. The first CT scan (not shown
CSF showed turbid fluid with 950 mg/dl of protein, 140 here) done after three months showed massive
cells with 80% polymorphs. This child was given BCG at hydrocephalus and evidence of basal exudates along the
5 months of age and had BCG adenopathy. However, vessels. An urgent shunt operation was done. Second CT
the initial tuberculin test was negative. A repeat CSF scan was done after shunt operation (Fig. 12.3.1A) which
181
Figs 12.3.1A and B: Advanced TBM with hydrocephalus, multiple cranial nerve palsies,
hemiplegia on right side and hemiballismus on the left but the child had complete recovery on treatment
shows that the hydrocephalus had become smaller. Child no convulsions or any disturbance in sensorium. He was
also had exudate in the posterior fossa. He improved with conscious and alert but had well marked meningeal signs
chemotherapy, steroids and ventriculoperitoneal shunt with cracked pot sound, hyperreflexia in both lower
(V-P shunt) and was completely normal clinically and limbs and extensor plantar response. However, he could
developmentally when seen at the age of two years. A not sit up, walk or talk (Fig. 12.3.2A). BCG had been given
third CT scan (Fig. 12.3.1B) done at the age of two years but scar was faint. CSF showed increased proteins, 182
showed the basal exudates present around the vessels mg/dl, glucose 31 mg/dl, chlorides 626 mg/dl and 96
as well as in the posterior fossa. There was a dense cells/cubic ml with 90% lymphocytes. Chest X-ray
shadow in the sylvian fissure which was probably due showed intrathoracic lymph node enlargement. The first
to thick exudate around the middle cerebral artery. A CT scan (Fig. 12.3.2B) showed dense basal exudate and
follow-up fourth CT scan (Fig. 12.3.1C) done at the age moderate hydrocephalus. Child was treated with
of three years revealed the ventricular system to be antituberculosis drugs and steroids. He improved
normal and exudate completely disappeared. remarkably in two weeks and could walk and talk, and
looked almost normal. However, he still had well marked
meningeal signs. A second CT scan (Fig. 12.3.2C) done
Comments
after two weeks showed dense basal exudate but
This case had many interesting points. (i) Initially it could hydrocephalus had improved. Hence surgery was not
not be made out whether the child had mixed meningitis necessary. Child was seen again after one week and CT
(both pyogenic and tuberculous types) or TBM with scan (not shown here) showed remarkable reduction in
multiple complications. He made complete recovery the size of the ventricles. The ventricles appeared only
clinically as well as CT imagingwise. (ii) The basal slightly dilated. Basal exudate was still present, but less.
exudate along the vessels as seen in CT scan after shunt There was also minimal vascularity (fine exudate in
operation (Fig. 12.3.1A) appeared to be denser in the third between the cortical gyri).
CT, 8 months after treatment, showing that often the
exudate persists for a long time. With this dense exudate Comments
child also had moderate hydrocephalus. However, the
fourth CT done at the age of three years (Fig. 12.3.1B), This case is a modified clinical picture of TBM in a
showed complete disappearance of exudate and vaccinated child.
ventricles became normal in size. This is an example of a
child who had advanced TBM with complications, but Case 3
recovered completely with therapy with four bactericidal
CT scan of a child who had TBM with localized basal
drugs and steroids.
meningitis, hydrocephalus and blindness
This female child of 18 months was first seen with
Case 2 irregular fever for 16 days, vomiting and failure to talk.
CT scan showing localized basal TBM with She also had uprolling of eyeballs and mild weakness of
hydrocephalus in a BCG-vaccinated child (conscious the right side of the body. Examination revealed a fairly
type of TBM) built and nourished child with a weight of 9 kg, a head
Child aged three years was brought with a history of circumference of 46 cm and chest circumference of 41
fever, vomiting off and on for three months. Child had cm. Macewan’s sign was positive. She had well marked
182
Figs 12.3.2 A to C: (A) Conscious child with TBM, (B) CT head showing dense basal exudates,
(C) CT head showing basal exudates with improvement in hydrocephalus
Figs 12.3.3A to C: (A) CT scan head showing basal exudates extending into sylvian fissure. (B) CT scan head after VP shunt, no improvement
in hydrocephalus. (C) CT scan head showing increasing hydrocephalus with infarction in right parietooccipital region
meningeal signs, dilated and fixed pupils, dazed look and almost the same and also the basal exudate. Within a
could not sit up by herself. BCG had been given two week of the second CT scan child started getting high
months ago and there was a scab at the site. She was irregular fever. Urinary infection was detected and
diagnosed as a case of TBM with hydrocephalus, treated but improvement was not satisfactory. She also
blindness and left sided weakness. CSF examination developed peritoneal infection as evidenced by severe
showed proteins 160 mg/dl, gulcose 20 mg/dl, chlorides abdominal distention and tenderness at the site of V-P
520 mg/dl and 20 cells/mm, 3 predominantly shunt. The child’s condition became worse, she became
lymphocytes. A first CT scan (Fig. 12.3.3A) done on three dull and developed hemiparesis on the left side. A third
days after admission showed basal exudates extending CT scan (Fig. 12.3.3C) done after another three week
into the sylvian fissure. She was kept on four bactericidal showed a slight increase in hydrocephalus with a
drugs and massive doses of dexamethasone and mannitol massive infarct in the right parieto-occipital region. She
for 7 days and then a V-P shunt was placed. Within 10 suddenly died after one week probably due to coning
days of treatment the child improved and could sit up, of the medulla.
stand with support, play with objects and identify familiar
voices but was still completely blind. As the child still
Comments
had evidence of increased intracranial pressure, a second
CT scan (Figs 12.3.3B) was done after three weeks. It This child developed TBM with hydrocephalus and
revealed that the extent of hydrocephalus remained blindness, probably because the child already had
183
Figs 12.3.4A to C: CT scan in a child with serous TBM, hemiplegia and infarction in the internal capsule
infection when BCG was given. Hence protection was scan shows basal exudate almost uniformly dense not
either absent or limited. Initially, child improved remar- tapering like cerebral arteries. The exudate is around the
kably except for the blindness, but in spite of V-P shunt middle cerebral arteries.
the changes in the CT scan did not regress significantly
and the third CT scan revealed worsening, with increase Comments
of hydrocephalus and development of massive infarct. It This is an unusual clinical picture with posttraumatic
is possible that the urinary infection, and localized serous TBM and hemiplegia due to infarction in the
peritonitis at the abdominal site of the shunt also led to internal capsule. The EEG showed abnormal spike and
the worsening of TBM. This was attributable to slow wave discharges on both sides.
Shwartzman’s phenomenon in which nontuberculous
bacterial infection leads to worsening of the local tuber- Case 5
culous lesion, viz. the brain in this child. It is also possible CT scan of a child with chronic tuberculous
that the large hypodense area is a result of progressive encephalopathy (modified clinical and CT scan pictures
vasculitis in spite of treatment. However, Shwartz man’s due to BCG) aggravated later with sudden withdrawal
phenomenon may also explain the progress of the lesion. of steroid therapy
A 1½ years old girl, was admitted with history of fever
Case 4 off and on, vomiting and difficulty in sitting and standing
CT scan in a child with serous TBM, hemiplegia and up for two months duration. There was no history of
infarction in the internal capsule convulsions. Child was healthy at birth and milestones
A three year male child, had a strongly positive in infancy were normal. She was given BCG at three
tuberculin test, history of contact with an adult case of months of age and a good scar was seen. There was
tuberculosis, and had mediastinal lymph node suspicious contact with a case of tuberculosis. Initially
tuberculosis. He was vaccinated at three months of age. the child developed intrathoracic tuberculosis with a
Because of the strongly positive tuberculin test and segmental lesion in the right upper zone and enlarged
intrathoracic tuberculosis, he was given two drugs— paratracheal nodes. CSF examination revealed increased
isoniazid and rifampicin. He had a fall from the bed proteins, mildly diminished sugar and pleocytosis
following which he developed hemiplegia on the left side predominantly lymphocytic. When seen five months later
within a few hours. When seen after three weeks he had
the child had well marked meningeal signs with neck
meningeal signs and spastic hemiplegia on the left side
retraction, positive Macewan’s sign, mild spastic
with greater involvement of lower limb, normal CSF
quadriparesis, mild involvement of upper limbs but
cytology and biochemistry. First CT scan (Fig. 12.3.4A)
severe spastic paralysis of lower limbs. The child was
of head showed hypodense area due to infarction in the
mentally alert, conscious and could talk. Tuberculin test
right internal capsule. Child improved over a period of
three weeks and recovered with mild weakness of the was strongly positive. Skull X-ray showed separation of
left foot. A second CT Scan (Fig. 12.3.4B) done after three sutures. The child had received treatment for five months
weeks revealed that the hypodense area was smaller and with only two drugs, isoniazid and ethambutol. A
better defined because of reduction of edema around the diagnosis of localized TBM, conscious type with spastic
infarct in the internal capsule. With antituberculosis quadriparesis was made. CT scan (Fig. 12.3.5) diagnosis
drugs and steroids he maintained his improvement and of leucodystrophy was made. However, clinical and
a third CT scan (Fig. 12.3.4C) after 15 weeks revealed a radiological data and CSF report supported the diagnosis
very well defined and smaller area of infarction. The CT of localized basal meningitis with quadriparesis and the
184
the diagnosis. In the absence of evidence of clinical,

biochemical and pathological data, other diagnoses
considered were Canavan’s and Alexander’s disease.
Case 6
Tuberculous encephalopathy in a BCG- vaccinated
child
A boy of 11 years was referred with a history of fever for
two months, headache, vomiting and right hemiparesis.
Child was vaccinated in the first three months of life.
Fig. 12.3.5: Head CT scan of 1½ year old child, showing hypodensity When seen by a pediatric colleague he had miliary
of white matter mimicking leukodystrophy. Brain biopsy in this child tuberculosis and TBM of conscious type. A chest X-ray
showed characteristic findings of tubercular encephalopathy showed characteristic picture of miliary tuberculosis and
enlarged hilar and paratracheal nodes. CSF showed
child was put on four antituberculosis drugs and steroids.
increased proteins, cells and reduced sugar and chlorides.
The child improved remarkably and in about four weeks
When seen by us he was fairly built and nourished,
time she could sit with support, eat biscuits without help conscious, alert with well marked meningeal signs and
and speak 5 to 6 words. The child was discharged but spastic hemiparesis on the right. Child was given four
unfortunately only antituberculosis chemotherapy was drugs—streptomycin, isoniazid, rifampicin and
given and parenteral steroids were discontinued. As a pyrazinamide. He was transferred to Bombay Hospital
result the child relapsed after two weeks and had well and three oral bactericidal drugs were continued
marked neck retraction, decerebrate fits and complete alongwith dexamethasone injections. He improved
blindness. Fundi showed optic atrophy. Second CT scan remarkably and within a period of three weeks, the chest
done after one month had small ventricles. A brain biopsy X-ray was almost clear. Figure 12.3.6A shows the child
revealed characteristic pathological findings of with remarkable improvement, barring slight internal
tuberculous encephalopathy. This child failed to improve squint, right facial weakness and ptosis of the right eyelid.
with three weeks treatment and was discharged on Till two months after admission to hospital the child
request. appeared to be almost normal and was conscious, alert,
smiling, standing and walking. CT scan done on
admission to hospital (not shown here) showed a well
Comments
marked hydrocephalus for which a shunt operation was
A female child of 1½ years was given BCG at three months. done. As he developed hepatotoxicity to rifampicin it was
The child had intrathoracic tuberculosis with enlarged stopped and replaced with ethambutol. A repeat CT scan
nodes for which the child was treated for a period of five done (Fig. 12.3.6B) showed no hydrocephalus but a cyst,
months with two antituberculosis drugs—isoniazid and probably a lacunar infarct in the middle temporal region,
ethambutol. The child developed meningitis and spastic with a hyperdense area in the right frontoparietal region
quadriparesis, with greater involvement of lower limbs. The due to localized surface meningitis (Fig. 12.3.6C). MRI
clinical picture was modified because of BCG vaccination. done showed mild hydrocephalus and the cystic lesion.
CT scan of brain changes showing bulky white matter was After 2 to 3 weeks of apparent improvement he started
suggestive of tuberculous encephalopathy. The diagnosis showing mental and neurological deterioration. He
was confirmed by pathological findings of myelin loss and stopped smiling, talking, was dazed and started passing
minimal inflammatory reaction by way of perivascular urine in bed. It was realized that the child was
cuffing of cells (because of massive steroid therapy). This progressing to edematous encephalopathy probably
child improved with treatment and relapse occurred because of aggressive microangiopathy. A CT scan done
because of sudden withdrawal of steroid therapy. Probably (Fig. 12.3.6D) showed a large cyst in the region of
steroid therapy helped to reverse the immunological thalamus and multiple lacunar infarcts; MRI confirmed
damage to the brain, and during second admission the three cysts. Even though the child had miliary
increased white matter bulkiness seen in CT scan did not tuberculosis initially and classical TBM with
respond to edema-reducing drugs. Such a clinical and CT characteristic CSF and CT scan showing hydrocephalus,
scan picture appeared to be due to an unusual progressive because of the cystic lesions, albendazole was given
immune reaction of the white matter. Had the child not empirically for neurocysticercosis. Antituberculosis
had evidence of intrathoracic tuberculosis, TBM and initial chemotherapy was continued with increase in the dose
improvement with steroids and chemotherapy, the of steroids. His hemiparesis improved, but his condition
diagnosis would have been difficult. Moreover, again deteriorated. A digital subtraction angiography
characteristic findings in brain biopsy helped to confirm (DSA) was done. There was no significant abnormality
185
Figs 12.3.6A to D: (A) Child with TBM having right facial weakness and ptosis of right eyelid.(B) Head CT scan of child, showing lacunar infarct
in middle temporal region with hyperdense area in right frontoparietal region due to localized meningitis. (D) Head CT scan after 1½ years
showing large cyst in region of thalamus and multiple lacunar infarct
in the large cerebral vessels and their branches. The particularly the older ones, there is a hyperimmune
patient died after a few days. Autopsy could not be done. response of the T lymphocytes which strip the myelin
and continue to produce arteriolar and venous damage
Comments with progressive edema. This is a dangerous but
This 11-year-old vaccinated child with a history of contact fortunately rare complication in a vaccinated child as
of tuberculosis developed miliary tuberculosis, TBM with acute and fulminating cases are likely to die.
hydrocephalus, multiple cranial nerve palsies which
improved remarkably with the administration of four PROFILE OF TBM: AIIMS EXPERIENCE
antituberculosis bactericidal drugs and large dose of
steroids within 3 to 4 weeks and became almost normal. None of the children had received BCG.
However, 2 to 3 weeks later he showed mental and neuro-
Case 7
logical regression and died of edematous encephalopathy
probably due to aggressive massive microangiopathy Tubercular meningitis with suspected secondary
(microvasculitis). Usually BCG vaccine helps to localize resistance
the disease and prevents diffuse damage to the brain. It A six-years-old boy presented to AIIMS with fever and
appears that in some of these BCG vaccinated children frontal headache for three months along with inability
186
to move the right side of the body for two months and
right focal seizures. At admission he was irritable and
had slurred speech, choreoathetoid movements, right
hemiparesis and right upper motor neuron facial palsy.
CSF examination revealed 450 cells/mm3 (240 lympho-
cytes, 110 polymorphs), sugar CSF/ blood: 46/114 mg/
dl and proteins 162 mg/dl. Mantoux test was 15 mm and
CT scan of head showed enhancing basal exudates with
mild dilatation of lateral, third and fourth ventricles. He
also had central diabetes insipi-dus. He was started on
four drug antituber-culosis treatment (INH, rifampicin,
ethambutol and pyrazina mide), dexamethasone,
mannitol, acetazola mide, glycerol, phenytoin and
chlorpromazine. Pyrazinamide was stopped after two
months and rest of antituberculosis drugs (ATT) were
stopped by parents on their own after 11 months. The
child had improved with ATT but four months after
discontinuing ATT, he developed fever, vomitings,
altered sensorium, seizures and aphasia. He was Figs 12.3.7A and B: Child with TBM with right hemiparesis and
dystonia on follow-up
readmitted and on examination had meningeal signs,
right hemiparesis, right facial nerve palsy upper motor
neuron type with flexion deformity of right wrist, elbow
and foot along with optic atrophy of the right eye.
Investigations revealed CSF 200 cells/mm 3 (90%
lymphocytes) sugar CSF/blood 120/171 mg/dl, proteins
333 mg/dl, CT Scan head-basal exudates with right
parietal granuloma, moderate hydrocephalus with
periventricular ooze. Besides supportive care, ATT (INH,
rifampicin, ethambutol, pyrazinamide, ofloxacin and
amikacin) was started. He developed dystonia of right
upper limb and lower limb. Amikacin and pyrazinamide
were stopped after two months and the rest continued
for one and half years. At present the child is afebrile,
has right hemiparesis and dystonia (Figs 12.3.7A and B)
which are improving and he is on trihexyphenidyl and
carbamazepine. His CT scan (Fig. 12.3.7C) shows a
lacunar infarct in the right caudate head with
Fig. 12.3.7C: CT head of a child with TBM showing lacunar infarct in
postischemic sequelae (L) basal ganglia and adjacent the right caudate with postischemic sequelae (L) basal ganglia and
temporoparietal cortex. adjacent temporoparietal cortex
Case 8
CSF proteins (175 mg/dl) with mononuclear cells,
Child with tuberculoma in midbrain Mantoux test 20 mm, fundus examination showed-
A six-year-old boy presented to AIIMS with history blurring of superior margins of optic nerve bilaterally.
of intermittent fever for four months with ataxia and MRI showed inflammatory granuloma of upper pons
other cerebellar signs for 3½ months. He was given and lower midbrain on right side causing indentation
steroids by a private practitioner following which he upon aqueduct with mild prominence of supra-
developed improvement in cerebellar signs. He tentorial ventricular system consistent with tuber-
developed abnormal behavior for two weeks prior to culoma (Fig. 12.3.8A). He was started on ATT (INH,
admission. At admission, examination findings rifampicin, ethambutol, pyrazinamide), prednisolone,
revealed bilateral sixth nerve palsy, scanning speech acetazolamide and glycerol. He became afebrile and
and other cerebellar signs, brisk reflexes with ill cerebellar signs showed marked improvement.
sustained ankle clonus. Investigations revealed high Steroids were stopped after six weeks, ethambutol
187
Fig. 12.3.8A: T1 weighted MR images of brain showing tuberculoma

of upper pons and lower midbrain
Fig. 12.3.8B: T1 weighted MRI brain images after six months of ATT
showing resolution of tuberculoma
Figs 12.3.8C and D: Head CT scan after 12 months of ATT showing

stopped after three months, pyrazinamide after four
hyperdense lesion right midbrain
months. He improved steadily and repeat MRI after
six months of ATT showed small discoid episodes of right sided complex partial seizures. There
enhancement on administration of contrast with no was associated headache but no history of fever,
dilatation of ventricles (Fig. 12.3.8B). After completing vomiting, weight loss, altered sensorium or visual
12 months of INH and rifampicin, CT head revealed complaints. History of contact with tuberculosis was
hyperdense lesion right midbrain (Figs 12.3.8C and positive.
D). INH and rifampicin given for total 21 months. At On examination, the child was well built with stable
present he is better and has some cerebellar signs vitals. The systemic and neurological examination was
persisting. Follow-up CT head is totally normal but within normal limits. Chest X-ray was normal and
follow-up MRI is showing gliosis in cerebellum Mantoux test was not reactive. Serology (IgG) for
explaining his symptoms. neurocysticercosis (NCC) was positive. CT scan revealed
presence of three ring enhancing lesions (9.6-13 mm in
Case 9 size) with enhancing eccentric foci in left frontal and both
parietal regions with mild to moderate perilesional
Child with tuberculoma differentiated from edema. There was no evidence of midline shift. The CT
neurocysticerosis by magnetic resonance spectroscopy diagnosis was multiple inflammatory granulomas more
(MRS) likely to be neurocysticercosis There was no evidence of
A five-year-old female child with normal papilledema/intraocular cysticercosis on ophthal-
development presented with sudden onset of multiple mological examination. The child was given conventional
188
Figs 12.3.9A and B: The arrow denotes the lipid peak identified in the spectrum obtained during MRS suggestive of
tubercular etiology of the lesion. Similar lipid peaks were seen in all the lesions
antiepileptics and first course of cysticidals (albendazole investigation. MRS could be a useful diagnostic aid to
for 28 days and steroids for 2 months). differentiate the two most common forms of
On follow-up, there was no clinical improvement and inflammatory granulomas (neurocysticercosis and
the child continued to have multiple seizures per day tuberculoma). There is absence of lipid peak in NCC.
despite increasing the dose of antiepileptic drug therapy
(AED) and trial with second line AEDs. The child Discussion
developed right lower limb paresis and papilledema The diagnostic dilemma of inflammatory granulomas is
while on cysticidal therapy and steroids.
highlighted from the case history discussed. Common
A repeat CT done weeks after the first cysticidal
causes of inflammatory granuloma include NCC
course showed persistence of the three ring enhancing
(common) followed by tuberculosis, toxoplasmosis,
lesions as in previous CT with increased perilesional
edema around the right parietal and left frontal lobe cerebral abscess and fungal lesions. This child presented
lesion as compared to previous CT. with seizures, showed a positive serological response
A repeat course of cysticidal was given with towards NCC and CT findings were compatible with
praziquantel and steroids three months after the first NCC (< 20 mm, regular outline with no midline shift).
course of cysticidal drugs. Seizures persisted even after Yet the child was suffering from tuberculous
the second course of cysticidal drugs. A repeat CT granulomatous lesions which were expected to be larger
showed no radiologic improvement with persistence of (> 20 mg) with an irregular outline and midline shifts.
perilesional edema. Magnetic resonance spectroscopy The patient was given two courses of cysticidals with no
(MRS), a noninvasive procedure utilizing the principle clinical/ radiological improvement which prompted the
of magnetic resonance, was planned. Proton MRS authors to review the diagnosis.
spectroscopy using 1.5 Tesla, Sonata, Siemens was *MR spectroscopy identified lipid peaks in the lesions
performed which identified a lipid peak in all the lesions and raised the suspicion of tuberculoma. A high peak of
(Figs 12.3.9A and B); thus, the diagnosis of tuberculoma lipids, more choline and less N-acetylaspartate and
was considered.
creatinine. The choline/creatinine ratio was greater than
The patient was subsequently started on four-drug
one in all tuberculomas but in none of the cysticerci.
antituberculosis drug therapy (ATT) comprising of
*Ref. Seth R, Kalra V, Sharma U and Jagannathan N.
isoniazid, rifampicin, pyrazinamide and ethambutol with
steroids (2 hrze 10 hr) in the first eight weeks (full dose Magnetic resonance spectroscopy in ring enhancing
and tapered over two weeks). The child has been on ATT lesion. Indian Pediatr 2010;47:803-4.
for the past six months and is showing clinical
improvement. The child is seizure free for the past five Case 10
months. The headache, monoparesis and papilledema Child with stage III TBM showing marked decerebrate
have also resolved. CT done six months after starting rigidity 11 months old male child presented to AIIMS
ATT showed the left parietal lesion calcification. A disc in 1992 in stage III of advanced TBM with decerebrate
enhancing lesion is seen in the left frontal region. The rigidity.
lesion in right parietal region shows gliosis with
reduction of perilesional edema. Perilesional edema Comments
around the left sided lesions (frontal and parietal) had
resolved. This eleven months old male child presented in the third
This shows that misdiagnosis of inflammatory stage of TBM with marked decerebrate rigidity in an
granulomas can occur using conventional methods of unconscious stage. He had convulsions and mild signs
189
of raised intracranial pressure. He was put on ½ SHRZE I, outcome is best in stage I and not so good in stage II
1½ HRZE and 8 HRE along with anticonvulsants, and worst in stage III. This child had not received BCG.
mannitol and oral glycerol in the initial week to reduce Figures 10.3.10A to K show the picture at presentation
raised intracranial pressure. He was on nasogastric feed, and during the course of treatment.
IV line was maintained for giving anticonvulsants. Oral
glycerol and acetazolamide was being given through Case 11
the nasogastric tube. This child did not require shunt, A female child, one-year-old presented with stage III of
improved to some extent in the first four weeks but was TBM with marked rigidity, convulsions and in a
left with marked sequelae in the form of convulsions, semicomatosed stage. She was put on anticonvulsants
mental subnormality. For increased tone, physiotherapy along with oral glycerol and IV mannitol for medical
was started in the ward and followed in the outpatient decompression. Antituberculosis regimen started was ½
department. It is important to diagnose a child in stage SHRZE 1½ HRZE 8-10 HRE. (Figs 12.3.11A to D).
Figs 12.3.10A to E: (A) Stage III TBM with decerebrate rigidity involving all the four limbs, (B) Advanced decerebrate rigidity involving all the four
limbs and the child is unconscious, (C) Advanced stage III of TBM showing scissoring of the lower extremities due to marked degree of decerebrate
rigidity and note opisthotonus, (D) Same child, note fisting of the upper extremities with closed wrists showing grasp reflex like in a newborn child.
He is still unconscious and showing marked decerebrate rigidity. Child is being fed with a nasogastric tube as he is still semicomatozed, (E) Same
child showing grade III of protein energy malnutrition with marked wasting of abdominal and intercostals muscles showing prominent intercostal
depression
190
Figs 12.3.10F to K: (F) Same child is still comatosed with dececrebrate rigidity. Baby on nasogastric feeds and IV therapy with anticonvulsant
drugs. There is a life line kept for intravenous medication during convulsions and mannitol for reducing raised intracranial tension, (G) Sensorium
slightly better but needs intragastric feeding. Right wrist showing fisting due to advanced decerebrate rigidity, (H) Same child showing fisting, note
the fisted right hand. The position of the hand is like grasp reflex of a newborn, (I) Same child showing fisting, i.e. grasp replex due to decorticate
rigidity, (J) Same child after one month of therapy with five antituberculosis drugs, steroids, anticonvulsants, IV mannitol, glycerol through the
nasogastric tube. Slight improvement in sensorium but still needs intragastric feed, (K) Same child still on intensive phase of antituberculosis
drugs with HRZE, streptomycin was stopped after 15 days. He is still on anticonvulsants and steroids. He is not on any medication for raised
intracranial pressure. Left upper arm still showing marked rigidity. Child though conscious but very irritable
191
Figs 12.3.11A to D: (A) The child in stage III of TBM with encephalopathy and severe malnutrition. Absolutely flaccid paralysis is obvious. Life line
for anticonvulsants and for medical decompression with mannitol is being maintained, (B) Child in comatozed stage III of TBM with marked flaccid
paralysis of both lower limbs. Hypertonicity in the left upper limb. Life line is being maintained for giving anticonvulsants and IV dexamethazone,
(C) The child showing similar features as described in Fig. 10.3.10A, except slightly better in the consciousness status, associated severe
malnutrition is evident with wasting of intercostal and muscles of the extremities, (D) Child is still semicomatozed and is showing severe degree
of malnutrition with wasting of muscles of the extremities and a scaphoid abdomen
Figs 12.3.12A to D: (A) Semiconscious child with marked decerebrate

rigidity, involving all four limbs, fisting, i.e. reappearance of grasp reflex,
(B) Again showing decerebrate posture, appearance of grasp reflex,
marked decerebrate rigidity and hypertonicity, upturning of the eye balls
making sclera visible indicative of raised intracranial pressure,
(C) Another picture of the same child with practically same findings,
(D) Another picture of same child, notice the upturning of the eye balls
with appearance of sclera, indication of raised intracranial pressure
192
Figs 12.3.12E to K: (E) Close up of face of the child, fully unconscious,

and still requires intragastric feed, (F) Whole body showing the features
of TBM encephalopathy, marked rigidity, appearance of grasp reflex,
(G) Notice marked degree of right sided foot drop and marked fisting in
an unconscious child, appearance of sclera, sign of raised intracranial
pressure, (H) Marked flexion of left hand with fisting, again due to
increased rigidity, (I) Same findings in the right hand, (J) No significant
improvement in consciousness, child still comatozed, being fed with
intragastric tube and medications are being given through the
nasogastric tube, (K) Same child showing right wrist fisting due to
increased rigidity – Grasp reflex reappearance
193
Figs 12.3.13A to D: (A) Ten months old stuperous child again showing feature of encephalopathy, decerebrate rigidity. This child did not have
raised intracranial pressure, (B) Different view but almost same clinical features, (C) Child with TBM, stage III with encephalopathy, dececrebrate
rigidity, with associated severe malnutrition, (D) Almost similar typical feature of encephalopathy slightly better as the child had received
antituberculosis drugs for 15 days while she was in the hospital. Slight improvement in the consciousness
Comments by nasogastric tube on discharge as there were lots of

sequelae. The child had lots of sequelae on follow-up.
The child presented with TBM and encephalopathy.
These picture were taken in the 1st two week of intensive Case 13
therapy when the child was getting antituberculosis
Ten months old female child presented with clinical
drugs, along with medical decompression. The child had
picture of stage III of TBM with encephalopathy figures
not received BCG. Mother had active pulmonary
12.3.13A to D. She had marked respiratory distress, X-
tuberculosis.
ray showed miliary tuberculosis. On asking for family
history, the mother was suffering from active tuberculosis
Case 12
and getting therapy form one of the TB centers. She had
Ten months old male child presented with stage III of not received BCG.
TBM with encephalopathy, marked decerebrate rigidity,
semiconscious. For medication both life line and HIGHLIGHTS
intragastric tube feeding had to be maintained. Again • PM Udani Case Studies:TBM presentations in
this child was put on ½ SHRZE 1½ HRZE 8-10 HRE along children who had received BCG
with anticonvulsants, medicines to decrease intracranial Cases of TBM presented by Dr PM Udani from
pressure. Mumbai had shown comparatively better outcome,
The various Figures (12.3.12A to K) were taken in the probably the pick up was at an earlier stage and
Ist week of hospital admission. After 4 weeks of intensive children were of older age. All had received BCG.
therapy the child was still semiconscious, had to be fed
194
Aggressive use of neuroimaging, timely institution 11. Dastur DK, Udani PM. Tuberculous encephalo-pathy
of antituberculosis drugs along with symptomatic with and without meningitis. Pathology, pathogenesis
relief for medical decompression, and institution of and clinical correlation. Proceedings of the Xth
V-P shunt when indicated for raised ICT, resulted International Congress of Neuropathology, 1965.
12. Dastur DK, Udani PM. Pathology and patho-genesis of
in some what better outcome.
tuberculous encephalopathy. Acta Neuropathologica
• AIIMS, New Delhi Experiences:
1966;6:311-26.
Most of the children were in the younger age group. 13. Chandramukhi A, Nayak P. Subacute and chronic
Though aggressive therapy was given, in few V-P meningitis in children—An immuno-logical study of
shut was also put in, but still the over all outcome cerebrospinal fluid. Indian
was much less rewarding. None of children had J Pediatr 1990;57:685-91.
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Outcome of this group except case no. 7 and 8 who 15. Joishy KN, Sant MV. Experience with the laboratory
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In:Kapila CC, Dastur DK, Singh B, Tandon PN (Eds).
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Tuberculosis of Nervous System. Monograph on the
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Proceedings of the Symposium, Bombay, India Feb 25,
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13 Osteoarticular Tuberculosis
PP Kotwal, PK Dave, BN Upendra
The disease tuberculosis is old and existed even in the The lesion in the bone is essentially a lytic lesion which
early ages. Descriptions of this disease can be found in the is evident radiologically, unlike in pyogenic infection
Rig Veda, Atharva Veda (3500-1800 BC) and also in Charak which is characterized by intense sclerotic activity. As the
Samhita (1000-600 BC). tuberculous lesions heal, sclerosis takes place. At certain
The incidence of tuberculosis had a dramatic fall in sites like the short long bones and in hand and feet or the
the Western world. However, it still continues to be a clavicle, there is intense sclerotic activity by layer of
problem in the developing countries. According to a subperiosteal bone and is characteristic of a tuberculous
WHO report it is still one of the chief causes of death and lesion. The tuberculous pus formed in the medullary canal
crippling in many countries of the world.1 The disease may travel distally or laterally thus, lifting the periosteum,
still remains a serious health problem and is increasing. may form an abscess and even burst giving rise to a
It is estimated that 1 to 6% of children with primary tuberculous sinus. Multifocal tuberculosis is occasionally
infection may develop bone and joint tuberculosis in 1 to seen in children involving multiple bones/joints.
3 years if left untreated.2,3 For purposes of description The response to a tuberculous lesion is often exudative
osteoarticular tuberculosis can be discussed under and may form a cold abscess, which is nothing but a
following heads: collection of necrotic material, caseous tissue and the
• Tuberculosis of joints exudative reaction. These cold abscesses then track through
• Bone tuberculosis the fascial planes or the neurovascular bundles and present
• Spinal tuberculosis at a distant site. Since this abscess is away from the area of
Infection of a joint or bone with Mycobacterium inflammatory activity, it has no signs of inflammation in
tuberculosis is almost always secondary to a primary focus, the skin overlying the abscess. These abscesses are, therefore,
in the lymphatic glands or lungs or mesentery, from where termed as “cold” abscesses. A superficial abscess may burst
it disseminates by hematogenous route. Malnutrition, and result into a sinus or an ulcer.
debilitating disease, poor sanitation, lack of sunshine and Granulation tissue is almost always present in the
fresh air increase the incidence of the disease. Patients tuberculous lesion. Ischemic necrosis of bone due to
with immunodeficiency disease or HIV infection are more endarteritis and thromboembolic phenomenon in bone
prone to develop tuberculosis. leads to formation of sequestra, which in osseous
Tuberculous lesions can involve any bone or joint in tuberculosis hap-pens to be small. Isolated large sequestrae
the body. The lesion in the joint can be: in osteoarticular tuberculosis are rare.
i. Extra-articular
ii. Intraarticular JOINT INVOLVEMENT
It can originate in the bone (osseous lesion) or in the
The tuberculosis of the joints is relatively less common. It
synovium (synovial disease).
mainly involves big joints (Tubercular arthritis). The
Osteoarticular tuberculosis can involve any bone or
common differential diagnosis includes pauciarticular
joint in the body, but vertebral involvement is the most
juvenile chronic arthritis and septic arthritis. The
common and is nearly equal to tuberculosis of all other
involvement of joint may be osseous or synovial but if not
regions put together.4-9
treated, one would infect the other. Tuberculous synovitis
There may be a history of trauma, under the effect of
leads to effusion in the joint and synovial membrane
which a small hematoma may form resulting in vascular becomes edematous. At this stage the joint would look
stasis in that area. The hematoma may become a nidus for swollen and movements may be present or limited due to
the tubercle bacilli to settle down and form a tuberculous muscle spasm. The radiological picture may show an
follicle with caseation, epitheloid cells, giant cells and increased joint space.
fibrosis at the periphery. The original follicles enlarge and The cartilage is resistant to tuberculous infection
may coalesce to form a tubercle, which may become visible because it contains a plasmin inhibitor and the bacilli do
to the naked eye. not possess the plasminogen activator unlike the pyogenic
201
Chapter 13 Osteoarticular Tuberculosis
bacteria. The articular cartilage is thus not attacked by the active stage of the disease. The ESR is often used as a
plasmin and remains intact.10 Later on the granulation guide in monitoring the progress of the disease during
tissue may extend from the periphery on to the articular treatment, however, it is not a reliable parameter.
cartilage or in the subchondral region in the form of a
pannus thus eroding it. Once the articular cartilage is Mantoux Test
eroded there is tremendous muscle spasm and all
movements are restricted. Because of the destruction of the A positive Mantoux test is seen in patients infected with
articular cartilage the joint space on X-ray looks M. tuberculosis which may be an active or a dormant
diminished. lesion. In children under two years of age, a positive
When the lesion is osseous, it involves the subchondral tuberculin reaction indicates an active tuberculous lesion.
bone which also leads to erosion of the cartilage. The lesion A nega-tive test may be seen in severe or disseminated
may start from the epiphysis in children or may be disease or in an immunocompromised patient.
metaphyseal in origin. When the disease begins to heal,
fibrosis occurs across the joint leading to a fibrous Synovial Fluid
ankylosis. At this stage the movements of the joint are Examination of the synovial fluid may occasionally help
restricted and may be painful. There is considerable muscle in diagnosis in the early cases of tuberculosis. It may show
spasm which may produce a deformity at the joint. leukocytosis (with predominently polymorphs), decreased
Prolonged muscle spasm may lead to subluxation or glucose content and raised protein content.
dislocation of the joint causing further deformity and
shortening. If sinus has formed, secondary infection may Serology
be superimposed on the tuberculous infection. Fibrous
ankylosis may be converted into bony ankylosis either due ELISA (Enzyme-linked Immunoabsorbent Assay) test
to complete healing or new bone formation due to was described by Engvall and Perlmann11 for antibody
superadded pyogenic infection. There are no movements to mycobacterial antigen-6, in the serological diagnosis
in the joint after bony ankylosis and it is also painless. of osteoarticular tuberculosis. Although they reported a
Radiologically, in bony ankylosis the trabeculae are seen sensitivity of 94% in the diagnosis of tuberculosis, it is
to be crossing the joint line. not considered a very reliable test in clinical practice as
the%age of false-negative and false-positive are very
Clinical Features high.
Osteoarticular tuberculosis mostly occurs during Radiology

childhood, however, it is seen at any age and in all
socioeconomic groups. It is characteristically insidious It can be diagnostic in view of the typical radio-logical
in onset, and starts as monoarticular or monoosseous appearance of the tuberculous lesions. In early stage of
involvement. The child complains of pain in the joint, the joint disease, capsular markings may become
aggravated by movement, and often wakes up at night prominent. The earliest sign is widespread osteoporosis
because muscle spasm gets reduced and causes pain. It around a joint. Lytic lesion and periosteal reaction are
is classically called “night cries”. Low-grade fever, loss seen, although latter is much more prominent in pyogenic
of weight and appetite are some of the symptoms of infection.
generalized toxemia usually seen. Joint movements are In case of joints, small bone erosions occur near the
painful and elicit muscle spasm on attempted movement. capsular reflection. Joint space decreases due to cartilage
In later stages when the cartilage gets eroded, all erosion and lytic lesions are seen in the epiphyseal area.
movements get restricted. Muscle atrophy around the joint The radiological signs of a healing lesion are absence of
is a predominant feature and occurs early. Sometimes an rarefaction and bony ankylosis.
abscess forms which bursts to form a sinus. It may get
secondarily infected and may alter the radiological Smear and Culture
picture. It has been seen that material scrapped from the
Tuberculous pus, joint aspirate, granulation tissue,
lining or the abscess is more likely to be positive for gram-
sputum, etc. may be examined by smear and culture for
negative bacilli than from the center of the lesion.
tubercle bacilli. These can be processed by various
techniques (described elsewhere).
Investigations The culture and sensitivity tests for various
Blood antituberculosis drugs also helpful in giving appropriate
chemotherapy in resistant cases or cases of multidrug
A low hemoglobin, relative lymphocytosis and raised resistant tuberculosis; which are seen quite frequently in
erythrocyte sedimentation rate (ESR) are often found in today’s clinical practice.
202
Isotope Scintigraphy in bone or from synovium is more likely to be positive.14,15

Biopsy can be done as an open biopsy or a needle biopsy
Most cases of osteoarticular disease can be diagnosed by
(CT guided).
clinicoradiographic correlation. However, there would still
Investigations should also be done to find out the
remain a number of cases where diagnosis may become primary focus of the disease. An X-ray of the chest should
difficult and doubtful. In such situations, radionuclide always be done. Some other investi-gations may include:
scanning using technetium-99 m can be useful particularly sputum smear examination and culture, routine urine
in differentiating soft tissue infection from osteomyelitis. examination for isolation of tubercle bacilli and an
Three phase bone scan and SPECT (single photone intravenous pyelogram for ruling out pulmonary and
emission tomography) are also useful in the follow-up for genitourinary lesions, respectively.
evaluating the response to treatment.
Management
Ultrasonography
The patient’s response to treatment is variable as anywhere
Ultrasonography can demonstrate soft tissue abscesses. It else in the body and is dependent upon the host resistance,
can also be used to judge the effect of treatment on the size severity of infection, and the stage of the disease when the
of these abscesses at periodic intervals. diagnosis is first made and treatment started. Eradication
of the disease and preservation of function are important
CT Scan both in osseous and joint diseases. In case of joints, joint
mobility and stability are also the early goals to be achieved.
CT scan is helpful in detecting small lytic/destroyed areas
It is possible only if treatment is started early, i.e. when the
in the bone. The destruction of bone due to the disease
disease is limited only to synovium. In case the articular
process and also the soft tissue swellings or abscesses can
be seen on CT scan better and much earlier. It also helps in cartilage is eroded the joint becomes unsalva-geable in
evaluating difficult areas in spine such as cervico-dorsal terms of function, mobility and stability. In such a situation
junctions, which cannot be seen properly on plain X-rays. the aim of treatment is to achieve a sound bony ankylosis
which is painless and gives stability, although the patient
MRI Scan will not have movements at that joint.
MRI scan is a far better diagnostic tool, than CT scan or General Measures
plain X-rays. It can demonstrate not only the bony lesions
Good nutrition consisting of a high calorie and protein
(destruction) but also the soft tissue abscess, changes in
diet is essential to build up the resistance. General rest
the spinal cord, etc. It can also pick up changes in the
and local rest to the specific bone and joint are essential
bones much earlier than the plain X-rays.
parts of the treatment. Local rest can be provided by means
of splints or plaster casts. However, in cases where the
Fine Needle Aspiration Cytology (FNAC)
articular surface is not involved a judicious blend of rest
Occasionally, even the most modern methods of imaging and mobilization exercises have to be resorted for
may not help the clinician to reach a final diagnosis, and restoration of function.
therefore, FNAC or biopsy may be undertaken to obtain Hospitalization may be required for cases with
tissue diagnosis. FNAC is now available for the cytological complications and also for cases having deformities. The
diagnosis of vertebral tuberculosis. Mondal et al 12 deformities may need treatment by traction.
recommend that fine needle aspiration biopsy is a safe
and a quick diagnostic procedure with high accuracy in Chemotherapy
the hands of trained cytopathologists. He recommends
that it should be practised in all diagnostic centers of our In bone and joint tuberculosis it is customary to give at
country, even for suspected vertebral tuberculosis. least four antituberculous drugs to start with. Seth et al16
Confirmation by FNAC has also been recommended by have recommended the use of 4 to 5 drugs in the intensive
Arora and Seth.13 phase. (described elsewhere). Combined drug therapy also
prevents the emergence of drug resistant strains.
Biopsy There is enough evidence that 85% of osteo-articular
lesions would respond to anituber-culous drugs17,18
Biopsy may have to be done in cases where there is doubt particularly if the therapy is started early in the vascular
about the diagnosis, particularly in the early stages of the stage of the disease.
disease. Biopsy from the bone or synovium can provide an It was earlier thought that the antituber-culosis drugs
early diagnosis for timely starting the treatment and do not penetrate into the diseased area in effective
preventing damage to the joint. Biopsy from a cystic lesion concentrations since the lesion was considered ‘avascular’.
203
However, various studies have shown that the • Spinal tuberculosis with paraplegia:
antituberculosis drugs do reach the lesion in effective – If paraplegia has occurred during chemotherapy,
concen-trations.19-23 Further, in case of persistently – If paraplegia is worsening in spite of ade-quate
draining sinuses which are secondarily infected, suitable chemotherapy,
broad spectrum antibiotics have to be given. About 15% of – Radiological increase in the size of the abscess, and
patients do not respond to chemotherapy alone if the lesion – If the paraplegia is of sudden onset.
contains much caseation and sequestra. In such situations
excision of the diseased focus not only removes the diseased The surgical procedures generally performed in children
toxic material but also increases vascularity and allows are:
the anti-tuberculosis drugs to reach the site of the lesion.
A standard drug regimen is given which includes • Drainage of an abscess
rifampicin, pyrazinamide, ethambutol, isoniazid, and • Excision of a focus
in some cases even streptomycin. The latter is useful • Curettage of the lesion
because it kills the rapidly multiplying extracellular • Synovectomy
tubercle bacilli in the lungs for the initial two months.19 • Costotransversectomy
After two months if the lesion shows signs of healing • Anterolateral decompression
clinically and radiologically, pyrazinamide is stopped The general principle of surgery in tuber-culosis
and isoniazid, rifampicin and etham-butol are demands that the abscess should be completely evacuated.
continued for one year. Since the recom-mendation of In case of an osseous lesion, all sequestra, granulation
the use of four to five drugs in the intensive phase, short- tissue and caseous material should be removed till new
course chemotherapy can be used as in neuro- bleeding bone is encountered, so that the drugs may reach
tuberculosis for a total period of 6 to 9 or at best 12 the site of lesion better. The cavities so produced should be
months if there is no surgical debridement. This has packed with autogenous bone grafts. Avoid dead spaces
been emphasized by Hazara, and Laha24A very recently. to prevent hematoma formation and close the wound
It has been shown in the review of literature by them primarily with or without suction.
justifying the use of short-course chemotherapy for 6 to Tuberculosis can involve any bone or joint of the body
9 months. If there is suspicion of multidrug resistant but in children it has a special predilec-tion for the hip
tuberculosis, the duration has to be prolonged may be and knee joints commonly, ankle and elbow joints are
up to 18 months. So is the case where there is association rarely involved. Tuberculosis of spine with or without
between HIV and tuberculosis. (described elsewhere) paraplegia is extremely common. Long bones are rarely
In some cases therapy may be required for longer period involved but the short long bone involvement is somewhat
for complete healing of the lesion. In case the infection is common. Diagnostic algorithm for osteoarticular
suspected to be with multidrug resistant organisms, other tuberculosis is given in Figure 13.1.
drugs such as ethionamide, ofloxacin, capreomycin,
kanamy-cin, etc. may have to be given (described
elsewhere).
Surgical Treatment
Surgical treatment is an adjunct to the anti-tuberculosis
drug therapy. It cannot be a substitute for the prolonged
course of the drug therapy. Surgical treatment has become
safe with the advent of powerful antituberculosis drugs
and one is no longer scared of a flare up of the lesion.
However, a trial of conservative treatment must be given
before surgical treatment is undertaken. The indications
for surgery are specific and are as follows:
• Doubtful diagnosis requiring excision of the focus or
curettage of the lesion.
• An abscess or a lesion increasing in spite of adequate
chemotherapy.
• Synovitis not involving the articular carti-lage;
synovectomy should be done to prevent the latter from
getting eroded.
• Curettage of a lesion in proximity of the articular
cartilage to prevent the latter from getting involved. Fig. 13.1: Diagnostic algorithm for osteoarticular tuberculosis
204
Fig. 13.2B: Stages of the tubercular arthritis of the hip
abduction and external rotation. Movements are painful

and limited in the terminal degrees. Radiographs may
show only soft tissue swelling—the capsular markings
appear distended due to effusion. There may or may not
be rarefaction of the bones of the hip joint (Fig. 13.2B).
Fig. 13.2A: Common sites of tuberculous involvement
around the hip joint
Stage II
With the progression of the disease, there occurs
TUBERCULOSIS OF THE HIP JOINT destruction/damage to the articular cartilage. At the hip
Tuberculosis of the hip is not uncommon and is seen joint, flexion, adduction and internal rotation deformity
after 3 to 4 years of age. The natural history of tuberculosis develops due to muscle spasm and capsular thickening.
of the hip joint depends upon the site of the lesion, its There is appreciable muscle wasting and mild shortening
duration and the treatment given. The lesion is seen in of the limb. All movements are limited. X-ray shows areas
the superior part of the head of femur or contiguous area of destruction, diminution of joint space and marked
in the acetabulum, the neck of femur, Babcock’s triangle osteoporosis (Fig. 13.2B).
or the greater trochanter24 (Fig. 13.2A). Tuberculosis of
the greater trochanter may involve the bursa overlying it Stage III
and is known as trochanteric bursitis. Destruction of the femoral head and acetabulum, and true
shortening are also added to the deformity as in stage II
Clinical Profile (Fig. 13.2B). Movements are grossly restricted. X-ray shows
marked erosion of the articular cartilage and areas of
The earliest complaint is pain in the hip joint often referred
destruction in the head and neck of femur and acetabulum.
to the knee. The child walks with a painful antalgic gait
As the destruction of the acetabulum or the head of
and suffers from night cries, i.e. pain due to eroded joint
femur increases further, it is likely to find a wandering
surfaces rubbing against each other resulting from relief
acetabulum or a frank dislocation of the hip. In some cases
of muscle spasm during sleep.
the floor of the acetabulum is considerably weakened so
There may be constitutional symptoms like low grade
as to cause protrusio acetabuli.
fever, particularly in the evening, loss of appetite,
It is rare to see patients during the synovitis stage. Most
irritability, etc. On examination, in the initial stages of the
often they present when the tuberculous disease has
disease, there will be only tenderness over the hip
already established. There is flexion, adduction and
anteriorly (at the base of the femoral triangle) or over the
internal rotation deformity of the hip with shortening. Not
trochanter. In association, there will also be spasm in the
uncommonly one comes across an unusual deformity, i.e.
lower abdominal muscles and in the adductor muscles of
flexion, adduction and external rotation of the hip even in
the hip. In an untreated case the disease follows through
arthritis stage. This is usually seen in patients treated by
the following stages:
traction, or spica or in the unlikely event of destruction of
the iliofemoral ligament.
Stage I Figure 13.3 shows the AP radiograph of the tuberculosis
This is the stage of tuberculous synovitis. In this stage, hip showing destruction of the head and acetabulum and
effusion in the hip joint causes a deformity of flexion, irregular joint space reduction on the right side.
205
Pannus does not proliferate over the area of joint cartilage.

Protective immunity is related to granuloma formation
and is seen in the ‘normal’, synovial type of tuberculous
hip disease. In the atrophic, traveling-acetabulum,
protrusioacetabuli and mortar-and-pestle types of
disease, irreversible damage has occurred before
presentation. It seems possible that tissue-destroying
hypersensitivity, causing subchondral erosion, may be
responsible for the atrophic hip , traveling-acetabulum,
protrusio-acetabuli, and mortar and pestle types. In the
‘normal’ type of disease chemotherapy almost invariably
gives a good or excellent result. Also Shanmug-
asundaram 25 reported that the mean duration of
symptoms in ‘normal’, Perthes, dislocating and atrophic
Fig. 13.3: AP radiography of the tuberculosis of right hip showing
types varied from 4 to 7 months, and for the traveling
destruction of the head and acetabulum and irregular joint space acetabulum, protrusio acetabuli and mortar and pestle
reduction with abduction deformity types, for 10 to 14 months.
The functional outcome of tuberculosis in other joints
also usually follows the amount of joint space preservation
on presentation. The lesser the joint space the worse is the
Although this is the usual clinicoradiological picture,
prognosis and vice versa.
one is often confronted with no cor-relation between the
clinical signs and the X-ray picture.21 Shanmugasundaram,25
therefore, evolved a clinicoradiological classification with Management
distinct radiological pattern which not only helps in Antituberculosis Drugs
formulating an appropriate treatment plan but also in
predicting the end result. A three or four drug regime is started initially and then
maintained on two drugs for a total period of about 12 to
Can we predict the final outcome of the disease in children at its 18 months. People now recommend therapy in the
initial presentation? maintenance stage for 9 to 12 months only.
Tuberculosis of the hip in children often ended in fibrous
ankylosis before the introduction of chemotherapy. With Immobilization
the induction of chemo-therapy, more favorable results
were seen with good range of motion and without pain on The joint is immobilized temporarily for a period of 2 to 4
completion of chemotherapy. However, the outcomes were weeks for relief of pain and to overcome muscle spasm
quite often poor even with effective chemotherapy. or deformity. This may be done by traction or plaster cast/
Shanmugasundaram25 (1985) showed that the radiological slab.
appearance of the hip at presentation accurately predicts
the final outcome. Aim of Treatment
Shanmugasundaram reported 7 types of radiological The primary aim of treatment is to provide painless
features at initial presentation: functional range of movement without deformity.
1. Normal type, However, this may not be possible in all cases. Since
2. Traveling acetabulum type , osseous lesions are more common than the synovial ones,
3. Dislocating type, many cases may present with destruction or damage to
4. Perthes type, the articular cartilage. Therefore, based on the clinical and
5. Protrusioacetabuli type radiological profile of a case, one must decide whether the
6. Atrophic type, and outcome of the treatment should be a mobile joint or a
7. Mortar and pestle type. fixed joint.
He demonstrated that hips of ‘normal’ type, Perthes
type and dislocating type with a normal joint space after
Mobile Joint
reduction will have a good result. A narrow joint space
after reduction (< 3 mm) predicted a poor result. Hips of One can achieve a mobile joint when (i) the disease is
atrophic, traveling-acetabulum. Protrusioacetabuli and entirely synovial and the articular cartilage is not involved,
mortar and pestle types have a poor result. In a ‘normal’ and (ii) the subchondral bone may be involved in an
hip, the disease is mainly localised to the synovium. osseous lesion but the articular surfaces are intact.
206
Fixed Joint in the gait. Arthrodesis (intra-articular) of hip is not only

difficult to achieve in children but is quite unacceptable in
A fixed or an ankylosed joint is usually the out-come when
India because of the social customs and sitting habits.
the articular cartilage is destroyed due to the disease
Extra-articular arthrodesis was done in the
process. Any attempted movements in such a case can be
preantituberculosis drug era so as not to attack the disease
painful and at times impossible.
directly for fear of disse-minating it, but it is not practised
now.
Treatment Directed to Achieve a Mobile Joint
In the early stage of the disease where there is an osseous TUBERCULOSIS OF THE KNEE JOINT
lesion without involving the articular cartilage, bilateral
skin traction is given to prevent spasm and deformity along Tuberculosis of the knee joint is predominantly a synovial
with anti-tuberculosis drugs. Intermittent gentle exercises lesion and becomes osseous only at a later stage. In the
are recommended in individual cases. After 12 to 16 weeks beginning the child complains of pain and limping; there
the traction is discontinued and non-weight bearing crutch is minimal synovial effusion with thickening. There is
walking is instituted, which is followed by the weight- considerable wasting of the thigh muscles. Spasm of
bearing one once the disease is under effective control. muscles may result in flexion deformity. Later on when
Careful monitoring of these patients is absolutely necessary the articular cartilage is involved, the joint gets destroyed
otherwise these patients may develop unwanted and the knee joint may get deformed due to spasm of the
deformities. hamstring muscles. This deformity is known as triple
In acute tuberculous arthritis arthrotomy of the joint is deformity and consists of flexion at the knee joint, posterior
urgently required to relieve tension and to preserve the subluxation of the tibia and external rotation of the leg.
articular cartilage. Postoperatively, the patient has to be The movements at this stage get comp-letely restricted.
kept on traction; the subsequent management is identical. X-ray appearance in the early stage may only show a soft
The concept of early surgery aiming at mobility and tissue shadow. Subse-q-uently involvement of the articular
stability has been proposed by Vora.26 The aim, according cartilage is shown by diminution of joint space, irregularity
to him, was to carry out excisional surgery without of the cartilage and areas of destruction in the epiphysis
dislocating the hip. This included partial synovectomy of (Fig. 13.4).
the hip, curettage of cavities in the head and neck of femur As time passes, if the destruction increases, further
and acetabulum. He claimed full movement in 60% of cases evidence of deformity may be seen and the joint may
and painless functional range of movement in 33% of undergo fibrous or bony ankylosis.
cases.
Lesions in the roof of the acetabulum without involving Treatment
the hip joint require curettage of the lesion from outside Aim of Treatment
without entering the joint.
The aim of treatment is to achieve a fully func-tional
Treatment Directed to Achieve a Fixed Joint painless joint. The outcome of treatment will depend upon
the extent of damage to the joint. Whether to achieve a
The aim here is to achieve fusion (ankylosis) of the affected mobile joint or a fixed joint can again be decided on the
joint in a functionally optimum position. same principles as discussed in the treatment of
If the patient already has involvement of the articular
cartilage and the movements are res-tricted, the joint as a
functional entity is finished. In such a situation a hip spica
should be applied in the functional position so as to get a
sound ankylosis.
Arthrodesis (fusion) of the affected joint may be
achieved by surgical intervention. The affec-ted joint is
excised and raw surfaces of the bones of the joint, thus
created, are opposed to each other and are compressed by
an internal or external fixation.
In case the head and neck are completely destroyed,
curettage, after dislocating the hip joint, is resorted to and
the hip is immobilized in a functional position.
Treatment of Late Sequelae

Fig. 13.4: AP radiograph of tuberculosis of right knee joint in an
Once the disease is healed, the deformity per-sists. A adolescent showing, irregular diminution of joint space and irregular
corrective osteotomy results in appre-ciable improvement destruction of epiphysis.
207
tuberculosis of the hip joint. The patient is started on

antituber-culosis drugs and in the early stage of synovial
disease the patient should be treated on skin traction so as
to keep the joint surfaces apart. This helps in preventing
deformities. After 3 to 4 weeks when the disease gets
controlled, nonweight-bearing exercises can be started and
maintained so that the chances of giving a good functional
recovery increase. In synovial disease if it is hypertrophied
and the response to antituberculosis drugs is poor,
synovectomy should be done.
In case the articular cartilage is involved the patient
should be treated by plaster cast immo-bilization and
antituberculosis drugs. In case there is a lytic area in the
epiphysis, curettage of the lesion should be carried out so
as to prevent the disease from destroying the articular Fig. 13.6: Tuberculous dactylitis involving second metatarsal head
cartilage. If the joint gets destroyed there is no chance of
achieving a satisfactory functional recovery and therefore,
the joint needs arthro-desis. Charnley’s compression
arthrodesis is performed using Charnley’s compression the lesion is healed and growth is complete, arthroplasty
clamps. Charnley27 believed that after a sound arthrodesis can be perfor-med. In the ankle joint, if the movements are
in children the epiphyseal cartilage continues to grow and lost, ankle arthrodesis can be performed after the growth
the growth is not hampered, but there is a possibility of period is complete.
hampering growth due to the compression effect.
These days, arthrodesis can also be perfor-med by TUBERCULOSIS OF THE SHORT LONG BONES
using Ilizarov apparatus. It perhaps gives more stability Tuberculosis commonly involves the metatarsals and
and allows early ambulation—full-weight-bearing with phalanges (Fig. 13.6).
crutches. The lesion starts in the diaphysis as opposed to the
metaphysis in the long bones. This is because of the blood
TUBERCULOSIS OF THE ANKLE AND ELBOW supply of the short long bones—the nutrient artery which
The lesion may be osseous or synovial in the ankle and enters the bone in the middle of its shaft. Within a short
elbow. The clinical picture is the same as elsewhere, giving period the finger becomes fusiform and enlarged and painful.
rise to pain, swelling around the joint due to synovial The skin becomes smooth and shiny and an abscess may
thickening and effusion, and limitation of movements once form. As the bone gets involved, new subperiosteal bone is
the articular cartilage is involved (Fig. 13.5). laid down giving rise to a typical enlargement of the shaft
When the lesion is near the joint, early curettage will (Figs 13.7A and B). The condition is also known as ‘spina
prevent it from getting involved. In the elbow joint once ventosa’. The prognosis in this condition is good. The lesions
heal completely with antituberculosis drugs alone. If the
diagnosis is in doubt or if there is a discharging sinus,
involvement of all the flatbones including ribs, mandible,
pelvic bones, patella and skull bones with tuberculosis have
been reported.28-31 The lesion should be curetted out.
TUBERCULOSIS OF THE SPINE (POTT’S SPINE)

Spine is the most common bone involved in tuberculosis27
and accounts for nearly 50% of all cases of osteoarticular
tuberculosis. Like all other skeletal tuberculosis, spinal
tuberculosis is secondary to a primary focus elsewhere in
the body. Spread is hematogenous either through the
arteries or through the Batson’s plexus of veins (Fig. 13.8).
Proximity of the cisterna chyli may cause lymphatic
spread of the infection from foci in the mesenteric lymph
nodes. According to a recent estimate more than two
Fig. 13.5: AP and lateral radiographs of tuberculosis of the ankle joint
showing epiphyseal and metaphyseal destruction of tibia and soft
million patients all over the world have active spinal
tissue swelling around the ankle tuberculosis and the incidence is increasing.
208
Figs 13.7A and B: ‘Spina ventosa’ of 4th metacarpals: note the destruction, thickening and soft tissue swelling
with discharging wound over dorsum of 4th metacarpals (For color version see Plate 5)
The tuberculous infection in the vertebra starts at any

of the following sites:
Central
In this variety the central part of the body of the vertebra
undergoes destruction and eventually may collapse under
the body weight resulting into a wedge shaped vertebra.
Metaphyseal
This is the most common type in which the disease starts
under the end plate of the vertebra (close to the
intervertebral disc) either at its superior or inferior end.
The adjacent parts of two vertebrae are generally affected
because the intercostal artery supplies the two adjacent
Fig. 13.8: Blood supply of vertebrae vertebrae. The vertebral end plates are destroyed and the
nutrition of the intervertebral disc suffers which gets
reduced in size. The radiographic finding of destruction
of a vertebra along with diminution of the intervertebral
Tuberculosis of the spine commonly affects the
disc space is considered to be pathognomonic of a tuber-
thoracolumbar spine, however, it is also seen in the other
culous lesion of the spine.
regions of the spine. The thoracolumbar spine is
commonly affected because of the excessive stresses and
strains it is subjected to, due to excessive mobility in this Anterior
region. This is a rare type where the disease starts in the vertebra
The disease is more severe in children less than 10 under the anterior longitudinal ligament.
years of age. The average vertebral involvement and A lesion under the posterior longitudinal ligament is
vertebral destruction is more in children leading to more extremely rare and is also termed as “spinal tumor
severe deformity and disability.32-35 Atypical spinal syndrome”.
tuberculosis mani-festing as an involvement of single
vertebral extradural extraosseous involvement Appendiceal
presenting as abscess, and isolated infections of the
neural arch and spinal tuberculosis in newborn have Vertebral appendages such as lamina, spinous process,
been reported.30,31 etc. are rarely involved in children.
209
Clinical Picture
A few patients may present with constitutional symptoms
such as fever, cough, loss of appetite and weight, but
generally pain is the predomi-nant symptom.
The child generally complains of pain in back, more at
night time. The pain is localized over the affected area of
the spine. Occasionally, the patient may feel referred pain
(called as girdle pains) along the intercostal nerves, in
tuberculosis of the dorsal spine. Tenderness at the local
site and spasm of the paraspinal muscles are also evident.
Any part of the spine can be affected but it most commonly
involves the lower dorsal and dorsolumbar regions.36,37
Cold Abscess
Tuberculous infection causes destruction, casea-tion and
necrosis of the vertebra. Pus forms and may come out of
the vertebra and present as an abscess. The abscess may
remain close to the vertebra and present, on the Fig. 13.9: Kyphosis due to collapse of vertebrae
radiography, as prevertebral or paravertebral abscess; or
may present clinically as a cold abscess.
Cold abscesses in tuberculosis spread along the fascial
amount of cartilage is present. Influence of growth during
planes or along the neurovascular bundles. In the cervical
childhood is a significant factor in the causation of
spine it collects behind the prevertebral fascia and many
deformity. When the metaphyseal region is destroyed the
present as a retropharyngeal abscess. It may also spread
posterior elements continue to grow; this differential
to posterior or anterior triangle in the neck. It can also
growth increases the deformity even though the disease
track in the mediastinum. In the thoracic region, it may
may become quiescent. The deformity itself may give rise
present as a paravertebral abscess or may track along the
to two dreaded complications, i.e. paraplegia and
intercostal vessels on the chest wall. In the lumbar spine it
cardiopulmonary complications, although it must be
tracks in the psoas sheath and may present as a psoas
mentioned here that deformity is not a common cause of
abscess or may present in the lumbar triangle at the back.
paraplegia.
The abscess may also present on the medial side of the
Since tuberculosis is more common in the dorsal or
upper thigh and may simulate as femoral hernia. Lesions
dorsolumbar spine, paraplegia is more common. In fact,
from the lumbosacral junction may present as a pelvic
paraplegia is quite often the presenting feature in
abscess and through the greater sciatic notch may find a
tuberculosis of the spine. Its incidence varies from 16 to
place in the gluteal region.
35%.38-40 Paraplegia in tuberculosis has crippling compli-
cations. Earlier, the paraplegia was differentiated into – (i)
Paralysis
paraplegia of early onset, and (ii) paraplegia of late onset;
Compression of the spinal cord can result into paralysis, but it is pragmatic to differentiate it between—paraplegia
the extent of which depends upon the level and area of the with or without active disease. Paraplegia associated with
cord involved. The para-lysis may be incomplete or active disease may be early or late.
complete with bladder and bowel involvement. The causes of paralysis in tuberculosis of the spine
When the infection is in the cervical region, quadriplegia are:
may develop; the upper limbs are involved before the lower • Pressure on the cord due to abscess, granula-tion tissue
limbs. or edema.
• Mechanical pressure on the cord by sequestra, pus,
Deformity and granulation tissue.
The disease causes collapse of the vertebra and a slight • Angular deformity of the spine with sub-luxation.
kyphosis may develop. As the disease progresses more, • Thrombosis of the anterior spinal artery.
vertebrae collapse and a more severe kyphosis results • Tuberculoma or diffuse extradural granu-loma of the
(Fig. 13.9) which causes development of secondary lordotic cord.
curves below and above the kyphotic curve. The collapse It must be appreciated that in a given patient, there
of vertebrae in children is more marked because a large may be more than one cause for paraplegia.
210
Unsteady gait (due to spasticity) is the earliest symptom Generally, speaking the following radio-graphic
and clonus is the most prominent early sign of paraplegia changes are seen:
(Pott’s paraplegia). • Diminution of the intervertebral disc space.
Paralysis may increase with varying rapidity through • Lytic lesion in the vertebra leading to collapse.
the following stages—girdle pain, muscle weakness, • Generalized osteoporosis of spine.
spasticity, incoordination, paraplegia in extension, and • Presence of a paravertebral abscess which may be
the pressure increases to paraplegia in flexion. Bowel and fusiform or more globular in nature.
bladder control are lost and in the most severe form the • In early stages there is a central vertebral lesion without
paralysis becomes flaccid. Sensory involvement is diminution of the intervertebral disc space.
uncommon and occurs usually late. Subsequently the disc also gets involved.
• In a large number of cases skip lesions at different levels
Investigations are also encountered.
• Bone scintigraphy with technetium-99 m will often show
Investigations are the same as for any other type of
a “hot spot”.
tuberculosis.
• Magnetic resonance imaging (MRI) provides an early
diagnosis since it can pick up changes like destruction
Radiology of the vertebra and soft tissue abscesses much before
Plain X-ray they become evident on plain X-rays. Therefore, MRI is
very useful in doubtful cases (Fig. 13.10C). Common
The anteroposterior and lateral views is often sufficient MRI findings in tubercular spondylitis are
for the diagnosis. The lateral view is particularly important hypointensity of the involved tissue on T1 weighted
as it gives more information than the anterior posterior images, hyperintensity on T2 weighted images (Fig.
(AP) veiw. The earliest features on lateral view are 13.10C) destruction of 2 or more adjacent vertebral bodies
diminution of the intervertebral disc space (Fig. 13.10A). with involvement of the intervening disc and epidural and
Later on one may also see destruction and collapse of the paraspinal extension and or abscess.
vertebra. Anteroposterior view may show destruction of Children have a higher deformity at presentation, a
the pedicle and a paravertebral shadow, cast by an abscess greater tendency for collapse during the active phase of
in that area (Fig. 13.10B). Even with resolution of the acute the disease, and continued and variable progression even
infectious process the kyphosis may continue and cause after the disease is cured, due to variable destruction of the
compression of the cord and late neurological sequelae. vertebral growth plates. Tuli et al42 observed that children
Figs 13.10A to C: Tuberculosis of the spine. A. Lateral view; B. AP view showing

destruction of D4-5 vertebrae; C. MRI Showing destruction and prevertebral and
epidural abscess (T2weighted)
211
< 10 years of age with more than 3 adjacent vertebral Myelography

involvement had a higher spinal deformity on follow-up.
Although myelography has largely been replaced now
In children, the changes during the period of growth are
more important than changes during the active period of by other imaging modalities, but in some unusual cases
the disease which usually determines the progress of of Pott’s paraplegia where the neurological picture does
deformity. Children prone for such late progressive not correspond to the osseous lesion, or when multiple
collapse can be identified during the early stages by the skip lesions are present, myelography may be useful in
presence of spine at risk radiologic signs. Four radiologic determining the level of obstruction (Fig. 13.10.C).
signs have been described by Rajasekaran43 to indicate
the presence of spinal instability in active stage (Fig. 13.11). Needle Biopsy
a. Facet joint separation (Subluxation), A needle biopsy of the vertebra done by using an image
b. Posterior body retropulsion, intensifier or CT guided, may be necessary in an unusual
c. Lateral translation and situation to clinch the diagnosis.
d. Tilt or toppling.
Each of these sign is given a score of one with a Treatment
maximum score of four. A spinal instability score of more
than two is associated with a significantly higher chances Chemotherapy
of progression of kyphotic deformity. These children need the same general treatment, i.e. good
These signs are useful clinically because they occur nutrition, rest and antituberculosis drugs. Drug therapy
early in the course of the disease and preventive surgery used to be given for a total period of 18 months. Minimal
for progressive collapse can be advocated. Late progression duration of therapy should be six months. In a systematic
and surgical correction of an established deformity is review41 of chemotherapeutic treatment for spinal TB, it
associated with a high rate of morbidity and can be avoided. was concluded that six months of therapy is probably
Presence of these “Spine at Risk” signs should alert the sufficient for the majority of cases. Both six and nine months
pediatrician/family physician to refer the patient to a treatment regimens give acceptable rate of recovery.
specialist dealing with spinal deformities for early surgical The United States Centers for Disease Control
intervention to avoid late onset paraplegia with recommend that for infants and children with miliary TB
progression of kyphosis. or bone and joint TB, treatment should last at least
Fig.13.11: Spine at risk radiologic signs

212
12 months. Treatment would probably be needed to be

to conservative therapy is not satisfactory.
prolonged in immuno-compromised subject such as HIV
• Mainstay of management is:
or malignancies. In children the response of conservative
– Short-course chemotherapeutic regimens lasting
management is generally good. The spine of these for 6-9-12 months depending upon the response
children has to be protected from collapsing, which can of the patients along with general measures of rest
be achieved by providing a plaster jacket for about three and good nutrition.
months. A plaster jacket in the initial stages of treatment – Indications of surgical intervention have been
can restrict the degree of kyphotic deformity of the spine. clearly defined depending upon the site of
The progress of the disease can be monitored by clinical involvement.
and radiological methods. Even in case of Pott’s
paraplegia the response to treatment is good. Most
REFERENCES
authors believe that the results of conservative treatment
in children are satis-factory.44 However, in some cases 1. Duthie RB, Bentley G. Skeletal tuberculosis. In: Mercer’s
the abscess or the paraplegia may increase despite (Ed). Orthopedic Surgery, 9th edn. London: Arnold
publications 1996;596.
adequate conservative treatment and may require surgical
2. Starke JR, Smith MHD. Tuberculosis. In: Feigin RD, Cherry
intervention.
TD (Eds): Textbook of Pediatric Infectious Diseases, 4th
edn. London: WB Saunders company 1998;1196-1239.
Indications for Surgery (Middle path regimen)42 3. Luckheie M. Tuberculosis of cervical spine. South Afr Med
J 1996;86:553-6.
i. Neurological deficit not improving with adequate trial 4. Wilkinson MC. Observations on the pathogenesis and
of chemotherapy (3 to 4 wks) treatment of skeletal tuberculosis. Ann R Coll Surgery
ii. Neurological deficit developing during antitubercular Engl 1949;4:168-71.
chemotherapy 5. Girdlestone GR, Somerville EW. Tuberculosis of bone
iii. Neurological deficit worsening during antitubercular and joint. 2nd edn. London: Oxford University Press; 1952.
chemotherapy 6. Mukhopadhyaya B. The role of excisional surgery in the
iv. Recurrence of neurological complication treatment of bone and joint tuberculosis. Ann R Coll Surg
v. Difficulty in deglutition/respiration with cervical Engl 1956;18:288-313.
abscess 7. Grewal KS, Singh M. Tuberculosis of spine. Indian J Surg
vi. Advanced acute neurological deficit with flaccid/ 1956;18:394-405.
flexor spasms and bladder involvement. 8. Mukhopadhyaya B, Mishra NK. Tuberculosis of the
In case of paraplegia associated with a ‘tense bird Spine. Ind J Surg 1957;19:59-81.
9. Tuli SM, Srivastava TP, Verma BP, et al. Tuberculosis of Spine.
nest’ type of paravertebral abscess, costotrans-
Acta Orthop Scand 1967;38:445 58.
versectomy may suffice. If on removing the rib and
10. Lack CH. Chondrolysis in arthritis. J Bone Joint Surg
transversed process, pus is not encountered one may
1959;41-B:384.
proceed to do an anterolateral decompression. In case 11. Engvall E, Perlmann P. Enzyme-linked Immuno-
of a healed vertebral body lesion (Fig. 13.9) resulting in absorbent Assay (ELISA) Test. Immunochemistry
an increasing defor-mity due to differential growth, 1971;8:871.
posterior spinal fusion must be done as a preventive 12. Mondal A, Mitra S, Mitra D, et al. Role of fine needle
measure. aspiration biopsy in cytological diagnosis of vertebral
tuberculosis. Indian J Tuberc 1996; 43:15-8.
HIGHLIGHTS 13. Arora S, Seth S. Isolated tubercular tenosynovitis in
children. J Pediatr Orthopedics 1994;14:752-4.
• Tuberculosis of the bones and joints is still common 14. Versefeld GA, Solomon A. A diagnostic approach to
in children in India. tuberculosis of bones and joints. J Bone Joint Surg 1982;64-
• It has been discussed under the following three hands: B:446.
– Bone tuberculosis 15. Jacobs JC, Lis C, Ruzal-Sharpino C, et al. Tuberculous
– Tuberculosis of the joints arthritis in children, diagnosis by needle biopsy of the
– Spinal tuberculosis. synovium. Clin Pediatr 1994; 33:344-8.
• Joint involvement is relatively less common. Mostly 16. Seth Vimlesh. Management of tuberculosis. In: Seth
big joints such as hip and knee are involved. Vimlesh and Kabra SK (Ed): Essentials of Tuberculosis in
• Spinal tuberculosis is most common. Children. 1st edn. New Delhi: Jaypee Brothers Medical
• Newer modalities in radiology, MRI are available for Publishers Pvt. Ltd. 2006; 530-8.
diagnosis in difficult cases and those whose response 17. Medical Research Council Working Party on Tuberculosis
of Spine. A controlled trial of ambulant outpatient
213
treatment and inpatient rest in bed in the management 29. Unuwar E, Oghuz F, Sadikooglu B, et al. Calvarial
of tuberculosis of spine in young Korean patients on tuberculosis. J Pediatr Child Health 1999;35:221-2.
standard chemotherapy. J Bone Joint Surg 1973;55-B:678. 30. Erasmus JH, Thompson JO, Vanerwesthinzen AJ.
18. Medical Research Council Working Party on Tuberculosis Tuberculous osteomyelitis of mandible report of a case. J
of Spine. A five year assessment of controlled trials of Oral Maxiflofac Surg 1998;56:1355-8.
inpatient and outpatient treatment with plaster of Paris 31. Dillon MS, Rao SS, Sandhu MS, et al. Tuberculosis of
jackets for tuberculosis of spine in children on standard patella. Skeletal Radiology 1998; 27: 40-2.
chemotherapy. J Bone Joint Surg 1976;58-B: 399. 32. Rajasekaran S, Shanmugasundaram TK, Prabhakar R, et
19. Fellander M, Hirtonn T, Wallmark G. Studies on the al. Tuberculous lesion of the lumbosacral region. A 15
concentration of streptomycin in the treatment of bone years follow-up of patients treated by ambulatory
and joint tuberculosis. Acta Tuber Scand 1952;27:176-89. chemotherapy. Spine 1998;23:1163-7.
20. Barclay WR, Elbert RH, Le Roy. Distribution and excretion 33. Tuli SM. Severe kyphotic deformity in tuberculosis of the
of radioactive isoniazid in tuberculous patients. J Am Med spine. Int Orthop 1995;19:327-31.
Assoc 1953;151:1384-8. 34. Beekarun DD, Govender S, Rasool MN. Atypical spinal
21. Haungren A. Studies on the distribution and fate of C 14
tuberculosis in children. J Pediatr Orthop 1995;15:
and T-labelled p-aminosalicylic acid (PAS) in the body.
148-51.
Acta Radiol (Suppl)1959;175.
35. Gupta DK, Gopal, Sharma SP, et al. Neonatal tuberculosis
22. Friedmman B, Kapur VN. Newer knowledge of
of the spine. Trop Doctor 1998;28: 119.
chemotherapy in the treatment of tuberuclosis of bones
36. Paus B. Treatment for tuberculosis of spine. Acta Orthop
and joints. Clin Orthop 1977;97:5-15.
Scand (suppl): 1964;72.
23. Tuli SM, Brighton CT, Morton HE, et al. Experi-mental
37. Hodgson AR, Yau ACMC. Anterior surgical approaches
induction of localized skeletal tuberculous lesions and
to the spinal column. In: Apley AG (Ed). Recent
accessibility of such lessions to antituberculous drugs. J
Advances in Orthopaedics. London: J and A. Churchill,
Bone Joint Surg 1974; 56-B:551-9.
1969; 289-323.
24. Somerville EW, Wilkinson MC. In: Girdlestone (Ed). Tuber-
38. Hodgson AR, Stock FE. Anterior spinal fusion for
culosis of bone and joints. London. Oxford University
tuberculosis of spine. J Bone Joint Surg 1960;42-A:295.
Press 1965;43.
39. Martin NS. Tuberculosis of the spine. J Bone Joint Surg
24a. Hazara A, Laha Baisakhi. Chemotherapy of osteoarticular
1970;52-B:613.
tuberculosis. Indian J Pharmacol 2005;37:5-12.
40. Tuli SM. Results of treatment of spinal tuberculosis by
25. Shanmugasundaram TK. Current concepts in bone and
middle path regime. J Bone Joint Surg 1975; 57-B:13.
joint tuberculosis. Chennai, Documentation Center, 41. Van Loenhout-Rooyackers JH, Verbeek AL, et al.
International Bone and Joint Club, 1985. Chemotherapeutic treatment for spinal tuber-culosis. Int
26. Vora PH. Role of early surgery in the management of J Tuberc Lung Dis 2002;6:259-65.
tuberculosis of the hip: In: Shanmugasundaram TK (Ed). 42. Tuli, S.: Tuberculosis of the Skeletal System, New Delhi,
Current concepts in bone and joint tuberculosis. Chennai: Jaypee Brothers Medical Publishers Pvt Ltd 1997;
Documentation Centre, International Bone and Joint Club, 241.
1985. 43. Rajasekaran S. The problem of deformity in spinal
27. Charnley J. Compression arthodesis. London: E and S. tuberculosis. Clinical Orthopaedics and Related Research
Livingstone Ltd. 1953. 2002; 398: 85-92.
28. Change JH, Kim SK, Lee WY. Diagnostic issues in 44. Moon MS, Kim I, Woo YK, et al. Conservative treatment
tuberculosis of ribs with a review of 12 surgically proven of tuberculosis of the thoracic and lumbar spine in adults
cases. Respirology 1999;4:244-53. and children. Int Orthopaedics 1987;11:314-22.
14 Genitourinary Tuberculosis
Arvind Bagga
Genitourinary tuberculosis is a common form of extra- process, ulceration, and tubercle formation in the vicinity
pulmonary tuberculosis, and is secondary to a of the ureteral meatus, with subsequent fibrosis of the
symptomatic or asymptomatic pulmonary lesion.1 Renal bladder wall.
involvement may occur secondary to miliary tuberculosis. Tuberculosis affects the whole male genital tract, with
Approximately 10% of patients with pulmonary lesions in the prostate, seminal vesicles, vas deferens,
tuberculosis are at risk of developing this complication.2 epididymis and testis. Genital tuberculosis in males most
The kidney is usually the primary organ involved and commonly involves the epididymis followed by the
other organs are involved by direct extension.3 The onset prostate. Tuberculous epididymitis is a result of blood-
and course of the disease is insidious, hence diagnosis borne infection, since it is often an isolated finding
and treatment are delayed, resulting in high rate of without urinary tract involvement. The disease usually
urogenital organ destruction and renal failure. In children starts in the globus minor, because it has a greater blood
the disease typically presents in late adolescence, chiefly supply than other parts of the epididymis.
due to the time lag between primary infection and
urogenital involvement. CLINICAL PRESENTATION
Classic symptomatic renal tuberculosis is late and
PATHOGENESIS uncommon complication in children, rarely occurring
Once inhaled, the bacilli multiply in the pulmonary alveoli less than 4 to 5 years after the primary infection.
with primary granuloma formation; the infection is Therefore, the condition is most commonly diagnosed
clinically silent and self-limited. The multiplying M. after adolescence. Adult studies have shown that 26 to
tuberculosis organisms might be implanted in other organs, 75% of renal tuberculosis coexists with active pulmonary
including the renal and prostate parenchyma. The patient tuberculosis and 6 to 10% of patients with sputum-
then enters a latent phase, with likelihood of disease positive pulmonary tuberculosis have renal involvement.
reactivation in the following 4 to 5 years. In most cases, Most children with the disease are asymptomatic.
latent foci are reactivated following reduction in immunity, They may present with symptoms related to the organ
secondary to malnutrition, measles or pertussis infection, involved or may have long standing unexplained
use of corti-costeroids and/or immunosuppressive agents urological problems. The common features at
and immunodeficiency.4 presentation are: (i) recurrent or resistant urinary tract
The mean latent period between pulmonary infection infection (UTI), sterile pyuria with or without hematuria;
and clinical features of urogenital tuberculosis is 22 years.5 (ii) irritative voiding symptoms, e.g. urgency, frequency,
After reactivation, infection progresses from a single dysuria; (iii) renal or epididymal mass; and (iv) impaired
focus, affecting one kidney and sparing the other. This renal functions. Occasionally the diagnosis of renal
accounts for the greater frequency of unilateral renal
tuberculosis is made incidentally in a patient with known
tuberculosis. The renal infection is progressive,
pulmonary tuberculosis.
asymptomatic, and highly destructive. 6 Kidney
destruction may be due to progression of the focal lesion, The patient may not manifest overt symptoms, but
with caseous granuloma formation, fibrosis and renal has persistent leukocyturia. Microscopic hematuria is
cavitation, and obstruction of the urinary collecting present in 50% cases. Undiagnosed and untreated renal
system. The spread to renal pelvis causes pyonephrosis tuberculosis may have a wide spectrum of clinical features,
like lesions, the ‘cement or putty’ kidney.7 Multiple which mimic other conditions including pyelonephritis,
stenoses may develop throughout the ureter, resulting renal colic, stones, sepsis and renal failure. Tuberculosis
in the ‘beaded or cockscrew’ ureter. The site commonly can cause renal failure by two mechanisms that involve
affected is the ureterovesical junction. In bladder intrinsic infection within the renal parenchyma or
tuberculosis, the earliest forms of infection start around obstructive uropathy. Patients with tuberculosis and AIDS
ureteral orifice followed by an acute inflammatory may show kidney and prostate abscesses.8
215
Chapter 14 Genitourinary Tuberculosis
Involvement of bladder is usually secondary to renal Imaging

infection and is found in one-third of patients. The chronic
• Plain Radiographs: Plain X-ray films may show
inflammation and decrease in bladder capacity cause
calcification in the renal areas and in the lower
symptoms of urinary frequency and urgency. Patients
genitourinary tract. Renal calcification may not
with ‘thimble bladder’ (due to mural fibrosis) present
represent inactive process.
with urinary incontinence. Chronic inflammation at
• Ultrasonography, Computed Tomography: Ultrasound
vesicoureteric junction leads to ‘golf hole ureter’.
examination may reveal renal calyceal dilation and
Involvement of the prostate gland, urethra and male
overt evidence of obstruction. Increased echogenicity
genitalia is rare in children. Tuberculous epididymitis
of the renal pelvis is a feature of advanced disease as a
may be the first and only presenting symptom of
result of fibrosis and scarring. Computed tomography,
genitourinary tuberculosis.
which can identify calyceal abnormalities, renal
parenchymal destruction and hydronephrosis, has
DIAGNOSIS replaced intravenous urography as the imaging
modality of choice.11
Screening Tests
• Intravenous Urography: Intravenous urography may
The tuberculin test is a standard screening tool for detection show changes in a single calyx with evidence of
of tuberculosis exposure. Patients with end-stage renal parenchymal necrosis. In more advanced disease,
disease have a compromised immune status that may mute urography will show calyceal distortion, ureteric
skin test response. QuantiFERON gold test and Elispot strictures and bladder fibrosis.
may offer a better method for detecting tuberculosis • Cystoscopy, Bladder Biopsy: Cystoscopy is rarely
infection in patients with end-stage renal disease. indicated for diagnostic purposes. Bladder biopsy
Definitive diagnosis of genitourinary tuberculosis involves should be avoided in the presence of acute
demonstration of M. tuberculosis by micro-biological, tuberculous cystitis to prevent dissemination of the
cytopathological and histopathological methods. disease, but may be done after 4 to 6 weeks of therapy.
Urine Examination Radioisotope Studies

Sterile pyuria is the classic finding on urinalysis and They are used to determine split renal function and for
culture. Detection of acid-fast bacilli from urine samples evidence of obstruction in advanced disease.
by microscopy (Ziehl-Neelsen acid fast stain) is not Radioisotope imaging with diethylene triamine
reliable, because of the possible presence of M. smegmatis, pentacetic acid (DTPA) provides information on
which are acid-fast bacilli too. At least three, but differential renal function and mercaptotriacylglycine
preferably five, consecutive early morning specimens of (MAG3) provides information on whether the collecting
urine should be cultured. Urine cultures require 6-8 weeks system is obstructed.12
in Lowenstein-Jensen medium and the sensitivity ranges
between 80 to 97%.9 THERAPY
Rapid Identification of Mycobacterium Genitourinary tuberculosis is a severe form of disease,

and the bacterial load is similar to cavitatory pulmonary
Radiometric liquid systems, i.e. BACTEC give rapid tuberculosis. If not treated aggressively, infection might
results and are highly sensitive. These methods have the lead to irreversible structural lesions. Yearly urine
limitations of requiring the need of radioactive materials assessment is advocated for all patients with history of
and expensive apparatus. In the mycobacteria growth pulmonary tuberculosis, especially in those who are
indicator tube (MGIT), growth of the organism is detected immunocompromised.13
by a nonradioactive detection system. This system helps Short-course anti-tuberculous therapy for 6 months
in early detection (7-12 days) of bacterial growth and is is an effective mode of therapy. Therapy includes an initial
useful for drug susceptibility testing. 2 months’ intensive phase with administration of 3 to 4
medications daily [rifampicin, isoniazid, pyrazinamide and
Polymerase Chain Reaction ethambutol (or streptomycin)] followed by 4 months’
Polymerase chain reaction for M. tuberculosis is a useful continuation phase with two drugs (rifampicin, isoniazid).
diagnostic tool since it provides results in 24 to 48 hours In the latter phase, the drug may be given twice or thrice
and allows diagnosis even when there are few bacilli. The weekly. In complicated cases (recurrence of tuberculosis,
investigation is highly (95.6%) sensitive and specific immunosuppression and HIV), longer duration (9-12
(98.1%).10 months) of therapy is necessary. In HIV-patients, the
216
antiretroviral therapy interacts adversely with rifampicin. • Polymerase chain reaction for M. tuberculosis
When rifabutin is used instead, therapy must be extended identification in the urine is a useful diagnostic tool
to 9 to 12 months. since it gives results in 24 to 48 hours and allows for
Short-term (4-9 months) treatment is justified because of diagnosis to be made even when there are few bacilli.
good renal vascularity, high urinary concentration of drugs, Appropriate imaging studies are highly sensitive for
low bacillary load in urine and similar efficacy compared to detecting urogenital tuberculosis.
longer duration regimens.14 Most investigators recommend a • Medical treatment for 6 months is the first line
10 years follow-up after pharmacologic treatment because of therapy for genitourinary tuberculosis. Patients with
the risks of late relapse. There is no evidence to support the recurrences of tuberculosis, immunosuppression
routine use of corticosteroids for preventing ureteric strictures and in the setting of HIV infection/AIDS require
in patients with renal tuberculosis.15 therapy for 9 to 12 months.
• Surgery may be ablative, with removal of the
Dose Modification in Renal Failure nonfunctional kidney or epididymis, or
reconstructive for unblocking the collecting system
Special considerations apply to the treatment of
or augmentation of the contracted bladder.
tuberculosis in patients with impaired renal function.
Rifampicin, isoniazid, pyrazinamide and ethionamide may
REFERENCES
be given in normal dosage. They are eliminated in the bile
or broken down to metabolites that are not excreted by 1. Chattopadhyay A, Bhatnagar V, Agarwala V, et al.
the kidney. Care is required in the use of streptomycin Genitourinary tuberculosis in pediatric surgical practices.
and ethambutol. These are wholly excreted via kidney. J Pediatr Surg 1997;32:1283-6.
2. Ferrie BG, Rundle JS. Genitourinary tuberculosis in
Surgical Treatment Glasgow 1970 to 1979: a review of 230 patients. Scott Med
J 1985; 30: 30-4.
Surgery might be required in the following instances: (i) 3. Leite OHM. Tuberculosis. Problems Gen Surg 2001;18:
drainage of hydronephrosis (ureteric stenting or 69-78.
4. Christensen WI. Genitourinary tuberculosis. Review of
percutaneous nephrostomy); (ii) drainage of abscesses and
102 cases. Medicine (Baltimore) 1974; 53: 377-90.
collections; (iii) partial nephrectomy; (iv) reconstruction of 5. Narayana AS. Overview of renal tuberculosis. Urology
the upper urinary tract; (v) bladder augmentation; and (vi) 1982;19:231-37.
reconstruction of the urethra.16 6. Eastwood JB, Corbishley CM, Granje J. Tuberculosis and
In most cases, patients should receive at least 4 weeks the kidney. J Am Soc Nephrol 2001;12:1307-14.
of intensive chemotherapy before surgery. Early ureteral 7. Clinman AC. Genitourinary Tuberculosis. Urology
1982;20:353-8.
stenting or a percutaneous nephrostomy may be useful in
8. Trauzzi SJ, Kay CJ, Kaufman DG, et al. Management of
patients with tubercular ureteral strictures, and enable the prostatic absess in patients with human
possibility of later reconstructive surgery and decrease the immunodeficiency syndrome. Urology 1994; 43: 629-33.
likelihood of renal loss. Every effort must be made to 9. Katoch VM. Newer diagnostic methods for tuberculosis.
preserve functioning renal tissue. In cases of a unilateral Indian J Med Res 2004;120:418-28.
nonfunctioning kidney, most experts recommend 10. Negi SS, Khan S F, Gupta S, et al. Comparison of the
conventional diagnostic modalities, BACTEC culture and
nephrectomy to avoid relapse, eliminate storage
polymerase chain reaction test for diagnosis of
symptoms, treat hypertension and avoid abscess tuberculosis. Indian J Med Microbiol 2005; 23: 29-33.
formation. Relapse is likely if a nonfunctional kidney is 11. Wang LJ, Wu CF, Wong YC, et al. Imaging findings of
not removed, since pharmacological treatment might not urinary tuberculosis on excretory urography and
sterilize all tuberculous foci.17,18 computerized tomography. J Urol 2003, 169:524-8.
12. Warren D, Johnson JR, Johnson CW, et al. Lowe:
Genitourinary Tuberculosis, Campbell’s Urology, 8th edn.
HIGHLIGHTS Philadelphia. Saunders 2002; pp 744-63.
• Genitourinary tuberculosis is rare in childhood. 13. Caminero JA. Treatment of tuberculosis In: Caminero JA,
Given the long latent period between onset of (Ed). A tuberculosis guide for specialist physicians. Paris:
International Union Against Tuberculosis and Lung
pulmonary and urogenital tuberculosis, the latter
Disease 2004; 8: 162-200.
diagnosis is usually made during adolescence. 14. Weinberg AC, Boyd SD. Short-course chemo-therapy and
• Kidneys are the chief organ affected; disease involving role of surgery in adult and pediatric genitourinary
the ureters and urinary bladder is often secondary. tuberculosis. Urology 1988;31: 95-102.
• The diagnosis of genitourinary tuberculosis is based 15. Cek M, Lenk S, Naber KG, et al. Members of the Urinary
on multiple urine cultures. Tract Infection (UTI) Working Group of the European
Association of Urology (EAU) Guidelines Office. EAU
217
Chapter 14 Genitourinary Tuberculosis
guidelines for the management of genitourinary 17. Lee KS, Kim HH, Byun SS, et al. Laparoscopic
tuberculosis. Eur Urol 2005; 48: 353-62. nephrectomy for tuberculous non-functioning kidney:
16. Global Tuberculosis Program, Treatment of Tuberculosis: comparison with laparoscopic simple nephrectomy for
Guidelines for National Control Program 3rd edition, other diseases. Urology 2002; 60:411-4.
Geneva. World Health Organization, 2003 (WHO/CDS/ 18. Wong SH and Lau WY The surgical management of non-
TB/2003.313). functioning tuberculous kidneys. J Urol 1980; 124: 187-91.
15 Tuberculosis and the HIV Infection
15.1 TB IN HIV-INFECTED CHILDREN

BJ Marais, PR Donald
EPIDEMIOLOGY Exposure
Globally, the tuberculosis (TB) epidemic remains rampant The HIV epidemic has caused a marked increase in the
in areas affected by poverty,1 war,2 and in particular by incidence of TB. In the case of pulmonary TB this is true
human immunodeficiency virus (HIV) infection.3-5 The HIV of both sputum smear-positive and smear-negative
epidemic and especially its impact on children, is also disease. In addition, there has been a pronounced age
greatly influenced by conditions of poverty.6 Children in and gender shift with a lowering in the peak age-
these areas carry a disproportionately large TB disease prevalence, the highest incidence of TB now occurs
burden that is frequently not appreciated.7,8 In an attempt among young adults (20-35 years),20-21 and an increase
to improve collection of the most relevant data, recent World in the proportion of women. The high prevalence of both
Health Organization (WHO) guidelines recommend that TB and HIV among adults in their reproductive years
National TB Programs should report 1) the HIV status of all increases the risk of TB exposure and infection at a very
TB cases9 and 2) the number of child TB cases; in two age young and vulnerable age.3 In high prevalence areas,
bands, less than 5 and 5-15 years of age.10 Hopefully this routine HIV-testing and active TB case-finding among
will raise awareness and improve data collection to better HIV-infected pregnant women should be implemented
quantify the extent of the child TB epidemic and the impact to decrease the perinatal risks for mother and baby.
of HIV. However, the data on children in the latest WHO Managing a baby born to a mother who is co-infected
report 10a is not available. with TB and HIV is difficult; ensure that the mother is
Initial evidence relating HIV infection and childhood optimally treated and regard the baby as being at risk for
TB appeared conflicting, as autopsy studies indicated that TB, HIV and other congenital infections. Counseling and
TB was an uncommon cause of death in HIV-infected preventive measures to reduce the risk of HIV transmission
children11 although clinical studies documented high HIV to the baby is needed together with appropriate HIV-related
prevalence rates among children diagnosed with TB.12,13 care. The possibility of active TB in the baby needs to be
However, more recent autopsy and clinical studies confirm considered and treated. If the baby does not have active
the high TB-related morbidity and mortality suffered by TB, then isoniazid preventive therapy (IPT) is indicated if
HIV-infected children,14-16 with an estimated 20 fold the mother remains symptomatic or has been on TB
increase in TB incidence compared to HIV-uninfected treatment for less than 2 months. During screening for
children.17 In a hospital-based study from South Africa, M. enrollment into a prospective IPT trial, TB exposure/
tuberculosis was one of the most common organisms isolated infection was documented in 77 (10.1%) of 766 HIV-
from children with community acquired pneumonia that exposed infants, demonstrating the high risk of TB
failed to respond to first line antibiotics; being present in exposure in HIV-affected families/households in TB
18% and 29% of HIV-infected and uninfected infants endemic areas.22
respectively (of those in whom an organism was identified), The overall effect of HIV on TB transmission within
versus 39% and 57% of those older than 1 year of age.18 communities has been debated, as HIV-infected adults
Another prospective study documented 23.4 cases of active with pulmonary TB are more likely to be sputum smear-
TB per 100 HIV-infected children per year.19 These high negative TB and/or present quicker for care, reducing
disease rates may be explained by 1) an increased risk of TB their transmission risk. However, reports from Tanzania
exposure/infection and/or 2) an increased risk of and Botswana indicate that most HIV-infected patients
progression to active disease following TB infection. are sputum smear-positive and/or are only diagnosed
219
Chapter 15 Tuberculosis and the HIV Infection
after a considerable period of symptomatic disease, and • CXR interpretation is frequently complicated by HIV-
so may make a significant contribution to TB transmission related comorbidity such as bacterial pneumonia,
in endemic areas.23,24 lymphocytic interstitial pneumonitis (LIP),
bronchiectasis, pulmonary Kaposi sarcoma (KS) and
Disease the atypical presentation of TB in immune compromised
The most important factors that influence a child’s risk of children.
developing TB following infection are age, with the highest Following TB exposure, the TST is generally used to
risk occurring in immune immature children (<3 years of indicate M. tuberculosis infection, but it has important
age), and the immune status of the child.25 In an HIV- limitations:
infected child this is determined by the degree of immune • Conversion may be delayed for up to 3 months
compromise and/or the severity of HIV-disease. In a following infection.
prospective study from Côte d’Ivoire, the risk of TB was 4 • Inability to indicate when primary infection occurred
times higher in children with CD4% below 15% than in or to register a reinfection event.
those with a higher CD4%, and 3 times higher with a • Poor sensitivity in immunocompromised children.
baseline plasma HIV RNA above 5 × 10log10.26 A study • Reduced specificity due to environmental mycobacteria
from South Africa demonstrated a markedly elevated risk and cross-reaction with BCG, although this is less of a
amongst HIV-infected children to develop TB (OR 16.6, confounder in TB endemic countries where BCG is
95% Confidence Interval 12.5-22.4) in the 9 months prior given during the neonatal period.
to the institution of highly active anti-retroviral therapy The poor sensitivity of the TST is the main limitation in
(HAART) compared to the period thereafter.27 HIV-infected children; only a minority of HIV-infected
children with bacteriologically confirmed TB record
DIAGNOSIS a positive TST, despite using a reduced induration size
cut-off of ≥ 5mm. 30 Novel T-cell-assays, utilizing
The diagnosis of childhood TB presents a major challenge M. tuberculosis specific antigens (ESAT-6 and CFP-10), seem
as bacteriologic confirmation is achieved in only a minority to offer higher sensitivity and specificity, but results remain
of children.28 In the absence of bacteriologic confirmation, unconvincing and conflicting.31 As for the TST, novel T-
the diagnosis of childhood TB is often based upon the cell-based assays do not differentiate M. tuberculosis
triad of 1) close contact with an index case; 2) positive infection from active disease. Identifying the correct
tuberculin skin test (TST); and 3) suggestive signs on the application of these novel T-cell-based assays in TB
chest radiograph (CXR). This triad is less helpful in endemic areas remains a priority for future research.
endemic areas where exposure to M. tuberculosis is common HIV-infected children seem prone to develop
and often undocumented.28 In these settings, the diagnosis disseminated and other forms of TB that reflect poor
of childhood TB depends mainly on clinical features and organism containment, but in general the clinical disease
presentation is similar to that seen in HIV-uninfected
the subjective interpretation of the CXR.
children.3,32 From a diagnostic perspective it is essential
The diagnostic problems are more pronounced in HIV-
to know a child’s HIV status as this guides clinical
infected children and all current diagnostic algorithms management; effective interventions such as trimethoprim-
perform poorly in this group.3,29 Factors contributing to these sulphamethoxazole (TS) prophylaxis and HAART have
additional diagnostic difficulties include: become more readily available.
• Children from HIV-affected households are more likely
to be exposed to an adult index case at home, although TREATMENT
the index case may be sputum smear-negative and the
transmission risk not fully appreciated. Preventive Chemotherapy
• The TST an extremely insensitive marker of TB infection WHO guidelines advise that all children under 5 years of
in HIV-infected children.30 age in close contact with a sputum smear-positive index
• Chronic pulmonary symptoms due to other HIV-related case should be actively traced, screened for TB, and
conditions such as gastro-esophageal reflux or provided preventive chemotherapy once active TB has been
bronchiectasis frequently coexist. excluded.10 It acknowledges that in settings where a TST
• Weight loss or failure to thrive are typical features of and CXR are not readily available, symptom-based
both TB and HIV. screening improves access to preventive chemotherapy for
• Rapid TB disease progression may occur in severely asymptomatic high-risk contacts.
immune compromised children, which reduces the Isoniazid preventive therapy (IPT) has proven efficacy
sensitivity of diagnostic approaches that focus on to prevent active disease after documented TB exposure
chronic symptoms and/or infection, but under standard programmatic
220
conditions adherence is often very poor.33 Restricting the immature) and/or immuno-compromised children.
focus to the groups at highest risk and identifying It is important to consider the cerebrospinal fluid (CSF)
alternative short-course preventive therapy regimens penetration of drugs as it is frequently associated with
remain important areas for future research. The diagnosis tuberculous meningitis (TBM).
of latent TB infection (LTBI) is important in HIV-infected Many studies have documented poorer response to
children due to the high risk of disease progression and treatment and higher mortality in HIV-infected children
the well-documented benefits of IPT in adults with LTBI. with TB compared to HIV-uninfected children.
IPT eradicates existing TB bacilli but does not protect
Possible reasons for the poor outcome include:3
against future re-infection, which explains the waning of
• Higher incidence of co-infections with other pathogens.
its beneficial effect after 2-3 years in endemic areas with a
• Poorer absorption and low levels of anti-TB drugs
high infection pressure. Due to the reduced sensitivity of
the TST in HIV-infected children, IPT seems warranted especially in the younger children.
(and is recommended by WHO) for any HIV-infected child • Misdiagnosis of TB in children with another HIV-
with documented exposure to an adult with pulmonary related lung disease.
TB irrespective of the child’s age or TST result, once active • Underlying chronic lung disease resulting in poor
TB has been excluded.10 penetration of drugs.
The effect of providing “blanket” IPT to all HIV-infected • Poor adherence to treatment because of chronic illness
infants in a TB endemic area was recently explored in a or parental death.
randomized controlled trial.19 The placebo arm of the study • Advanced immunosuppression and severe
was discontinued after interim analysis of the first 263 HIV- malnutrition.
infected children of whom 132 (50.2%) had been assigned In adults, a large proportion of HIV/TB-related deaths
to isoniazid. The mortality rate was significantly lower in occur in the first few months after TB therapy has
the isoniazid group (8.3%) compared to the placebo group commenced; the situation in children is similar.
(16%) as well as the incidence of confirmed or probable TB Present recommendations are to treat HIV-infected
(isoniazid 4.5% vs placebo 9.2%), however, this did not children with TB in a similar fashion to HIV-uninfected
explain the difference in mortality.19 It remains uncertain children.10 Thiacetazone was discontinued in HIV-
whether blanket IPT is more effective than conscientious endemic regions due to fatal Stevens-Johnson reactions in
post-exposure IPT; a second randomized controlled trial is HIV-infected individuals. Ethambutol was introduced in
currently underway to help in guiding public health policy. many countries to replace thiacetazone, but concerns exist
There are valid concerns that IPT may promote the about the toxicity of ethambutol in young children. Seth et
development of drug resistance, especially if the presence al33a have shown no ocular toxicity in children above three
of active TB disease is not adequately excluded. However, years of age on ethambutol therapy in the dosage of 20
the provision of IPT to young children poses a negligible mg/kg by measuring visual evoked response and latency
risk, because they usually develop pauci-bacillary disease, at 3, 6 months during therapy with ethambutol. A recent
rarely acquire drug resistance and contribute little to disease WHO report concluded that the use of ethambutol is safe
transmission. at the recommended dose of 15-25 mg/kg/day, although
serum levels may be sub-optimal.34 Achieving effective
Curative Treatment serum antibiotic levels is particularly important in
The main variables that influence the success of immunocompromised children; little data exist to guide
chemotherapy, apart from primary drug resistance, are optimal dosing and the effect of suboptimal drug levels
the bacterial load and the anatomical distribution of bacilli. on disease outcome has not been adequately studied.
For treatment purposes the wide spectrum of pathology There is an increased risk of disease relapse in HIV-
observed in children with intrathoracic TB can be reduced infected children3,35 and consideration may be given to
to three main categories: prolong the treatment duration from 6 months to 9 months,
1. Sputum smear-negative, low organism load: Success of the particularly in the face of more extensive cavitating disease,
standard regimen of three drugs (2RHZ) for the although there have been no randomized controlled trials
intensive phase and of two drugs (4RH) for the to substantiate this.
continuation phase is well established; the risk of
acquired drug resistance is low. Drug Interactions
2. Sputum smear-positive, high organism load: As for adults, TB is frequently the presenting disease in children with
four drugs (2RHZE) during the intensive phase are previously undiagnosed HIV infection who may have
warranted. This group has high risk of acquiring drug advanced HIV disease requiring HAART.27 The Centers
resistance. for Diseases Control and Prevention (CDC) has
3. Disseminated/miliary TB: Disseminated/miliary TB established guidelines for initiating HAART in adults
occurs predominantly in very young (immune presenting with TB and for initiating TB treatment in
221
those already on HAART. The guidelines are regularly Immune Reconstitution Inflammatory
revised; see the relevant CDC website for the latest Syndrome (IRIS)
recommendations. 36 No pediatric guidelines are
provided, but issues regarding initiation of HAART, Transient worsening of symptoms such as fever, increasing
drug interactions, overlapping side-effects and lymphadenopathy, exacerbation of intracerebral
adherence concerns are similar. Since both HIV and TB tuberculomas, pleural effusions and even adult respiratory
have its highest mortality during infancy, most distress syndrome have been reported after the initiation of
clinicians caring for very young children would start ART in severely immunocompromised patients. This
HAART as soon as possible after initiating TB treatment. temporary exacerbation of TB symptoms and signs is mainly
In older children, in the absence of severe immuno- ascribed to the effects of immune reconstitution, although a
suppression, it seems reasonable to complete the TB “hypersensitivity” reaction to antigens released by killed
treatment first. TB bacilli may also contribute. It does not indicate treatment
Significant drug interactions occur between the failure and usually subsides spontaneously, although
rifamycins, especially rifampicin, and some of the severe cases may require treatment with corticosteroids. In
nonnucleoside reverse transcriptase inhibitors (NNRTIs) a recent prospective survey of 152 Thai children with low
and/or protease inhibitors (PIs). Rifampicin is regarded CD4 % (<15%), IRIS was documented in 19%, usually
as being compatible with all nucleoside reverse within 4 weeks of ART initiation. The majority of IRIS cases
transcriptase inhibitors (NRTIs), although it promotes were due to atypical mycobacteria; 3/14 were due to M
the glucoronidation and elimination of zidovudine tuberculosis and 2 due to BCG.39 BCG-related IRIS, presenting
(AZT). Abacavir, another NRTI that has been used with massive right sided axillary adenitis, is a well
in triple NRTI regimens, is also eliminated by documented complication following HAART initiation.40
glucoronidation. Little pharmacokinetic information is
currently available on the interaction of these drugs in BCG Vaccination
children. Using a triple NRTI regimen is an option in BCG offers variable protection in different settings, but it is
patients on TB treatment, but the regimens not performed generally accepted that BCG offers significant protection
well in comparative efficacy studies.3 In the absence of against disseminated (miliary) disease in young HIV-
rifabutin (which is frequently used to replace rifampicin uninfected children (<2 years of age). The protection
in developed countries) current recommendations are to provided by BCG vaccination in HIV-infected children
retain a double NRTI backbone in combination with remains uncertain, while it poses a considerable risk of
efavirenz (NNRTI) or ritonavir (PI) as the levels of these disseminated BCG disease. 40 In the absence of a
two drugs are least affected by rifampicin. An alternative comprehensive risk-benefit analysis, current consensus
PI strategy would be to boost lopinavir/ritonavir with guidelines advise BCG vaccination of all asymptomatic HIV-
additional ritonavir. exposed infants in TB endemic areas with careful
monitoring for the development of BCG-related disease.41
Other Relevant Issues
HIGHLIGHTS
Trimethoprim-sulphamethoxazole (TS)
Prophylaxis • The burden of child TB is highest in areas where the
adult epidemic is poorly controlled.
Studies have demonstrated that TS prophylaxis • HIV-infected children are particularly vulnerable to
significantly reduces the risk of Pneumocystis jiroveci TB infection and disease.
(PCP) pneumonia, invasive bacterial infections and • Routine HIV testing should be viewed as an essential
malaria in HIV-infected adults. A randomized controlled part of the diagnostic work-up in HIV affected
trial of TS prophylaxis in HIV-infected Zambian areas, as it guides diagnostic interpretation and
children of 2 years and older showed significant management.
survival benefit. 37 Routine TS prophylaxis is • Inspite of multiple challenges, the management
recommended by WHO for all HIV-infected children of HIV-infected children with TB exposure/infection
including those with TB. TS prophylaxis is also or disease can be greatly improved by better
recommended for HIV-exposed, but uninfected infants implementation of readily available interventions.
as PCP is also common in this group.38
222
15.2 TUBERCULOSIS AND HIV INFECTION
Tuberculosis is increasing in prevalence in many An estimated 1.3 million people died from TB in 2008.
countries. It is now the leading cause of death due to The highest number of deaths was in the South-East Asia
infectious disease worldwide. HIV infection has emerged Region, while the highest mortality per capita was in the
as the most important predisposing factor for developing Africa Region.
overt tuberculosis in people coinfected with M. tuberculosis In 2008, the estimated per capita TB incidence was
and an important reason for the recent worsening of the stable or falling in all six high incident WHO regions.
global tuberculosis epidemic. However, the slow decline in incidence rates per capita is
offset by population growth. Consequently, the number of
EPIDEMIOLOGY OF HIV-TUBERCULOSIS new cases arising each year is still increasing globally in
the WHO regions of Africa, the Eastern Mediterranean
Pediatric HIV infection today represents a major setback to and South-East Asia.
child health. HIV infection affects the health of children in HIV and TB form a lethal combination, each speeding
India and other high incident countries and by itself can the other's progress. HIV weakens the immune system.
cause fungus infection of pulmonary organs. HIV also Someone who is HIV-positive and infected with TB is at a
increases the risk of deadly infection in immune much higher risk of developing serious form of TB in
compromised children such as cancer, kidney disease for comparison to that who is HIV-negative. TB is a leading
which the children are on long term steroid therapy and cause of death among people who are HIV-positive. It
cancer chemotherapy. In vertical transmission (from the accounts for about 13 percent of AIDS deaths worldwide.
mother) children cannot be protected by BCG which is In Africa, HIV is the single most important factor
available in the universal program of immunization, determining the increased incidence of TB in the past 10
because it precipitates a severe reaction and at times TB years.3 Historically HIV and TB coinfection has been a
disease. At the end of December 2008, it was estimated that problem since 1990s as emphasised by Bakshi et al3a in
approximately 33.4 million (potential range 31.1-35.8 New York. Epidemiology and clinical features of infection
million) people were living with HIV/AIDS worldwide. Of with Mycobacterium tuberculosis in human immuno-
these 2.1 million (potential range 1.2-2.9 million) were deficiency virus (HIV)-infected children and their families
children under 15 years of age. In the same year, it was has been described. Sixty families of children with HIV-
estimated that there were 2.7million people newly infected infection and seroreverters uderwent follow-up in a
with HIV, of which 0.43 million were children and there comprehensive multidisciplinary program for children
were 2 million deaths.1 Latest estimates show that about 2.5 and families. Infection with M. tuberculosis was diagnosed
million (1.8-2.9 million) people were living with HIV in India either by TST positivity or a positive culture, M. tuberculosis
in 2007; with an estimated adult HIV prevalence of 0.34% infection was detected in seven children from four families.
(0.25-0.43%).2 Serious epidemics are underway in several Six of seven children had a history of exposure to M.
states in India. In TamilNadu, HIV prevalence of 50 percent tuberculosis in an HIV-infected adult (parent) who was
has been found among sex workers, while in Andhra either an intravenous drug user, homeless or a
Pradesh, Karnataka, Maharashtra and Nagaland, HIV noncompliant with the medical regimen. Pulmonary
prevalence has crossed the 1 percent mark among pregnant tuberculosis was found in all HIV-infected children and
women.2 It is quite disheartening that inspite of aggressive one serorevertor. Only one child died of complications of
efforts of National Aids Control Organization (NACO) with tuberculosis and HIV infection. M. tuberculosis isolated
financial help of government of India and International from this child was resistant to isoniazid, rifampicin and
agencies, the prevalence in southern states (Tamil Nadu) in streptomycin sulfate. It is concluded that tuberculosis is a
sex workers is as high as 50 percent. growing problem among children born to HIV-infected
The major burden of HIV infection is in the sub-Saharan parents. Tuberculosis was of the severe variety as a
Africa and Asia; these areas are the parts of world where reflection of what was prevalent in the community at that
tuberculosis is rampant. Advent of HIV epidemic has led time. The burden of tuberculosis (TB) worldwide is
to a significant increase in the number of all new TB cases. influenced by the human immunodeficiency virus (HIV)
WHO estimates that the largest number of new TB cases in epidemic. Between 1990 and 2004, the incidence of
2008 occurred in the South-East Asia Region, which tuberculosis stabilized or fell steadily with the exception
accounted for 34% of incident cases globally. However, of Africa. HIV and HIV-associated TB affects young adults
the estimated incidence rate in sub-Saharan Africa is which may result in increased rate of TB transmission in
nearly twice that of the South-East Asia Region with over children. HIV-infected children are at increased risk of TB
350 cases per 100,000 population.3 and of more severe forms of TB compared with
223
immunocompetent children. TB is more common in PREVALENCE OF TUBERCULOSIS IN

children living in households affected by HIV. Owing to HIV-INFECTED CHILDREN
higher mortality during and after treatment of TB, the
outcome of TB is also worse among HIV-infected children, It is estimated that by end of 2000, 11.5 million HIV-infected
with lower cure and higher recurrence rates. Available adults worldwide were coinfected with M. tuberculosis;
reports still show low levels of drug resistance among Africa and South-East Asia accounted for 70 percent and
children. Continued surveillance will be important to detect 20 percent respectively.6 In India, it is estimated that about
any increase in TB. Research needs to be focused on better half of all HIV-infected individuals are co-infected with M.
methods of preventing TB as BCG is still the only vaccine tuberculosis and approximately 200,000 of these coinfected
available. The development of better diagnostics for individuals will develop active TB disease each year.7
infection and disease will improve the management of TB Similar pediatric data is now available in India. Some
in children.3b conclusions can be drawn upon from various reports in
The impact of the HIV epidemic on pediatric TB has children with HIV infection. In contrast to the developed
been reported in several studies. A prospective cohort countries, tuberculosis has been reported in 14 to 54 percent
study of children with TB diagnosed in Addis Ababa of Indian children with HIV/AIDS8-15 (Table 15.2.1). In
from December 1995 to January 1997 in which HIV- the series, at AIIMS,14 10 of the 29 children with HIV-TB
positive children were compared with HIV-negative co-infection, had disseminated/miliary TB. In a report from
children, reported that HIV-positive children were Tambaram (Chennai), 1115 of 1768 HIV infected children
younger, more underweight and had a six-fold higher who accessed care had tuberculosis; 14.9 and 20.6 percent
mortality than HIV-negative children.4 The tuberculin children had extra-pulmonary TB and disseminated TB
skin test was less sensitive and chest radiography was respectively.15
less specific in HIV-infected patients. Adherence to
treatment was high (96%), and the cure rate was 58 HIV Seroprevalence in Children with Tuberculosis
percent for HIV-positive and 89 percent for HIV-negative The HIV seroprevalence in children with tuberculosis is
pediatric TB patients. The study concluded that HIV- likely to vary with the background HIV seroprevalence.
positive children are at increased risk of diagnostic error The rates will be higher in areas where HIV infection is
and hence delayed diagnosis of TB. Clinical more prevalent. The figures are likely to increase as HIV
manifestations were more severe and progression to death seroprevalence increases. HIV seroprevalence in adults
was more rapid than in HIV-negative children. with tuberculosis at a tertiary care hospital in New Delhi
Malnutrition estimated by weight for age may be used to was reported to have increased from 0.4 percent in 1994-
identify children at high risk of a fatal outcome. 1999 to 9.4 percent in 2000-2002.16,17 In another study from
In a retrospective study of 118 culture proven the same center, a seropositivity rate of 8.3% was reported
tuberculosis patients in Durban, South Africa; 57 (48%) in adults with TB.18 In a South African study on children
children were detected to be HIV-1 infected, 44 (37%) nonhospitalized with tuberculosis, the HIV prevalence was
HIV-1-infected, and in 17 (14%) HIV-1 status was not found to be 42 percent.19 In other African studies the
determined.5 In contrast to previous studies, this study prevalence of tuberculosis in HIV-infected children has
has shown that TB-HIV coinfection in children is been reported to be between 10 percent20 and 56 percent.21
common (48% of all culture-proven cases), the It indicates that almost half of the children having TB run
presentation of tuberculosis may be acute (43%), and the risk of being HIV positive.
supportive tests are individually useful in confirming A few Indian studies have addressed this issue.
the diagnosis in a third of cases. All cultures for M. Merchant and Shroff reported HIV seroprevalence of 18
tuberculosis were positive by 8 weeks. Clubbing and age percent in children with disseminated TB.22 Karande et al23
over two years were the most reliable indicators of
underlying HIV-1 disease in a child with tuberculosis,
while clinical features, radiology and supportive tests Table 15.2.1: Tuberculosis in HIV-infected children in India
were found to be similar between HIV-infected and Author N Tuberculosis (%)
noninfected TB cases. Hospital-related mortality was Shah I, 20058
317 43.4
higher (17.5%) in HIV-1-infected children compared to Shah SR, et al 20059 50 38
the noninfected group (11.4%). The changing pattern of Madhivanan P, et al 200410 58 35
presentation of childhood tuberculosis and the high Verghese VP, et al 200211 88 12
prevalence of TB in HIV endemic areas have made it Merchant RH, et al 200112 285 29.5
imperative to maintain a high index of suspicion, with Dhurat R, et al 200013 55 67.5
culture evaluation being an important part of clinical Lodha R, et al 200014 29 26.7
practice.5 Rajasekaran S, et al15 1768 63
224
reported prevalence of 16.2 percent in children with substantial genetic homogeneity.

disseminated tuberculosis. In a more recently published This mapping is expected to help in constructing
study, Shahab et al reported 2 percent HIV seroprevalence "specific drug response/disease predisposition maps"
in children with tuberculosis; all 5 children with HIV-TB to help in making policy decision for drug dosage
coinfection had disseminated tuberculosis.24 Unlike the interventions and disease risk management especially
other studies, this study is from a low HIV seroprevalence infectious diseases.
area. In a another study, 270 pediatric patients with active A new subtype of AIDS virus was found by French
Tuberculosis (TB) disease attending the OPD of a medical scientists which jumped from gorilla to humans. The new
college in Agra were screened for Human Immunodeficiency strain was found in a woman from Cameron, West Africa. It
Virus (HIV)-1/2 antibodies. Of these, 23 (8.5%) were found is a part of the HIV-1 family of microbes that account for the
to be HIV-positive.25 Among the HIV-positive children with vast majority of cases of human immunodeficiency virus
TB 86 (75%) were of pulmonary and 13.04% were of (HIV). The new subtype is called P, adding to the three
extra-pulmonary type. All these studies suggest that the established HIV-1 subtypes. M being the most prevalent, O
prevalence of HIV-TB coinfection varies with the and N are rare (Times of India, 3rd August 2009).
geographical region. There is a greater probability of There is also an HIV-2 which is a minority viral family.
detecting HIV infection in children with disseminated This also has origin in nonhuman primates. The women
tuberculosis. carrying this virus had moved from Africa to Paris where
she tested positive for HIV. She responded to diagnostic
tests for HIV-1 but further subtype could not be pinpointed.
Genemapping of People in India for HIV
In 2006 a form of HIV was found in wild gorillas in
Genemapping exercise of the "people of India" has shown western Central Africa. It was the first time the virus was
that Indians are more vulnerable to HIV-AIDS than many identified in primates other than chimps and humans.
other population groups around the world. This is because The gorilla virus was widespread and was closely
of the virtual absence of a protective gene marker against correlated to HIV-1 group 0, one of three HIV groups known
HIV-1. It has also been shown that there is increase in risk to infect humans. The same virus was detected from the
as one moves from north to south India. Further Indian chimpanzees in South East Cameron which is the primary
genepool is quite varied and is not homogenous at all. It reservoir of the HIV-1 group M virus. At the same time it
includes several variations across population groups was detected that for Group N strain of HIV-I, chimps
spread across the country. were the reservoir and was extremely rare in human
Antenatal clinical HIV prevalence survey done in population.
2005 reports a high frequency of HIV in South Indian
population. This gene mapping study was carried out by PATHOGENESIS
more than 150 scientists and researchers from six control
HIV and TB form a lethal combination, each speeding the
centers of Council of Scientific and Industrial Research
other's progress. The estimated annual risk of reactivation
(CSIR) of India.
among those co-infected with HIV and TB is about 5 to 8
This has been perhaps the largest scientific endeavor
since the green revolution effort of 1970 of Indian Council of percent with a cumulative lifetime risk of 30 percent or
Agricultural Research. The mapping covered four main more compared to a cumulative lifetime risk of 5 to 10
linguistic families of Indian-Austro-Asciatic, Tibeto- percent in HIV-negative adult patients.26,27
Burman, Indo-European and Dravidian. The study Cell-mediated immune response is essential for defence
encompasses Indian population defined by distinct against M. tuberculosis. HIV infection primarily affects the
religious communities, hierarchial castes and subcastes, components of cell- mediated immunity. This leads to
and isolated tribal groups. increased susceptibility to M. tuberculosis. After primary
The study part of the Indian Genome Variation infection, there is poor containment of the infection, leading
Initiative has generated information on over 4,000 genetic to progressive disease and also risk of dissemination. In
markers from more than 1,000 biomedically important and individuals with latent TB infection (LTBI), HIV-induced
pharmacogenetically relevant genes in reference groups. immunosuppression leads to increased risk of reactivation.28
The study reveals a high degree of genetic differentiation In addition to the evidence that HIV infection worsens
among Indian Ethnic groups. Hence, in India "pooling" of the risk and course of TB, there is increasing clinical
endogenous population without regard to "ethno- evidence that coinfection with M. tuberculosis accelerates
linguistic factors" will result in false inference. Hence it is the progression of disease. It has been observed in HIV-
not right to refer people of India as 'Indian' in many infected adults matched for CD4 counts, that the mortality
population genetic studies because Indian population is in patients with HIV/TB coinfection was higher in those
not genetically homogenous. However, it is possible to having lower CD4 counts than in patients with higher
identify large clusters of ethnic groups that have count.29,30 The increase in mortality is not due to TB but to
225
an increased occurrence of other opportunistic infections. infection called primary "HIV infection or acute
Recent studies have documented increase in viral seroconversion syndrome". Incubation period is short (2
replication in TB patients. Areas of lungs involved with to 4 weeks), the clinical symptoms vary from fever to a
tuberculosis have an upto 1000 fold increase in HIV-1 viral variety of neurological symptoms. Diagnosis is made
particles in comparison to uninvolved lung areas.31 The infrequently as one usually does not suspect it and the
viral load is higher in bronchoalveolar lavage fluid than standard ELISA tests are negative. Demonstration of HIV
that found in plasma, suggesting that there is high local
RNA in plasma is diagnostic of the disease.
viral replication in the lung.
i. The next stage is asymptomatic HIV Infection having
The immune response to pulmonary tuberculosis is
a long and variable latent period for onset of AIDS.
characterized by delayed type hypersensitivity. There is
granuloma formation, recruitment of CD4 cells to the lung, Duration could be as long as 10 years in adults. In
and elaboration of various cytokines-TNF-α, IFN- γ, IL-1α, children it is about 2 years.
IL-6 and IL-8. TNF- α, M. tuberculosis and its cell wall ii. Persistent generalized lymphadenopathy (PGL). It is
component-lipoarabinomannan, increase HIV-1 viral defined as persistent generalized lymphnodes (PGL)
replication.32 There is increased risk of mutations in these involving atleast two sites often cervical and inguinal
areas of high viral replication. nodes. This is followed by HIV related disease and
Spread of HIV epidemic in sub-Saharan Africa has AIDS. This last stage is the stage of advanced
resulted in notification rates of TB increasing upto 10 times. immunosuppression, referred to as AIDS.
When there is an overlap of TB and HIV-coinfection, it is
due to the increase in the occurrence of TB on an underlying Impact of HIV on TB
HIV infection/AIDS disease. Even in countries with a well About a third of HIV infected individuals world wide are
established and control program of TB, associated HIV coinfected with TB infection. In sub-Saharan Africa, upto
infection becomes a major killer due to massive TB disease. 70% patients with smear-positive pulmonary TB are HIV-
Hence TB and HIV/AIDS control programs have to go hand positive. HIV promotes the progression to active disease
in hand. India has started action in this direction. both in people with recently acquired TB infection and
Incidence of TB is 1.8 million cases occurring annually. with latent M. tuberculosis infection which is reactivated to
With the presence of HIV, TB could go upto 2 million. Hence active disease by HIV infection. HIV increases the rate of
the task/major control of this dual infections is a real recurrence of TB disease which may be due to either
challenge. endogenous reactivation (true relapse) or exogenous
During the initial (primary) infection of immuno- infection. This increase in tuberculosis cases poses an
competent person with M. tuberculosis, macrophages ingest increased risk of TB transmission to general community.
the organisms and after processing present the antigen to T In developing countries like India, the potential burden of
cells. CD4+ T cells secrete lymphokines and then enhance extra TB cases attributable to HIV could tilt the balance of
the ingestion and killing of M. bacilli by macrophages. In health budget in countries like sub-Saharan Africa.
most people the tuberculosis infection does not become a
disease. It is only 10% of individuals who are immuno-
Impact of HIV on the Clinical Course of TB
competent develop the disease either soon after primary
infection or years later (reactivation of latent TB infection). In addition to the increase in the number of TB cases, HIV
These are due to defects in the functioning of T cells or also alters the course of disease. Due to increase in
macrophages. immunosuppression due to HIV infection, there is increase
Hallmark of HIV infection is a progressive in the incidence of smear negative pulmonary TB and
lymphocytes depletion and dysfunction of CD4+ T extrapulmoanry TB. TB is more disseminated and more
lymphocyte cells coupled with defects in monocyte and difficult to diagnose. The mortality in coinfected patients is
macrophage function. These cells have a central role in also very high, to the tune of 25% in smear positive and 40-
anti-mycobacterial defenses; dysfunction of these cells 50 % in smear negative pulmonary TB patients.
exposes the individual to high risk of primary TB infection
or reactivation of latent TB which is quite significant. Immunopathology in HIV Infection
HIV replication and disease progression is increased in
Natural History of HIV-Infection HIV-infected individuals. This is due to increased immune
Without treatment, a HIV infected individual has a life activation. Plasma markers of immune activation are
span of approximately nine years with a range of 8-12 neopterin, beta-2-microglobulin (β2M) and soluble tumor
years. With the advent of effective highly active necrosis factor alpha receptor type 1 (sTNF α-R1). These
are increased and can be measured by ELISA in patients
antiretroviral therapy, (HAART) life span has been
with active TB. CD4+T cells count ≤ 200 cells / μl have the
extended. This is dependent upon the stage of HIV
highest level at baseline. There is steep fall in neopterin
226
and sTNFα-R1 during treatment. However, the levels do p24 antigen level correlated well with that of CD4
not drop to normal. β2M levels remain persistently high lymphocyte count (<50 CD4 cells r = 0.626, p= <0.001 and
despite completing TB treatment. These findings suggest 50-200 CD4 cells, r=0.531, p=0.016). The lowest level of
the synergism between TB and HIV infection. The p24 antigen measurable was 1,905 fg/ml in a patient with
persistence of these immune markers in TB and HIV CD4 cell count of 222 cells/μl. p24 antigen could be
coinfection indicate underlying immune activation. estimated even in patients on ART with stably suppressed
However, none of the markers are specific enough and
viremia.
cannot be used to assess cure of TB. The three diagnostic
Hence to summarize it can be stated that plasma
markers which have significance in relation to HIV infection
concentration of immune activation markers are elevated
are HIV viral load, CD4+T cells levels and plasma levels of
the above mentioned soluble markers.32a in patients infected with HIV and the increase is related to
the stage of HIV disease. This coinfection has additive
Immune Status in HIV Infection effects on the immune system resulting in mutually
unfavorable effects. This incomplete recovery of immune
Immune stimulation occurs very early in HIV infection system even after 6 months of ATT indicates that rate of
indicated by seroconversion. In addition to specific immune restoration does not match the microbiological
immune response, there is occurrence of widespread
clearance and resolution of TB.
activation of CD4+ and CD8+T cells, B cells, natural killer
(NK) cells and macrophages. Immune cell activation results
CLINICAL FEATURES
in increased production of many cytokines and increased
expression of cytokine receptors. Soluble products of Tuberculosis can occur in HIV-infected individuals at any
activation can be quantified in plasma or serum. Presence CD4 count. This is in contrast with other opportunistic
of clinical TB in HIV infected individuals results in infections which generally occur when there is significant
continuous cellular activation resulting in viral decline in CD4 counts percent. When HIV infected children
replication and progression of disease. Changes in soluble develop tuberculosis, the clinical picture tends to be typical
activation markers are more closely related to viral load of childhood tuberculosis as in the immunocompetent
than to CD4+T cells changes. Immune activity is indicated
patient, although the disease, as in adults, tends to progress
by increased levels of neopterin in blood and urine.
more rapidly and the clinical manifestations are more
Increased production of β2M in plasma strongly reflects
severe.33-36 There may be an increased tendency for
the progression of HIV infection to AIDS. sTNF-α receptor
levels correlate with their induction by TNF-α resulting extrapulmonary disease and dissemination along with
in active expression of HIV in monocytes and lymphocytes. involvement of unusual sites and atypical chest
There is progressive increase in levels of IFN? and radiograph. The most striking feature of tuberculosis in
neopterin when HIV-seropositive individuals are stratified patients with HIV infection is the extremely high frequency
on the basis of CD4+ T cell counts, with the highest levels of extrapulmonary involvement usually with concomitant
in those patients who have CD4+ T cell counts < 200 cells pulmonary involvement. Extra-pulmonary involvement
/μl. Treatment with ATT results in the decreased plasma occurs in more than 70 percent of patients with tuberculosis
levels of neopterin and sTNFα-R1 in both HIV-positive and and preexisting AIDS or AIDS diagnosed soon after but
HIV negative TB patients. only in 24 to 45 percent of patients with tuberculosis and
37,38
ATT results in successful elimination of the pathogen in less advanced HIV infection. Thus extrapulmonary
six months, but the effect of TB in HIV positive patients on tuberculosis appears to be more common in patients with
immune system takes much longer to resolve. sTNFα-R1 is more severe HIV-induced immunosuppression.
predominantly associated with TB and β2M with HIV and Diagnosing extrapulmonary tuberculosis in patients
hence these could serve as independent markers of TB and with HIV infection is important because it is an AIDS
HIV-disease activity. defining illness while pulmonary tuberculosis is not. Adult
HIV and tuberculosis coinfected patients have been noted
Status of CD4+ T Cell Counts and its Relation to p24 to have lesser upper zone involvement, greater nodal
antigen disease, higher rates of pleural/pericardial disease.
Although they are less likely to be smear-positive, but are
Baveja et al32b demonstrated a correlation of CD4T cells equally infectious to close contacts. The most important
counts and levels of p24 antigen. CD4T cell counts at denominator, however, is the degree or stage of
baseline showed that the superiority of p24 measurement immunosuppression since the more atypical the clinical
was more pronounced at lower levels of CD4 cells (< 200 features, the more likely is the CD4+ T cell count to be low.
cells/μl). p24 antigen level may be of interest as a simple In adults, the clinical features were typical until CD4+ cell
and inexpensive predictive marker of disease progression. count was less than 500/cumm.
227
In a child infected with HIV-1, evaluation of M. The mortality rate during the study was 13.4 percent in
tuberculosis is mostly undertaken after failure to respond HIV-infected children compared with 1.5 percent in non-
to broad spectrum antibiotics started due to prolonged HIV infected children (P = 0.03).
fever, respiratory symptoms, and atypical chest Kumar et al have reported the clinical feature of culture
radiograph. HIV disease manifestations in children are confirmed TB in children with HIV infection.40 In their
distinct from that of adults with early signs and symptoms cohort of 213 children with vertically transmitted HIV
being nonspecific and distinguished only by their infection, a total of 76 (36%) children were suspected to
persistence and severity, e.g. failure to thrive, generalized have tuberculosis based on their clinical presentation
lymphadenopathy, persistent diarrhea and oral thrush. together with either a positive Mantoux test or AFB
Frequently, these children develop diseases which can positivity and treated for TB. Twenty four children had
mimic an initial picture of tuberculosis. Many children culture positive TB. The median age at diagnosis of TB in
with HIV-1 infection have features of chronic lung disease these children was 16 months. Over half of these children
with abnormal chest radiograph thus making the diagnosis had some immunodeficiency. Common presentations were
of pulmonary tuberculosis even more difficult.39 fever (87%), history of contact with an open case of TB
Clinical signs that suggest HIV infection in a child (79%), cough for more than 2 weeks (75%), malnutrition
include: (71%), hepatosplenomegaly (71%), chronic diarrhea (67%)
i. Failure to thrive in a breast-fed infant before 6 months and generalized lymphadenopathy (58%). Chest
of age roentgenograms were abnormal in all the children, with
ii. Recurrent bacterial infections hilar and/or paratracheal nodes (62%) and lobar or
iii. Generalized symmetrical lymphadenopathy segmental opacification (57%). Twenty one (87%) children
iv. Extensive oropharyngeal candidiasis had pulmonary TB at the time of their diagnosis. One or
v. Generalized rash more sites of extrapulmonary TB were confirmed in 10
vi. Bilateral nontender parotid gland enlargement (41%) patients.
vii. Clubbing.
HIV infection makes the diagnosis and management DIFFERENTIAL DIAGNOSIS
of tuberculosis in children even more difficult than usual
for the following reasons: i. Lymphocytic Interstitial Pneumonitis
i. Several HIV-related diseases may present in a similar
Lymphocytic interstitial pneumonitis (LIP) is a very
way as TB.
common cause of lung disease in HIV-infected children
ii. A HIV-infected child is more likely to have a negative
over 2 years of age. LIP may be difficult to differentiate
tuberculin test.
from PTB or miliary TB. Clinical features (other than
iii. Management of TB may be more difficult as the family
respiratory symptoms/signs) that are commonly
is likely to have more than one HIV-infected
associated with LIP include symmetrical, generalized
individual.
lymphadenopathy (painless and mobile), bilateral chronic
In a study carried out in Johannesburg, South Africa to
nontender parotid enlargement, and finger clubbing.
define the prevalence of human immunodeficiency virus
Diagnosis is often clinical as it can only be confirmed by
(HIV) coinfection and differences in clinical presentation
lung biopsy. Typical chest radiograph findings are bilateral
between HIV-infected and noninfected hospitalized
diffuse reticulonodular pattern and enlarged mediastinal/
children with tuberculosis, 161 children were enrolled. Forty
hilar lymph nodes. In pulmonary tuberculosis, the
two percent children were HIV-infected, including 67/137
radiological abnormalities are often unilateral. However,
(about 50%) with pulmonary tuberculosis (PTB) and 1/24
LIP presents with a broad spectrum of clinical and
(4%) with extra-pulmonary disease (EPTB).19 Positive
radiological features. Bacterial pneumonia is a common
microscopy or bacteriology did not differ by HIV status for
complication and further confuses the radiological
children with either pulmonary tuberculosis (PTB) or
findings.
extrapulmonary tuberculosis (EPTB). Although age did not
differ between HIV-infected and noninfected children with
ii. Pneumocystis Jiroveci (Previously Carinii) Pneumonia
PTB, non-HIV-infected children with EPTB were
significantly older than those with PTB only (median age Pneumocystis jiroveci pneumonia (PCP) is a common
32 months versus 14.5 months, p = 0.004). Chronic weight problem in HIV-infected children and usually presents as
loss, malnutrition and the absence of BCG scar were more an acute, severe pneumonia in infants less than 6 months
common in HIV-infected children with PTB. HIV-infected of age. Compared with TB in infants, PCP is characterized
children were also more likely to show cavitation (p = 0.001) by hypoxia. The commonest chest radiograph abnor-
and miliary TB (p = 0.01) on chest X-ray. Reactivity to malities are diffuse interstitial infiltration and
tuberculin (> 5 mm and > 10 mm in HIV-infected and hyperinflation. In developing countries, PCP is a very
noninfected children, respectively) was significantly lower unlikely diagnosis of persistent respiratory disease in
in HIV-infected children, as were CD4+ lymphocyte levels. children after infancy. In countries where there is antenatal
228
HIV screening and routine cotrimoxazole prophylaxis in disorders whose radiologic findings are similar to those in
HIV-infected infants, PCP is now unusual. pulmonary tuberculosis.
iii. Bacterial Pneumonia Interferon-Release Assays

Bacterial pneumonia is common in HIV-infected children These are new assays for diagnosis of latent TB infection
and recurrent bacterial pneumonia is a feature of children (For details please refer to chapter on Tuberculin test). These
with AIDS. The commonest cause is Streptococcus pneumoniae tests have been evaluated in children with HIV-TB co-
and response to treatment is usually satisfactory. Other infection. In a recently published study on 36 HIV-1
causes include Haemophilus influenzae, Salmonella, infected children and adolescents, with microbiologically
Staphylococcus aureus, Klebsiella pneumoniae and Escherichia and/or histopathologically confirmed TB co-infection the
coli. The presentation of PTB in infants can be acute, so sensitivity was 38.8% for TST, 47.2% for IGRA
PTB should be considered when there is a poor clinical (QuatiFERON Gold In tube test) and 11.1% for ELISA.43
response to standard antibiotics and a family member has Out of 24 patients with severe immunosuppression (CD4+
tuberculosis. Pneumonia due to Staphylococcus or Klebsiella < 200 cells/mm3), 6 had positive TST, i.e. sensitivity 25%,
may be a problem in HIV-infected children with chronic 10 positive QFT-G results, i.e. sensitivity 41.6%. In another
lung disease. These bacteria can cause cystic changes and study, the aim was to measure the agreement of two
cavitation. interferon-gamma release assays (IGRAs) and the
tuberculin skin test (TST) for the detection of M. tuberculosis
Bronchiectasis infection in human immunodeficiency virus (HIV) infected
adults and children in a setting highly endemic for
This is usually a complication of LIP but may also
tuberculosis (TB).44 The authors concluded that there was
complicate TB. A cough productive of copious purulent
a poor to moderate agreement between the TST and IGRAs
and sometimes blood-stained sputum, finger clubbing,
in HIV-infected adults and children. T-SPOT. TB may have
and halitosis are typical features.
improved sensitivity for detection of M. tuberculosis infection
in HIV-infected individuals compared to the Quantiferon
Others test and the TST.
Other conditions to be considered in the differential
diagnosis includes fungal pneumonia, e.g. due to candida Pediatric Tuberculosis Score Chart
or cryptococcus, nocardiosis and pulmonary lymphoma, and The pediatric tuberculosis score chart (TSC) has a low
rarely pulmonary Kaposi sarcoma. specificity in diagnosing tuberculosis in HIV endemic
areas and leads to overdiagnosis of tuberculosis.45
Investigations
Radiology
Diagnosis of tuberculosis in HIV-infected children poses
at least as many difficulties as in non-HIV-infected child. The radiologic findings in pulmonary tuberculosis are
likely to be same as in non-HIV-infected children,
Bacteriology particularly those without severe immunosuppression.
However, children with both HIV and TB may have
Demonstration of M. tuberculosis on smear or culture atypical radiographic features and cavitation.39
remains the gold standard. However, there are difficulties The diagnostic work up for extrapulmonary tuberculosis
in obtaining appropriate specimen (please see Chapter on is similar to that in immunocompetent children.
Pulmonary tuberculosis). However, all efforts should be
made to demonstrate the organism. This may be achieved Immunity Test for AIDS
by sputum examination in older children, gastric aspirate
The CD+4 count test used to gauge immunity levels of an
or induced sputum in younger children. Bronchoalveolar
HIV-infected patient and was considered sufficient to
lavage (BAL) may be performed in tertiary care centers.
There are some reports that suggest lower yields on culture decide that the damage caused by the virus requires life-
in HIV-infected children.41 saving antiretroviral therapy (ART). CD count test is done
at no cost to all patients. This was the decision of National
Aids Control Organization (NACO). The objective was to
Tuberculin Test
detect the cases early and reduce mortality. At present India
The tuberculin test is less sensitive, especially in children has 58 CD-4 counting machines.
with low CD4 counts.42 Chest radiograph is also less specific Blood samples of HIV patients are taken at ART centers
in HIV-infected children because of presence of other and then processed at centers where the CD-4 cell count
229
machines are available. This test only predicts risk of future subjects who complained of discomfort with the finger
infections to 52,000 patients who are on ART in India testing method.
against estimated 5.2 million who are infected with HIV. Oral test just requires rubbing the stick against the gum
The CD-4 count is used in combination with the viral load twice, once against the upper jaw and then on the lower
test which measures the level of HIV in blood. The test is jaw from one end to the other to collect the oral mucosal
ordered as a baseline measure when the patient is first transudate fluid normally secreted in the oral cavity. The
diagnosed. Test are repeated in every 6 months. The CD4 applicator on the stick is a strip of synthetic proteins which
count in healthy adults ranges from 500 to 1,500 cells per detects HIV antibodies just in 20 minutes. In the standard
cubic millimeter of blood. In HIV infected people it goes HIV test with blood sample, the patient has to wait for two
down by 60 cells per cubic millimeter of blood per year as weeks for the result. According to CDC Atlanta, 33% of
HIV progresses. ART is administered when an HIV- tested never pick up their results.
positive person registers a CD-4 count under 200. Oraquick test has been approved by the US Food and
Drug Administration. This being a noninvasive, simple,
Other Tests for Diagnosis of HIV accurate and oral fluid-based has the potential to make a
big impact on HIV screening. This makes it almost a home-
A simple gum swab in place of an invasive blood test can
based HIV testing facility.
tell whether one is positive for HIV. What is even better
that the result is obtained in just 10-20 minutes. This saliva
New Test to Detect Drug-Resistant Virus in AIDS
based test has been standardized by a team of Indo-
Canadian scientists. The accuracy rate is 100%. The Indian Patients
scientists are from Mahatma Gandhi Institute of Medical Scientists at Duke University Medical Center have
Sciences (MAIMS) Sevagram. The test is based on oral developed a new blood test that detects whether the HIV/
mucosal transudate (OMT), a fluid that is secreted at the AIDS patient is infected with a drug-resistant virus.
base of the gums before it becomes saliva.46 Detecting resistant strain quicker will help the doctor to
Level of antibodies in oral mucosal test (OMT) is keep patients healthy longer, reduce treatment costs and
comparable to that of blood plasma, making it an excellent help to cut an infected person's risk of spreading HIV. At
sample for HIV testing. This wide-spread use of oral tests present tests available pick up drug-resistant strains when
for HIV available over the counter will not scare the they represent a significant portion of the virus circulating
patients from undergoing the test for HIV. The test requires in the blood stream. This development will help countries
only rubbing the stick against the gum twice to collect oral like India and South Africa which have a heavy HIV
fluid and hence easy to adopt in the field conditions. The burden.
test has got easy application to test the pregnant women An estimated 5.2 million people are living with HIV in
for HIV and if positive, the patient can be referred for India of which only 52,000 patients are on life saving
treatment with in 40 to 60 minutes. Globally in 2007, about antiretroviral drugs. India provides just the first-line drugs.
2.1 million children were detected positive for HIV According to India's National AIDS Control Organization
infection. 90% of them had acquired it via maternal fetal only 2.3% of the 52,000 patients have become resistant to
transmission. No available intervention to prevent mother first line drugs. A test for knowing resistance costs Rs 15,000.
to child transmission (PMTCT) is possible unless a rapid India had planned to upscale therapy to 100,000 people by
diagnostic test is available. With antiretroviral drugs the 2007. The new test is able to pick up resistant strains that
probability of transmission is 30 to 35%. make up less than 1% of the virus circulating in the patient's
In the labor room, due to inconsistent availability of blood. Existing tests pick up drug-resistant HIV strains only
blood-based rapid tests, many women fail to get tested. In if they make up 20% or more of the total virus in the patient's
2005, 4,755 infants were detected for HIV positivity due to system.
mother to child transmission. The present test detects resistance when drug treatment
The advantages of the oral test are that the test result is fails and virus spreads in the blood, making an infected
available with in minutes and can be performed by health person more contagious. The new test, 1000 times more
workers with minimal training eliminating the need for sensitive than current methods will save time which is a
specialist laboratory technicians. 450 individuals tested crucial factor for an HIV infected person.
for HIV infection at Mahatma Gandhi Institute of Medical
Sciences found 32% to be positive for HIV. The Indo- Lacunae in Treatment
Canadian team then compared the accuracy of the
(Times of India, Oct 1 2009)
Oraquick test for two samples-one obtained from oral fluid
(gums) and the other blood-based finger prick-with Some lightening facts about HIV-infection.
traditional blood tests. There was only one false positive • 33 million people lives with HIV globally.
case with the oral gum swab test having 99.7% specificity. • 4 million HIV positive people were receiving
The added advantage was that there was no discomfort antiretroviral therapy at the end of 2008.
reported with the oral test as compared to 60% of the • 5 million HIV positive still have no access to treatment.
230
• 1/3rd of HIV positive children die before the age of 1.5 11 lakhs require it. The number of children younger than
yrs., ½ by 2 years. 15 years who received ART in this period is 23,400 while
• 27 lakh people, new infections recorded in 2007; 3.7 47,000 require its 49% coverage only.
lakh were kids.
• 40% drop in the case of most commonly antiretroviral TREATMENT OF TB
drugs.
• 37% was the coverage in South East Asia region in In HIV infected patients, early diagnosis of TB and its
2008 up from 29% in 2007. treatment is critical for curing TB. Its negative effect on TB
• 21 % of pregnant women receive HIV test in 2008 world and reduction in the transmission of TB in the community
wide up from 15% in 2007. is worth while. Even in the absence of HAART, proper
• 45% HIV positive pregnant women received ART to case management of active TB can significantly prolong
prevent mother-child transmission. At the end of 2008, the lives of HIV positive persons with tuberculosis.
more than four million HIV positive adults and Standardized regimens of RNTCP for treating TB are
children were receiving the life saving antiretroviral equally effective both in HIV positive or HIV negative
drugs in low and middle income countries and it was individuals.
one million more than the figures in 2007 and a 10 fold Due to opportunistic infections, mortality in HIV-
increase in the last five years. More than 9.5 million
infected patients is higher. Worse outcome is due to delayed
out the total 10 million HIV positive have no access to
diagnosis of TB in HIV infected patients, short-course
antiretroviral therapy. 33 million are living with HIV.
therapy is more effective as compared to 12 months course
India is among the top 20 countries which recorded
the highest percentage increase in the number of people in HIV infected patients. This is due to broad range activity
receiving ART between 2007 and 2008 from 1.58 lakhs of rifampicin which is responsible for decreased death
to 2.34 lakhs (48% increase). The number of facilities rates in HIV infected patients.
with HIV testing and counselling facilities in India Direct observation of treatment of TB in HIV infected
increased from 4269 in 2007 to 4817 in 2008. patients is very important. Self administration of drugs is
According to a new report released by WHO, UNICEF, responsible for increased death rates. In HIV-infected patients
UNAIDS on 30th Sep 2009 the situation looks grim for adherence to therapy is very important. Relapse rate of TB in
India. While 80,000 pregnant women living with HIV fully compliant, rifampicin containing RNTCP regimen
positivity require treatment with ART to prevent passage lowers the death rates in HIV-infected patients. Regimen
of deadly virus to the infants only 10,673 received specific containing isonizid and ethambutol and unsupervised long
therapy. Only 16 % of pregnant women get tested during regimen is responsible for high death rates.
pregnancy. The DOTS strategy can prevent the emergence of multi-
drug resistant TB (MDR-TB). Failure to persue DOTS can
Children lead to an explosive spread of TB and rapid increase in
drug resistance among HIV-infected individual.
Just about 22% children born to HIV positive infected
Standard RNTCP regimens containing rifamcipin
mothers were receiving ART to prevent mother-to-child
transmission. Only 56% of the target sex workers in India should be used.
have been reached with HIV preventive program in the
past 12 months. Only 34% of sex workers and 32% of men Combating TB-HIV Infection
who have sex with men in India, population most at risk
The two epidemics need a joint effort from both TB as well
of infection were tested in the past one year for infection
as HIV/AIDS control programs. With prevention and
and who know the results. Around 7% of injecting drug
intervention, the HIV epidemic should be curbed since a
users of India have got infection with HIV.
According to the report more than half of the people cure is not yet available. In India since 2001, this synergetic
having HIV infection know their results. WHO Director action plan is in place.
General Margrat Chan said, "This report shows
tremendous progress in global HIV/AIDS response". But National Action Plan for Joint TB-HIV Coordination
at least 5 million people living with HIV infection have no
• Sensitization of key policy-makers to address the
access to life prolonging treatment and care. Although
importance of TB-HIV co-infection.
there is increasing emphasis on women and children in
the global HIV/AIDS response, the disease continues to • Joint Training Program for service providers involved
have its devastating impact on their health, livelihood and in RNTCP and NACP
survival. • Voluntary counselling program and confidential
The South East Asian region too has abysmal figures testing centers (VCCTC)-Designated Microscopy
of 4.43 lakhs who received ART till December 2008 while Centers (DMC) coordination
231
• Sensitization of NGOs and PPs working for NACP and induction of the enzyme inducing activity of rifampicin
RNTCP prior to commencement of antiretroviral therapy
• Infection control measures (ARVS).
• Information, education, and communication • ATT for patient on ARTS: If a patient on ARTS
• Treatment services for tuberculosis and HIV drugs develops TB then the antiretroviral therapy
• Monitoring and evaluation of coordination of both the should be modified, to be compatible with RNTCP
programs: regime.
a. Revised national tuberculosis control program. • Treatment of TB patients coinfected with HIV cannot
be envisaged without rifampicin. In these co-infected
b. National AIDS control program.
patients, TB should be treated first with one of the
c. Voluntary counseling and confidential testing
RNTCP regimens and ART should be started only after
centers.
completing the antiTB regimen. Very low CD4+ T cell
d. Designated microscopy centers. counts require concomitant ART therapy and anti-TB
The key part in the action plan is the coordination therapy in which ART regimen should be modified by
between the designated microscopy center (DMC) of the replacing nevirapine with favirenz on completion of
TB control program and the voluntary counselling anti-TB regimen.
program and confidential testing centers (VCCTCS) of the
HIV/AIDS control program for minimizing stigma due to Prevention of TB Disease among
HIV/AIDS coinfection, confidentially is maintained by Coinfected Individuals
VCCTCS. TB is treated irrespective of HIV status.
Primary onus lies with the VCCTCS to identify the potential
Anti-retroviral Therapy Rollout beneficiaries. Then comes the use of tuberculosis
preventive therapy with isoniazid and use of
Six highly prevalent states in India are Andhra Pradesh, antiretrovirals.
Karnataka, Maharashtra, Manipur, Nagaland and Tamil
Nadu. Eight states with modest HIV prevalence are Delhi, Isoniazid Preventive Therapy
Gujarat, Himachal Pradesh, Kerala, Orissa, Punjab,
Rajasthan and West Bengal. The National HIV/AIDS Isoniazid preventive therapy (IPT) for TB/HIV coinfected
control program has started the roll-out of anti-retroviral patients reduces the development of TB in HIV infected
drugs from 1st April 2004. Stavudine, + Lamivudine + individuals. TB in these individuals is usually reactivation
Nevirapine are the three drugs being given to high prevalent of endogenous infection of dormant focus.
areas. Due to interaction between nevirapin and rifampicin Preventive therapy in developing countries has been
leading to unpredictable bioavailability of both of these difficult because:
drugs, there is limitations in the program. • Difficulty in identifying high-risk patients among a
large number of infected couples
Actions of Anti-Retroviral Treatment • Difficulties in ensuring compliance
• Limited benefit as the rate of active disease in
• Life is prolonged due to reduction of viral replication seronegative individuals is comparatively low
in HIV/AIDS patients. • Correctly ruling out the individuals with active disease
• Appropriate drug combination are nucleoside reverse in extrapulmonary and smear negative cases.
transcriptase inhibitors (NsRTIs) like zidovudine (ZDV), Need of the hour in India is also strengthening control
didanosin (ddl) stavudine (d4t), Lamivudine (3TC) and program for TB/HIV co infected patients.
abacavir (ABC) can be safely coadminstered with anti TB
drugs.
TREATMENT OF CHILDREN
• Coadministration of rifampicin and protease inhibitors
(PIS) or nonnucleoside reverse transcriptase inhibitors Treatment of tuberculosis in children with HIV infection
(NNRTIs) is not recommended due to drug interactions. follows the same principles as treatment of HIV-uninfected
Rifamycin induces P450 and PIs/NNRTIs may children. However, there are several important differences
induce/inhibit the isoenzymes resulting in nonreliable between children with and without HIV infection. These
concentration of rifamycin in serum. Rifabutin is less differences include following:
potent inducer of cytochrome P450 and can be i. The potential for drug interactions, especially between
concurrently used with NNRITs and certain PIS, e.g. the rifampicin and antiretroviral agents.
indianavir, nelfinavir. Rifabutin is presently not ii. Paradoxical reactions that may be interpreted as
available in India. clinical worsening.
• If a PI or (NsRTIs) is to be started after giving rifampicin, iii. The potential for the development of acquired
that should be given atleast two weeks after the last resistance to rifampicin when treated with highly
dose of rifampicin. This time gap is necessary for intermittent therapy.
232
Antiretroviral Drugs (ARV) Starting HAART

ARV drugs belong to two main classes: When to start antiretroviral therapy in patients who have
a. Reverse transcriptase inhibitors (RTIs) tuberculosis is a balance between potential overlapping
b. Protease inhibitors. (PIs) toxicities, drug interactions and possible immune
RTIs are further divided into three groups: reconstitution versus the risk of further immune
i. Nucleoside reverse transcriptase inhibitors (NsRTIs) suppression with its associated increase in morbidity and
ii. Non-nucleoside reverse transcriptase inhibitors mortality. As per BHIVA HIV treatment guidance, the
patients who have a CD4+ counts consistently > 200 cells/
(NNRTIs)
ul while receiving antituberculosis therapy should wait
iii. Nucleotide reverse transcriptase inhibitors (NTRTIs).
until their antituberculosis therapy is completed before
The following table gives the antiretroviral drugs in starting HIV therapy. For patients with CD4 counts
each group with abbreviations and dose (Table 15.2.2). between 100 and 200 cells/ul, HIV therapy is deferred
Table 15.2.2: Antiretroviral drugs with respect to there age, weight and dose.
Name of the Drug Age Group/weight Dose in mgs.
Nucleoside reverse transcriptase inhibitors (NsRTIs) < 4 weeks 4 mg/kg BD

• Zidovudine (ZDV) 4 weeks to 13 year 180 mg/m2 BD
Maximum dose
> 13 yrs 300 mg BD
• Lamivudine (3TC) < 30 days 2 mg/kg BD
> 30 days and < 60 kg 4 mg/kg BD
Maximum dose:
> 60 kg 150 mg BD
• Didanosine (ddl dideoxyinosine) < 3 months 50 mg/m2 BD
3 months to 13 yrs 90 mg/m2BD
Maximum dose
13 years or > 60 kg 200 mg BD
• Stavudine (d 4T) < 30 kg 1 mg/kg BD
30-60 kg 30 mg BD
Maximum dose
> 60 kg 40 mg BD
• Abacavir (ABC) < 16 years or < 37.5 kg 8 mg/kg BD
(over age 3 months) Maximum dose
> 16 years or > 37.5 kg 300 mg BD
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Nevirapine (NVP) 15 to 30 days 5 mg/kg OD for
Cannot be used with rifampicin to 13 years 2 weeks, then
200 mg/m2 BD
> 30 days 120 mg/m2 OD
200 mg/m2 BD
Maximum dose
> 13 years 200 mg OD for
2 weeks, then 200 mg
• Efavirenz (EFZ) 10-15 kg 200 mg OD
(Only for children over 3 years)
15-25 kg 250-300 mg OD
25-33 kg 350 mg OD
33-40 kg 400 mg OD
Maximum dose
> 40 kg 600 mg OD
Contd....
233
Contd....
Protease Inhibitors (PIs)
• Nelfinavir (NFV) < 1 yr 40-50 mg/kg
TDS or 75 mg/kg
BD
> 1 yr to < 13yrs 60 mg/kg BD
Maximum dose
> 13 yrs 1250 mg BD
• Lopinavir / ritonavir (LPV/r) 7-15 kg 12 mg/kg
(For 6 months of age or older) LPV
3 mg/kg
Ritonavir BD
15-40 kg 10 mg/kg LPV
2-5 mg/kg
ritonavir BD
Maximum dose
> 40 kg 400 mg LPV
100 mg ritonavir
For estimating the surface area, consult a standard textbook of pediatrics.
until completion of intensive phase of antituberculosis However, substantial pharmacokinetic interactions occur
treatment. For patients with < 100 cells/ul, they should be between the rifampicin component of antituberculosis
recruited to ongoing clinical trials as far as possible. treatment and antiretroviral drugs especially, protease
inhibitors (PIs) and nonnucleoside reverse transcriptase
Short-course Chemotherapy with Antituberculosis inhibitors (NNRTIs).53
Drugs The key therapeutic principles underlying the
treatment of HIV-TB are:
It is generally accepted that short-course chemotherapy is i. Treatment of TB always takes precedence over the
adequate for the treatment of tuberculosis in persons with treatment of HIV infection.54
HIV infection.47,48 There is evidence that response to ii. In patients who are already on HAART, the same has
treatment is similar in HIV-infected and HIV seronegative to be continued with appropriate modifications both
adult patients given short-course chemotherapy.49 Similar in HAART and antituberculosis treatment.55
controlled trials in children are not reported. In observational iii. In patients who are not receiving HAART, the need
studies it has been noticed that HIV-infected children have and timing of initiation of HAART have to be decided
higher mortality and also significant side effects.50 The after assessing the short-term risk of disease
higher mortality in the intensive phase of therapy may be progression and death, based on CD4+ count and
due to tuberculosis and that later in the course due to other type of TB, on an individualised basis.56 There are no
AIDS-related infections/illnesses. separate pediatric guidelines available.
The American Thoracic Society recommends the
minimum duration of therapy for tuberculosis in HIV- Treatment of TB/HIV in Relation to Immune Status of
infected adults of 6 months which may be extended if the the Child
response is sub-optimal.51 Although there is no such data
on which to base recommendations, in children, the i. If a HIV-infected child is diagnosed to have
American Academy of Pediatrics recommends that for tuberculosis, and immunosuppression is not severe
HIV-infected children the minimum duration of therapy (CD4 counts > 15%) and there are no significant HIV-
of tuberculosis should be 9 months.52 related illnesses, the child should be treated for
tuberculosis first and the child should be monitored
carefully for any worsening of the immune status.
Treatment of HIV-TB Coinfection
ii. If a HIV-infected child is diagnosed to have
Availability of highly active antiretroviral therapy (HAART) tuberculosis, and immunosuppression is severe (CD4
has significantly improved the outcome of HIV/AIDS, in counts < 15%) or there are significant HIV-related
terms of prevention of overt illness as well as mortality. illnesses, the child should be treated concurrently with
234
antitubercular therapy and modified efavirenz based persons with a positive tuberculin skin test but with no
antiretroviral therapy. evidence of active disease, found that isoniazid alone,
iii. If a child is on antiretroviral therapy (protease isoniazid plus rifampicin, isoniazid plus rifampicin plus
inhibitor or nevirapine based regimes) and develops pyrazinamide or rifampicin plus pyrazinamide had
tuberculosis, the antiretroviral therapy is modified similar protective effects against active tuberculosis for
and efavirenz is used instead of nevirapine or people with positive skin tests.63
protease inhibitor and antitubercular therapy is Because of problems with adherence, toxicity, and
started. After completion of antitubercular therapy, increasing resistance associated with 6- to 12-month
one may switch to the initial antiretroviral therapy isoniazid regimens, an alternative short-course tuberculosis
regime. preventive regimens are needed. An international
In adults, immune reconstitution inflammatory randomized trial done in adults showed that a daily 2-
syndromes (IRIS) have been described. This paradoxical month regimen of rifampicin and pyrazinamide is similar
reaction might occur during the course of tuberculosis
in safety and efficacy to a daily 12-month regimen of
treatment when anti-retroviral therapy restores the immune
isoniazid. This shorter regimen offers practical advantages
function. Hectic fever, lymphadenopathy and worsening
to both patients and tuberculosis control programs.64
of ongoing tuberculous lesions can occur, however, patients
generally feel well and in exceptional circumstances, short- However, this protocol has been abandoned in view of high
term steroids can be used. toxicity.65
In a recently published trial in adults to determine the A study had been carried out by Zar et al to investigate
optimal time to initiate antiretroviral therapy in patients the impact of isoniazid prophylaxis on mortality and
incidence of tuberculosis in children with HIV.66 Data on
with HIV and tuberculosis coinfection who were receiving
263 children (median age 24.7 months) were available
tuberculosis therapy, the initiation of antiretroviral therapy
when the data safety monitoring board recommended
during tuberculosis therapy significantly improved
discontinuing the placebo arm; 132 (50%) were taking
survival.57 isoniazid. Median follow-up was 5.7 (interquartile range
In a study to assess the effect of anti-tubercular therapy 2.0-9.7) months. The mortality was lower in the isoniazid
on the CD4 count in HIV infected children with tuber- group than in the placebo group (11 (8%) Vs 21 (16%),
culosis, Mukherjee et al58 demonstrated that children who hazard ratio 0.46, 95% confidence interval 0.22 to 0.95,
received both ART and ATT had a rise in CD4 count P=0.015) by intention to treat analysis. The incidence of
(209.33 ± 381.62/µL), while those who received ATT alone tuberculosis was lower in the isoniazid group (5 cases,
showed a fall in CD4 count (-75.3 ± 247.69/µL, p< 0.01) at 3.8%) than in the placebo group (13 cases, 9.9%) (hazard
6 months. Of 13 children who received ATT alone, 9 showed ratio 0.28, 0.10 to 0.78, P=0.005). All cases of tuberculosis
a decline in the CD4 count in 6 months compared with 4 confirmed by culture were in children in the placebo group.
out of 12 children who received both ATT and ART The authors concluded that prophylaxis with isoniazid
(p=0.07). had an early survival benefit and reduced the incidence of
tuberculosis in children with HIV. Prophylaxis with
Treatment and Prevention of Latent Tuberculosis isoniazid in children significantly reduced mortality by
In patients with HIV, as in others, chemopro-phylaxis with about 50% and incidence of tuberculosis by about 70%.
INH appears to be highly effective in inhibiting progression The reduction in mortality occurred in all categories of
of tuberculous infection to active tuberculous disease.54-57 clinical disease, in children in all age groups, and for
Preventive therapy in HIV infected children should be given varying degree of immune suppression.
if tuberculin positivity is 5 mm or more with no signs of Thus it has been demonstrated that prophylaxis with
active tuberculous disease irrespective of BCG status and to izoniazid has an early survival benefit and reduces
those allergic children exposed to active tuberculosis if the incident of tuberculosis in children with HIV. Prophylaxis
organism is known to be sensitive to INH. To identify high may offer an effective public health intervention to reduce
risk patients, besides tuberculin status and irrespective of mortality in such children in settings with a high
BCG, treatment of latent tuberculosis is to be done after careful prevalence of tuberculosis.
exclusion of active tuberculosis.59 However, probably 6
months of a regimen containing. INH and rifampicin will PROGNOSIS
also be sufficient in developing countries. Due to high rate When tuberculosis disease develops in an HIV- infected
of relapse of tuberculosis in absence of continued INH child, the prognosis is often poor, though it depends on
prophylaxis, some authors in absence of continued INH the individual's degree of immunosuppression and
prophylaxis, have even advocated INH for life in patients response to appro-priate treatment. The adverse
with dual infection.60-62 interactions between tuberculosis and HIV have been
Interestingly in a study by the Cochrane database to discussed above. The observed mortality rate for HIV-
study drugs to prevent tuberculosis in HIV-infected infected adults with tuberculosis is approximately 4 times
235
greater than the rate of tuberculosis patients not infected treatment; also rifampicin absorption may be affected by
with HIV and the one year mortality rate for treated HIV ketoconazole resulting in possible failure of tuberculosis
related tuberculosis ranges for 20 to 35 percent with little treatment. Finally, one also has to keep in mind that
variation between cohorts from industrialized and malabsorption of ATT is also a known influence of HIV
developing countries.67-68 A case control study from South infection on M. tuberculosis infection. Therefore, monthly
Africa has shown poor response to antituberculosis follow-up is recommended to monitor for signs and
treatment in the form of poor patient survival after 6 months symptoms of adverse effects, especially liver damage, along
of treatment in children with dual infection, as compared with compliance and development of active tuberculosis.
to those without HIV infection.69 A definite cause for this
finding could not be ascertained, but residual tuberculosis BCG Vaccination
disease was considered as the most likely reason;
continuing HIV infection, other opportunistic infections, The WHO has recommended that all asymptomatic HIV-
malabsorption of ATT and multidrug-resistance were other infected children should receive BCG except those with
speculated factors. The mortality of culture proven symptoms of AIDS related complex (ARC)/AIDS. The local
tuberculosis in HIV-infected adults from a developing adverse reaction rates to BCG vaccination in
country, in one recent study was 21 percent but was still immunocompetent children have been found to be
considered low since the patients could not afford any comparable to adverse reaction rates in children with HIV
antiretroviral treatment.70 Despite few reports, treatment infection.69 Therefore, in developing countries, where
of tuberculosis in HIV-infected children is by and large prevalence of tuberculosis is high; and where extensive
effective and mortality results mainly from failure to testing for HIV serotype is neither practical nor possible,
diagnose, poor compliance, drug resistance, and advanced BCG vaccination is recommended in all infants (irrespective
HIV disease. HIV related immunosuppression with its of HIV serotype) since the risks of tuberculosis far outweigh
attendant reduction of CD4+ T cell count has been the complications for immunization. Profoundly
observed to be a critical risk factor in prognosis of childhood immunocompromised patients may develop disseminated
tuberculosis patients with HIV.71 infection after BCG vaccination; however, the true incidence
of long-term dissemination in an immunocompetent HIV-
Drug Toxicity infected child after BCG vaccination is still unknown. In a
prospective study from Africa, it was documented that the
HIV-infected individuals are more prone to develop adverse
bloodstream dissemination of M. tuberculosis and M. bovis
reactions to antituberculosis drugs and need to be carefully
BCG is uncommon in HIV-infected children vaccinated with
monitored. The risk of adverse drug reactions (ADRs)
BCG.74
increases with advanced immunosuppression and majority
World Health Organization policy on BCG vaccination
of the ADRs occur in the first two months of treatment.72 in infants and children infected with HIV is as follows:
These include skin rash, usually caused by thiacetazone
There are few case reports of local complication after
and sometimes by rifampicin and streptomycin,
BCG and disseminated BCG disease in HIV infected
gastrointestinal disturbances and drug-induced
children. In vast majority of cases BCG immunization is
hepatotoxicity among others.5 Thiacetazone can cause fatal
considered safe.
ADRs and hence is contraindicated in HIV- infected
patients.73 HIV-infected patients are more prone to develop
isoniazid-induced peripheral neuropathy and all HIV-TB HIGHLIGHTS
patients receiving isoniazid should be given pyridoxine i. Patterns of HIV infection and disease are changing.
supplementation (10-25 mg/day).68 The guidelines for HIV will soon enter the top five causes of death
children are not available but similar principles may apply. worldwide and is now believed to cause more
The use of rifampicin with protease inhibitors or deaths than malaria.
nonnucleoside reverse transcriptase inhibitor is ii. HIV infection is lowering life expectancy and
contraindicated due to untoward effects resulting from reversing gains in child survival. HIV-TB coinfection
the interaction of these drugs on the hepatic cytochrome is an important problem in most of the developing
P450 enzyme system. The nucleoside reverse transcriptase countries.
inhibitors (zidovudine and lamivudine) however, are not iii. A great deal of work has been accomplished in AIDS
metabolized by cytochrome P450 enzyme system and thus research and associated infections especially
can be used along with rifampicin. Efavirenz can be used tuberculosis. However, unlike adults, the natural
with rifampicin. The commonly used antifungal agents history of tuberculosis in HIV-infected children still
ketoconazole and fluconazole also interact with isoniazid has to be elucidated, especially in relation to the
and rifampicin (both hepatic enzyme inducers) and results epidemiological parameters prevailing in
in reduced serum levels and ineffective antifungal developing countries.
236
iv. HIV infection per se does not appear to be a 11. Lucas SB, Peacock CS, Hounnou A, et al. Disease in children
infected with HIV in Abidjan, Cote d’Ivoire. Lancet 1996;
predisposing factor for the development of MDR-
312: 335-8.
TB. Studies by Asch et al75 and Spellman et al76 have
12. Ikeogu MO, Wolf B, Mathe S. Pulmonary manifestations
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not more common among people infected with HIV. Dis Child 1997; 76: 124-8.
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985-90.
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Tuberculosis and HIV-some questions and answers Manifestations and outcome of extrapulmonary
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section10/section18/section356/section421-1624.htm. coinfection. Int J Tuberc Lung Dis 2005;9: 485-539.
Accessed on November 3, 2008. 8. Chintu C, Mwaba P. Tuberculosis in children with human
2. Tripathy S, Myo panng, Narain Jai P. Tuberculosis and immunodeficiency virus infection. Int J Tuberc Lung Dis
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extensively drug-resistant tuberculosis. Wkly Epidemiol lines for TB/HIV infection February 2005. http:
Rec 2006; 81: 408. www.bhiva.org.
16 Tuberculosis and Childhood
Malignancy
Rachna Seth
INTRODUCTION The clinical profile at presentation may be altered in

such children as is suggested by sporadic cases.9 The use
Pulmonary infections are the most common complications of broad spectrum antibiotics some with antitubercular
in immune compromised cancer patients and may progress activity are likely to contribute to this variability.
rapidly to cause respiratory failure. Mucosal destruction,
There is scarcity of data on the incidence of reactivation
humoral and cellular immune deficiency secondary to
of TB in patients undergoing anticancer chemotherapy. The
primary disease itself and chemotherapy facilitate local
available literature is also conflicting. Certain malignancies
infection and may lessen clearance of aspirated micro-
and anticancer therapy schedules are considered a risk
organisms. Immune compromised patients such as those
factor for development of TB.10 The prevalence of TB in
undergoing chemotherapy for a childhood malignancy
patients with hematological malignancies has been
theoretically are at an increased risk for developing
reported to be from 0.72 to 2.6%.11 It has the potential to be
infections from unusual pathogens like mycobacteria,
particularly high in hematological malignancies with
nocardia, aspergillus and chlamydia. This is specially true
T-cell immune deficiency caused by disease or by treatment.
for leukemia and lymphomas. There is paucity of
In patients with underlying malignancy, there are
information in this regard.
three main issues when TB is considered:
There are some reports in the literature on patients
i. Diagnostic dilemma between TB and malignancy
with malignancy who developed tuberculosis (TB) during
versus coexistence of both.
or after intensive chemotherapy.1,2 Also, the role of repeat
ii. Increased predisposition for TB due to impaired
tuberculin testing and INH prophylaxis for children who
immunity underlying malignancy and cytotoxic
have a positive tuberculin test but no evidence of
therapy.
active disease in such children needs to be ascertained. iii. Atypical presentation and or behavior of TB
Clinically evident TB can antedate malignancy, both may resulting in delayed diagnosis and possibility of poor
present simultaneously or TB may develop after treatment outcome with standard antitubercular treatment.
of the malignant disorder.3,4 The following aspects need elaboration
The overall survival of children with cancer has • Immunology of tubercular infection
increased over the past few years. This is attributed to • Prevalence of TB in leukemia
advances in diagnostics, therapeutics and improvements • Differences in clinical features
in supportive care. This has resulted in better follow-up, • Diagnosis
identification of atypical infections such as tuberculosis, their • Misdiagnosis as pulmonary metastasis
unusual presentations and outcomes. Also the increased • TB in bone marrow transplant recipients
utilization of antineoplastic agents in the treatment of acute • Reactivation of TB by chemotherapy
leukemia and other malignancies is associated with an • Response to therapy.
increase in the incidence of opportunistic infections like M.
tuberculosis that may be complicated by systemic
IMMUNOLOGY OF TUBERCULAR INFECTION
dissemination and multiorgan failure.5
In literature, there are opposing views on whether Challenges
leukemia was a risk factor for development of
tuberculosis. Miller stated that leukemia was a risk factor It is not easy to ascertain the burden of tuberculosis in
for the development of mycobacterial infections.6 children. This is primarily because of difficulties in
According to other experts, Mycobacterial infections were establishing a definite diagnosis, lack of a standard case
uncommon in children with cancer. There are sporadic definition, increased prevalence of pulmonary tuberculosis
cases of mycobacterial infections in non-HIV immune in adults and low priority of childhood tuberculosis on
compromised children.6,7 Pizzo and Poplack suggest that public health agenda. The WHO data for tuberculosis in
mycobacterial infections are uncommon in children with children are specified only for smear-positive cases for acid
cancer.8 fast bacilli (AFB). Children are not always positive for AFB
242
and with the understanding that many children may present Pathophysiology of Infections in Cancer
with unusual symptoms more true for immune
compromised children, cough not being a constant Cellular immune deficiency can lead to infections with
symptom for such children. Also the clinical presentation intracellular pathogens like cytomegalovirus (CMV),
of pulmonary TB overlaps with other opportunistic Herpes simplex, HIV, candida, aspergillus, pneumocystis
pulmonary infections. Immune compromised children may and mycobacterium. T-cells elaborate an array of
have TB and other pulmonary diseases concurrently and cytokines capable of activating macrophage bacterial
thus initially improve with broad spectrum antibiotics like activities. It is this cell mediated response to infection with
amino-glycosides and quinolones. M. tuberculosis that controls the spread of primary
infection. Factors that compromise this cell mediated
Disease and Infection immunity like HIV infection, therapy with steroids or
chemotherapeutic drugs and malignancy permit the
No standard case definition exists that may be applied infection to spread to cause disease. It is because of this
easily to childhood TB. Diagnosis of TB infection in that TB in immune compromised patients is most of the
children is based on a positive Mantoux test with no times already in advanced stages before they are
signs/symptoms of TB and a normal chest X-ray. recognized by the physician.15
Diagnosis of TB disease is based on isolation of AFB,
gastric aspirates (staining for AFB, culture), Mantoux test,
positive family history and chest X-ray. Suggestive
Prevalence of TB Infection and Disease in Children with
symptomatology of fever, persistent cough in the absence Acute Leukemia
of AFB is given significant weightage. Immune compromised patients such as those diagnosed
Children are more likely to develop TB disease after with leukemia and are on chemotherapy are at increased
infection compared to adults. The risk of developing risk of developing tuberculosis. Medina et al16 studied the
TB disease after infection in non-HIV infected children prevalence of TB infection and disease among children
is estimated at 15% in adolescents, 24% in children with acute leukemia on maintenance phase of
below 5 years and as high as 43% in children under chemotherapy. Of the 29 patients that were included, 45%
1 year.12 had TB infection, but none of the patients proved to have
active disease. There was thus a high rate of TB infection
Host Infection but a low rate of TB disease in this population of patients.
It is a known fact that only a minority of people develop The authors have emphasized the importance of tuber-
disease after becoming infected with M. tuberculosis. This culin testing as the rate of anergy was low and have
is dependent on many factors like nutrition, intercurrent recommended annual testing for patients with continuous
infection, age at infection, length of time after acquiring exposure to TB.16 The proposed explanations for the low
infection, recent versus old infection and host resistance, occurrence of TB disease in children with leukemia are
i.e. effective functioning of the cell-mediated and humoral that the chemotherapeutic drugs given to these patients
immunity. This is further exemplified by the epidemic of are also effective against mycobacterium . The widespread
HIV which reduces cell mediated immunity. Studies have use of antibiotics with antitubercular action could also be
shown a variability of clinical presentation in HIV positive responsible for this observation.
children with tuberculosis varying with the level of cell - Indian data is also not very conclusive. Choudhary et
mediated immune function.13 al.17 do not suggest higher prevalence of tuberculosis in
immune compromised children.17
Immunopathology of TB In a study by Mishra et al.18 130 consecutive cases of
Mycobacterial infection is asymptomatic in majority of adult acute leukemia over a 2 year period were followed
healthy persons as the infection is contained by the host prospectively for possible development of TB. They
immune system. A positive tuberculin test simply identified 9 cases (6.9%) with active tuberculosis. Eight
indicates presence of infection. Whether this will cause patients with TB had acute myeloid leukemia. The
disease depends on a large number of factors as incidence of active TB disease is less despite the fact that
discussed. In subjects who are immune suppressed for in patients with acute lymphocytic leukemia (ALL), there
any reason, the proportion who develop disease is much is wider use of steroids, the duration of therapy is longer
greater.14 The state of immune system plays a significant leading to prolonged immune suppression and use of
role in the development of disease. It is the cell mediated radiotherapy in ALL protocols. Most of these patients were
immunity that is more important in dealing with managed with standard antitubercular therapy. Treatment
intracellular organisms like M. tuberculosis. of TB did not delay the course of chemotherapy.18
243
Chapter 16 Tuberculosis and Childhood Malignancy
CLINICAL FEATURES at Korea over a period of 18 years. The median age of

these patients was 14 (2 to 18) years. The underlying
Children who undergo treatment for malignancies are at diseases were acute lymphoblatsic leukemia (ALL) in
high risk for infection with both typical and opportunistic seven, acute undifferentiated leukemia (two), acute non-
pathogens. Fever in these children prompts extensive lymphoblastic leukemia (one) , mixed lineage leukemia
evaluation and empiric treatment with broad spectrum (one) and Burkitt lymphoma (one). The disease categories
antimicrobials. Children are not always positive for AFB were seven pulmonary tuberculosis, two acute-
and many children may present with unusual symptoms tuberculous pleurisy, one miliary tuberculosis, one bone
this being more true for immune compromised children, and endobronchial TB and one tuberculous meningitis.
cough not being a constant symptom for such children. The famiily history of TB was positive in one case. The
Also, the clinical presentation of pulmonary TB overlaps suggestions towards the disease were persistent fever
with other opportunistic pulmonary infections. despite broad spectrum antibiotics, and/or antifungal
There have been a few reports about the differences agent therapy in 9 children.
in clinical findings between immune compromised Two children had chronic cough and one child had
patients and nonimmune compromised patients with chest pain. Diagnosis was based on AFB positivity in
pulmonary tuberculosis. Retrospective data of 840 adult culture in 4, AFB smear positivity in 3, polymerase chain
patients (312 immune compromised and 528 non- reaction (PCR) was positive in 2; one child was diagnosed
immunecompromised) with pulmonary tuberculosis by pleural biopsy, transbronchial biopsy and chest X-
(culture positive for M. tuberculosis) over a period of 10 ray and CSF examination each.21
years was reviewed by Yoshihiro et al. 19 The main At times, an empirical antituberculous therapy should
differences as observed in the immune compromised be employed to prevent further clinical deteriorations
patients were: and a possible lethal outcome that may be associated
i. An increase in number of patients with respiratory with delayed diagnosis and late institution of anti TB
symptoms during the period of follow-up of drugs.22
underlying diseases.
ii. An increase in the number of patients in an RISK FACTORS
undernutritional state and with a negative response i. Certain malignancies and anticancer therapy
for the tuberculin skin test. schedule are considered as high risk for develop-
iii. An increase in the number of microbio-logically ment of TB.10
smear-positive sputum specimens. ii. Impairment of host defenses.
iv. An increase in the number of patients with atypical iii. Poor nutrition and debility.
radiological findings such as a few cavities or
calcification, bilateral and expansive consolidation, DIAGNOSIS
miliary shadows and mediastinal and/or hilar
lymphadenopathy. The clinical diagnosis of tuberculosis in immune
v. An increase in the patients with a misdiagnosis as competent children is straight forward and consists of a
pneumonia at admission. suggestive history, often an exposure to a case, a positive
vi. An increase in the mortality rate. tuberculin test, and an abnormal chest radiograph.
Therefore, among the immune compromised patients In contrast, clinical symptoms are much less specific
with pulmonary tuberculosis, there were many patients among children who are malnourished, immune
with atypical radiological findings and with smear- compromised or suffering from HIV. Often these children
positive findings for acid fast bacilli examination. present with prolonged fever.
Sputum examination for acid fast bacilli must be done in The gold standard for establishing the diagnosis of
patients with fever and continuous cough and tuberculosis is sputum smear microscopy for acid fast
antituberculosis therapy started as early as possible. bacilli which may be confirmed by mycobacterial culture.
Tuberculosis (TB) should also be considered as a As many as 95% of children younger than 12 years of
possible cause of hepatosplenic abscesses during the age have negative sputum smears,23 this diagnostic tool
prolonged periods of neutropenia following the courses is not freely available. Culture of gastric aspirate/
of cytotoxic chemotherapy given to such patients in areas bronchoalveolar lavage is positive in less than 50% of
that are endemic for TB.20 cases.24,25
Lim et al.21 retrospectively evaluated the importance Induced sputum may be used for demonstration of
of prevention and early diagnosis of tuberculosis in cancer AFB in smear and culture. Sputum induction can be
patients. Twelve patients were diagnosed as having performed with hypertonic saline delivered by ultrasonic
tuberculosis during cancer chemotherapy in a hospital nebulization.
244
Radiological Experience at All India Institute of Medical Sciences New

Evidence of pulmonary tuberculosis usually includes
Delhi India (AIIMS)
lymphadenopathy (hilar/mediastinal) and lung A Case Study
parenchymal changes. The most common parenchymal
An 11-year-old female child treated for Hodgkin
changes are segmental hyperinflation, atelectasis,
lymphoma at the Pediatric Oncology Clinic at AIIMS;
alveolar consolidation ,pleural effusion and rarely a focal
after completion of chemotherapy for continued
mass.26 Cavitation is rare in young children. Delacourt et
remission, it posed a problem. This child developed fever,
al27 found that 60% of children with tuberculous infection
cough with expectoration and weight loss. There was no
had normal chest radiographs. In such cases, contrast
history of contact with tuberculosis. Chest X-ray had
enhanced CT scan of chest may, however, be a more
shown a nodular opacity which was confirmed on CT
useful modality for diagnosis of tuberculosis. CT scan
chest. A radiological diagnosis of recurrence of disease
findings suggestive of tuberculosis include enlarged
with metastasis was considered. However, a clinical
lymph nodes which frequently are necrotic, parenchymal
possibility of tuberculosis was also entertained which was
lesion, early cavitation pleural effusion and bronchiectasis
confirmed by sputum positivity for acid fast bacilli. The
may be seen.26,27
child was treated with antituberculosis drugs and
responded favorably.
Role of Bronchoscopy and bronchoalveolar Lavage (BAL)
Pulmonary metastasis might be a close differential
Fluid Examination but one should be aware of other medical conditions
The role for BAL in diagnosis of tuberculosis is still for a pulmonary nodule that may coexist. It is necessary
controversial and not many centers have facilities for this to consider the possibility of tuberculosis when a lung
procedure. The culture from BAL fluid for M. tuberculosis mass is newly detected during treatment or follow-up
is usually lower than for three properly obtained gastric in patients with childhood cancer in an endemic
aspirates.25 However, BAL may be useful in the diagnosis area.
of endobronchial tuberculosis and excluding/isolating
other causative agents such as opportunistic infections PULMONARY TUBERCULOSIS AND BONE MARROW
particularly in immunocompromised children. The major TRANSPLANT (BMT) RECIPIENTS
limitation of the bronchoscopy for BAL fluid examination Bone marrow transplantation (BMT) is associated with
besides availability is the presence of thrombocytopenia extreme iatrogenic bone marrow suppression during
in many children who are on chemotherapy which which the recipient is highly susceptible to opportunistic
precludes its usage. infections. Little is known about the profile of infection
Pleural biopsy or lung biopsy (transbronchial or with M. tuberculosis in bone marrow transplant recipients.
otherwise) may also be used occasionally. Serological tests Series that have reviewed infections in bone marrow
are of not much use in diagnosis. transplant recipients have reported incidences of M.
tuberculosis to the tune of less than 0.1 to 2.2%.28-32
Misdiagnosis as Pulmonary Metastasis Following this, Mary et al. 33 conducted a prospective
evaluation of 183 consecutive BMT recipients and 10
The differential diagnosis for a pulmonary nodule in
patients were found to develop pulmonary tuberculosis
cancer patients undergoing chemotherapy should include
post BMT, yielding an incidence of 5.5%. The median age
pulmonary tuberculosis, particularly in developing
of the 10 patients who developed tuberculosis was 29
countries like India. years. The median time for onset of symptoms was 150
In a retrospective analysis of 422 cancer children less days following the transplant. The presenting complaints
than 18 years undergoing cancer therapy, the medical primarily were fever, cough and pulmonary infiltrates. The
records were reviewed to ascertain the incidence and sputum was positive for acid fast bacilli in 3 of these
clinical features of pulmonary tuberculosis that were patients and culture for M. tuberculosis was positive in 8 of
misdiagnosed as pulmonary metastasis radiologically these patients. Antitubercular treatment was given for a
during their period of follow-up. Episodes of lung longer duration (10 months in place of 6 months) and was
metastasis of primary tumor and tuberculosis were found to be effective. The absence of relapse after
reviewed. There were five cases of tuberculosis confirmed termination of treatment suggested that secondary
after surgery which were initially regarded as metastasis. prophylaxis would not be necessary as long as the immune
Two patients had respiratory symptoms such as cough function has been restored. The risk factors identified in
and sputum but other three patients had no respiratory this population, cohort for the development of tuberculosis
symptoms. One child had history of contact with a included allergenic BMT, total body irradiation and chronic
tuberculosis patient. Mantoux test was positive in 2 cases.9 graft versus host disease.33
245
It is to be noted that the immune suppressed state diffuse pneumonic consolidation with right paratracheal,
would magnify infectious disease that are endemic in the precarinal mass image consisting of conglomerated
locality explaining the high incidence of pulmonary lymph nodes. Bronchoalveolar lavage was done. The
tuberculosis as 5.5% in this setting at Hong Kong. sample was positive for M. tuberculosis on culture. The
Similarly a BMT center in Spain where TB is also endemic, child responded to antituberculosis therapy of 9 months
an incidence as high as 2.2% (higher than that reported [2 months of intensive phase (3 drug) and 7 months of
in the US and UK) has been observed. It is important to consolidation phase (2 drug)]. Follow-up CT scan
bear a high index of suspicion of M. tuberculosis as a revealed a normal scan after completion of therapy except
pathogen in marrow transplant recipients. thickening of right major fissure.
In the series of 400 childhood cancer survivors at the
SHORT-COURSE CHEMOTHERAPY AND REACTIVATION Pediatric Cancer Survivor Clinic at AIIMS (acute
OF TB leukemia, Hodgkin lymphoma, nonHodgkin lymphoma,
retinoblastoma, LCH, etc.) there has been history of
There is scarcity of data on the incidence of reactivation tuberculosis in one child of acute lymphoblastic leukemia
of TB in patients undergoing anticancer chemotherapy. while on chemotherapy. This child is under follow-up
The available literature is also conflicting. Certain for one year post chemotherapy and has not developed
malignancies and anticancer therapy schedules are reactivation of TB.
considered as risk factor for development of TB. 10 The proposed mechanism for absence of reactivation
Impairment of host defenses, poor nutrition, and debility are that immune suppression induced by cytotoxic
were proposed as attributing factors for the high chemotherapy is short lasting and cyclical not significant
incidence of TB in this group in few studies. The enough to cause the reactivation of tuberculosis (TB).
prevalence of TB in patients with hematological Suppression of T-cell immunity may not be significant
malignancies has been reported to be from 0.72 to 2.6%.11 with the above used chemotherapy.
The prevalence is particularly high in hematological
malignancies with T-cell immune deficiency caused by CLINICAL CHARACTERISTICS AND TREATMENT RESPONSES
disease or by treatment.
OF TUBERCULOSIS IN PATIENTS WITH MALIGNANCY
These observations have been negated in a study
which prospectively followed 174 patients with newly
RECEIVING ANTICANCER THERAPY
diagnosed lymphoproliferative disorders for more than Although, the risk of tuberculosis increases in patients
two years. None of the patients developed reactivation with malignant disease, the clinical response of
of TB despite lack of antitubercular prophylaxis.34 tuberculosis to antituberculosis treatment in patients
In a retrospective analysis of 141 adult treated receiving anticancer therapy has not been well known
patients with high grade nonHodgkin lymphoma 8 except in a few case series36-39 involving a small number
patients had a past history of tuberculosis. These 8 of patients with inconsistent results.
patients were followed for a median period of 5 years The efficacy of anti-TB chemotherapy in patients with
after receiving cyclical high dose chemotherapy. None hematological malignancies is well documented.10,40
of these developed reactivation of tuberculosis. However, drug-resistance, noncompliance with
The proposed mechanisms suggested that medications and the presence of advanced and miliary
cytotoxic chemotherapy induces short-term and cyclical forms of TB remain real challenges. Kim et al.40 studied
immunesuppression not enough to cause the reactivation the clinical characteristics and treatment responses of
of tuberculosis, and the suppression of T-cell immunity tuberculosis developing in adult patients receiving
may not be significant with above used chemotherapy anticancer therapy. With regard to radiographic and
which is a major defense mechanism against M. clinical responses to antitubercular treatment TB
tuberculosis. developing during anticancer chemotherapy is not
Gulen et al. 35 have reported a seven-year-old girl clinically different from TB developing in ordinary
diagnosed with T-cell nonHodgkin lymphoma who was situations. Findings in this study suggest that anticancer
admitted after completion of chemotherapy with the chemotherapy is not an obstacle to treating TB.
complaints of fever, cough and respiratory distress. She Mishra et al.18 studied 130 adult consecutive cases of
was found to be hypoxemic. Chest X-ray showed acute leukemia over a period of 2 years and identified 9
pneumonic infiltration in middle and lower lobe of right cases (6.9%) with active TB. Eight patients with TB had
lung. The child did not respond to broad spectrum acute myeloid leukemia (AML). Patients with AML were
antimicrobials. Tuberculin test was negative; sputum and more prone to develop TB as compared to acute
gastric aspirates were negative for AFB. In view of no lymphoblastic leukemia despite the use of steroids and
response and persistence of radiologic infiltrates, the child radiotherapy in ALL protocols. This may partly be
underwent a CT chest which showed the presence of because in adults the commoner hematological
246
malignancy is AML and not ALL. All but one of the 4. Kindler T, Schindel C, Brass U, et al. Fatal sepsis due to
diseased children were successfully managed using Mycobacterium tuberculosis after allogenic bone marropw
current antituberculosis therapy. TB neither causes delay transplantation. Bone Marrow Transplant 2001;27:217-8.
in chemotherapy nor flare-up during subsequent 5. Misonou J, Kikuchi Y, Aizawa M, et al. An autopsy case
chemotherapy. of severe miliary tuberculosis in a patient with acute
Gulen et al. 35 have reported a seven-year-old girl lymphoblastic leukemia. Gan No Rinsho 1987;33:703-13.
diagnosed with T-cell nonHodgkin lymphoma at the age 6. Menon BS, Maziah WM, Aiyer S, et al. Disseminated
tuberculosis in acute leukemia. Pediatrics International
of 6 years complaining of fever, persistent cough and
2001;43:161-3.
respiratory distress after completion of chemotherapy. Chest
7. Kornreich L, Goshen Y, Horev G, et al. Mycobacterial
X-ray showed a pneumonic infiltration in middle and lower
respiratory infection in leukemic children. European J
lobe of right lung. The child did not respond to broad Radiol 1995;21:44-4.
spectrum antibiotics. Tuberculin test and gastric aspirates 8. Pizzo P, Poplack D. Infectious complications in pediatric
for AFB were negative. CT chest showed diffuse pneumonic cancer. In: Principles and Practice of Pediatric Oncology
consolidation with right paratracheal precarinal mass image 5th edns Pizzo P, Poplack D (Eds): Lippincott Williams
consisting of conglomerated lymph nodes. Bronchoscopy and Wilkins, 2002; 1269-329.
and bronchoalveolar lavage were done which revealed M. 9. Lee HJ, Kim DW, Lee KM, et al. Pulmonary tuberculosis
tuberculosis. The child responded to 9 months of misdiagnosed as lung metastasis in childhood cancer
antituberculosis therapy. patients. Korean J Pediatr 2009;52:904-9.
10. Kaplan MH, Armstrong D, Rosen P. Tuberculosis
complicating neoplastic disease: A review of 201 cases.
HIGHLIGHTS
Cancer 1974;33:850-8.
• Pulmonary infections frequently complicate the 11. Karachunski MA, Pivnik AV, Luldasheva NE.
course of cancer treatment in children. These are Tuberculosis in patients with hemosiderosis. Probl
empirically treated with broad spectrum antibiotics Tuberk 2002;12:24-7.
and antifungals in most of oncology centers in 12. Walls T, Shingadia D. The epidemiology of tuberculosis
developing countries in Europe. Arch Dis Child 2007;92: 726-9.
13. Jones BE, Ryu R, Yang Z, et al. Chest radiographic studies
• Optimal treatment of lung infections in cancer
in patients with tuberculosis with recent or remote
patients requires identification of the infectious
infection. AM J Resp Crit Care Med 1997;156:1270-3.
agent. A high index of suspicion should be present 14. Selwyn PA, Sikell BM, Alcabes P, et al. High risk of active
for such uncommon infections. Infections such as TB in HIV infected drug users with cutaneous anergy.
tuberculosis should be included in the diagnostic JAMA 1992;268:504-9.
workup of such immune compromised children, 15. Furst D, et al. Preliminary guidelines for diagnosing and
particularly with pulmonary symptoms that are treating tuberculosis in patients with rheumatoid
unusually prolonged, are not responsive to conven- arthritis in immunesuppressive trials or being treated
tional therapy or in situations where fever persists with biological agents. Ann Rheum Dis 2002; 61(Suple
for prolonged periods without obvious focus II)ii62-ii63.
• Children cannot produce sputum easily, gastric 16. Medina MYL, Lazarte CM. The prevalence of TB infection
and disease among children with acute leukemia. PIDSP
aspirates/bronchoalveolar lavage fluid induced
Journal 2009;10(1).
sputum should be obtained at early stages for
17. Pulmonary tuberculosis in children with acute lymphatic
microbial identification leukemia. Indian J of Pediatr 1981.
• The course of antituberculosis therapy may also be 18. Mishra P, Kumar R, Mahapatra M, et al. Tuberculosis in
prolonged in cases which are diagnosed with acute leukemia: A clinico-hematological profile.
tubercular disease. Hematology 2006;11:335-40.
19. Yoshihiro Y, Mouri K, Yagi S, et al. J Infect Chemother
REFERENCES 2007;13:405-10.
20. Lee DG, Chol JH, Kim YJ, et al. Hepatosplenic tuberculosis
1. Waecker NJ, Stefanova R, Cave MD, et al. Nosocomial mimicking disseminated candidiasis in patients with acute
transmission of Mycobacterium bovis bacilli Calmette- leukemia. Int J Hemato 2001;73:119-21
Guérin to children receiving cancer therapy and their 21. Lim JH, Lee YJ, Choi EJ, et al. Tuberculosis in pediatric
health care providers. Clin Infect Dis 2000;30:338-62. cancer patients during chemotherapy. Korean J Pediatr
2. Aljurf M, Gyger M, Alrajhi A, et al. Mycobacterium Hematol-Oncol 2000;2:278-86.
tuberculosis infection in allogenic bone marrow 22. Luldashiva NE, Karachunskii MA, Pivnik AV. Various
transplantation patients. Bone Marrow Transplant. approaches to tuberculosis diagnosis in patients with
1999;24:551-4. hemoblastosis. TerArkh 2002; 74:35-8.
3. Libshitz HL, Pannu HK, Elting LS, et al. Tuberculosis in 23. Jereb JA, Kelly GD, Porterfield DS: The epidemiology of
cancer patients: An update. J Thoracic imaging 1997;12: tuberculosis in children. Semin Pediatr Infect Dis
41-6. 1993;4:220-31.
247
24. Pomputius WF 3rd, Rost J, Dennehy PH, et al. 33. Mary S M IP, Yuen K Y, Patrick C V Woo, et al. Risk factors
Standardization of gastric aspirate technique improves for pulmonary tuberculosis in bone marrow transplant
yield in the diagnosis of tuberculosis in children. Pediatr recipients. Am J Respir Crit Care Med 1998;158:1173-7.
Infect Dis J 1997;16:222-6. 34. Harakati SE. Tuberculosis in patients with
25. Abadco D, Steiner P. Gastric aspirate is better than lymphoproliferative disorders: Is it as common as
bronchoalveolar lavage for isolation of Mycobacterium historically stated? Kuwait Med J 2001;33:325-28.
tuberculosis in childhood tuberculosis. Pediatr Infect Dis 35. Gulen HG, Erbay A, Gulen F, et al. Resistant pneumonia
J 1993;11:735-8. in a child with non Hodgkin lymphoma In remission: A
26. Shingadia D, Novelli V. Diagnosis and treatment of case of M. tuberculosis. The Internet journal of Hematology
tuberculosis in children. Lancet Infect Dis 2003;3:624-32. 2005;2(1).
27. Delacourt C, Mani TM, Bonnerot V, et al. Computed 36. Tubura E. Pulmonary tuberculosis in the compromised
tomography with normal chest radiograph in tuberculous host: Report of the 30th B series of controlled trials of
infection. Arch Dis Child 1993;69:430-2. chemotherapy: Cooperative Study unit of chemotherapy
28. Navari RM, Sullivan KM, Springmeyer SC, et al. of tuberculosis of the national sanatoria in Japan. Kekkaku
Mycobacterial infections in marrow transplant patients. 1991:66:95-9.
Transplantation 1983;36:509-13. 37. Liu SF, Liu JW, Lin MC. Characteristics of patients
29. Kurrock R, Zander A, Vellekoop L, et al. Mycobacterial suffering from tuberculous pleuritis with pleural effusion
infections after allogenic bone marrow transplantation. Am culture positive and negative for Mycobacterium
J Med 1984;77:35-40. tuberculosis and risk factors for fatality. Int J Tuberc Lung
30. Hoyle C, Goddman JM. On behalf of 18 UK bone marrow Dis 2005; 9:111-5.
transplant teams. Life threatening infections occurring 38. Tamura A, Hebisawa A, Tanaka G, et al. Active
more than 3 months after BMT. Bone Marrow Transplant pulmonary tuberculosis in patients with lung cancer.
1994;14:247-52. Kekkaku 1999;74:797-802.
31. Roy V, Weisdorf D. Mycobacterial infections following 39. Komatsu H, Nagai H, Satou K, et al. Association of active
bone marrow transplant (BMT): A retrospective review pulmonary tuberculosis and malignant diseases: A
of 20 year-experience. Blood 1995;86(Suppl 1):861A. clinical study. Kekkaku 1995; 70: 281-4.
32. Martino R, Martinez C, Brunet S, et al. Tuberculosis in 40. Kim DK, Lee SW, Ko DS, et al. Clinical characteristics
bone marrow transplant recipients: report of two cases and treatment responses of tuberculosis in patients with
and review of the literature. Bone Marrow Transplant malignancy receiving anti-cancer chemotherapy. Chest
1996;18:809-12. 2005;128:2218-22.
17 Unusual Manifestations of
Tuberculosis
Vimlesh Seth
TUBERCULOSIS OF EYE AND CONJUNCTIVA and the scleral vessels are not affected. In the early stage,
the phlyctenule has a round surface but in a day or two
Tuberculous lesion of the eye are usually thought to be this is eroded, and becomes irregular with the
uncommon but its knowledge is of great importance in disappearance of the nodule. With the fading of one crop,
the diagnosis and understanding of the natural history of the others erupt so the attack seems continuous. With the
primary infection. ulceration of the cornea, the left over opacities can affect
vision. There is free lacrimation but if there is purulent
Primary Infection of Conjunctiva discharge it indicates secondary infection. The
Infection of the conjunctival sac can occur without preauricular nodes are not enlarged.
producing any local symptoms. First complain may be
softening, swelling of the preauricular lymph node. At Incidence
times tonsillar glands may be enlarged. On evertion, upper
Like erythema nodosum, the common age affected is 5 to 15
and lower eyelids are swollen and may show hypertrophic
years but is more frequent in children less than five years.
granulation tissue. Biopsy is recommended but often a
therapeutic test proves diagnosis by showing instant Malnutrition is a common association. Conjunctivitis due
improvement. to other infections can follow phlycetenular conjunctivitis.
Differential Diagnosis Differential Diagnosis

Preauricular node can be affected due to any infective lesion Gray spots are characteristic and hence diagnosis from
of the eyelid or conjunctiva. In tuberculosis there is no other infections is not difficult. If there is sharp foreign
pain and it appears slowly. Viral infection, foreign body, body embedded in the conjunctiva or sclera, it can pose
trachoma can be the other causes of conjunctival infection. difficulty in diagnosis. Herpes virus can be the other cause
of corneal ulceration. Clinical diagnosis depends upon
Phlyctenular Conjunctivitis seeing a fresh phlyctenule, and the presence of other
symptoms and signs suggestive of tuberculosis.
It is a painful, recurrent form of conjunctivitis due to the
hypersensitivity phenomenon in the early stage of the Treatment
disease.1 Unlike erythema nodosum, it can be caused by
antigens other than those arising from M. tuberculosis, In the presence of primary infection—systemic therapy is
e.g. other acid-fast organisms such as BCG 2 or by required. If the lesion is localized to the eyes, local therapy
B. hemolytic streptococcal infection. It marks the onset of with steroids is sufficient. In the presence of corneal
primary infection. Phlyctenular conjunctivitis can occur ulceration due to causes other than tuberculosis, local
at any time in a tuberculin sensitive person, and is often therapy with steroids is contraindicated.
recurrent.
Choroid Tubercles
Clinical Picture
The presence of choroid tubercles establishes the
Each attack begins with irritation, lacrimation and diagnosis of tuberculosis even when there is no
soreness in one or both eyes simultaneously or with a radiological evidence of TB. If the choroid tubercles are
short interval in between. With the infection of cornea, numerous and the child is looking ill, it is an indication of
pain and photophobia are intense. On examination it can disseminated disease such as miliary tuberculosis or
be recognized as a small gray spot, single or grouped, at tubercular meningitis. It is uncommon in recent primary
the limbus (junction of cornea and sclera) in a number of infection but is present in almost 60 to 70 % of children
places around the circumference. There is a small leash of with radiological evidence of miliary tuberculosis. It is
infected conjunctival vessels. Iris and pupils are normal less in tubercular meningitis.
249
Chapter 17 Unusual Manifestations of Tuberculosis
Description and Course of Healing of Tubercle Cardiac Complications

Usually more than one tubercle is present and at times Pericardial Abscess
they are numerous. They are located along the line of a
branch of the central artery. Most of the tubercles are Pericardial abscess due to tuberculosis is a rare
present within two disk diameters of the center of the disk. manifestation and is a complication of constrictive
Sometimes the vessel seems to run through the faintly pericarditis.5 The diagnosis is suspected when a patient
yellow, rounded body within an indefinite edge which is shows symptoms and signs of constrictive pericarditis
the appearance of a recent tubercle. It is usually half the clinically. Echocardiography shows a pericardial mass.
radius of the disk. On chemotherapy, the tubercles recede Computed tomography (CT) and magnetic resonance
quickly. Even without chemotherapy, the smallest may imaging (MRI) T2-weighted are required to give the
diagnostic clue of pericardial abscess. Thirteen patients
never progress beyond the first stage of yellow center,
out of 120 over a period of 9 years (1-15 years age group)
indefinite edge and ultimate recession does not leave any
were diagnosed by CT and MRI.
trace.
In large tubercles, the edge slowly becomes more
HEMATOLOGICAL COMPLICATIONS
clearly defined, central area fades imperceptibly from
yellow to white with the appearance of spots of black The hematological complication such as severe
pigment at the periphery. This results in a white scar with autoimmune hemolytic anemia (AIHA) as a complication
a deeply pigmented black edge and is sharply defined of disseminated childhood tuberculosis has been reported
from the pink of the fundus. It takes three months to reach by Bakshi et al.6 in an 8-year-old girl who presented with
this stage. If followed, the white patches progressively get severe autoimmune hemolytic anemia in association with
completely filled with black pigment. This is the natural mediastinal widening on chest X-ray. CT scan of chest
course. On systemic therapy, the lesions are yellow areas showed large paratracheal, pretracheal, precarinal,
with illdefined edges. These disappear without a trace retrocarinal and bilateral hilar lymphadenopathy.
with the use of local steroids given along with systemic Mantoux test was nonreactive. FNAC of the
steroids in miliary and meningeal tuberculosis. supraclavicular lymph node was unsuccessful for
diagnosis by mediastinoscopy. Biopsy of mediastinal
Panophthalmitis lymph nodes was performed. This revealed large areas of
It is a rare manifestation and has been reported as a case confluent necrotizing granulomatous inflammation which
confirmed the diagnosis of tuberculosis.
report3 in a 12-year-old female child in a tertiary care center.
The child had painless progressive loss of vision in the
right eye for two months duration. Examination revealed
Treatment
diffuse corneal haze with deep vascularization, iris In addition to multiple transfusions, the patient was started
nodules and scleral necrosis. Enucleation of the eye had on 2HRZE in the intensive phase, with which the patient’s
to be done and histopathology revealed necrotizing hemoglobin normalized with no evidence of hemolysis on
granulomatous inflammation. Multiple epithelioid cell peripheral blood smear. There was regression of hepato-
granulomas and cells along with large area of caseous splenomegaly to normal. Patient became afebrile with
necrosis were found. Chest X-ray revealed right hilar regression in size of the left supraclavicular lymph node.
lymphadenopathy with right lower zone infiltration with The child had a relapse of hemolytic anemia after 2 months
a small pleural effusion. It was diagnosed as disseminated still being on antituberculosis therapy. For this, along with
tuberculosis and child was treated with four drugs in the antitubercular drugs, she was put on steroids in the dose of
intensive phase (HRZE), and two drugs (HR) in the 2 mg/kg to start with. She still had poor response and hence
maintenance phase, i.e. 2HRZE, 4HR. the steroid dose was increased to 4 mg/kg/day.
Review of literature by Chawla et al.3 revealed that in In the continuation phase the child in addition to
some cases local steroids had to be used along with their antituberculosis therapy (4HR) along with steroids in the
systemic administration. If the cornea is involved, the dose of 2 mg/kg/day, tapered to 1 mg/kg/day followed
ophthalmologist’s opinion must be sought. Absence of by 1 mg/kg on alternate days till the last month when
pain, presence of nodule on or within the eyeball, only 0.5 mg/kg/day of steroids were given. She is doing
spontaneous perforation are clinical features and high fine, the regimen followed was 2HRZE 4HR with tapering
index of suspicion is necessary for early diagnosis to doses of steroids. In the literature only 7 cases of tuber-
prevent the development of panophthalmitis. Ocular culosis associated with AIHA have been reported.7-13
tuberculosis has been described in a five months old Table 17.1 shows the association of AIHA with different
infant.4 types of tuberculosis.
250
Table 17.1: Characteristics of TB-related autoimmune hemolytic anemia (AIHA) cases

reported in English literature7-13
Author/year Country Age/sex Site Hb Retic (%) Treatment

(g/dL)
Cameron SJ England 58 M Pulmonary 4.4 15 Blood transfusion,
19747 ATT, Prednisolone
Semchyshyn et al Canada 39 F Genitourinary 7.5 8.8 ATT, Prednisolone
19758
Murray HW USA 49 M Pulmonary 10.3 6 ATT
19789
Kim SW et al Korea 52 M Cutaneous 11.2 1.2 ATT, Prednisolone,
199510 Azathioprine
Siribaddana et al Sri Lanka 37 M Lymph Nodal 6.6 10 ATT
199711
Blanche P et al France 42 M Miliary 3.7 — ATT, Prednisolone,
200012 Splenectomy
Kuo PH et al Taiwan 26 M Disseminated 5 21 ATT
200113
Ref. 6 Indian J Pediatric 2004; 71: 549-51.
ESOPHAGEAL TUBERCULOSIS from lungs, mediastinal lymph nodes or thoracic spine,

14 by retrograde lymphatic or hematogenous spread.16 There
Sathiyascbararn and Shivbalan have described a case are very few indications of diagnosing pulmonary
of esophageal tuberculosis in a 14-year- old boy. He tuberculosis in children by CT scan. However, if a child
presented with vomiting, cough, low grade fever and has difficulty in swallowing, vomiting without pain in
anorexia for two months. Vomiting was nonbilious, not the abdomen, Chest CT is a must which will give a clue to
associated with pain in the abdomen but occurred while diagnosis of tuberculosis of the chest as an etiology of
eating or soon after taking food. Family history of TB was gastrointestinal symptoms.
positive. The child did not have significant clinical The usual signs of esophegeal TB are dysphagia,
findings of pulmonary TB except few crepitations at the cough, pain in the chest in addition to weight loss and
left base. fever. The other complications which can occur are
bleeding, perforation or fistula formation.17
Investigations There are three types seen on gross examination:
Mantoux test was strongly positive. Upper GI endoscopy i. Hypertrophic
showed an irregular ulcer with raised edges in the mid ii. Granular
esophagus. Histopathology of the lesion showed caseating iii. Ulcerative
granuloma suggestive of tuberculosis, no AFB were seen. The patient described above had the secondary
Chest CT showed findings of consolidation, pleural ulcerative form of tuberculosis of esophagus. He being
thickening with mediastinal and hilar adenopathy. Hence, immune competent, responded to chemotherapy with
a diagnosis of pulmonary tuberculosis with secondary antituberculosis drugs.
involvement of esophagus was made. He was put on 2
HRZE + 7HR. Repeat endoscopy was normal, child TUBERCULOUS OTITIS MEDIA AND MASTOIDITIS
became asymptomatic.
It presents as a chronic painless, suppurative disease
Esophageal tuberculosis is the least common among
which may be associated with hearing loss, lower motor
all tuberculous lesions of the gastrointestinal tract.15 The
neuron facial palsy and cervical lymphadenopathy.
squamous epithelium, peristalsis, mucus and saliva
Tuberculosis of the lung is often associated. It is relatively
coating the esophagus have a protective effect. It is of two
rare and is seen most commonly during the first year of
types:
i. Primary life. On examination, beyond the tympanic membrane,
ii. Secondary granulomatous middle ear mucosa is seen. If perforation
The primary disease of the esophagus is uncommon of the membrane occurs, it protrudes through the tympanic
and the secondary infection of the esophagus can occur membrane. Although uncommon, the possibility of
due to swallowed infected sputum, direct involvement tuberculosis of the middle ear should be considered in
251
any case who is not responding to conventional therapy. Plain abdominal radiograph showed a reniform shaped
It may be more common in children with HIV infection calcification with lobulations suggesting calcified right
and AIDS. kidney (cement kidney) and a beaded, tubular-shaped
calcification extending parallel to the vertebral column (L4 –
ISOLATED HEPATIC INFERIOR VENA CAVA THROMBOSIS S2) suggestive of calcified right ureter. Chest X-ray showed
IN A CASE OF TUBERCULOSIS old, healed, calcified parenchymal and pleural lesions in the
Gogna et al.18 have reported a case of pleuropulmonary left upper zone. Ultrasonographic examination of abdomen
tuberculosis developing isolated inferior vena cava (IVC) revealed a calcified right kidney with compensatory
thrombosis with raised anticardiolipin antibodies and enlargement of the left kidney.
antinuclear factors during the course of therapy. Recently A diagnosis of renal tuberculosis with renal failure was
the association between inflammation and acute phase made. Antitubercular therapy with modified dosages was
reactants with hemostatic changes is thought to result in started. Fever subsided and hematuria stopped alongwith
hypercoagulable state which may cause deep vein improvement in general condition of patient. After two
thrombosis in cases of severe pulmonary tuberculosis.19 months of follow-up, the patient was doing well.
In these cases there is thrombocytosis, elevated plasma
fibrinogen, fibrin degradation products, tissue PRIMARY TUBERCULOSIS CLINICALLY PRESENTING AS
plasminogen activator (t-pa) and inhibitor (t-pi) with GINGIVAL ENLARGEMENT: A CASE REPORT
depressed antithrombin level. Fibrinogen is seen to rise
within the first two weeks of therapy, which normalizes Tuberculosis is a chronic systemic granulomatous disease
within 12 weeks. This coupled with impaired fibrinolysis which rarely affects the oral cavity. Oral lesions can be
may result in deep vein thrombosis. The increased levels either primary or secondary to systemic tuberculosis, the
of anticardiolipin antibodies and antinuclear factors can former being rare. Sharma et al.22 reported a case of
be associated with deep vein thrombosis, but also isolated primary tuberculosis presenting as a localized diffuse
venous thrombosis at unusual sites like hepatic IVC. gingival enlargement in an 11-year-old Indian female
Casanova-Roman manuel et al.20 from Spain have reported patient. The diagnosis was established by identification
transient elevation of proteins and anticardiolipin of posture histopathological features, tuberculosis test,
antibodies in a 4-year-old boy with pulmonary tuberculosis presence of antitubercular antibodies confirmed by a
and deep vein thrombosis. They observed that two or more polymerse chain reaction (PCR). It is suggested that in
anomalies in the coagulation system are necessary for view of the recent increase in the incidence and provalence
causing venous thrombosis.20 of tuberculosis it is reasonable to include tuberculosis in
the differential diagnosis of gingival enlargment.
CEMENT KIDNEY: RENAL TUBERCULOSIS
Punia and Kumar21 presented an 18-year-old girl with SIMULTANEOUS TUBERCULOUS
fever and anorexia since twenty days, and recurrent MENINGOENCEPHALITIS IN TWO SIBLINGS
painless hematuria with oliguria since one year. There
Meyer et al.23 reported two siblings (2-year-old boy and 4-
was history of pulmonary tuberculosis in her childhood
year-old girl) with simultaneous tubercular
for which she had received antituberculosis therapy for 6
meningoencephalitis (TBM) in Germany. Early diagnosis
months. Physical examination was normal except for
of TBM was delayed and antituberculosis treatment was
presence of pallor.
not initiated syspecting it to be viral meningoencephalitis.
Urinalysis showed albumin +, 25 to 30 RBCs/hpf, 10 to
There was hydrocephalous and signs of inflammatory
12 pus cells/hpf, no urinary casts, malignant cells or
cerebral disease. After the diagnosis of TBM was
bacteria. Repeated urine cultures were bacteriologically
established the boy died due to drug induced hepatic
sterile. Hemoglobin – 7.3 gm/dl, ESR – 65 mm/1st hr,
failure, the sister survived with severe neurological
serum creatinine – 5.1 mg/dl, blood urea – 278 mg/dl, sequlae. Contact tracing revealed that TB had been
serum Na+ – 136 mEq/L, serum K+ – 3.4 mg/dl, serum transmitted by a household contact with proven
calcium – 10.6 mg/dl, serum phosphorus –3.4 mg/dl, pulmonary TB who had refused antituberculosis
serum alkaline phosphate – 77 IU/L, serum parathyroid treatment. It was concluded by the authors that to prevent
hormone – 35 pg/ml. Coagulation tests were normal. ELISA severe neurological sequelae, early antituberculosis
for M. tuberculosis IgG antibody was positive. Mantoux test therapy should be considered in infants and children with
was positive. Early morning urine cultures on three a clinical impression of meningitis. A rigid implementation
successive days yielded acid-fast bacilli. of antituberculosis treatment of infected individuals and
252
contact tracing is mandatory in order to prevent system tumor is around 0.5 to 4%, where as in developing
dissemination of TB in the community particularly countries it is 15 to 30%. It mainly affects children and
vulnerable section of children. BCG is a must for all young adults. An accurate diagnosis by biological,
newborns to prevent the development of dissemination. hormonal and imaging scan examination can be made
and medically treated. The case described by the authors
CHILDHOOD TUBERCULOSIS DIAGNOSED AND encountered difficulties in diagnosis because of a normal
MANAGED AS ASTHMA: A CASE REPORT scan due to thickening of pituitary stalk. PCR was helpful
in the diagnosis.
Kurokawa et al.24 have emphasized that although the
diagnosis of tuberculosis is well established in adults, in MULTIFOCAL SKELETAL TUBERCULOSIS
children it is difficult. They reported a 3 years and 8 months
Multifocal skeletal tuberculosis is an uncommon
old child who had chronic wheezing, classified as moderate
manifestation in immunocompetent children. Nonspecific
to severe asthma, had recurrent pneumonia, and was not
clinical manifestations and multiple osteolytic
responding to the management with beta adrenergic agents. radiological lesions of multifocal skeletal tuberculosis
Chest X-ray showed heterogeneous opacity in the middle mimic hematological malignancies, neuroblastoma and
lobe and in the CT scan there was an increase in pulmonary secondary metastases. Histopathological examination is
transparency in the same lobe. After four months of treatment mandatory for the confirmation of the diagnosis.
with antituberculosis agents, there was a significant Antituberculosis therapy is the cornerstone of treatment
improvement in symptoms, disappearance of pulmonary with surgery having a limited role. Indumathi et al.28
medium lobe consolidation and persistent fibroatelectic band reported this entity in a female child, aged 15 years who
in lingula. presented with intermittent fever of five months duration.
She had significant weight loss followed by swelling of
TUBERCULOSIS OF THE BREAST IN AN ADOLESCENT dorsum of right foot since a month. She also gave history
GIRL of pain in the left foot 2 months ago which subsided after
a week. There was no cough or history of contact with
Tuberculosis (TB) of the breast is a rare condition and tuberculosis. There was no history of arthalgia, arthritis,
usually affects women in the reproductive age group. It is rash, progressive pallor or bleeding manifestations.
further rare in children even in India, where TB is rampant, The child was malnourished and had mild pallor. There
poses challenges in its diagnosis. Histopathology plays an was no significant lymphadenopathy, rash or skin bleeds.
important role in the diagnosis of the condition. Indumathi Systemic examination was unremarkable. There was
et al.25 have reported a case of TB of the breast in a 15-year- nonpitting edema on the right foot along with tenderness.
old girl proved by histopathological study. Investigations revealed HB 8.2 gm/dl, TLC = 6800/
cumm, DLC-N-78%, L-18%, E-2%, M-2%, platelets 4.2
ESOPHAGEAL STENT IMPROVES VENTILATION IN A lakhs/mm. 3 Peripheral smear was suggestive of
normocytic normochromic anemia ESR 86 mm/hr. HIV
CHILD WITH A BRONCHOESOPHAGEAL FISTULA CAUSED
was negative, so was Mantoux test. Chest X-ray showed
BY MYCOBACTERIUM TUBERCULOSIS miliary tuberculosis and induced sputum was negative
Goussard et al.26 have described in a 12-month-old boy for AFB. Ultrasound of the abdomen revealed granuloma
the role of an esophageal stent who presented with in liver. MRI of foot revealed multiple lytic lesions with
respiratory failure requiring ventilation. The child had sclerotic borders in most of the right tarsal bones, lower
ends of right tibia and right fibula as well as in the left
tubercular bronchoesophageal fistula and air leak via the
tibia. A bone biopsy showed nonspecific inflammatory
fistula led to inadequate mechanical ventilation. The
changes with acid-fast bacilli. She was put on category I
deployment of a stent resulted in successful ventilation,
antituberculosis therapy 2HRZE 7HR. During hospital
closure of the fistula and eventual successful treatment. stay she developed left pneumothorax. During first follow-
up after 2 months of intensive therapy she gained 3
PITUITARY STALK TUBERCULOSIS kilograms and was afebrile. Then she was lost to follow-
up.
Stalldecker et al.27 have reported an exceptionally rare
manifestations of pituitary stalk tuberculoma. The authors Skeletal tuberculosis accounts for 10 to 35% of
have suggested that even with no evidence of systemic extrapulmonary tuberculosis and 2% of all cases of
tuberculosis, it is important to recognize these lesions in tuberculosis. Lung is the primary focus in 75% of cases
the differential diagnosis of the intrasuprasellar tumors and it is secondary to hematogenous dissemination.
because they are curable. In developed countries the Common sites include spine, hip, and knee joints followed
frequency of intracranial tuberculoma of the nervous by short bones of hands and feet. Skeletal lesions can be
253
solitary or multiple. Osteoarticular lesions that occur • Lupus vulgaris–syphilis need to be distinguished
simultaneously at two or more locations in the skeletal • Papulonecrotic tuberculosis–papular urticaria in young
system, are termed multifocal skeletal tuberculosis. This children.
is an uncommon entity even in endemic countries and
accounts for <5% skeletal tuberculosis in all age. HIGHLIGHTS
Multiple lesions are commoner in children compared • Unusual manifestations involving different systems
to adults. Peripheral skeleton is involved more in children by tuberculosis in children have been described
where as there is axial skeleton involvement more • Eye and conjunctiva
predominant in adults. It has insidious onset with vague • Cardiac complication–pericardial abscess
symptomatology like low grade fever, loss of weight and • Hematological–autoimmune hemolytic anemia
appetite. Soft tissue swelling, pain and restricted mobility • Cement kidney – a rare tuberculosis
at involved sites are also common symptoms. Active • Esophageal tuberculosis
tuberculosis is present in 50% of cases. • Skelatal tuberculosis
Plain radiograph of bones may be normal and subtle • Pituitary stalk tuberculosis
changes are often missed. An MRI is the investigation of • BCG related complication
choice that reveals osteolytic cystic lesions without • Isolated inferior vena cava thrombosis.
significant marginal sclerosis or reactive bone formation.
Lesion are less sclerotic in children (<20%) as compared to
adults. Nonspecific clinical presentation, functional REFERENCES
disability and radiological lesions of multifocal skeletal 1. Stein H, Freiman I. Phlyctenular conjunctivitis in African
tuberculosis mimic rheumatological conditions, children. Arch Dis Childhood 1958;33:292-4.
hematological malignancies, pyogenic and mycotic 2. Domato FJ. BCG vaccine and phlyctenular conjunctivitis.
osteomyelitis, chronic relapsing multifocal osteomyelitis, British J Ophthalmol 1951;35:416.
neuroblastoma and secondary metastases. It is rare and is 3. Chawla R, Grag S, Verikatgh P, et al. Case report of
considered after a diagnosis of malignancy. Bone Scan is tuberculosis panophthalmitis. Med Sci Monit
helpful in detecting other lesions. 2004;10:CS57-9.
4. Morese ML, Karr DJ, Mandman OM. Ocular tuberculosis
Eighty-five to ninety percent of cases respond to
in a five months old infant. Infect Dis J 1988;7:514-6.
antituberculosis therapy alone in 6-12 months. Excision of
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anemia complicating disseminated childhood
BCG RELATED COMPLICATIONS tuberculosis. Indian J Pediar 2004;71: 549-51.
7. Cameron SJ. Tuberculosis and the blood: A special
The complication of BCG vaccination can lead to local relationship? Tubercle 1974;55:55-7.
abscesses, secondary bacterial infections, lupus vulgaris, 8. Semchyshyn S, Cecutti A. Abdominal pregnancy
lymphadenitis, scrofuloderma like lesions, papulonecrotic complicated by genital and renal tuberculosis and
tuberculide and local keloid formation. In immune hemolytic anemia. Fertile Steril 1975;26:1142-5.
compromised children, it can be fatal. 9. Murray HW. Transient autoimmune hemolytic anemia
and pulmonary tuberculosis. N Engl J Med 1978;299:488.
10. Kim SW, Choi SW, Cho BK, et al. Tuberculosis cutis
Differential Diagnosis orificialis: An association with Evan’s syndrome. Acta
Skin biopsy and the opinion of a dermatologist may be Derm Venereol 1995;75:84-5.
required to give a definite diagnosis of tuberculosis of the 11. Siribaddana S, Wijesundara A. Autoimmune hemolytic
skin. anemia responding to antituberculous treatment. Tropical
Doctor 1997;27:243-4.
Primary inoculation tuberculosis may resemble as an
12. Blanche P, Rigolet A, Massault D, et al. Auto-immune
indolent pyogenic infection and a typical mycobacterial
hemolytic anemia revealing miliary tuberculosis. J Infect
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• Cat scratch fever may cause a slow-healing skin lesion 13. Kuo PH, Yang PC, Kuo SS, et al. Severe immune
accompanied by regional adenitis like deep fungal hemolytic anemia in disseminated tuberculosis with
disease and leishmaniasis response to antituberculosis therapy. Chest 2001;119:
• In scrofuloderma, actinomycosis, discoid lupus 1961-3.
erythematosus, sarcoidosis, leprosy must be 14. Sathiyascbararn M, Shivbalan SO. Esophageal
distinguished tuberculosis. Indian J Pediatr 2004;71:457-8.
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15. Sood A, Sood N, Raj Kumar, et al. Primary tuber- 22. Sharma CG, Pradeep AR, Karthikeyan BV. Primary
culosis of esophagus. Indian J Gastroenterol 1996; tuberculosis clinically presenting as gingival enlargement
15:75. a case report. J Contemp Dent Pract 2006; 7: 108-14.
16. Gordon AH, Marshall JB. Esophageal tuberculosis; 23. Meyer S, Shamdein MG, Wiillenweber J, et al. Simultaneous
definitive diagnosis by endoscopy. Am J Gastroenterol tuberculosis meningo-encephalitis in two siblings. Wien
1990;85:174-7. Med Wochenschr 2007; 157: 37-42.
17. Fahmy AR, Guinde R, Farid R. Tuberculosis of esophagus. 24. Kurokawa La Scale CS, La Scale CR, et al. Childhood
Thorax 1992;24:254-6. tuberculosis diagnosed and managed as asthma: case
18. Gogna A, Grover SB, Prun S, et al. Isolated hepatic inferior report. Altergol Immunopathol (Madr) 2006; 34: 276-9.
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2004;5:266-8. the breast in an adolescent girl-a rare presentation. J
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18 Cutaneous Tuberculosis
Neena Khanna, Seemab Rasool
EPIDEMIOLOGY Table 18.1: Underlying systemic involvement in

cutaneous tuberculosis
Prevalence
Underlying tuberculosis Prevalence (%)
Childhood tuberculosis represents 5 to 15% of all cases Lymphadenitis 29.2
of tuberculosis, with pulmonary tuberculosis being Lungs 12.6–20
commonest form of tuberculosis seen in children. Bone 5.8–10
Cutaneous tuberculosis represents 1.5 % of all cases of Abdomen 5.8
extra pulmonary tuberculosis.1 In an Indian series of 402
patients with cutaneous tuberculosis 18.7% were found quiescent, with reactivation of the organism occurring
to be children.2 when conditions become favorable for the bacilli.
• Reinfection: May also occur in patients with healed
Demographic Parameters infection after many years, especially in regions of
high prevalence.
Most cutaneous tuberculosis is seen in the age group of
10 to 14 years, 2 with no significant gender preponderance. CLASSIFICATION
Cutaneous tuberculosis is classified based on morpho-
ETIOLOGY
logy, mode of infection and previous sensitization (Table
Cutaneous tuberculosis is caused: 18.2). The two most common forms of skin tuberculosis
• Usually by Mycobacterium tuberculosis reported in India are scrofuloderma and lupus vulgaris.5
• And rarely by :
– M. bovis CLINICAL FEATURES
– Attenuated bacille Calmette-Guerin (BCG) Scrofuloderma
organism.
Underlying systemic involvement is commoner in Scrofuloderma is the most common form of cutaneous
children compared with adults, being seen in 12.7 to 53.4% tuberculosis in children.2 It results from the direct inva-
of the children (Table 18.1).3-6 sion of the tubercle bacilli into the skin from an under-
lying tuberculous focus, usually in the lymph nodes and
less frequently in the bones, joints and testes.6, 7
PATHOGENESIS (TABLE 18.2)
Skin is infected by M. tuberculosis either from an Table 18.2: The classification of cutaneous tuberculosis
exogenous source (usually from infected adults)4 or the
Source Clinical presentation
organism reaches the skin from an endogenous focus. The
manifestations depend on the immunity of the host and Endogenous
Contiguous spread Scrofuloderma
method of spread.
Hematogenous spread Lupus vulgaris
• Exogenous infection: Infection from an exogenous source
Acute miliary TB
leads to tuberculous chancre, if the person who is being Metastatic TB abscess
exposed for the first time or tuberculosis verrucosa cutis Gumma
in a person who already has a high immunity. Auto-inoculation Orificial TB
Sometimes lupus vulgaris develops at the site of BCG Exogenous source TB chancre (nonsensitized)
vaccination. TB verrucosa cutis (sensitized)
• Endogenous infection: The focus is most frequently in Tuberculosis caused by
the lungs and sometimes in the skin, mucosae or BCG vaccination
lymphnodes. Often, the source of infection is clinically Eruptive Tuberculids
256
Morphology
• Scrofuloderma in children is more severe than in
adults.4
• Usually starts as firm subcutaneous nodules (Fig.18.1,
see color version, Plate 00) or as well defined freely
movable asymptomatic plaque(s) overlying an
involved lymph node, less frequently bone, joint and
testes which subsequently rupture over a period of
months to form sinuses discharging watery or caseous
material. The mouth of the sinus is typically
undermined and bluish. Ulcers, when present are
typically shallow with bluish undermined margins
(Fig. 18.2, see color version, Plate 00) and a floor with
granulation tissue and the base is formed of the Fig.18.1: Scrofuloderma: Firm asymptomatic
underlying tubercular focus. Widespread localized subcutaneous nodule (For color version see Plate 5)
lesions sometimes present as multiple swellings and
ulcers with irregular, finger-like scrofulous extension
involving large areas.8
• Spontaneous resolution may occur after many
months or years, healing with characteristic puckered
scars.
Sites of Predilection
• Usually unilateral. However multifocal lesions
involving axillary, inguinal, and other bony areas, and
symmetric scrofuloderma from an underlying bony
focus on both ankles have been reported.
• Cervical group of lymph nodes are most commonly
affected.2 Other groups of lymph nodes that can be
involved are axillary, inguinal, parasternal,
epitrochlear, pre- and postauricular, submandibular, Fig. 18.2: Scrofuloderma ulcer: Shallow, undermined with bluish
margins and a floor with granulation tissue (For color version see
occipital, and supraclavicular nodes. Other common
Plate 5)
sites include scrofuloderma of shins rising from
tuberculous osteomyelitis of tibia, skin over the
sternoclavicular joint and scrotum.
Lupus Vulgaris (LV)

Lupus vulgaris is more common in adults than
scrofuloderma but is less frequent in children.2 It is a post
primary, paucibacillary form of skin tuberculosis that
usually occurs in previously sensitized individuals.4
Morphology
• Single or few lesions of variable size can affect a large
area of the body.
• Begin as asymptomatic, indurated papules and
plaques which spread slowly to form a well- Fig.18.3: Lupus vulgaris: Well demarcated annular plaque with
demarcated, skin-colored or erythematous annular central scarring (For color version see Plate 5)
plaque with deep-seated, tiny nodules at the periphery
that can be seen as yellow-brown macules (apple-jelly area and activity in another (in forms of nodules) is
nodules) on diascopy. Over time the center becomes the hallmark of lupus vulgaris (Fig. 18.3, see color
atrophic and paper thin. Healing and scarring in one version, Plate 00).
257
Chapter 18 Cutaneous Tuberculosis
Sites of Predilection vesicles which develop central necrosis and crusts are
seen.
In children, the lower extremities and gluteal region are • Sometimes, neonates born to tuberculous mothers
the commonly affected sites.4 develop a milder form of the disease, with limited
visceral involvement and only a few scattered
Variants
papules.
• Classic plaque LV (keratotic type): Being the most
common. Sites/Systemic Involvement
• Hypertrophic LV: Appears as a soft mass with a
Disseminated lesions occur on all parts of body,
nodular hyperkeratotic surface.
particularly on trunk. Miliary TB may occur in an
• Ulcerative LV: Ulceration occurs when underlying
individual organ (very rare, <5%), in several organs, or
tissue is affected by progressive necrosis.
throughout the whole body (>90%), including the brain.4
• Atrophic LV: Atrophy may occur with or without prior
ulceration.
Tuberculous Metastatic Abscesses
• Mutilating LV: When fibrosis is prominent mutilation,
deformity and contractures occur. Also called tuberculous gumma, tuberculous metastatic
abscess, is caused by the hematogenous spread of
Rare Variants Mycobacteria from a primary focus. It is usually seen in
• Multifocal, symmetric LV: Affecting the knees, possibly malnourished or immunosuppressed children.
caused by exogenous inoculation of the organism, has
been reported. Morphology
• Sporotrichoid pattern: Due to lymphatic spread.
• Single or multiple non tender dermal or subcutaneous
Develop on partially healed lesions of scrofuloderma.6
nodules.
• Post BCG vaccination.
• Lesions may invade overlying skin and break down
• LV of mucous membranes: Usually involved as an
to form necrotic ulcers and fistulous tracts, quite like
extension of the skin lesions and manifest as easily scrofuloderma.
bleeding small, soft, gray or pink papules, ulcers, or
granulating masses.4 Sites of Predilection
• Lupus postexanthematicus: Multiple disseminated
lesions may arise due to hematogenous spread from a Extremities, trunk and head.
latent focus, after a transient impairment of immunity.
Primary Tuberculous Chancre
Complications of LV
Tuberculous chancre, also known as primary inoculation
• Ulceration, often slow to heal. tuberculosis or tuberculous primary complex, is rare and
• Disfigurement: facial lesions scar and often cause is mostly seen in high endemic areas. It is due to
ectropion, nasal deformities. Genital distortion may inoculation of Mycobacteria into skin in previously
occur due to genital lesions. unsensitized persons forming a tuberculous primary
• Contractures, if close to joint due to scarring. complex (tuberculous chancre and regional lymph
• Squamous cell carcinoma, rarely. nodes). The organisms are usually introduced at the site
of minor injury or abrasion.
Acute Miliary Tuberculosis
Acute miliary tuberculosis with skin manifestation is rare Morphology
in India, with only a few cases in children having been • Skin lesion develops about 4 weeks after inoculation.
reported. 9, 10 It is due to the hematogenous dissemination It begins as an asymptomatic papule that breaks down
of Mycobacteria from an internal focus usually the lungs to form a shallow ulcer with granulomatous base and
or meninges. The disease often manifests after undermined bluish margins, which heals over a
immunosuppression due to infections such as measles period of time (similar to a tuberculous primary
and HIV.4 complex elsewhere). The organisms remain dormant
and may get reactivated under favorable conditions.
Morphology • Regional lymphadenopathy develops 3 to 8 weeks
• Cutaneous lesions consist of erythematous papules, after the inoculation.
pustules and,purpuric lesions. Rarely umbilicated • Inoculation of the finger may manifest as paronychia.4
258
Tuberculosis Verrucosa Cutis (TVC)

Tuberculosis verrucosa cutis, otherwise known as warty
tuberculosis, occurs as a result of exogenous inoculation
tuberculosis in previously sensitized individuals.
Morphology
• Begins as a small single verrucous papule, which
slowly extends to form large irregular verrucous
plaques (Fig. 18.4, see color version, Plate 00). Surface
usually shows deep fissures or clefts that may extrude
pus and perilesional erythema is frequent. Irregular
small areas of scarring often hidden by the
verrucosity.
• The lesion may persist for many years and progress
slowly.6, 8 At times, it is difficult to distinguish it from Fig. 18.4: Tuberculosis Verrucosa Cutis: Irregular verrucous plaque
the hypertrophic variant of lupus vulgaris. (For color version see Plate 5)
The following are no longer included as tuberculids:

Sites of Predilection • Rosacea-like tuberculid
• It typically occurs on the acral parts of the extremities • Lupus miliaris disseminatus faciei
(sites of trauma). • Lichenoid tuberculid.4
Orificial Tuberculosis Lichen Scrofulosorum

Tuberculosis cutis orificialis is rare form of tuberculosis • Is commonly seen in children and young adults.
caused by autoinoculation of mycobacteria in patients • Usually indicates an underlying tuberculous focus in
who have advanced internal tuberculosis.8 the lymph nodes, especially the cervical, hilar, and
mediastinal nodes, bones, and sometimes lungs.
Morphology Rarely, it can be seen in association with tuberculous
meningitis and miliary tuberculosis. 11, 12 It has also
• A small yellowish or reddish nodule appears usually been observed after BCG vaccination.
in the mucosa of the mouth or anus.
• The nodule breaks down to form a shallow, Morphology
granulomatous ulcer with a punched out appearance
and undermined edges. • It presents as asymptomatic small, scaly yellow-brown,
or lichenoid, firm, follicular papules which may be flat
Tuberculides topped or spiny (Fig. 18.5, see color version, Plate 00).
• Completely resolves with ATT.
Tuberculides are delayed sensitivity reactions to M.
tuberculosis in patients with a strong immune response.
Criteria for Diagnosis

• Absence of organisms in the smear and negative
culture from the lesions.
• Strongly positive Mantoux reaction.
• Resolution of the lesions with antituberculous
treatment (ATT).
Classification
The tuberculides include:
• Lichen scrofulosorum
• Papulonecrotic tuberculide
• Erythema induratum
• Erythema nodosum Fig. 18.5: Lichen scrofulosorum: Grouped follicular lichenoid papules
(For color version see Plate 6)
259
Sites of Predilection Complications of BCG Vaccination

Usually confined to the trunk. BCG vaccine is a live, freeze-dried vaccine derived from
an attenuated strain of M. bovis (BCG). It is given routinely
Papulonecrotic Tuberculides at birth to all infants at risk of early exposure to
A rare condition seen in areas with high prevalence tuberculosis in dose of 0.05 mL intradermally. Usually, 2
occurs preferentially in children and young adults. weeks after vaccination, a small papule develops which,
over a period of 6 weeks enlarges, ulcerates and
Morphology eventually heals with a scar.
• Lesions consist of symmetric eruptions of necrotic Nonspecific Complications

papules.
• Resolves spontaneously leaving pitted scars. BCG vaccination may be followed by several nonspecific
complications like keloids, eczema, maculopapular rash,
Sites of Predilection erythema nodosum, infections, poor healing, ulceration
and abscess formation.
Extensor aspect of the extremities and buttocks.
Specific Complications
UNUSUAL PATTERNS OF TUBERCULOSIS
Occasionally, M. bovis induced complications like lupus
• Sporotrichoid tuberculosis: Sporotrichoid pattern vulgaris, verrucous tuberculosis, tuberculous chancre,
though rare (3% of all patients with cutaneous lymphadenitis, Koch’s phenomenon, disseminated BCG
tuberculosis) is mostly reported in children. Lupus infection and tuberculids have been reported. 4
vulgaris, scrofuloderma, and TVC can all present in
sporotrichoid pattern due to lymphatic spread. It is DIAGNOSIS OF CUTANEOUS TUBERCULOSIS
characterized by linear lesions confined to an
extremity often with a cord-like thickening of the The diagnosis is usually based on the characteristic
lymphatics in between the lesions. Though frequently clinical morphology and laboratory testing. In addition
to the routine laboratory evaluation, all children should
confused with sporotrichosis, the presence of
be evaluated for underlying systemic tuberculosis.
enlarged regional lymph nodes or ulceration favors
the diagnosis of tuberculosis.13, 14
• Inverse sporotrichoid pattern: Or segmental form is
Histopathology
characterized by involvement of the proximal half of Though the histopathological hallmark of tuberculosis
the lower limb due to retrograde lymphatic spread is a caseating granulomas, there may be differences
from the inguinal lymph nodes. 15 between morphological variants (Table 18.3). The
• Tuberculous dactylitis: Presents as granulomatous clinicohistologic correlation can be seen in 64% to 80.6%
swelling of the finger, most often the index or middle cases of cutaneous tuberculosis in children. 3,15 The
finger. It is always associated with underlying histopathologic correlation is found in 47% to 65.7% of
tuberculous osteomyelitis, especially of the proximal cases of scrofuloderma and 73% to 80% of cases of lupus
phalanges. 2 vulgaris (Table 18.3). 3, 15
• Orofacial tuberculosis: Usually starts as a papule or
plaque in the perioral area usually of the upper lip, Mantoux or Tuberculin Test
which over course of time, extends into the oral
mucosa, including the tongue and nose. If untreated, Response to different types of cutaneous tuberculosis is
it leads to severe mutilation and complications like variable (Table 18.4).
destruction of the nasal septum, and involvement of
the palate, nasolacrimal duct, and middle ear. Demonstration of the Organism
Orofacial tuberculosis needs to be differentiated from The gold standard for the diagnosis of cutaneous
orofacial granulomatosis (especially in India), which tuberculosis is the direct demonstration of the organism
is a nonspecific descriptive term used for various
either in a
conditions characterized by persistent swelling of the
• Tissue smear
orofacial tissues histopathologically showing
noncaseating granulomas.16, 17 The important clue to • Biopsy
the diagnosis of tuberculosis is that the biopsy in these • Culture.
cases demonstrates caseating granulomas, which is Demonstration of organism is often difficult
further supported by the Mantoux test. especially in paucibacillary cases because of the scanty
260
Table 18.3: Histopathology of various types of tuberculosis
Type Histopathology
Scrofuloderma Tuberculoid granuloma with considerable necrosis and inflammation.

Lupus vulgaris Tuberculoid granulomas with epithelioid cells and Langhans giant cells, along with epidermal changes.
Necrosis is usually not seen. Fibrosis may be seen in the areas of scarring and healing.
Acute miliary TB Microabscesses containing neutro-phils and numerous organisms that may be surrounded by macro-phages
and giant cells.
Metastatic TB Massive necrosis with copious abscess amounts of mycobacteria.
Orificial TB Massive nonspecific inflammatory infiltrate and necrosis; in deep dermis tubercles with deep caseation
may be seen.
TB chancre Nonspecific inflammatory reaction and later there is tuberculoid appearance and caseation.
TB verrucosa cutis Massive pseudoepitheliomatous
(sensitized) hyperplasia and granulomatous infiltrate with necrosis.
Tuberculids Vasculitis and a wedge-shaped area of necrosis. Nonspecific infiltrates or tuberculoid granuloma may be seen
surrounding the necrosis. 4
number of organisms. AFB have been seen in the biopsy Table 18.4 Mantoux test in different type of cutaneous
sections of scrofuloderma and lupus vulgaris in 36.8% tuberculosis
and 13.6%, respectively 3 while in cytology specimens it Clinical manifestations Mantoux test
can be demonstrated in 39.5% and 18.2% respectively.
Culturing the organisms in the Lowenstein-Jenson Tuberculous chancre Negative initially
medium is tedious and positivity is even lower (18.4% Tuberculosis verrucosa cutis Positive
in scrofuloderma and 12.5% in lupus vulgaris). However Lupus vulgaris Variable
with improved techniques using multiple media, and the Acute miliary tuberculosis Negative
use of Kirchner’s liquid medium for storage of the tissue, Tuberculids Strongly positive
the culture positivity is better.
Polymerase Chain Reaction (PCR)

Though the diagnostic specifity of PCR in cutaneous TREATMENT OF CUTANEOUS TUBERCULOSIS
tuberculosis is debatable, it has considerable sensitivity Cutaneous tuberculosis can be treated with the standard
especially in paucibacillary cases. The combination of dot regime used for pulmonary tuberculosis. Currently, the
hybridization with PCR markedly increases the treatment of cutaneous tuberculosis is by the directly
sensitivity and specificity of PCR. This may be a useful observed treatment, short-course strategy, implemented
tool in the diagnosis of tuberculosis when conventional by the World Health Organization. This program has
methods fail. been fully adopted by the Revised National Tuberculosis
Control Program (RNTCP) of the Government of India.
Therapeutic Trial of Antituberculous Drugs According to these guidelines, cutaneous tuberculosis is
classified as category III. When the lesions are extensive,
A therapeutic trial of antituberculous drugs may be a or when more than one group of lymph nodes are involved
useful diagnostic tool in developing countries like India. as in scrofuloderma, then the category I regime can be
A four-drug regimen (HRZE) is usually given over a given (Table 18.5).18
period of 6 weeks. Gratifying response at the end of 6
weeks is the rule and proves the diagnosis of cutaneous Surgical Intervention
tuberculosis. Patients who have not responded by 6 weeks
are unlikely to do so with further treatment and their • In scrofuloderma, reduces morbidity and shortens
diagnosis should be reviewed. period of chemotherapy.
261
Table 18.5: Treatment of cutaneous tuberculosis
Category Intensive phase 8 weeks Maintenance phase 16 weeks
Category III Isoniazid 5 mg/kg Isoniazid 5 mg/kg

Rifampicin 10 mg/kg Rifampicin 10 mg/kg
Pyrazinamide 30 mg/kg
Category I Isoniazid 5 mg/kg Isoniazid 5 mg/kg
Rifampicin 10 mg/kg Rifampicin 10 mg/kg
Ethambutol 15 mg/kg
Pyrazinamide 30 mg/kg
• Small lesions of lupus vulgaris or tuberculosis

verrucosa cutis can be excised. • Surgical intervention reduces morbidity and
shortens the duration of chemotherapy. Excision or
• Plastic surgery has a role in mutilation due to long
plastic surgery may be indicated in certain cases.
standing cutaneous tuberculosis. 4
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19 Adolescent Tuberculosis:
Prelude to Future Infertility
Suneeta Mittal, JB Sharma, Sangeeta Sharma
Out of eight million people developing active renal disease and renal failure and hemodialysis patients and
tuberculosis (TB) each year world-wide about two million coinfection with HIV.1-3,5,6 8 Genital TB almost always occurs
die.1 Developing countries contribute 95% of new TB secondary to pulmonary (commonest) or extrapulmonary
cases and deaths. There has been a rise in TB cases TB like gastrointestinal tract, kidneys, skeletal system,
throughout the world due to co-infection with human meninges and miliary TB.6-8 The site of involvement in
immunodeficiency virus (HIV) infection, more liberal primary genital TB can be cervix or vulva.6-8 The spread of
immigration from high risk to low risk areas and TB from lungs and other sites is usually by hematogenous
emergence of multidrug-resistant (MDR) and extreme
or lymphatic route. Less commonly, direct contiguous
drug resistant (XDR) TB, which are caused by poor case
spread from nearby abdominal organs like intestines or
management. World Health Organization declared TB a
abdominal lymph nodes can cause genital TB. The various
global emergency in 1993 and promoted Directly
Observed Treatment Short-course (DOTS) strategy. 2 genital organs affected by TB in order of frequency are
Women including adolescent girls are more prone to fallopian tubes (90-100% cases), endometrium (50-80%
tuberculosis due to poor nutrition, lesser seeking of health cases) ovaries (20-30% cases), cervix (5-15%) and rarely
care. Their involvement in care of other pulmonary TB vagina and vulva (1% cases).6-8
cases at home makes them more vulnerable to acquire The exact incidence of FGTB is not accurately known
the disease. A higher incidence of pulmonary as it is under reported due to asymptomatic cases and
tuberculosis (PTB) in female children at all age groups lack of reliable confirmatory investigations. 6,7 The
has been reported, where overall PTB was affecting 61.7% reported incidence varies in different countries from 1%
girls as compared to 39.3% boys; being 56.2% and 43.8%, in USA to 1 to 19% in various parts of India.7,8 Genital TB
54.5% and 45.5% and 71% and 29%, in <5 yrs, 6-10 years was responsible for 0.02% and 1% of all gynecological
and >10 years old girls and boys respectively3 The admissions in Sweden and India respectively.6-8. Genital
extrapulmonary tuberculosis was also seen more TB was found on autopsy in 1 to 12% of women dying
commonly in females than in males in cases of TB with pulmonary TB.8 Tripathy and Tripathy 9 performed
lymphadenitis, skeletal TB, TB meningitis and abdominal diagnostic laparoscopy on sputum positive pulmonary
TB.4,5 TB cases and found bands of adhesions, tubercles and
Although pulmonary TB remains the commonest and hyperemia in 60% cases, intestinal adhesions in 24%,
the most infectious type of TB, extrapulmonary TB (EPTB) tubercles on fallopian tubes in 22% women and adhesions
is becoming more prevalent especially in young women in pouch of Douglas in 11% women.
throughout the world.6 Female Genital TB (FGTB), being
noninfectious has been neglected by health care Tuberculosis of Fallopian Tubes
providers but is an important cause of significant
morbidity and short- and long-term sequelae for the The fallopian tubes are involved in almost all women
affected women.6,7 with genital TB and the involvement is usually
bilateral.8 Depending upon whether it is hematogenous
Epidemiology and Pathogenesis of Adolescent Female spread or direct spread from intestines, disease may
Genital Tuberculosis (FGTB) start in the muscularis mucosa of tube or on the
peritoneal surface, but involvement of mucosa is always
Tuberculosis is caused by Mycobacterium tuberculosis complex there. In order of frequency, ampulla is the commonest
(M. tuberculosis, M. bovis, M. africanum). Human disease in site to be involved followed by isthmus and interstitial
immunocompetent individuals is mostly caused by M. part of the tube (rare). The severity and the stage of the
tuberculosis. Predisposing factors for TB are poverty, disease affect the gross appearance of the tubes. Initially,
overcrowding with improper ventilation, inadequate access there is congestion of fallopian tubes, ovaries and
to health care, malnutrition, diabetes mellitus, smoking, peritoneum of the pouch of Douglas with flimsy
alcohol and drug abuse especially injectable drugs, end stage adhesions and miliary tubercles on their surface. In later
264
stages, thick and vascular plastic adhesions are formed

between tubes and adjacent pelvic organs.10 In more
severe cases, there may be multiple adhesions in
peritoneal cavity with obliterated pouch of Douglas.10
Varying grades of Fitz-Hugh-Curtis syndrome (violin
string adhesions between liver and diaphragm or
anterior abdominal wall) is often seen in upto 48% cases
of female genital TB.11,12 Usually the characteristic
feature is presence of yellowish grey tubercles on the
peritoneal surface of the tubes and mesosalpinx with
fimbrial end of tube remaining open in half the cases.13,14
In advanced stage, tubes become dilated, retort
shaped and loculated. The leakage of infected material
from tube causes development of peritubal abscesses, TB
Fig. 19.1: Operative specimen of tuberculus tubo-ovarian mass
peritonitis and ascites. In chronic cases, a fibrotic stage excised on laparotomy (For color version see Plate 6)
develops resulting into thickened, hard and beaded tubes
with calcification and tubal blockade. 13,14 In TB of
fallopian tubes, tubal damage is due to endosalpingits, Ovarian TB
exosalpingitis or interstitial salpingitis. Tubo-ovarian
masses are due to peri-oophoritis, hydrosalpinx, Isolated TB oophoritis is rare. It is more often seen as
pyosalpinx or massive adhesion formation (Fig. 19.1). On part of TB peritonitis or with TB of other genital organs
microscopic examination, appearances vary depending (tubes or endometrium). Depending upon the severity
upon the severity and activity of the disease.14 TB and stage of disease, there may be tubercles on the ovary,
granulomas with Langhans giant cells with chronic adhesions, caseation, tubo-ovarian cyst or mass
inflammatory cells (lymphocytes) with or without formation. 6,8 Sometimes ovary may be completely
caseation may be observed. However, tubal mucosa may destroyed by the disease. Primary ovarian abscess
be totally destroyed or there may be fusion of papillae in secondary to ovarian tuberculosis has been reported.17
the endosalpinx making women more prone to ectopic
pregnancy and infertility.13,14
Peritoneal TB
Endometrial TB TB may involve pelvic or abdominal peritoneum due to
8,13,14 disseminated TB with tubercles all over the peritoneum,
Endometrium is involved in 50-80% cases. Gross
intestines and omentum. This may cause ascites and
endometrial appearance may be unremarkable due to
abdominal mass and may masquerade as ovarian cancer
repeated menstruation minimizing the disease. Initially,
as even CA-125 levels are raised in peritoneal TB. CT
there is no macroscopic disease but caseation and
scan and MRI also give similar picture and diagnosis may
ulceration occurs later with progression of TB and in
be made only on laparotomy done for suspected ovarian
advanced stages, there is distortion of cavity, varying
cancer. In such cases ascitic fluid tapping for biochemical
from slight distortion to complete obliteration due to
analysis and peritoneal biopsy may confirm the diagnosis
adhesions.14 Total destruction of endometrium may
of TB and thus avoiding a needless laparotomy.18 On
result in Asherman’s syndrome like picture resulting in
laparotomy there may be vague masses without a line of
amenorrhoea secondary to end organ failure. We found
cleavage with adherent loops of bowel or omental masses
genital TB to be an important cause of Asherman’s
mimicking secondaries from ovarian cancer.
syndrome in India leading to secondary amenorrhea and
infertility with poor prognosis for treatment. 15
Tuberculosis of Cervix, Vagina and Vulva
Microscopically, TB granulomas with or without
caseation, epithelioid cells and Langhans cells may be Their involvement is rare and is usually secondary to
seen especially in the premenstrual phase and close to extension from endometrium but may rarely be primary
the surface of endometrium. However, typical due to transmission from an infected partner. There may
granulomas may not always be seen due to repeated be a hypertrophic lesion or a non healing ulcer on the
shedding of endometrium at the time of menstruation.16 cervix, vulva or vagina mimicking malignancy. Biopsy
Some authors have suggested that even in absence of and histopathological examination is usually needed to
typical granulomas, endometrial TB may be diagnosed confirm the diagnosis and to rule out malignancy.19
by presence of focal collection of lymphocytes with or Rarely TB of the vagina can cause involvement of
without presence of dilated glands and destruction of Bartholin’s glands with, vesicovaginal and rectovaginal
epithelium.16 fistula formation.20
265
Chapter 19 Adolescent Tuberculosis: Prelude to Future Infertility
Adolescent Tuberculosis and Future Infertility Table 19.1: Symptoms in genital TB

Adolescent pulmonary or extrapulmonary TB may 1. Asymptomatic (upto 11%)
involve genital tract secondarily causing significant 2. General systemic symptoms
a. Fever with night sweats
genital morbidity like menstrual dysfunctions especially
b. Anorexia
hypomenorrhea, oligomenorrhea and amenorrhea. c. Weight loss
Sharma observed a very high prevalence of menstrual d. Poor general condition
dysfunction in pulmonary and extrapulmonary TB in 3. Menstrual dysfunction
adolescent girls. Out of 28 girls with tuberculosis only 4 a. Puberty menorrhagia
were having normal periods while 24 (85.7%) were having b. Menorrhagia
some menstrual dysfunction like hypomenorrhea, c. Postmenopausal bleeding
d. Oligomenorrhea
oligomenorrhea or primary or secondary amenorrhea
e. Hypomenorrhea
which could be due to involvement of endometrium or toxic f. Amenorrhea (primary and secondary)
effect of TB.21 4. Infertility (primary and secondary) in married
Infertility is the commonest presentation of genital adolescent girls.
TB with reported incidence of infertility being between 5. Lump in abdomen
40 to 80%. Both primary and secondary infertility may 6. Abdominal pain
occur. The average incidence of genital TB in infertility 7. Chronic pelvic pain
8. Acute abdomen (in rupture of tubo-ovarian
clinics world over is 5-10 % and varies from 0.69% in
abscess or flaring up of TB after coitus, exercise,
Australia to 17.4% in India.8 The reason for infertility is menstruation)
involvement of fallopian tubes (blocked and damaged 9. Abnormal vaginal discharge
tubes), endometrium (nonreception and damaged 10.Unusual symptoms
endometrium with Asherman’s syndrome) and ovarian a. Ulcers in vagina or vulva
damage in TB. 8,10,15 Past history of pulmonary or b. Labial swelling
extrapulmonary TB especially abdominal tuberculosis c. Retention of urine
d. Urinary incontinence
can be elicited in many women of genital tuberculosis
e. Fecal incontinence
presenting in reproductive age group for infertility or
abdominal or pelvic mass or pain. Hence, there is a real Table 19.2: Signs in genital TB
need of diagnosing and treating adolescent pulmonary 1. No physical sign (common)
or extrapulmonary TB (EPTB) on time to avoid 2. Systemic examination
permanent damage to genital organs which is a cause of a. Fever
significant long-term reproductive morbidity in women. b. Lymphadenopathy (in lymph nodes TB)
Also one needs to make out involvement of genital organs c. Crackles and rales on chest examination (PTB)
d. Other systemic signs depending on site of
in cases of pulmonary TB or EPTB especially abdominal
EPTB
TB, as 6 months standard treatment given for pulmonary 3. Abdominal examination
TB may not be sufficient if genital organs are involved, a. Mass abdomen (vague or definite)
as until recently a 9 to 12 months ATT treatment was b. Ascites
routinely given for genital TB. c. Doughy feel of abdomen
4. Vaginal examination ( avoided in unmarried girls)/
Rectal examinations
Clinical Presentation of Female Genital a. Uterine enlargement (Pyometra)
b. Adnexal tenderness
TB in Adolescent Girl c. Adnexal induration
The clinical presentation of genital TB depends upon site d. Adnexal masses
e. Tubo-ovarian mass
of involvement of genital organs and is shown in Table
f. Fullness and tenderness in pouch of Douglas
19.1. Up to 11% women with genital TB may be 5. Unusual signs
asymptomatic.6,8 Though the age of presentation is a. Hypertrophic lesions in cervix, vagina or
reproductive age group, adolescent girls can also present vulva.
with menstrual dysfunction or pelvic mass. b. Ulcerative lesions in cervix, vagina or vulva.
c. Labial mass (Bartholin swelling)
d. Vesicovaginal fistula
Clinical Signs e. Rectovaginal fistula
f. Tubovesical fistula
The various signs of FGTB depend on the site of g. Tuboperitoneal fistula
h. Tubointestinal fistula
involvement of genital organs and are detailed in Table
i. Uterocutaneous fistula
19. 2.6,8
266
Differential Diagnosis Table 19.3: Differential diagnosis (DD) of genital TB

As genital TB may manifest in different ways with no The differential diagnosis will vary according to clinical
characteristic symptoms and signs, the differential diagnosis presentation.
varies depending upon the clinical presentation and is shown 1. For girls presenting with pain and adnexal mass
following possibilities should be considered.
in Table 19.3. 6,7,14
a. Acute and chronic bacterial pelvic infections
b. Ectopic pregnancy
Diagnosis c. Ovarian malignancy
Being a paucibacillary disease, demonstration of M. d. Endometriosis
e. Appendicitis
tuberculosis is not possible in all the cases. A high index
2. The differential diagnosis of granulomatous
of suspicion is required. The diagnostic dilemma arises lesions in the pelvis after laparotomy should
due to varied clinical presentation, diverse results on include the following possibility:
imaging and endoscopy and availability of battery of a. Crohn’s diseases
bacteriological, serological and histopathological tests b. Actinomycosis
which are often required to get a collective evidence of c. Leprosy
the diagnosis of genital TB.6,8 The diagnostic approach d. Granuloma inguinale venereum
e. Syphilis
used is family history of TB or history of antituberculous
f. Histoplasmosis
therapy (ATT) in a close family member or a past history g. Brucellosis
of TB or ATT in the patient may show recrudescence of h. Silicosis
TB in the genital region. Detailed general physical i. Schistosomiasis
examination for any lymphadenopathy, any evidence of j. Filariasis
TB at any other site in body (bones, joints, skin, etc.), chest 3. Ulcerative or hypertrophic lesions
examination (PTB), abdominal examination (abdominal a. Vulval cancer
b. Vaginal cancer
TB), examination of external genitalia (vulvar or vaginal c. Cervical cancer
TB), speculum examination (cervical TB), bimanual d. Bartholin abscess
examination (endometrial or fallopian tube TB) aids in e. Condyloma acuminate
the diagnosis of genital TB. f. Condyloma lata
Not all tests are required for all cases of genital TB. g. Vulval and vaginal warts
The tests will depend upon the site of TB and its clinical h. Vaginal cyst
presentation. The various tests done are as follows:
based sandwiched enzyme linked immunosorbent
1. Complete Blood Count with erythrocyte sedim-
assay (ELISA) and can detect only about half to two-
entation rate (ESR) may show anemia, leukocytosis
with lymphocytosis and raised ESR in TB. However, thirds of the HIV negative TB positive patients with
these are nonspecific markers of TB and may be raised multibacillary extensive disease, but few in HIV
in many other conditions. positive TB positive cases and paucibacillary patients
2. Chest X-ray (posterior-anterior film) to exclude or like genital TB.24,25 Serological tests are not sensitive
confirm coexisting pulmonary TB. and specific enough to be of great value in diagnosis
3. Mantoux (Tuberculin) Test: Its role in genital TB is of genital TB.
controversial as the positive reaction (more than 10 5. Menstrual blood for AFB, microscopy, culture or
mm of induration) indicates that the person is or has polymerase chain reaction (PCR) sample:
been infected with M. tuberculosis, but does not prove Endometrial biopsy or aspiration in the
that she is suffering from the disease. Moreover, with premenstrual phase is the best method for the
severe TB and or advanced immuno-suppression, diagnosis of genital TB. However, most adolescent
tuberculin test may be negative in infected persons. girls, being unmarried, endometrial biopsy is
In women with laparoscopically diagnosed genital avoided in them. Menstrual blood should be
TB, Mantoux test was found to have only limited collected in a sterile container and should have
utility as it had a sensitivity of 55% and specificity of adequate blood or blood clots in it. One part of the
80%.22,23 Women with positive tuberculin test may menstrual blood is sent in formalin solution for
be subjected to more recent interferon – gamma histopathological testing for granuloma formation
release assays – immunological testing. But, it is (it rarely forms). The other part of the blood is sent
expensive and is not available everywhere.24 in normal saline for acid-fast bacilli (AFB) smear,
4. Serological Tests: They depend upon the 38 k Da culture. Even polymerase chain reaction (PCR) can
antigen of M. tuberculosis or monoclonal antibody be done on the same specimen.
267
The aspirate, menstrual blood (within 12 hours of examination of AFB requires the presence of at least
onset of menses in unmarried girls), secretions from 10,000 organisms ml–1 in the sample,29 culture is more
vaginal or cervix, peritoneal fluid or peritoneal or sensitive requiring as little as 100 organisms ml–1
tubal biopsy from tubercles are subjected to smear while PCR may be positive in presence of as low as
examination for AFB and culture on Lowenstein – 1-10 organisms ml.-1 However, PCR has its own share
Jensen (LJ) medium taking upto 6 to 8 weeks to of disadvantages; it can be false negative due to
provide results. The positive yield of LJ culture was contamination with heparin or high salt concentration
found to be 57% while guinea pig inoculation showed of specimen which may interfere with PCR results.
positive results in only 11% cases in endometrial TB As it can’t distinguish between live and killed bacilli,
cases.26 The latter is not done any more these days as there is a small risk of false positive results. Some
sophisticated culture media are available. authors have advised that PCR should not be used
Sheth et al27 have highlighted the lack of diagnostic for rapid diagnosis of TB. Because of insufficient
value of guinea pig test for diagnosis of TB. While LJ reliability, results obtained by PCR should be used
culture has a low sensitivity (30-35%), the radiometric neither to initiate nor to stop ATT.30 In authors’
culture BACTEC 460 developed by Becton Dickinson experience, false positivity of PCR is high as it can
based on generation of radioactive carbon-dioxide pick up even single M. tuberculosis and may not be
from substrate palmitic acid has a higher sensitivity able to differentiate between infection and disease as
(80-90%) with quicker results (5-10 days) and is most of Indian people may show positive PCR
particularly useful for drug susceptibility testing and without suffering from the disease. It is our policy
is particularly suited for genital TB and multidrug not to start ATT just on the basis of positive PCR
resistant TB.28 Other rapid diagnostic methods are unless there is some other evidence of FGTB on
Mycobacteria growth inhibitor tube (MGIT, clinical examination or on investigations like presence
Radioactive detection system using fluorochromes), of tubercles or other stigmata of TB on laparoscopy.
MB/BACT (colorimetric detection of bacterial 6. Imaging Methods
growth), Septi-chek system. The growth can be a. Ultrasonography (USG): Being noninvasive and
established by rapid methods based on lipid analysis with no radiation hazard, USG can be used in
and specific gene probes, PCR-RFLP methods and diagnosis of FGTB and may show bilateral solid
ribosomal RNA sequencing.28 However, all these tests adnexal masses with scattered small calcifications
are expensive and are not routinely available and are with free fluid in pouch of Douglas.6,7,14 However,
only performed in research settings or for culture in absence of pelvic masses, USG has a very limited
sensitivity in MDR-TB. role in diagnosis of genital TB.22
Polymerase Chain Reaction (PCR): It can be done b. Computerized axial tomography (CT scan): It is a
on menstrual blood or endometrial or peritoneal useful modality for pelvic and abdominal masses
biopsy. It is a rapid, sensitive and specific molecular especially when the lesion may resemble malignant
biological method for detecting mycobacterial DNA ovarian tumour. In TB, there is low density ascites,
in both PTB and EPTB samples from suspected TB multiple pelvic, abdominal, hepatic or splenic
patients. PCR assays targeting various gene segments lesions with or without lymphadenopathy
including a 65 k Da protein encoding gene, the IS 6110 especially in young infertile women (Fig.19.2).6,7,14
element and the mpt 64 gene.28 Bhanu et al29 studied In fallopian tube TB or ovarian TB, CT scan may
samples from endometrial aspirates, endometrial help in delineation of tubo-ovarian masses.22
biopsies and fluid from the pouch of Douglas from c. Magnetic resonance imaging (MRI): It is used more
25 women with infertility suspected to be suffering often in modern gynecology in presence of
from genital TB on laparoscopic findings for the abdominal and pelvic masses and has better
presence of mpt 64 gene of M. tuberculosis. Over all resolution than CT scan and may avoid the
PCR demonstrated M. tuberculosis DNA in 56% cases necessity of laparotomy as the differential
compared to 1.6% smear positive and 3.2% culture diagnosis is usually from ovarian tumor. The
positive cases. PCR was positive in all women with presences of hypodense masses with rim
laparoscopic findings suggestive of TB, in 60 % of those enhancement abutting the pelvic walls are
with probable diagnosis, in 33% of those with suggestive of TB (Fig.19.3).22
incidental findings and even in one case with normal 7. Blood Markers in Genital TB: CA 125 is a useful
laparoscopic findings. 30 They recommended a tumor marker for epithelial ovarian cancer in which
combination of PCR with the other available levels are markedly raised (normal levels < 35 U/ml).
techniques for achieving sufficient sensitivity and However, it is a nonspecific marker and is also raised
specificity for the diagnosis of FGTB. Microscopic in endometriosis and in genital TB. Usually, the levels
268
Fig. 19.2: CT scan finding in genital tuberculosis: CT scan image showing Fig. 19.3: MRI finding in genital tuberculosis: MRI film showing bilateral
multiple retroperitoneal lymphadenopathy with mesenteric lymph node tubo-ovarian masses her laparoscopic surgery revealed and 6 cm sized
enlargement in patient with genital koch’s tuboovarian abscess, filled with turbid pus
in genital TB are only moderately raised (usually

< 200 U/ml) and CA 125 is not a very reliable marker
for diagnosis of FGTB.
8. Endoscopy
Laparoscopy: A laparoscopy is the most reliable tool
to diagnose genital TB especially for tubal, ovarian
and peritoneal disease. 10 Morphological abnor-
malities of the fallopian tubes can be seen directly.
The various abnormalities of genital TB on
laparoscopy by different authors are shown in Table
19.4 and are as follows:10,31,36
1. In sub acute stage: There may be congestion, edema
and adhesions in pelvic organs with multiple fluid
filled pockets. There are miliary tubercles, white
Fig. 19.4: Laparoscopy showing multiple tubal block with beaded
yellow and opaque plaques over the fallopian appearance in a proven case genital Koch (For color version see
tubes and uterus. Plate 6)
2. In chronic stage: There may be following abnor-
malities:
a. Yellow small nodules on tubes (nodular
salpingitis).
b. Short and swollen tubes with agglutinated
fimbriae (patchy salpingitis) or beaded tubes
with multiple blocks (Fig. 19.4).
Table 19.4: Laparoscopic findings in genital

tuberculosis10, 31-36
S. No. Laparoscopy finding Percentage
1. Normal finding 0-10
Fig.19.5: Large hydrosalpinx (Laparoscopy finding in genital
2. Tubercles on tubes/peritoneum 30-100
tuberculosis) (For color version see Plate 6)
3. Caseation/granulomas 20-100
4. Beaded tubes 32-48 c. Unilateral or bilateral hydrosalpinx with retort-
5. Blocked tubes 45-50
shaped tubes due to agglutination of fimbriae
6. Adhesions 47-100
(Figs 19.4 and 19.5).
7. Hydrosalpinx 32-100
8. Tubo-ovarian Mass 15-54 d. Pyosalpinx or caseosalpinx : The tube (usually
9. Encysted effusions 2.5-60 bilateral is distended with caseous material with
10. Fitz Hugh Curtis Syndrome 30-45 ovoid white yellow distension of ampulla with
poor vascularization
269
e. Adhesions: Various types of adhesions may be DOTS (Directly observed treatment short-course):
present in genital TB covering genital organs American Thoracic Society 38 and British Thoracic
with or without omentum and intestines. The Society and NICE (National Institute of Clinical
adhesions are usually vascular and it has been Excellence) Guidelines (2006)39 recommend that first
the author’s experience that adhesiolysis in such choice of treatment should be the ‘standard
women may be associated with significant recommended regimen’ using a daily dosing schedule
bleeding and there is risk of injury to the bowel using combination tablets and does not consider DOTS
in presence of dense adhesions. Even peritoneal necessary in management of most cases of TB in
biopsy from the lesions can cause excessive developed countries who can adhere to treatment and
bleeding and needs careful hemostasis with recommend DOTS only for street and shelter dwelling
cautery. homeless people with active TB or patients likely to have
Various other abnormalities on laparoscopy in genital poor adherence. DOTS was vociferously argued for by
TB include adhesions, granuloma, plaques, exudates, WHO after declaring TB a global emergency in 1993.
tubo-ovarian masses and pelvic congestion in upto 88.6% Poor compliance with standard long-term treatment
cases.36 Mittal et al10 observed dilated, tortuous and regimens compounded by over crowding, poor living
blocked fallopian tubes (32.5%), peritubal and conditions in low socioeconomic situations has fuelled
periovarian adhesions (45%), omental adhesions (45%) the epidemic of multidrug resistant (MDR-TB) in parts
and bowel adhesions (37.5%) with more than one type of of the world. To prevent MDR and for better results,
lesions in many women in 40 proven genital TB cases.36 DOTS strategy has been proven to be cost effective
Sharma et al11,12 also observed very high prevalence (48%) throughout the world. The patient is first categorized
of Fitz–Hugh–Curtis syndrome on laparoscopy in FGTB to one of the treatment categories and is then given
cases. treatment as per guidelines for national programs by
The final diagnosis is made from good history taking, WHO (Table 19.5).40
careful systemic and gynecological examination and Genital TB is classified under category 1 being
judicious use of diagnostic modalities like endometrial seriously ill extrapulmonary disease. As M. tuberculosis
biopsy in conjunction with imaging methods and divides very slowly (18 hours), thrice weekly treatment
endoscopic visualization especially with laparoscopy. is as effective as daily treatment. However, it must be
Some authors have developed an algorithm for accurate reiterated that intermittent treatment can only be given
diagnosis of FGTB by combining history taking, under direct observation as even one dose should not be
examination and investigations.36 missed to avoid development of MDR disease. After
diagnosis of FGTB is made and decision to start ATT by
TREATMENT the treating physician is made, she should be sent to a
DOTS center near her area of residence, as in India whole
Medical Treatment country is now under DOTS strategy. To ensure quality
Treatment and care should take into account each assured drugs in adequate doses a full 6 months course
pack box is booked for an individual patient in the DOTS
patient’s individual needs and preferences and she only
center. The woman is given a fixed drug combipack (FDC)
should make informed decision about her care and
of isoniazid (INH), rifampicin, pyrazinamide and
treatment. Good communication between health care
ethambutol thrice a week for first 2 months (intensive
professionals and patient is essential, supported by phase) under direct observation in front of a health worker
evidence-based information and should be tailored to the at DOTS center. Compliance is ensured by the DOTS
needs of the individual patient. Treatment, care and center providers of the center by reaching the homes of
information should be culturally appropriate and the care any defaulters. In the continuation phase, she is given a
takers and relatives should be involved in the care with combination blister pack of isoniazid and rifampicin thrice
the consent of the patient. Multiple drug therapy in a week for next four months with at least one of the weekly
adequate doses and for sufficient duration is the main dosage administered under direct observation and
stay in the treatment of TB including FGTB. In olden days compliance is ensured by seeing empty blister packs
before rifampicin, the antituberculous therapy (ATT) was brought by the patient on each weekly visit.
given for 18 to 24 months with significant side effects Rarely FGTB cases can have relapse or failure
and poor compliance. The development of short-term, categorizing them into category II (Table 19.5). The
cost effective chemotherapy for TB was a major diagnosis of all such cases should be made by the
achievement for clinical medicine. Short-course attending physician and should be supported by culture
chemotherapy for 6 to 9 months has been found to be or histological evidence of current active TB in these
effective for medical treatment of FGTB.36,37 cases. Such women are categorized as others in category
II and are given treatment accordingly which includes
270
Table 19.5: Category-wise treatment regimens for tuberculosis including FGTB21,40,41

TB diagnostic TB patients TB treatment regimens
category Initial phase Continuation phase
(daily or 3 times weekly) (daily or 3 times weekly)
I New smear-positive patients. 2HRZE 4HR
New smear-negative pulmonary TB
with extensive parenchymal involvement.
Severe concomitant INH 600 mg
HIV disease or severe forms of Rifampicin 450 (600 mg Rifampicin 450 (600 mg
extrapulmonary TB (FGTB included) if > 50 kg) if > 50 kg) for 4 months
Pyrazinamide 1500 mg
Ethambutol 1200 mg for
2 months
II Previously treated sputum smear- 2 HRZES/IHRZE 5 HRE
positive pulmonary TB: Dose RHZE as in Dose
Relapse (FGTB included) category I above. INH 600 mg
Treatment after default (FGTB Injection streptomycin Rifampicin 450
included) 0.75 gm daily or thrice (600 mg if >50 kg)
Treatment failure (FGTB included) weekly (DOTS) for 2 Ethambutol 1200 mg
months followed by 1 for 5 months
month of RHZE
III New smear-negative pulmonary TB 2HRZ 4HR
(other than in Category 1). Less severe
form of extrapulmonary TB
IV Chronic and MDR-TB cases (still Drug Dose (mg) Dose (mg)
sputum-positive after supervised if weight if weight
re-treatment/or culture positive or < 45 kg > 45 kg
histopathologically proven FGTB).
Kanamycin (IM) 500 750
Ofloxacin (O) 600 800
Ethionamide (O) 500 750
Pyrazinamide (O) 1250 1500
Ethambutol (O) 800 1000
Cycloserine (O) 500 750
Ethionamide (O) 500 750
Ethambutol (O) 800 1000
IM = Intramuscular
O = Oral
two months intramuscular injections of streptomycin tablet of ethambutol (800 mg) plus isoniazid 300 mg at a
thrice weekly along with other four drugs (RHZE) of very economic price which has to be taken every day for
category I under direct supervision of DOTS center health two months, followed by combination of rifampicin (450
worker for first two months followed by four drugs mg if body weight <50 kg, 600 mg if >50 kg) and isoniazid
(RHZE) thrice a week for another month (Intensive 300 mg, as a combipack to be taken daily at a very
phase). The continuation phase is with three drugs economic price.
isoniazid (H), rifampicin (R) and ethambutol (E) thrice a
week for another 5 months with at least one of the three
times a week dose being administered under direct
Monitoring
observation. Most girls tolerate ATT safely. They should be counseled
about the importance of taking ATT regularly and
Alternative Treatment (Non DOTS) consumption of good and nutritious diet during ATT and
For the adolescent girls who want to buy their medicines, should report in case of any side effects of the drugs.
daily treatment is given. Convenient market, combipacks Liver function tests are no longer done regularly unless
are available containing one capsule of rifampicin (450 there are symptoms of hepatic toxicity. Similarly
mg), two tablets of pyrazinamide (750 mg each), one pyridoxine is not routinely prescribed with ATT unless
271
there are symptoms of peripheral neuropathy with HIGHLIGHTS

isoniazid. Rarely hepatitis can be caused by isoniazid,
• One of the important causes of infertility is
rifampicin and pyrazinamide and optic neuritis by
tuberculosis of the reproductive system. This
ethambutol and auditory and vestibular toxicity by problem is preventable as its diagnosis in
streptomycin in which case the opinion of an expert adolescence is possible by doing ultrasound of
should be sought for restarting the ATT in a modified abdomen. The pulmonary tuberculosis with which
form. these children present is treated for 6 months under
RNTCP program of Government of India. However,
Surgical Treatment involvement of the reproductive organs would
require longer treatment. If these children (females)
The medical therapy especially the modern short-
are given only short-course therapy under RNTCP,
course chemotherapy consisting of rifampicin and
they need better follow-up and under the different
other drugs, is highly effective for the treatment of
categories of treatment, these children would require
FGTB with rare need of surgery. In spite of surgery,
longer treatment, i.e. category II or may be I under
full course of ATT has to be given. With modern short-
the program conditions.
course chemotherapy, need for surgery is very rare. Even
• The infertility can be a tell tale mark of pulmonary
fistulas heal spontaneously on ATT.20 Similarly, MDR
tuberculosis in adolescence or earlier age period or
disease needs treatment with DOTS Plus regimen rather
other types of TB. Now enough data is available to
than surgery for best results. There are also much higher
show that almost 40% of children in the age groups
chances of complications during surgery in women with
10-18 years of age have fulminant pulmonary
genital TB like increased perforation rates in
tuberculosis of the adult type, may be sputum-
hysteroscopy, more bleeding during adhesiolysis on
positive or negative but with massive changes in
laparoscopy and excessive hemorrhage and non
chest X-ray. Probably this group (females) can be
availability of surgical planes at time of laparotomy with
screened by ultrasound abdomen to see the changes
higher risks of injury to the bowel and other pelvic and
in the uterus, fallopian tubes and ovaries for
abdominal organs. In a case of abdominopelvic TB, bowel
tuberculosis necessitating, optimum (9 months)
loops may be matted together with no plane between
antituberculosis chemotherapy to them.
them and uterus and adnexa may be buried underneath
• The diagnostic work up of extrapulmonary TB in
the plastic adhesions and bowel loops and are
adolescent girls as a routine also must have an
inapproachable. Even trying to perform a diagnostic
ultrasound of the abdomen for diagnosis of TB of
laparoscopy or laparotomy in such cases can cause injury
reproductive organs. Treated appropriately to
to bowel necessitating a very difficult laparotomy and
prevent this becoming a cause of infertility in future
resection of injured bowel. It is better to just take biopsies
in these girls.
from the representative areas and close the abdomen
without pelvic clearance in such girls opened for ovarian
tumor but found to be tubercular at laparotomy and give REFERENCES
them full ATT. However, limited surgery like drainage
of abscess from pelvis or tubo-ovarian abscesses, 1. Dye C, Watt CJ, Bleed DM, et al. Evolution of tuberculosis
pyosalpinx can be performed followed by ATT for better control and prospects for reducing tuberculosis
results. incidence, prevalence and deaths globally. JAMA
American Thracic Society5,6 only recommends surgery 2005;293:2790-3.
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authors’ experience women undergoing surgery WHO/ TB/ 94.177. Geneva: World Health Organization,
1994.
(Laparotomy, hysterectomy, laproscopic surgery, etc) with
3. Sharma S, Sarim R, Khalid UK, et al. The DOTS strategy
pelvic and peritoneal TB bleed much more than other
for treatment of pediatic pulmonary tuberculosis in South
women. Delhi, India. Int J Tuberc Lung Dis 2007;11:74-80.
4. Sharma S, Sarin R, Khalid UK, et al. The DOTS strategy
Future of TB Research for treatment of pediatric tuberculosis lymphadenitis. Int
There has been a renewed interest in research in TB at J Tuberc (In Press).
global level.41 New drugs are needed to treat TB because 5. Sharma S, Sarin R, Khalid UK, et al. The DOTS strategy
for treatment of pediatric tuberculosis pleurisy. Int J
the current drugs combinations have significant
Tuberc (In Press).
disadvantages.42 New drugs, effective against strains that 6. Kumar S. Female genital tuberculosis. In: Sharma SK,
are resistant to conventional drugs and requiring a Mohan A (Eds). Tuberculosis, 2nd edn. Delhi: Jaypee
shorter treatment regimen are being developed. Medical Publishers (Pvt) Ltd., 2009;463-78.
272
7. Sharma JB. Female genital tuberculosis revisited. Obstet antibody based sandwiched enzyme linked immuno-
Gynaecol Today 2007;12:61-3. sorbent assay (ELISA). Tuber Lung Dis 1993;74:200-3.
8. Schaefer G. Female genital tuberculosis. Clin Obstet 26. Seward PG, Mitchel RW. Guinea pig inoculation and
Gynaecol 1976;19:223-39. culture for mycobacteria in tuberculosis in infertile
9. Tripathy SN. Laparoscopic observations of pelvic organs in women. A study of cost effectiveness. S Afr Med J
pulmonary tuberculosis. Int J Gynecol Obstet 1990:32: 1985;67:126-9.
129-31. 27. Sheth SS. Lack of diagnostic value of guinea pig test for
10. Gupta N, Sharma JB, Mittal S, et al. Genital tuberculosis tuberculosis. Lancet 1991;337:124.
in India infertility patients. Int J Gynecol Obstet 28. Katoch VM. Newer diagnostic techniques for
2007;97:135-8. tuberculosis. Indian J Med Res 2004;120:418-28.
11. Sharma JB, Malhotra M, Arora R. Fitz-Hugh-Curtis 29. Bhanu NV, Singh UB, Chakraborty M, et al. Improved
syndrome as a result of genital tuberculosis: A report of diagnostic value of PCR in diagnosis of female genital
three cases. Acta Obstet Gynecol Scand 2003;82:295-7. tuberculosis leading to infertility. J Med Microbiol
12. Sharma JB, Roy KK, Mittal S, et al. High prevalence of 2005;54:927-31.
Fitz-Hugh-Curtis syndrome in female genital 30. Grosset J, Mouton Y. Is PCR a useful tool for the diagnosis
tuberculosis. Int J Gynecol Obstet 2007;99(1):63-3. Epub of tuberculosis in 1995? Tubercl Lung Dis 1995;76:183-4.
2007, Apr 24. 31. Bhide AG, Parulekar SV, Bhattacharya MS. Genital
13. Schaefer G. Tuberculosis of the genital organs. Am J tuberculosis in females. J Obstet Gynaecol Ind
Obstet Gynecol 1965:91:714-20. 1987;37:576-8.
14. Arora R, Rathore A. Female genital tract tuberculosis. In: 32. Parikh F R, Nadkarni S G, Kamat S A, et al. Genital
Arora VK, Arora R (Eds). Practical Approach to tuberculosis: A major pelvic factor causing infertility in
Tuberculosis Management, 1st edition. Delhi: Jaypee, Indian women. Fertil Steril 1997;67:497-500.
2006;113-9. 33. Kumari C, Sinha S. Laparoscopic evaluation of tubal
15. Sharma JB, Pushparaj M, Mittal S, et al. Genital tuber- factors in cases of infertility. J Obstet Gynaecol Ind
culosis: An important cause of Asherman’s syndrome in 2000;50:67-70.
India. Arch Obstet Gynecol Arch Gynecol Obstet 34. Tripathy SN, Tripathy SN. Infertility and pregnancy
2008;277:37-41. outcome in female genital tuberculosis. Int J Gynecol
16. Bazaz–Malik G, Maheshwari B, Lal N. Tuberculosis Obstet 2002;76:159-63.
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Br J Obstet Gynaecol 1983:90:84-6. in female genital tuberculosis. Arch Gynecol Obstet 2008
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Int J Gynecol Obstet 2000;68,263-4. 36. Jindal UN. An algorithmic approach to female genital
18. Barutcu O, Erel HE, Saygili E, et al. Abdominopelvic tuberculosis causing infertility. Int J Tuberc Lung Dis
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Imaging 2002;27:465-70. analysis of short course chemotherapy in female genital
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Ind 2001:51:176. 39. National Institute for Health and Clinical Excellence.
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25. Rattan A, Gupta SK, Singh S, et al. Detection of antigens
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of M. tuberculosis in patients of infertility by monoclonal
2005;293:2705-7.
20 Endocrine Manifestations of
Tuberculosis
Anju Seth, Rajni Sharma
The clinical endocrine manifestations of tuberculosis may Table 20.1: Endocrine manifestations of tuberculosis
be due to tubercular involvement of the particular
Organ Endocrine manifestation
endocrine organ or the result of chronic illness due to
systemic disease (Table 20.1). Chronic illness due to Short stature
systemic tuberculosis Failure to thrive
Delayed puberty
ENDOCRINE EFFECTS OF TUBERCULOSIS DUE TO (hypogonadotrophic
CHRONIC SYSTEMIC DISEASE hypogonadism)
Sick euthyroid syndrome
Any prolonged systemic illness, including tuberculosis
CNS tuberculosis Syndrome of Inappropriate
can result in growth failure affecting the weight and
Tubercular meningitis Antidiuretic Hormone
ultimately the height. Hence tuberculosis should be ruled (SIADH)
out in any child presenting with growth faltering or short Cerebral salt wasting
stature, especially if accompanied with a low weight for Diabetes insipidus
height. History and examination generally provide clues Growth hormone
to the diagnosis. deficiency
Chronic illness due to systemic TB is also associated with Delayed puberty
delayed puberty due to delayed activation of hypothalamo- (hypogonadotrophic
pituitary-gonadal axis. In adult males serum testosterone hypogonadism)
levels have been reported to fall due to impaired pulse ACTH deficiency
Obesity (hypothalamic
frequency of LH release. In a study of 50 adult patients with
hyperphagia)
active pulmonary TB, 72% males had hypogonadotrophic
Hydrocephalus
hypogonadism.1 Suprasellar/sellar Precocious puberty
Sick euthyroid syndrome is often present in tuberculoma Hypopituitarism
tuberculosis with one study showing a 92% prevalence Adrenal tuberculosis Adrenal insufficiency
in adult patients with pulmonary TB.1 It is characterized Thyroid tuberculosis Goiter
by low free T3, normal or low free T4 state with low or Thyroid nodule
normal (rarely high) TSH. The exact mechamism Hyperthyroidism
underlying this low thyroid hormone state is not known * Pancreatic tuberculosis
but may represent reduced hypothalamic stimulation Genitourinary
leading to reduced stimulation of the thyroid gland. Low Testicular Infertility
Ovarian Infertility
thyroid hormone levels in protracted illness may
Primary amenorrhea
represent an adaptive or protective mechanism against a
Secondary amenorrhea
hypercatabolic state.2 Menstrual abnormalities
CNS TUBERCULOSIS * Diagnosis by examination of pathological specimen
CNS tuberculosis due to tubercular meningitis

or tuberculomas results in varied endocrine manifesta- common cause, i.e. syndrome of inappropriate
tions apart from the neurological deficits. antidiuretic hormone (SIADH).3,4 Nevertheless, it is
important to rule out other causes of hyponatremia such
as cerebral salt wasting or adrenal insufficiency because
Tubercular Meningitis (TBM)
restriction of fluids (to treat a wrong diagnosis of SIADH)
Hyponatremia (serum Na + <135 mmol/l) is often may prove fatal in these cases. 5 Mechanisms
observed in TBM with a reported incidence of 65%3 in for development of SIADH consist of meningeal
some studies and prompts one to think of the most inflammation resulting in leakage of ADH from the
274
posterior pituitary, excretion of ADH from granulomas, The classical manifestation of hypothalamic lesions
and brain edema with raised intracranial tension. SIADH is Frohlich syndrome consisting of short stature, obesity,
is essentially a diagnosis of exclusion and one has to rule hypogonadism and delayed puberty.11 Hypothalamic
out other conditions that may lead to hyponatremia like lesions may also result in isolated obesity due to hyper-
renal, adrenal and thyroid insufficiency, congestive heart phagia. In contrast, lesions of the posterior hypothalamus
failure, nephrotic state, cirrhosis, diuretric use or which usually inhibits pituitary gonadotrophin release,
dehydration. The urine osmolarity is high, usually can result in central precocious puberty. This may be due
greater than 100 mosm/l and urine Na+ is greater than to direct involvement of the hypothalamus or due to
25 mmol/l. The treatment consists of restricting pressure effect of hydrocephalus.
intravenous fluids to two-third maintenance with careful
avoidance of hypovolemia. Pituitary Tuberculoma
Cerebral salt wasting syndrome (CSWS) has been
reported with a variety of cerebral lesions including Tuberculoma of the sellar and parasellar region is extremely
TBM.6,7 It is defined as renal loss of sodium due to rare and presents as a mass lesion with panhypopituitarism,
intracranial disease leading to hyponatremia, natriuresis, headache, raised intracranial pressure and vision loss. The
dehydration in response to volume and salt replacement. diagnosis is often made by biopsy of the lesion which reveals
Increased serum brain natriuretric peptide levels is the a granulomatous inflammatory lesion with epitheloid and
most likely of CSWS. In CSWS, the patient is volume Langhans giant cells with central caseous necrosis consistent
with the diagnosis of tuberculosis. Demonstration of AFB
depleted with postural hypotension whereas in SIADH
on staining or after culture is rare from these lesions. In a
the patient is euvolemic. Serum osmolarity is decreased
case series of 18 patients with pituitary tuberculoma, 6 were
in both but urine output is increased and urine sodium
under 18 years of age with a female preponderance.12 Only
is extremely higher in CSWS. Serum uric acid and urea
one third of the patients had a past history of tuberculosis
are normal or raised in CSWS but decreased in SIADH.5 or coexistent TB elsewhere.12 Pituitary tuberculomas are
Treatment of CSWS consists of aggressive volume and seen on computed tomography as an intrasellar enhancing
salt replacement with isotonic fluids. Acute hyponatremia mass indistinguishable from pituitary adenoma. MRI may
that has developed rapidly at the rate of >0.5 mmol/l/hour reveal thickening of the pituitary stalk and dura at the skull
(due to either CSWS or SIADH) is treated aggressively as base. Extension of the lesion to the sphenoid sinus and
death may result from cerebral edema and herniation. involvement of the clivus are other supportive evidence
Unlike chronic hyponatremia, rapid treatment is associated for the diagnosis of tuberculosis. A preoperative diagnosis
with marked neurological improvement and less of pituitary tuberculoma may do away with the need of
danger of cerebral pontine myelinolysis. The mineralo- surgery unless required for neurological or vision loss. PCR
corticoid fludrocortisone helps in distal tubular sodium for M. tuberculosis DNA done on the surgical specimen can
resorption and may be helpful to reverse the sodium also aid in the diagnosis.
wasting in CSWS. It is used in a dose of 0.2 to 0.4 mg per
day with careful watch for side effects like hypertension ADRENAL TUBERCULOSIS
and hypokalemia. Thomas Addison first described autopsy findings in 6
patients with adrenal tuberculosis in 1855 and it
Sequelae of TBM continues to be the most important cause of adrenal
Long-term sequelae of TBM in the form of granulation insufficiency in the developing world. In a study from
tissue or calcification may affect the hypothalamic- India, tuberculous etiology was ascribed to 47% of adult
pituitary axis resulting in various endocrine mani- patients of Addison’s disease.13 In another study from
China, review of autopsy findings in adult patients with
festations years later. Involvement of the posterior
tuberculosis revealed that out of 871 cases of tuberculosis,
pituitary leads to central diabetes insipidus.8,9
adrenal involvement was found in 52 (6%).14 Among
Deficiency of one or more anterior pituitary hormones
those with adrenal tuberculosis, isolated adrenal gland
may be due to direct involvement of the pituitary or of
involvement was seen in 25%.
its stimulatory input from the hypothalamus. In a Adrenal insufficiency manifests with weakness,
retrospective study of 49 patients with TBM in childhood, weight loss and hypotension. Progressive hyper-
10 had hypothalamic-pituitary dysfunction on invest- pigmentation may be noticed by the patient. Laboratory
igation in follow-up.10 Growth hormone deficiency was findings consist of hyponatremia, hyperkalemia and
most commonly observed followed by gonadotropin hypoglycemia. Low morning serum cortisol levels and
deficiency. Other abnormalities consisted of hyper- failure of cortisol to rise with ACTH (Synacthen) injection
prolactinemia and ACTH deficiency. is diagnostic.
275
Chapter 20 Endocrine Manifestations of Tuberculosis
Early in the course of adrenal TB, CT findings consist of pancreatic tuberculosis was reported.20 It is postulated
of unilaterally or bilaterally enlarged adrenals. The normal that mycobacterium may be destroyed by the pancreatic
contor of the gland is distorted. Central caseous necrosis enzymes making the pancreas relatively resistant to
appears as a hypodense area.15 On contrast administration tubercular infection. Three forms of mycobacterial
there is a heterogenous uptake by the mass with peripheral infection of the pancreas have been described (1)
rim enhancement. Free fluid may be present in the Generalized (miliary) TB due to M. tuberculosis (2) Spread
abdomen. 16 In addition to tuberculosis, adrenal to the pancreas from celiac and other retroperitoneal
enlargement may rarely be due to other causes like fungal nodes due to M. bovis infection (3) Localized pancreatic
infection, hemorrhage or malignancy. Once chronic TB due to M. tuberculosis secondary to primary tubercular
tubercular sequelae set in, CT scan reveals atrophic or infection of the intestinal tract. The presenting symptoms
normal size adrenals with calcification.15 Extra-adrenal of pancreatic TB include abdominal pain, abdominal
tuberculosis is present in up-to half the patients of mass, anorexia, weight loss, fever, back pain and
tubercular adrenal insufficiency which may aid in the jaundice. Ultrasound examination shows a hetero-
diagnosis. Therapeutic trial of antitubercular drugs, CT genously echoing mass in the head of the pancreas. CT
guided aspiration biopsy and follow-up CT scans help to scan shows a pancreatic mass with heterogenous opacity
confirm the diagnosis of tuberculous infection. with or without calcification of the pancreas and
Acute adrenal crisis should be managed with peripancreatic nodes. Less than half the patients have
intravenous fluids and parenteral hydrocortisone 100 past history of tuberculosis or evidence of pulmonary
mg/m2 is divided doses. Maintenance therapy is with tuberculosis on chest X-ray. The diagnosis is made by
hydrocortisone at 10 mg/m2 and mineralocorticoid the pathological specimen obtained during laparotomy/
fludrocortisone to augment blood pressure. Overall, the laparoscopy or ultrasound guided fine needle aspiration
prognosis for adrenal tuberculosis is good with low which shows caseating granulomas with or without
mortality provided regular medical follow-up is ensured. organisms on acid fast staining. 21,22 DNA of M.
tuberculosis may be demonstrated by PCR reaction or on
THYROID TUBERCULOSIS culture. It may often be difficult to diagnose and
distinguish pancreatic TB from a pancreatic tumor. A
Thyroid tuberculosis is a rare condition even in countries preoperative diagnosis if made, may obviate the need
with high prevalence of tuberculosis. In one case series for surgery since the disease is effectively treated with
from India, out of 353 thyroidectomies performed for an antitubercular drugs.
enlarged thyroid, only 3 specimens showed evidence of
thyroid TB on histopathology.17 This may be because the GENITAL TUBERCULOSIS
thyroid gland is said to be relatively resistant to tubercular
invasion due the lack of reticuloendothelial cells. Female Genital Tuberculosis
There are two types of tuberculosis of the thyroid- Female genital tuberculosis is common in countries with
miliary and caseating. The miliary type is commoner, and high incidence of tuberculosis. Genital tuberculosis most
is seen at autopsy in association with generalized miliary often involves the fallopian tubes (95-100%), uterine
TB. The caseating type can present with goiter, isolated endometrium (50-60%) or ovaries(20-30%). This results in
nodule of the thyroid or thyrotoxicosis.18,19 The lesion tubal dilatation and block, endometrial synechiae, peritubal,
periovarian, omental and bowel adhesions.23 In 92% of cases
may grow rapidly and cause pain and pressure
genital tuberculosis is secondary to a focus in the lungs,
symptoms like dyspnea, dysphagia and dysphonia. A
lymph nodes, urinary tract, bones or joints. The clinical
slow inflammatory process causing caseation necrosis manifestations range from primary or secondary infertility
may also result in abscess formation. The diagnosis is (45-55%), pelvic pain (50%), menstrual abnormalities (20%)23
made by fine needle aspiration cytology of the thyroid.19 to primary or secondary amenorrhea. Tubercular etiology
If the diagnosis is not made earlier, the patient may be was implicated in 6.3% of cases of primary amenorrhea seen
operated for a suspicion of thyroid malignancy and the at a tertiary care hospital24and 5 to 10% of infertility cases.23
postoperative specimen may give the diagnosis. As many as a quarter of patients may have a past history of
tuberculosis. Diagnosis is made by a combination of
PANCREATIC TUBERCULOSIS ultrasonography, hysterosalpingography, laparascopic
findings and pathology. Demonstration of AFB by stain/
Abdominal infection with tuberculosis commonly affects culture or M. tuberculosis DNA. PCR on endometrial
the spleen, liver and ileocecal region. Pancreatic histopathologic studies also aids in diagnosis. 25 The
tuberculosis is an extremely rare disease even in regions treatment consists of antitubercular therapy (ATT). Surgery,
with high prevalence of tuberculosis. In a case series of if required, should be undertaken only on completion of
300 patients of abdominal tuberculosis, not a single case ATT.
276
Male Genital Tuberculosis26 8. Haslem RHA, Winternitz WW, Howieson J. Selective

hypopituitarism following tuberculous meningitis. Am
The male genital organs most commonly affected by J Dis Child 1969;118:903-8.
tuberculosis are the epididymis and prostate; the testes 9. Shenoi A, Deshpande SA, Marwaha RK. Diabetes
are affected less commonly. The modes of infection insipidus and growth hormone deficiency following
include descending infection from the kidneys, direct tubercular meningitis. Ind Pediatr 1990;27:624-6.
invasion from the surrounding tissues and 10. Lam KSL, Sham MMK, Tam SCF, et al. Hypopitituitarism
hematogenous spread. The infection may mimic tumors, after tuberculous meningitis in childhood. Ann Intern
cysts and other infections of the genital tract. Med 1993;118:701-6.
11. Asherson RA, et al. Abnormalities of development
associated with hypothalamic calcification after tuberculosis
HIGHLIGHTS meningitis. Br Med J 1965; 2:839-43.
• Systemic tuberculosis can result in various endocrine 12. Sharma MC, et al. Intrasellar tuberculoma – an enigmatic
manifestations as a result of chronic disease and pituitary infection: a series of 18 cases. Clin Neurology
should be ruled out in all cases of growth faltering Neurosurgery 2000;102: 72-7.
and delayed puberty. 13. Agarwal G, Bhatia E, Pandey R, et al. Clinical profile and
prognosis of Addisons’s disease in India. Natl Med J India
• Isolated endocrine tuberculosis is infrequently seen,
2001;14:23-5.
but is a great mimicker of other diseases. It can 14. Lam KY, Lo CY. A critical examination of adrenal
manifest in a wide variety of ways and should be tuberculosis and a 28-year autopsy experience of active
considered in the differential diagnosis especially in tuberculosis. Clin Endocrinol 2001;54:633-9.
countries with high prevalence of tuberculosis. 15. Buxi TBS, Vohra RB, Sujatha, et al. CT in adrenal
• Endocrine manifestations are not uncommon in the enlargement due to tuberculosis: a review of literature
course of tuberculous meningitis. The clinician with five new cases. Clin Imaging 1992;16:102-8.
should be alert to the subsequent development of 16. MM Patnaik, Deshpande AK. Diagnosis– Addison’s
hypopituitarism in these patients. disease secondary to tuberculosis of the adrenal glands.
Clin Med Research 2008;6:1-29.
17. K Sivanagaman, G Suvarnakumari, CA Aruna, et al.
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19. Bulbuloglu E, Ciralik H, Okur E, et al. Tuberculosis of the
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Pediatr Infect Dis J 1991;10:837-42. 2004;74:368-71.
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tuberculosis – always the adrenals? Nephrol Dial genital tract. J Indian Med Assoc 1996;94:345-6.
Transplant 2008;23:393-5. 24. Kumar A, Mittal S. Primary amenorrhea: analysis of 48
6. Nagotkar L, Shanbag P, Dasarwar N. Cerebral salt cases. J Indian Med Assoc 1998;96:119-20.
wasting syndrome following neurosurgical intervention 25. Gupta N, Sharma JB, Mittal S, et al. Genital tuberculosis
in tuberculous meningitis. IInd Pediatr 2007;45:598-605. in Indian infertility patients. Int J Gynaecol Obstet
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21 Congenital Tuberculosis
Vimlesh Seth
INTRODUCTION All infants and health care workers who had

conversion of TST were given isoniazid prophylaxis.
Congenital tuberculosis is rare, inspite of tuberculosis Given the nonspecific nature of presenting signs and
being a common infection with around 300 cases reported
symptoms (because of lack of host response) and the fatal
worldwide till 1989.1 With the increase in the number of
outcome in the absence of early therapy, the importance
multidrug resistant tuberculosis and human immuno-
of early diagnosis is underscored and treatment often
deficiency virus (HIV) cases, there is resurgence of
delayed. Most important factor for early diagnosis is the
tuberculosis in women of reproductive age and in their
presence of tuberculosis in the mother. It is still
off spring. 58 more cases were reviewed by Abughali et
al1a in 1994. From 2001 to December 2005, 18 more cases documented in the literature as case reports only.23-26
have been reported. Even though tuberculosis among However, with increase in cases of multidrug resistant
pregnant women is not uncommon, documented cases of tuberculosis and HIV there is resurgence of tuberculosis
congenital TB are still rare. It is because placenta forms a in women of childbearing age and in children born to
protective barrier against the infection of the fetus by the them.27-29 Balaka et al30 have reported from Africa that
tuberculous organisms. It is assumed that infection has despite the rising prevalence of tuberculosis due in part
been acquired in utero, because of— (i) the age of the infant, to HIV pandemic in Africa, there have been few reports
(ii) absence of any known contact with an open case of TB describing neonatal or congenital tuberculosis. In a
and (iii) generalized dissemination of the disease. The risk prospective study, they investigated all neonates admitted
of TB in pregnancy has increased owing to recent changes to the teaching hospital for diagnosis of tuberculosis
in epidemiology of the disease which has led to an having symptoms compatible with tuberculosis. The
increased risk of congenital TB. Although a rare disease, clinical profile of tuberculosis in the newborn was
congenital TB should be distinguished from the more correlated with that of the mother with or without HIV
frequent neonatal TB, in which the infant is infected after infection, perinatal tuberculosis was diagnosed in 13 of 79
birth by an adult suffering from the disease. Congenital (about 16%) newborns investigated including 8 whose
TB may occur as a result of maternal TB when it involves mothers were co-infected by HIV and tuberculosis during
the genital tract or placenta. a two year study-period. Seven cases (almost 8%) were
In the decade spanning from 1995 to 2005 there have been classified as congenital tuberculosis.
a number of case reports with rare manifestations of this Diagnosis of maternal HIV and tuberculosis infection
disease2-4 Chotpitaysunondh and Sangtawesin5 have done was never made prior to the newborn’s admission to the
a retrospective analysis of nine patients in Thailand. They
ward. Four newborns and two mothers died within three
have described in detail the clinical features and
months after child birth.
investigations for confirming the diagnosis. Since 2005,
more than 20 cases have been described.6-21 Recent Recently in India31 from a private hospital in Delhi
reports6,8,9 have described congenital tuberculosis as case where comparatively patients with better socioeconomic
reports in preterm neonates born after in vitro fertilization. status are treated, a case of congenital tuberculosis was
These mothers had tuberculosis during pregnancy. reported diagnosed by liver biopsy in an eight week old
Mouchet et al 22 have investigated the risk of infant presenting with acute abdomen.
nosocomial transmission of tuberculosis among infants,
family members and health care workers (HCWs) caring PATHOPHYSIOLOGY
for a congenitally infected infant. In their prospective
study they used the conversion of tuberculin skin test Mode of Infection
(TST), X-ray chest for contact survey for diagnosis. Their
findings are briefly summarized below: Congenital tuberculosis is mostly described to be acquired
Category Number TST conversion % by two mechanisms: (i) Transplacentally gaining
Infants 97 40 hematogenous spread through the umbilical vein from an
HCWs 139 19 infected placenta to fetal liver and lungs and (ii) By
Visitors 180 Nil aspiration and swallowing of infected amniotic material either
278
in utero or during passage through the birth canal leading CLINICAL FEATURES
to primary infection in the lungs or gastrointestinal tract.
However, infection can also be acquired early in life by The age at the time of presentation has been noted to be
inhalation or ingestion of infected droplet from the few hours after birth to beyond neonatal period. The
mother or an open case among the family, friends or onset of illness in congenital tuberculosis may be hard to
caretakers. Often it is difficult to differentiate in a given define given that many of the signs and symptoms are
neonate whether the infection is truly congenital or nonspecific as illustrated in the earlier description.
acquired postnatally. Some authors would consider the Diagnosis in our setting should be suspected in (i) any
distinction between the two as primarily epidemiological neonate with persistent pneumonia or fever and
since the modes of presentation, treatment and prognosis hepatomegaly wherein the usual infective etiologies have
do not differ significantly.1,24 Transplacental infection been ruled out or (ii) in an infant with nonspecific
usually occurs late in the pregnancy when tubercle bacilli symptoms born to a mother suffering from tuberculosis.18
reach the fetal liver via umbilical vein leading to the A number of case reports,34-36 reviews and guidelines for
development of the primary focus with involvement of diagnosis and management of congenital tuberculosis
periportal lymph nodes. The bacilli may pass through have been given. Miller37 way back in eighties explained
the liver and hematogenously spread to lung, brain and the mode of transmission of tuberculosis and emphasized
adrenals forming multiple foci. However, only the the role of placenta as a barrier to the development of
primary complex in the liver is the sine qua non of congenital tuberculosis. From this, it may be derived that
congenital tuberculosis whereas all other lesions may be in spite of resurgence of tuberculosis due to associated
acquired either congenitally or postnatally.1 HIV/AIDS, and multidrug resistant tuberculosis there
Infection by the ingestion or inhalation of amniotic may not be a very large increase in the incidence of
fluid may occur when a caseous lesion the placenta congenital tuberculosis in normal newborns with good
ruptures directly into the amniotic cavity. This usually birth weight. However, the clinical suspicion should be
leads to multiple primary foci in the lungs or gut and strong and a newborn with pneumonia not responding
middle ear with enlarged bronchial or mesenteric lymph to usual effective antibiotic therapy, with significant
nodes or both. Middle ear involvement leading to hepatomegaly, can be a candidate of congenital
multiple perforations or total destruction of the tympanic tuberculosis. In Cantwell’s review38 of the 29 cases
membrane and otorrhea described in some reports is not published since 1980 revealed that median age at
surprising because eustachian tube in newborn permit presentation was 24 days (range 1 to 84).
ready access to pharyngeal fluids thus seeding the Pillet et al39 described three cases, one presenting at
tubercle bacilli.32 Involvement of the liver and parotid the age of 45 days with bilateral bronchopneumonia, the
gland are rare.33
second presented at the age of 22 days with respiratory
distress, icterus and hepatosplenomegaly. Both these
Condition of the Mother
babies in spite of starting isoniazid, rifampicin and
In developing countries in spite of rampant tuberculosis, pyrazinamide died due to multivisceral failure. In the
the cases of congenital tuberculosis are reported rarely. second child the postmortem liver biopsy confirmed the
It is because there are two ways in which the mother diagnosis of tuberculosis. The third child developed
suffers from tuberculosis during pregnancy: jaundice on day 4. He had opacities at the top of the right
i. There is disseminated infection; either with rapidly lung. This baby was given isoniazid, rifampicin and
progressive disease and hematog-enous spread with pyrazinamide as well. He also had hepatomegaly.
clinical illness.
Breastfeeding was stopped and the neonate had poor
ii. Recent primary infection and subclinical dissemi-
weight gain upto 25 days but later improved. Thus it is
nation.
emphasized that the frequency of congenital tuberculosis
In the first category miliary lesions can usually be
found in the placenta whereas in the 2nd category these is probably underestimated. Its early diagnosis is essential
are absent. In the European literature, the incidence of but often difficult as the early recognition of initial
tuberculosis in the infants of tuberculous women is very manifestation is often delayed. Hence, it is recommended
low because the caseous lesions are found in the placenta that improved screening of women at risk in the antenatal
and the infant usually escapes because the bacilli remain period can result in early diagnosis in the mother and
localized in the placenta and do not enter the infants the same in the newborn.
blood stream. From this background knowledge it is Another case report has been cited in French literature
worth doing histopathological examination of placenta by Pham et al40 in 1998. It has been highlighted by them
looking for caseous granuloma and acid fast bacilli in that congenital tuberculosis is an uncommon but
the developing countries. probably underestimated entity. All cases occurring in
279
Chapter 21 Congenital Tuberculosis
developing countries are not published. The diagnosis Table 21.1: Signs and symptoms noted in congenital
of congenital tuberculosis is different from postnatal tuberculosis
tuberculosis. Recently defined criteria are bacteriolo- • Main findings
gically proven tuberculosis in a newborn with at least – Respiratory distress
one of the following: – Fever
i. Specific hepatic granulomatosus. – Hepatic and/ or splenic enlargement
ii. Tuberculosis infection of the placenta or maternal – Poor feeding
– Lethargy and/or irritability
genital tract.
– Lymphadenopathy
iii. Exclusion of possible postnatal transmission. • Other findings
The most common presenting symptoms are – Abdominal distension
hepatosplenomegaly, respiratory distress, fever, growth – Failure to thrive
failure and lymphadenopathy. Besides, the other features – Skin lesions
described are lethargy, irritability, seizures, meningitis, – Obstructive jaundice due to glands in porta hepatis
– Seizures
ear discharge and jaundice.6-21, 28- 41 Berk and Sylvester2
– Meningitis is uncommon
have described a case of congenital tuberculosis – In a small percentage of cases, otitis media with or
presenting as progressive liver dysfunction, in the without mastoditis is the first sign of congenital TB.
absence of respiratory symptoms. Several uncommon
features were present, including petechiae, cutaneous ii. Primary complex in liver.
lesions, ascites and peritoneal fluid positive for AFB. iii. If primary complex is lacking in the liver, then tuber-
Another case of congenital tuberculosis has been culosis can be considered to be congenital only if:
described by Centers for Disease Control and Prevention a. Tuberculous lesions are present in a fetus or a few
(CDC).4 This child with the usual presentation of days old newborn.
respiratory distress and sepsis had a mother who was b. Or in an older infant, extrauterine infection can be
having cerebral tuberculosis. In this rare disease maternal excluded with certainty.
tuberculosis was associated. There are reports of cases Beitzke’s criteria are fully met by many of the reported
of congenital tuberculosis presenting as sepsis syndrome cases of congenital tuberculosis. These criteria are less
and septic shock.42,43 Mortality resulting from congenital applicable in the present day setting because of the higher
tuberculosis is very high. In most reviews it is about 50%. survival rates with proper chemotherapy. This is due to
Delay in diagnosis is a significant cause of mortality. In the difficulty in documentation of hepatic primary
Hageman’s review, 9 of the 12 patients who died were complex. This, as it involved an invasive procedure of liver
diagnosed at autopsy whereas of the 17 patients biopsy.38, 39 In the present day setting a carefully done
diagnosed antemortem 14 survived.35 Verma et al44 have ultrasound guided liver biopsy, demonstration of mesenteric
also emphasized that congenital tuberculosis is an under lymph nodes on CT scan and ultrasound of the abdomen
diagnosed entity. It has been highlighted by them that are available for early diagnosis. These should be done
diagnosis should be suspected early to have a favorable because it is a treatable condition and very gratifying.
outcome. Table 21.1 gives the signs and symptoms which The criteria for diagnosis of congenital tuberculosis
should alert the pediatrician to keep this diagnosis as as described by Beitzke in 193534 were modified by
not so rare an entity as thought until now. Miller37 into three types:
Fatality rate was 33.3% with no sequel in the 1. Neonates with a primary focus in the liver and a mass
survivors. Hence, it is suggested that newborn with at porta hepatis. Few of these patients may have a
pneumonia unresponsive to aggressive appropriate primary complex of the lung also.
antibiotics usually lumped as sepsis should be 2. Group that does not have a primary lesion in liver
aggressively investigated for congenital tuberculosis.44 but has a large number of tuberculous foci scattered
The pulmonary involvement can be so severe though throughout both the lung fields and caseation in hilar
rarely3 that the neonate may require extracorporeal
and mediastinal lymph nodes.
membrane oxygenation.
3. A group in which the mode of transmission of
infection is oropharyngeal, taking place at birth or
DIAGNOSTIC CRITERIA FOR CONGENITAL
shortly afterwards. This is a very rare presentation.
TUBERCULOSIS
The mode of infection in the first group is
In 1935, Beitzke34 presented the following criteria for the transplacental, whereas that of second and third group
diagnosis of congenital infection: is infection through aspiration of amniotic fluid, material
i. Bacteriological proof of tuberculosis by isolation of from the genital tract or mouth to mouth breathing by
M. tuberculosis from the infant. an infected adult at child’s birth. Of the 29 cases published
280
after 1980 only 3 met Beitzke’s criteria.34 Cantwell et al38 in upto 80% in Cantwell’s 38 review and the
in 1994 proposed revised criteria to address the abnormalities described were nonspecific. However,
limitations of Beitzke’s criteria. According to them, infant in Hageman’s 35 review about 50% infants had
must have proven tuberculosis lesions and at least one miliary pattern.
of the following: ii. Seth46 showed that tuberculin test in the infant is
i. Lesions in 1st week of life. often negative initially but it is still worth doing
ii. A primary hepatic complex or caseating hepatic because it is extremely important if reactive. The
granulomas. administration of BCG at birth may occasionally lead
iii. Tuberculosis infection of the placenta or the to false positive results.46 However, the size of
maternal genital tract. induration in babies after BCG vaccination is usually
iv. Exclusion of the possibility of postnatal transmission up to 5 mm and very few babies have 6 to 9 mm of
by a thorough investigation of contacts including induration. Seth has further emphasized that any
the infant’s hospital attendants or birth attendant. baby having more than 10 mm of induration after
The advantages of the revised criteria38 include tuberculin test should be considered as infected and
increased diagnostic sensitivity, better applicability in treated with antituberculosis drugs.46
iii. Hageman33 showed that gastric aspirates provided
present setting and emphasis on evaluating the mothers
the diagnosis of tuberculosis in 10 of the 12 patients.
of the infants with suspected congenital tuberculosis
Similarly, high yields from gastric aspirates were
potentially improving the detection of subclinical
found by Cantwell and Coworkers.38 Now with the
tuberculosis in these women. Theoretically, there is a
availability of rapid methods of staining of smear
small chance of misclassification as caseating hepatic
and culture for AFB, these investigations should be
granulomas can also occur in postnatally acquired
given their due importance. More than 3 gastric
tuberculosis but they have been found to be extremely
aspirates need to be examined.
uncommon in a large series (less than 2%).39 Also the iv. Bone marrow aspiration cytology and/or biopsy of
infant of a mother suffering from genital tuberculosis can lymph node and liver would be other diagnostic
acquire infection from her in the postnatal period leading modalities which should be considered.
to overdiagnosis of congenital tuberculosis. v. Positive smear and/or culture results can often be
Based on findings from published case reports, Patel obtained from gastric washings, spinal fluid, ear
and Destantis45 suggested that congenital tuberculosis discharge and endotracheal aspirate.
should be considered in the differential diagnosis of vi. Newer modalities like polymerase chain reaction
newborns who have (1) nonresponsive, worsening (PCR) are highly beneficial in the diagnosis of
pneumonia, especially in regions with high rates of congenital TB.
tuberculosis, (2) nonspecific symptoms, have a mother vii. Recently, phage typing has been used to establish
diagnosed with tuberculosis, (3) high lymphocyte counts
the identity of mycobacteria isolated from mother
in the cerebrospinal fluid without an identified bacterial
and the infant.
pathogen, or (4) fever and hepatosplenomegaly.45
Obtaining mother’s history regarding symptoms of
tuberculosis during pregnancy especially pleural effusion,
INVESTIGATIONS miliary or meningeal disease suggesting primary
Congenital tuberculosis is a rare entity and diagnosis is lymphohematogenous spread or history of endometritis
usually delayed due to the non-specific nature of the signs is an important diagnostic tool. Work-up of the mother
and symptoms. Imaging studies facilitate the early diag- should include a histological examination of placenta at
nosis of the disease and institution of appropriate birth, Mantoux test, chest X-ray and endometrial aspiration
therapy. Neyaz et al14 reported imaging findings of and curettage.34,36,47,48
congenital tuberculosis in three infants. Imaging findings The diagnosis is based on positive smear and/or
of the chest included multiple pulmonary nodules, culture results obtained from gastric washings, liver
consolidation with cavitation, extensive bronchopneumo- biopsy, lymph node biopsy, spinal fluid, ear discharge,
nia and necrotic mediastinal adenopathy. Abdominal endotracheal aspirate or bone marrow biopsy and
imaging findings included hepatomegaly with or with- mother’s history of tuberculosis in antenatal period.
out splenomegaly, multiple focal lesions in the spleen and To summarize congenital tuberculosis is still
retroperitoneal lymphadenopahty. presented as case reports even with the availability of
Once the diagnosis is suspected in an infant, modern diagnostic techniques. To illustrate this a few
diagnostic procedures should be carried out rapidly. case studies reported in the last five years are discussed
i. Chest skiagrams of the infants were abnormal below.
281
Congenital Tuberculosis with Multisystem Involvement: +++ AFB on smear. Ultrasonography of abdomen was
A Case Report normal except hepatosplenomegaly. On screening of family,
the mother was the source of infection. She had pleural
Boro et al49 reported a three-month old boy, first child of
effusion, sputum was positive for AFB. The endometrial
nonconsanguineous parents, presented with a history of
biopsy showed noncaseating epitheloid cell granulomas in
fever, cough, vomiting since birth. He had bronchop-
neumonia and splenomegaly at first week of life. He was between endometrial glands, Langhan’s giant cells and
started on nonspecific antibiotics. He was fed on formula. collection of epitheloid cells suggestive of tubercular infection.
On examination, he had pallor, fever 38.7°C, tachycardia, Treatment was given with four drugs HRZS. Hepatic
tachypnea, malnutrition, bronchopneumonia and functions were monitored. Child improved over a period
congestive heart failure. His liver was 5 cm, splenic of 10 days, started breast feeding. It is inferred that for the
enlargement of 3 cm. He had leukocytosis, elevated diagnosis of congenital tuberculosis, high index of suspicion
serum CRP levels, respiratory acidosis and impaired liver is necessary and antitubercular therapy is life saving.
function tests. In spite of antibiotics, his liver increased Wanjari et al10 reported a 2-day-old male premature infant
to 7 cm and spleen was 10 cm below costal margin. X- (28weeks) with fever, respiratory distress syndrome and
ray chest showed extensive broncho-pneumonia. hyperbilirubinemia. The baby had septicemia due to
Abdominal ultrasound showed portal lymphanodes Candida krusci. Mother had miliary tuberculosis. The baby
was investigated on the line of tuberculosis. Treated
besides hepatosple-nomegaly. Because of poor response
successfully with antitubercular and antifungal therapy.
to antibiotics, possibility of congenital TB was
Thapar et al51 also reported a neonate presenting as
entertained. Tuberculin test was 16 mm positive. Early
septicemia at the age of 2 months. The source was mother.
morning gastric aspirate yielded acid fast bacilli on smear
Infant was investigated on the line of congenital tuberculosis
microscopy on three consecutive days. Cerebrospinal
and treated successfully.
fluid showed proteins 117 mg/dl, glucose 3 mg/dl, with
serum glucose level of 88 mg/dl, 55 polymorphs,
TREATMENT
lymphocytes 44/mm. 3 Tomography chest revealed
broncho-pneumonic changes, cavitation and hilarme- Treatment with antituberculosis drugs instituted in time
diastinal lymphadenopathy. Family history was strongly can result in a favorable outcome in the neonate.41
positive. Both parents and one of the uncles had Congenital tuberculosis being so rare, no therapeutic trial
pulmonary TB. can determine optimal treatment. Cantwell et al38 suggest
The infant was administered antituberculosis treatment with INH 10 to 15 mg/kg, rifampicin 10 to 20
treatment INH (10 mg/kg), rifampicin (RMP) (10 mg/ mg/kg, pyrazinamide 15 to 30 mg/kg/day. It is further
kg), pyrazinamide (PZA) and streptomycin (30 mg/kg) recommended by them that streptomycin 20 to 30 mg/
for 2 months followed by INH and rifampicin for 9 kg/day or ethambutol 15 to 25 mg/kg/day for the first
months. He responded and after completion of therapy 2 months followed by INH and rifampicin for 4 to 10
(ATT), liver was only 2 cm and spleen of 1 cm only. X- months depending on the severity of the disease. This 3-
ray chest was completely normal. drug regimen, though easier to administer than
streptomycin containing initial 4 drugs regimen suffers
Late Neonatal Respiratory Distress: A Presentation of from the danger of nonresponse to treatment in case the
Congenital Tuberculosis disease causing strain is resistant to INH. The prompt
treatment with specific drugs is necessary because of the
Prasad et al50 reported a case of late neonatal respiratory seriousness of the disease.
distress: a presentation of congenital tuberculosis. A twenty
day old male neonate, weighing 2.6 kg presented with a A Paradoxical Reaction during Antituberculosis Therapy
history of fever for ten days, fast breathing for 2 days and for Congenital Tuberculosis
refusal to feed for one day. It was a normal full term delivery.
A paradoxical tuberculosis (TB) reaction is defined as the
On examination, the child had 102°F fever, was icteric and
clinical or radiological worsening of preexisting TB
dyspnoeic with respiratory rate of 90/minute. On
lesions or the development of new lesions during
examination of chest, there was marked subcostal retraction
treatment. Park et al52 reported a paradoxical reaction in
on inspection, rest of the examination of chest was normal. a 21-day-old female infant who was diagnosed with
There was profuse nasal secretion and hepatosplenomegly congenital TB and was being treated with antituberculous
(liver span: 10 cm and spleen: 2 cm below left subcostal drugs. A paradoxical reaction has been reported in 5 to
margin). Liver function tests were markedly deranged. 35% of patients receiving treatment for tuberculosis (TB)
Blood, CSF and urine culture were sterile. Gastric aspirate mostly immunocompromised patients (such as those
showed M. tuberculosis by PCR. Gastric aspirate also showed with HIV). A 21-day-old female child was admitted with
282
respiratory distress symptoms and signs and was being HIGHLIGHTS

treated with antibiotics for sepsis and pneumonia. With
• M. tuberculosis infection in utero can be indistin-
this therapy, the child did not have any improvement.
guishable from perinatal or early postpartum
Patient’s mother was diagnosed TB with pleursy one infection.
month ago. The baby was investigated for TB. Gastric
• The most common presenting symptoms are
aspirate contained acid fast bacilli (AFB) on smear and
hepatosplenomegaly, respiratory distress, fever,
culture. PCR for M. tuberculosis was positive. growth failure and lymphadenopathy.
Computerized tomography (CT) of the lung revealed
• Newborn with pneumonia unresponsive to
enlargement of the lymphnodes in the sybcarinal and
aggressive antibiotic therapy usually lumped as
bilateral hilar regions along with diffuse multiple nodules
sepsis should be aggressively investigated for
in both lung fields. A diagnosis of congenital TB was congenital tuberculosis.
made. Baby was put on ATT, INH, RMP, pyrazinamide
• The most recent set of criteria for congenital TB
and streptomycin was started in the dose of 10 mg/kg
requires the infant to have tuberculosis lesions
for isoniazid and rifampicin, 25mg/kg of pyrazinamide (infiltrates on the chest radiograph) and at least one
and streptomycin 20 mg/kg. The clinical symptoms of the following:
improved and she was discharged. However, she was
i. Onset during the first week of life, reported range
readmitted to hospital two months later with fever, is 1 to 84 days.
cough, wheezing and respiratory difficulty. Follow-up
ii. A primary hepatic TB complex or caseating hepatic
showed aggravation of findings on CT. There was no
granuloma.
evidence of Mycoplasma pneumoniae or Pneumocystis
iii. Infection of the placenta or maternal genital tract.
jiroveci. Oral prednisolone was added in the dose of 1
iv. Exclusion of postnatal transmission by a contact
mg/kg which was gradually topered off over 6 weeks.
investigation.
The clinical symptoms improved and chest radiograph
showed nearly complete resolution of the TB lesions.
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management. J Perinatol 1998;18: 389-94. tuberculosis with multi system involvement a case report.
28. Adhikari M, Pillay T, Pillay DG. Tuberculosis in the Turkish Respiratory Journal 2007;8:36-8.
newborn: An emerging disease. Pediatr Infect Dis J 50. Prasad R, Muthusami S, Pandey M, et al. Late neonatal
1997;16:1108-12. respiratory distress. A presentation of congenital
29. Starke JR. Tuberculosis. An old disease but a new threat tuberculosis. The Internet Journal of Pediatrics and
to the mother fetus and neonate. Clin Perinatol Neonatology 2007;7: Number 1.
1997;24:107-27. 51. Thapar K, Dhawan G. Congenital tuberculosis presenting
30. Balaka B, Bakande B, Douti K, et al. Tuberculosis in the as sepsis syndrome. Pediatric on cell [serial online] 2006
newborn: Recrudescence in areas with high endemic HIV [cited 2006 August 1] 3, Art # 28.
infection. Med Trop (mars) 2004; 64:367-71. 52. Park Ji AE, Park SS, Park SE. A paradoxical reaction
31. Kumar R, Nomeeta G, Arvind S, et al. Congenital during anti tuberculosis therapy for congenital
tuberculosis. Indian J Pediatr 2005;72:631-3. tuberculosis. International Journal of Infectious Diseases
32. Naranbai RC. Congenital tuberculosis localised to the ear. 2009;13:e 279-e281.
Arch Dis Child 1989;64:738-40. 53. Skevaki CL, Kafetzis DA. Tuberculosis in neonates and
33. Scnbil N, Sahin F, Caglar MK, et al. Congenital infants: Epidemiology, pathogenesis, clinical man-
tuberculosis of the ear and parotid gland. Pediatr Infect ifestations, diagnosis and management issues. Paediatr
Dis 1997;16:1090-1. Drugs 2005;7:219-34.
SECTION 5
DIAGNOSIS
• Pitfalls in Diagnosis and Treatment of Childhood

Tuberculosis
• Tuberculin Test
• Newer Tuberculins: Profile in Developing Countries
• Laboratory Diagnosis of Mycobacterial
(Tuberculosis) Infection in Children
– Conventional Methods
– Molecular Diagnostic Methods
• Imaging of Tuberculosis in Children
• Pathologic Spectrum
• New Approaches to TB Diagnosis in Children
22 Pitfalls in Diagnosis and Treatment of
Childhood Tuberculosis
YK Amdekar, Vimlesh Seth
Establishing diagnosis of tuberculosis in children can be important to document fever and not depend on mere
challenging. This is true especially in early stages of the impression. Fever can be of any type though rarely high.
disease and much more in diagnosing latent infection Cold and wheezing accompanying fever and cough
that may progress into a disease, if not suitably managed. denotes involvement of upper and lower respiratory tract
Early stage of the disease is often silent in the majority of and is commonly due to viral infection and not due to
children with only vague symptoms that may be easily tuberculosis. Symptoms of tuberculosis are known to be
overlooked. Physical examination is mostly normal. Thus “off and on.” However, recurrent symptoms with normal
diagnosis must depend upon high degree of suspicion. intervening period are not relevant for suspicion of
Triad of confirming diagnosis in children consists of tuberculosis. In such a situation, it is important to confirm
contact with tuberculosis, positive tuberculin test and normality during intervening period. Mere absence of
chest radiograph demonstrating pulmonary lesion. Each fever and cough is not an evidence of normality but
of these three factors has their own limitations. Demons- normal intervening period is better defined by regaining
tration of AFB is still the gold standard of diagnosis and of appetite, weight and normal activity. Recent loss of
can be positive at best only in 30% of children. Further, appetite may be relevant but unexplained recent loss of
with the disease being common in India and with the weight adds to the suspicion of tuberculosis; static
threat of dissemination especially in infancy and early weight/not growing well, especially beyond infancy, in
childhood, overdiagnosis is a rule, often based on flimsy absence of any other complaints, are not significant
grounds. While at times, early diagnosis is missed due symptoms. However, presence of a contact in the family
to improper interpretation of history, physical should arouse suspicion of latent tuberculosis.
examination and laboratory tests. Positive contact history is a strong contributory
Treatment also poses few problems. Standard proto- factor. In a symptomatic child, contact with a person with
cols have been updated by RNTCP (Revised National any form of active tuberculosis within last two years is
Tuberculosis Control Program) and IAP (Indian considered significant. Prolonged contact carries far more
Academy of Pediatrics) that ensure “cure” in the majority risk than occasional contact. It is not only the history of
of patients. Unfortunately they are often not followed contact that must be enquired but definite attempt must
for various reasons. Compliance is a major issue and at be made to trace the contact. In clinical practice, it is not
times non-availability of drugs adds to the problem. Irre- uncommon for parents to deny any history of TB in the
gular treatment leads to drug resistance and poses a great family. History of chronic cough in any of family
challenge. Logistic issues come in the way of ideal members and history of prolonged treatment for cough
therapy. may suggest probable TB and further enquiry may
No wonder, there exist many pitfalls in the diagnosis confirm it. Family members at risk of TB include elderly
and treatment of childhood tuberculosis in clinical persons with cough and those with diabetes. If necessary,
practice. Problems lie at multiple levels such as private they need to be proactively screened for tuberculosis. On
practitioners, medical institutions and government the other hand, diagnosis of tuberculosis in an adult
programs. Many of these issues can be addressed demands screening of all children in the family. This is
properly with commitment from everyone concerned. often ignored in clinical practice.
This chapter discusses existing pitfalls in diagnosis and Diagnosis is more likely in presence of risk factors
treatment of childhood tuberculosis and probable such as age < 1 year, recent episode of Measles or
solutions. It is the pulmonary primary complex which is whooping cough, protein energy malnutrition (PEM)
a starting point, irrespective of further course of disease grade 3 and 4 and immunocompromised state including
and hence discussion will be mainly focused to PPC. prolonged steroid therapy. Persistent lower respiratory
tract infection not responding to antibiotics may suggest
PITFALLS IN HISTORY ANALYSIS a probable diagnosis of tuberculosis.
Fever and/or cough of recent onset lasting for > 3 weeks It is important to realize that none of the above
should initially arouse suspicion of tuberculosis. It is mentioned facts in isolation can help in diagnosis of
288
Section 5 Diagnosis
tuberculosis but it is a constellation of multiple factors commonly caused by recurrent infections in draining area
that need proper evaluation. Finally, beyond infancy, if such as enlarged posterior cervical lymph nodes due to
history does not lead to suspect tuberculosis strongly, scalp infection or submandibular lymph nodes due to
close observation and periodic follow-up evaluation repeated tonsillar infections. In majority of such
would sort the problem and hurried investigations may situations, such lymph nodes do settle with antibiotics
not be justified as they may end up in further confusion. and even if they persist, they are not enlarging. Thus
However, in an infant, even a small degree of suspicion clinical follow-up does help to rule in or rule out
demands further work-up. diagnosis of tuberculosis. Only when tuberculosis is
Amongst extra-pulmonary TB, meningitis is a serious strongly suspected, further tests are useful. Otherwise it
disease that must be diagnosed in an early stage. TB is not uncommon to end up with inconclusive test results.
meningitis is more common < 5 years of age and so in a Physical findings suggestive of pleural effusion or
high-risk setting mentioned above, any undiagnosed chronic fibrocaceous cavitory lesions strongly support
fever with vague neurological symptoms should arouse probable diagnosis of tuberculosis and can be easily
suspicion and immediate further work-up would be confirmed further by appropriate laboratory tests.
mandatory. It is important to suspect TBM in stage 1 so Hepatosplenomegaly of unexplained etiology may be a
as to improve outcome of therapy. presentation of disseminated tuberculosis and needs
proper evaluation in case of corroborative history.
Unexplained failure to thrive even without any
TBM in stage 1 must be recognized with minimum
significant suggestive symptoms of tuberculosis does
physical signs such as mild drowsiness and subtle
justify further investigations.
meningeal signs. On close careful examination, one may
Resolution of symptoms under nontuberculous be able to pick up signs of hydrocephalus and raised
therapy does not rule out tuberculosis as at times, intracranial pressure.
symptoms seem to abate temporarily to reappear again. Phlyctenular conjunctivitis and erythema nodosum
Moreover, even when presenting symptoms disappear, are nonspecific signs of immune response to antigens—
other minor symptoms such as not being well and loss not necessarily of tuberculosis. Though with other
of weight/appetite go unnoticed. corroborative evidence, further tests may be justified.
On the other hand, history of improvement after anti- Diagnosis of tuberculosis should never be made on
TB treatment may not prove the diagnosis, especially if the basis of history and physical examination alone. Every
sequence of recovery do not match with expected attempt must be made to prove the diagnosis on
outcome. laboratory tests. Therapeutic trial with anti-TB drugs has
Similarly past history of tuberculosis must be no place in clinical practice.
enquired into details as more often than not, diagnosis
may have been made on flimsy grounds and one may Pitfalls in Laboratory Tests
have to ignore such a history when deciding further
management. When should the tests be ordered?
As majority of laboratory tests have their own limitations,
Pitfalls in Physical Examination it is important to emphasize that strong clinical suspicion
In majority of patients of pulmonary primary complex on history and physical examination is a prerequisite to
ordering laboratory tests. It is not uncommon in clinical
(PPC), physical examination does not reveal any
practice to observe diagnosis made on laboratory tests
abnormality. Rarely hilar lymphadenopathy may result
without correlation with symptoms and physical signs.
in localized collapse or emphysema that is evident on
No single test in isolation is diagnostic of tuberculosis
physical examination.
except gold standard of bacteriological proof. Thus
Presence of enlarged superficial lymph nodes must
laboratory tests must be used in conjunction with clinical
be looked for in every case of suspected PPC, as they
profile and then only reasonably correct diagnosis is
may be picked up in nearly 40-50% of children. Lymph
possible.
nodes are considered pathological if they are more than
1.5 cm in inguinal region and more than 1 cm in other Pitfalls in Tuberculin Test
superficial sites. Clinical correlate of diagnosis of
tuberculosis includes progressive enlargement of lymph This is an important test in support of natural infection
nodes for more than 2 weeks, firm, minimally tender or and needs proper technique and cautious interpretation.
not tender, fluctuating, further may get matted and There are many variables such as amount of antigen,
develop chronic sinus formation. depth of injection and host immune response.
It is a common mistake to consider persistent palpable Test material must be clearly mentioned on the report
superficial lymph nodes as due to tuberculosis. They are as different strength of tuberculin is used in different
289
Chapter 22 Pitfalls in Diagnosis and Treatment of Childhood Tuberculosis
laboratories. Test material must be injected intradermally 10 to 20% > 10 years

and it is not easy to do so without experience. Even General risk of disease 5 to 10% during lifetime
measurement of reaction is observer dependent and there It is important for clinicians to realize limitations
is inter-observer variation up to 4 mm—that may make of tuberculin test. Though as it is the most useful test
a difference in interpretation. in diagnosis of childhood tuberculosis, adequate
Standard tuberculin test is Mantoux test. Till recently caution in technique and interpretation is mandatory.
commercially available tuberculin was PPD RT23 5 TU, Of course it is well known that test may be negative in
but now ITU PPD RT23 with tween 80 is also available. active disease. In any case, tuberculin test is always
Test is read 48 to 72 hours after an injection and maximum interpreted in conjunction with other parameters and is
diameter of reaction in any plane is noted for never considered alone in diagnosis of tuberculosis.
interpretation. It is an induration and not the erythema
that should be measured. Reaction of 10 mm or more is Bacillus Calmette-Guerin (BCG) Test
taken as evidence of natural infection. Few reports in Indian literature led to misinterpretation
Besides many variable factors mentioned above, of this test. Unfortunately it continues to be used at times
interpretation of test result is most controversial. Even then, in clinical practice, especially when tuberculin test is
attempts are made to standardize it as per the protocol negative. However, there is no place for BCG test in the
formulated by IAP. diagnosis of childhood tuberculosis.
Reaction of 10 mm or more as depicted of natural This test has many variables and so is not useful in
infection is based on epidemiological studies in India. It the diagnosis of tuberculosis. Unlike Mantoux test, it is a
also takes into account that prior BCG vaccine usually poorly standardized test in terms of tuberculin
does not result in reaction 10 mm or more. concentration, measurement of response and evolution
However, earlier studies were done with PPDS that of reaction over time. Interpretation of tuberculin reaction
considered 10 mm of reaction as a cut-off point for natural is standardized. BCG test introduces variable high
infection. This was generally equivalent to 2 TU PPD concentration of tuberculin and hence cannot diffe-
RT23. As 5 TU PPD RT23 is commercially available and rentiate natural infection from vaccine-induced infection,
is used commonly in clinical practice, it is seen to result infection from disease and active disease from old healed
in higher reaction by 5 mm, Hence, National Tuberculosis disease. The test has high sensitivity at the cost of poor
Institute survey considered 14 mm as a cut-off point for specificity that leads to overdiagnosis. As tuberculosis is
natural infection in India. still common in India, test must be more specific than
In immunocompromised children and children sensitive though ideal test should have both high
suffering from PEM grade III and IV, lower cut off point specificity and sensitivity. Thus BCG test is not
for natural infection may be considered as 5 mm recommended in diagnosis of tuberculosis.
Any cut-off point is likely to overlap naturally infected
and not infected population. Cut off point of 14 mm may
Pitfalls in Chest Radiograph
miss few patients of active disease but cut off point of 10
mm may over diagnose normal children as diseased. It is important to ensure ideal technique for correct
Our problem is mainly over diagnosis and hence cut interpretation. It must be preferably done in upright
off point of 14 mm may be ideal. This is irrespective of position, has to be well centered, in an inspiratory phase
previous BCG vaccine as BCG vaccine is unlikely to and with optimum exposure. Posterioanterior view is
induce a reaction more than 12 mm. It is also well mostly adequate. However, localizing lesion near the
accepted that hypersensitivity after BCG vaccine does hilum or heart borders can be better visualized by lateral
wane off over a year and hence would not pose difficulty view.
in interpretation of tuberculin test. It is important to Digital X-ray is highly technician dependent and
reiterate that cut-off point refers to natural infection and should not be interpreted on same parameters as
not active disease. conventional X-ray though it can offer an advantage
Risk of disease after natural infection varies with age provided experienced reader interprets it correctly.
and hence age is an important criterion in interpretation As it is difficult to obtain an ideal chest X-ray, clinician
of tuberculin test in the diagnosis of active disease. must be cautious to interpret soft signs that may be false
Younger the age more the risk of active disease as positive. Expiratory film may reveal apparent media-
depicted below. By adolescence risk increases again. stinal widening with hilar prominence and widened
30 to 40% < 1 year cranial angle that may wrongly be diagnosed as enlarged
10 to 20% between 1 and 2 years lymph nodes. Similarly shadows on rotated film may
5 between 2 and 5 years appear as enlarged lymph nodes while in effect they may
2% between 5 and 10 years represent part of bony structures of thoracic cage.
290
Section 5 Diagnosis
Presence of thymus in infants is confused with Most of the clinicians lack motivation and have
mediastinal lymphadenopathy. Further even if enlarged developed “culture” of not looking for AFB. Under the
lymph nodes are diagnosed on chest X-ray, it may not pretext of limitations of bacteriological tests, it has been
suggest tuberculosis, as lymphoma may be a close a routine to diagnose tuberculosis without bacteriological
differential diagnosis. Prominent costochondral junctions proof. This is also true in most of infective diseases. For
as seen in rickets may often be mistaken for lung lesions. example, typhoid fever is rarely proved by culture in
Prominent minor interlobar fissure may be mistaken for private practice even when it is easy to culture Salmonella
lung lesion. for definitive proof. Though in teaching institutions, it is
In case of doubt, it is better to repeat a chest X-ray for a rule to prove the diagnosis of typhoid fever and so also
comparative interpretation. It is not rare for radiological an attempt to prove diagnosis of tuberculosis.
abnormalities to disappear after few weeks. As a rule, in
case of clinical recovery, persistent radiological lesion Sputum collection: It is possible in older children with
should not be a reason to diagnose tuberculosis. extensive and cavitatory disease. However, induction of
Chest X-ray defines pathology and not etiology. There sputum by nebulized hypertonic saline may be tried in
are no pathognomonic radiological signs of tuberculosis. children > 4 months of age. It may occasionally lead to
Normal chest X-ray does not rule out active disease as bronchospasm in a child and exposure of tubercle bacilli
10% of culture positive patients have normal chest X- to the investigator. One sample of induced sputum may
ray. In relevant clinical setting, following radiological equal to three samples of gastric aspirates in terms of
lesions may strongly suggest tuberculosis and they bacillary yield. Gastric aspirate can be collected on three
include military, chronic fibrocaceous cavitatory and consecutive mornings even in an ambulatory patient and
unilateral pleural effusion. Unresolving pneumonia after the yield on microscopy in progressive primary complex
adequate antibiotic trial in a symptomatic child raises in infants and in extensive disease may be as high as 60
the possibility of tuberculosis. However, right upper lobe to 70%. There is no need to hospitalize a child for collec-
lesion in infants may persist radiologically even after
tion of gastric sample as studies have shown no statistical
clinical improvement and may disappear over weeks
difference between yield of tubercle bacilli in hospitalized
without further intervention.
and ambulatory patients. Thus, gastric aspirate offers
Repeat chest X-ray in tuberculosis may be necessary
equal benefits and is much easy to carry out.
ideally at the end of successful treatment to confirm
radiological clearance. However, it may be considered Nasopharyngeal aspiration and bronchoalvelolar lavage: These
early in case of unanticipated clinical progress. are other modalities to collect samples for bacteriological
Ultrasonography of chest is helpful to assess pleural examination but in routine clinical practice, gastric
fluid collection, although decubitus chest x–ray film may aspirate is the most suitable sample to examine. String
also reveal similar information. test with a capsule is another method but still in
CT scan is rarely necessary and is not cost and experimental stage and the yield may not be as high.
radiation effective. Attempts have been made to find out body fluids that
Chest CT scan may reveal additional information such are easy to collect and may grow AFB. Urine culture has
as mediastinal caseating necrotic lymphadenopathy that been found to be helpful in few patients. This may need
may favor tuberculosis and may offer an opportunity for further research to define sensitivity and specificity vis-à-
CT guided biopsy for tissue diagnosis. Such modalities vis sputum examination.1 There is no role of urine
are reserved for situations of uncertain diagnosis. examination in routine practice for diagnosis of
CT scan of brain is useful for diagnosis of TBM. Basal tuberculosis.
exudates, hydrocephalus, infarcts and cerebral edema are Ziehl-Neelsen stain can reveal AFB only if sample
features suggestive of TBM. contains > 10,000 bacilli per ml. Different culture methods
are used, such as LJ medium, BECTEC and MIGT but
Pitfalls in Bacteriology they are all equal in efficacy. Culture assumes special
Demonstration of AFB in sputum is the gold standard of significance in case of suspected MDR-TB.
diagnosis of tuberculosis. Such a proof is often lacking Clinicians must get used to prove diagnosis of tuber-
in childhood tuberculosis because of difficulty in collec- culosis in children by appropriate bacteriological tests.
tion of sputum sample and also due to paucibacillary They are possible at all levels of practice and it is a sheer
disease in children. However, studies do show as high habit of not doing such a test. Once clinicians start
as 77% yield in advanced cases and 33% even in hilar conducting such procedures to collect appropriate
adenopathy and thus every attempt must be made to samples for detection of AFB, laboratories would also
prove the diagnosis in every case of suspected get used to find AFB. It is time that pediatricians try to
prove the diagnosis of tuberculosis so as to minimize
tuberculosis.
291
errors in diagnosis. This is the only way we can succeed Thus, no decisions can be made only on the basis of
in early and correct diagnosis that would pave the way serology or PCR tests and hence these tests are not
for better control of TB in India. recommended in clinical practice at present.
There are several laboratories in the country that
Pitfalls in Other Diagnostic Tests perform PCR but their competence and reproducibility
is in question and so clinicians should not depend on
With limitations of bacteriology in routine practice, such tests carried out by commercial laboratories.
several newer tests have been tried but most of them have
failed to fulfill the need of diagnosing suspected case of Pitfalls in Diagnosis of MDR-TB
tuberculosis or to differentiate infection from active
disease. Initial drug resistance to INH varies from 10 to 20% and
As mycobacterial antigens overlap in different stages for RMP 1 to 2% and acquired drug resistance to INH 40
of infection and disease, there are no specific antigens to 70% and for RMP 20 to 30% Thus, MDR-TB does exist
that can confirm natural infection or active disease. in India and clinicians must be aware of it. Diagnosis of
Besides, antigen tests vary widely and are often negative MDR-TB essentially must be proved bacteriologically.
in paucibacillary disease. Antibody tests share similar However, it can be suspected by a clinician and then further
problems for interpretation and in addition cannot proved by appropriate tests. Delay in diagnosis of MDR-
differentiate natural infection from BCG vaccine induced TB may be dangerous, far more than delay in diagnosis of
drug sensitive disease.
infection and active disease from old healed disease. Thus
It may be suspected prior to starting therapy in case
both antigen and antibody tests are in general poorly
of contact with known MDR-TB. It is also likely in a child
sensitive and specific. There have been attempts to
who has had ATT in the past or had been non-compliant
evaluate role of specific antigens and antibody in
with prescribed therapy. Unanticipated deterioration on
diagnosis of tuberculosis.2 However, no sufficient data
compliant treatment may warrant looking for multidrug
exists at present to recommend serological tests in the
resistance. Persistence of positive sputum for more than
diagnosis of tuberculosis. 5 months in spite of compliant therapy is a proof of drug
It is a pity that serological tests are often pursued in resistance and culture would prove diagnosis of MDR-
private practice for diagnosis of tuberculosis. Labo- TB. Polybacillary lesions are more likely to be drug
ratories report such tests without mentioning specific resistant than paucibacillary. HIV infection itself does not
antigen or antibody that is tested. For an average predispose to MDR-TB. However, malabsorption of anti-
practitioner, positive tests mean so much and so also for TB drugs in such patients may lead to suboptimal
a patient or his parents. Such tests are worth banning in concentration of drugs in spite of compliance. Due to
clinical practice, as all attempts at educating pediatricians frequent hospital visits, they may come in contact with
seem to have failed. Laboratory personnel also owe a MDR-TB.
responsibility by performing such useless tests. Common pitfall in the diagnosis of tuberculosis in
QuantiFERON and Gold tests measure interferon children is not to prove the diagnosis by gold standard.
gamma in response to PPD and are just sophisticated If this trend continues, MDR-TB will be difficult to
Mantoux test. Elispot and T-spot tests measure T-cells diagnose and hence not treated properly. It would be a
producing interferon gamma and offer no more threat to the community and a big hurdle in control of
information. At present, most of these tests are not yet tuberculosis in India. It is not acceptable to treat a child
standardized and hence these tests do not add to the with second line of drugs on clinical basis of diagnosis of
diagnostic yield of tuberculosis in children. However, MDR-TB. While it may be prudent to start such a treatment
they may hold promise for future application. There is on strong clinical judgment, it is equally mandatory to
some evidence to suggest that QuantiFERON test would prove MDR-TB and more importantly to select right
become positive before tuberculin test and could be of combination of sensitive drugs. So, general clinicians must
some use especially in starting early treatment.3 It is develop a habit of looking for bacteriological proof.
therefore not recommended to use these tests in routine
clinical practice. Pitfalls in Treatment of Tuberculosis
PCR is highly technical test with wide variability in
sensitivity and specificity as implemented in most of the Treatment of tuberculosis is very much standardized as
laboratories. It cannot differentiate living from dead per the protocol of RNTCP and IAP. IAP has recently
bacilli and so continues to be positive even after updated treatment protocol and it is in line with that
successful treatment. PCR is +ve in 95 to 100% of culture devised by RNTCP so as to bring in uniformity and avoid
+ve cases but only in 50 to 60% of culture –ve cases. It confusion. These protocols are based on scientific
may be false +ve in 1% to 30% of cases. foundations and have been tried with success.
292
Section 5 Diagnosis
Choice of anti-TB drugs is based on several deter- This protocol as applied to children has been
minants such as bacillary and metabolic subpopulation, debatable. However, it has been tested in children and
bacillary load, drug resistant strains, lag period of found to be feasible and practical. 4 Three disease
bacterial population, pharmacokinetic profile and categories primarily depend upon results of smear testing
pathological factors There are different types of bacillary and this can be objectionable as majority of children are
population in every case of tuberculosis and hence diagnosed without smear microscopy and more so in
specialized drugs are selected to be administered in routine clinical practice. Category 3 includes smear
combination to attack entire bacillary population for total negative tuberculosis and so there is no problem to apply
success. it in children. Category 1 includes progressive primary
INH and RMP contain fast growing bacilli, PZA takes complex that is estimated to be smear-positive in at least
care of intracellular organisms in acidic medium while 60% of cases. Other diseases included in this category
extracellular slow growing bacilli are best controlled by are more serious and disseminated forms of disease and
RMP. Thus every case of tuberculosis must be treated hence are rather easily recognizable irrespective of smear
minimally with these three drugs. There are naturally positivity. As mentioned earlier in this chapter, it is ideal
occurring mutants to the tune of 105 to 10.7 Higher the to attempt smear microscopy and even in absence of such
bacillary load, higher would be the resistant mutants. a smear examination, disease categories do make sense
Thus in case of disease caused by higher bacillary load, for effective uniform application.
more drugs are necessary including additional drugs in Unfortunately, many practitioners are unaware of
intensive therapy especially in smear, positive cases. . such a protocol and hence prescribe drugs in a haphazard
Single daily peak of a drug is adequate as dividing manner. Such a practice is hazardous as it would pave
time of TB bacilli is about 21 hours. All the drugs are the way for suboptimal response leading to increasing
administered in such a way that they achieve peak drug resistance.
concentration all at one time so as to hit bacilli hard. Thus It is a common knowledge that in case of suspicion of
multiple drugs are employed in a single daily dose. drug resistance, minimum two drugs must be added to
Early bactericidal activity makes a patient non- pre-existing regime. However, in RNTCP, in category 2,
infectious quickly while sterilizing efficacy of drug makes only one drug has been recommended to be added to
relapse less likely. Both facts are as much relevant in the pre-existing regime. While this may not be totally
effective control of tuberculosis. scientific, it serves better purpose in community program
Based on above mentioned facts, disease is for the reasons cited below.
categorized into three types for the purpose of uniform
treatment protocol. Issues Regarding Category to Therapy
Category 1 includes newly diagnosed smear +ve
This category includes relapsers, treatment defaulters
cases, sputum –ve severe and extensive disease and TB
and treatment failures due to drug resistance. It is
with HIV. Hence, category 1 justifies four drug intensive
important to realize that there is no risk of drug resistance
phase therapy for two months followed by two drug
in a relapser and hence same drug schedules can be used
therapy in continuation phase for next four months. TBM
is treated with one extra drug—Streptomycin in intensive safely.
phase. Treatment defaulters and treatment failures due to
Category 2 includes relapsers, treatment defaulters drug resistance obviously need modification of therapy.
and treatment failures due to drug resistance. They need It is generally considered to add two drugs to the failed
five drug therapy in intensive phase followed by three regime till culture and drug sensitivity reports are
drugs in continuation phase for five months. available. However, RNTCP has considered addition of
Category 3 includes smear –ve less severe forms of a single drug—streptomycin—to a failed regime. This
diseases such as primary pulmonary complex, isolated apparently may sound irrational. However, such a
lymphadenitis and unilateral pleural effusion. This is best protocol is based on ground level reality. Considering
treated with three-drug therapy in intensive phase for the fact that INH resistance is around 10% and combined
two months followed by two-drug therapy in conti- RMP/INH resistance around 5%, addition of a single
nuation phase for four months. drug like streptomycin to four-drug regime would ensure
It is clear that every case of tuberculosis must be therapeutic success with three or four sensitive drugs.
treated with minimum three drugs in intensive phase, Most often drug resistance is limited to two-drug
irrespective of type of lesion. In clinical practice, it is often resistance—either HR or HE. Except for multidrug resis-
not followed and it is a disturbing fact that even a single tance with bacilli resistant to three or more drugs, this
drug is used or two-drug treatment is not uncommon. regime would work well. Such a regime is also cost
Physician needs to understand the logic behind minimum effective as second line drugs are not only costly but also
three-drug intensive phase that cannot be modified. toxic. This is of course a “waiting regime” till culture and
293
drug sensitivity reports guide ideal therapy or there is In clinical practice, steroids are often misused and it
clinical treatment failure. is important to follow the recommended protocol. If
However, in clinical practice, one may opt for a steroids are used prior to firm diagnosis, it may cause
“waiting regime” or add two or more drugs as per the harm as well. Duration of steroid therapy needs to be
facility and affordability. In any case, proper bacterio- individualized as it depends upon therapeutic indication.
logical evaluation is mandatory for further therapeutic As an immunosuppressant, it must be continued for a
planning. period that inflammation persists as evident clinically
RNTCP suggests intermittent therapy under DOTS or by investigations. Routinely duration of steroid
program. This has an edge over daily therapy. Defaulter therapy may extend up to 3 months but at times longer.
rate is around 18% in daily regime as against 6% in
intermittent therapy. It is also comparatively easy to Fixed Drug Combination (FDC)
supervise intermittent therapy than daily therapy. Both While FDC is patient friendly, there are some relevant
daily and intermittent regimes will work equally well issues about them. Firstly there is no data on clinical
provided compliance is assured and in clinical practice, efficacy of FDC in children. Though, INH and RMP
one could opt for either of them based on individual combination has been shown to be effective in children.
convenience. Far more important is to ensure compliance; While INH is absorbed from intestine, other drugs are
it is an important step next only to correct diagnosis and absorbed from stomach. Bioavailability of liquid
standard treatment. formulations is not dependable and splitting of a tablet
is not recommended. Serious problem with FDC is
Latent Infection inability to titrate the dose to the individual needs and
hence FDC may prove to be toxic due to overdosing in
Risk of disease after infection varies with age. Infants
infants. Four drug fixed drug combination has been
have 43% risk of developing active disease after an shown to be equally effective in adults in attaining –ve
infection while toddlers up to 5 years of age run a risk of sputum status within 2 months as compared to drugs
around 24%. Children >5 years of age have low risk of given separately. In fact side effects such as GI upsets
developing disease after infection but risk increases again were less common with FDC and so also muscle and joint
during adolescence up to 15%. In general, there is 10 to pains. For convenience, four-drug combination
15% lifetime risk of developing disease after infection formulation may be used.
and half the infected population develops disease within
first 5 years after infection. Pitfalls in Implementation of Effective Therapy
Chemoprophylaxis is considered based on risk of
developing disease and 6 hr or 3 hr is recommended. With MDR-TB and TB with HIV, burden of disease has
Same regime is considered for primary chemoprophy- increased. In spite of effective chemotherapy, control has
laxis in high-risk situation. Chemoprophylaxis in case of not been achieved due to poor implementation and
MDR-TB has not been worked out and at present there compliance of therapy. RNTCP has evolved to take care
of these problems that includes DOTS. RNTCP embarks
is no recommendation for the same.
on diagnosis by sputum microscopy, supervised drug
Such a recommendation assumes no drug resistance
therapy at least in intensive phase (followed by weekly
in an index patient. 3 hr may be a better option if cost is
visit to the clinic when one dose is administered under
not an issue. It is important to realize that RNTCP and
supervision and two doses are given to the patient to
IAP protocols serve good purpose for the community
take them at home subsequently), regular drug supply,
with minimum intervention. However, competence of
patient tracking (progress to be monitored till end of
the regime may be marginally improved in clinical
therapy) and administrative and political commitment.
practice by small modification. However, the principle
Each patient on diagnosis has entire box of drugs
of management does not differ. Hence these recom-
allocated though not handed over to ensure supervised
mendations are useful for baseline application, over
uninterrupted therapy. DOTS is expected to achieve
which one may modify to an extent that serves better
>85% patients completing therapy as prescribed. DOTS
purpose to an individual patient.
may not be necessary for all patients but should be
considered in patients likely to default for various
Steroids in Tuberculosis reasons.
Definite indications include military TB, TBM and Though RNTCP has strived hard to formulate
pericarditis. There is no clear evidence in favor of steroids uniform guidelines for diagnosis and management of
in TBM in HIV infected children. They are not indicated tuberculosis and also strategies to implement the same,
in lymphadenitis and pleural effusion. They may be used there have been many gaps in actual execution of the
in endobronchial tuberculosis. program.
294
Section 5 Diagnosis
Gaps in Effectiveness of RNTCP communication and monitoring side effects. Label of

“defaulter” may have to be changed as it is disturbing a
Health service related factors, health provider related patient and may lead to noncooperation.
barriers and drug related issues pose problems in RNTCP DOTS could be replaced by POTS —parent observed
that come in the way of intended success. therapy. Any health care facility including private clinics
Health service related factors include need for long can function as DOTS center.
distance to travel, inconvenient clinic timing and lack of
facility in case of family emergency.
This resulted in poor compliance at each point of Problems with RNTCP Dosing
diagnosis, registration, treatment and monitoring. Study The program offers ready packets for different weight
from West Bengal showed 14% patients did not give three groups of 6-11/11-17/18-25/26-30 kg. Each weight group
samples for diagnosis, 90% completed intensive phase gets the same dose so it is right dose for first 1 to 2 kg
and 67% continuation phase and 30% found inconvenient weight in the group and other children in the group
to attend DOTS center regularly. 28 percent centers would be underdosed. Further if child gains weight over
lacked expected facilities and they had inconsistency in a month of treatment and happens to go into succeeding
supplied drug boxes. 75 percent of recorded addresses group, he would be further underdosed as he continues
could not be verified and so defaulter retrieval was not to get the previous group drug dose. Hence it may be
possible in 45% of patients.5 ideal to device two subgroups in each group for ideal
Provider related issues include lack of attention and dosing. However, it may pose logistic problems.
support, poor interpersonal communication and diffi- Drug packages that are supplied in RNTCP have
culties in reentering the program in case of defaulting. product code and schedule numbers that are very
Patient’s conception of equating well-being with cure and confusing. It may be much easy if package carries simple
inability of staff to take care of side effects add to poor label that is self-explanatory. For example, for 5 kg weight
compliance.6 group, label could be Ped TB I5 and Ped TB C5—I denotes
Provider delays is a major contributory factor as intensive phase and C denotes continuation phase while
patients have to visit several times before definitive 5 denotes weight group. Such simple changes would help
diagnosis is made. It is much better when private practi- in easy implementation of treatment protocols.
tioner is a part of such a process. Once registered in Though there may be technical difficulty at the
RNTCP, there was no delay in starting treatment.7 Thus, manufacturing level to produce many pediatric weight
public–private mix should be encouraged. Unfortunately, categories, the overall compliance will definitely be better
provider adherence to standard protocols is suboptimum as even paramedicals and parents will easily understand
at all levels including private practitioners and insti- the above. Instead of allotting the work to one pharma-
tutions.8-9 Tertiary care center had far better success rate ceutical company if few are chosen to manufacture same
due to availability of senior faculty member in the composition, the job will be simplified.
center.10 Defaulter, failure and death prevalence in All the pharmaceutical companies should be advised
tertiary DOTS center was 3%, 2% and 1% respectively to follow the same formula to avoid confusion. However,
due to better communication by senior member of the the pharmaceutical company can add their company
team.11 name as suffix or prefix along with the recommended
Success rate of RNTCP has gone beyond benchmark uniform guidelines. The implementation of the above may
of 85%. MDR-TB is a challenge as diagnosis of MDR-TB reduce inadvertent errors. Since the success of the entire
needs sophisticated laboratory help. If not treated program depends on the appropriate drug supply to the
properly, there could be increasing prevalence of drug patient, the pharmaceutical company should be advised to
resistant TB in the country and that needs to be avoided.12 follow the same strictly.
Five percent of patients diagnosed in RNTCP did not
start treatment and there is a need to trace them.13 HIGHLIGHTS
Males are diagnosed three times more often than
females in RNTCP14 • Pitfalls in diagnosis and treatment of childhood
Molecular polymorphism in the population decided tuberculosis result from scientific and logistic
variable prevalence of hepatic drug toxicity and further limitations but more often are due to non-
research is needed to define such a variation in the implementation of standardized protocols that are
population.15 devised after careful analysis of available studies. It
Practical measures must be employed in terms of is only when physicians adhere to standard protocols
flexible clinic hours, allowances for poor patients to come of diagnosis and treatment that the disease is likely
to the clinic and training of health workers for respectful to be controlled. If not, problems would increase in
295
4. Kabra SK, Lodha R, Seth V. Category based treatment of

terms of increasing drug resistance and spread of tuberculosis in children. Indian Pediatr 2005;41:299.
tuberculosis 5. Sen TK, Das DK, Saha S. Persistence of gaps in
• At all levels, it is best to document points in favor of implementation of revised national tuberculosis control
diagnosis and assign a patient a category that would program in an area of West Bengal. Indian J of Public
automatically pave the way for standardized health 2007;51:246-8.
treatment protocol. This is especially important to 6. Jaiswal A, Singh V, Ogden JA, et al. Adherence to
tuberculosis treatment: lessons from the urban setting of
follow for private practitioners who take individual
Delhi, India. Trop Med Int Health 2003;8:625-33.
decisions without any supervision and patients do 7. Kelkar-Khambate A, Klelmann K, Pawar S, et al. India’s
hold them in high esteem and in good faith and thus Revised National Tuberculosis Control Program: looking
are likely to follow their advice—irrespective of it beyond detection and cure. Int J Tuberc Lung Dis
being right or wrong. Institutions are better placed 2008;12:87-92.
for adherence to standardized protocols though it 8. Davidson H, Schluger NW, Feldman PH, et al. The effects
may not be taken for granted and adequate of increasing incentives on adherence to tuberculosis
directly observed therapy. Int J Tuberc Lung Dis 2000;4:
supervision by a senior member is essential
860-5.
• At the community level, in RNTCP, emphasis must 9. Greaves F, Ouyang H, Pefole M, et al. Compliance with
be on patient friendly management that would DOTS diagnosis and treatment. Recommendations by
ensure better compliance. Finally, it is the tripartite private practitioners in Kerala, India. Int J Tuberc Lung
responsibility of government agencies, research Dis 2007;11:110-2.
institutions and private practitioners that would 10. Tahir M, Sharma SK, Rohrberg DS, et al. DOTS at a
tertiary care center in northern India: successes,
minimize pitfalls that seem to occur presently,
challenges and the next steps in tuberculosis control.
coming in the way of anticipated control of
Indian J Med Res 2006;123:702-6.
tuberculosis. 11. Sharma S, Sarin R, Khalid UK, et al. The DOTS strategy
for treatment of pediatric pulmonary tuberculosis in
South Delhi India. Int J Tuberc Lung Dis 2008;2:74-80.
12. Chauhan LS. RNTCP 2007; looking ahead to future
REFERENCES challenges. J Indian Med Assoc 2007;105:192,194-6.
1. Gopinath K, Singh S. Urine as an adjunct speciment for 13. Sai Babu B, Satyanarayana AV, Venkateshwaralu G, et
the diagnosis of active pulmonary tuberculosis. Int J al. Initial default among diagnosed sputum smear
Infect Dis 2008 Nov 1. positive pulmonary tuberculosis patients in Andhra
2. Kumar G, Dagur PK, Katoch VM, et al. Diagnostic Pradesh India. Int J Tuberc Lung Dis 2008;12:1055-8.
potential of Ag85C in comparison to various secretary 14. Ganapathy S, Thomas BE, Jawahar MS, et al. Perceptions
antigens for childhood tuberculosis. Scand J Immunol of gender and tuberculosis in a south Indian urban
2008;68:177-83. community Indian. J Tuberc 2008;55:9-14.
3. Mosby Inc. (copyright) Performance of QuantiFERON – 15. Roy PS, Majumder M, Roy B. Pharmacogenomics of anti-
TB testing in a tuberculosis outbreak at a primary school. TB drugs-related hepatotoxicity. Pharmacogenomics
J Pediatr 2008;52(4). 2008;9: 311-21.
23 Tuberculin Test
The tuberculin skin test has been the traditional method Are there any Risks from Having the
of diagnosing infection with M. tuberculosis. Appropriate PPD Skin Test?
use of the skin test requires a knowledge of antigen used
There is a very slight risk of having a severe reaction to
(tuberculin), the immunologic basis for the reaction to
this antigen, the technique(s) of administering and the test, including swelling and redness of the arm, in
reading the test; and the results of epidemiologic and people who have had either tuberculosis or have received
clinical experience with the test.1 Simple questions which BCG. Allergic reaction are also rare.
need to be answered before discussing the test in details Till date, tuberculin skin test was the only method to
are as follows: diagnose latent tuberculosis infection. Recently a new
test quantiFERON-TB test (QFT) was approved by the
What is Tuberculin Skin Test? United States Food and Drug Administration (USFDA)
as an aid for diagnosing latent M. tuberculosis infection.1a
The tuberculin skin test (also known as PPD test) is a test This is an in vitro diagnostic aid that measures a
used to determine if some one has developed an immune component of cell-mediated immune reactivity of
response to the bacterium that causes tuberculosis (TB). M. tuberculosis. It is based on the quantification of
This response can occur if some one currently has TB, if interferon-gamma (IFN-γ) released from sensitized
they were exposed to it in the past or if they received lymphocytes in whole blood incubated overnight with
BCG vaccine against TB. The World Health Organization purified protein derivative (PPD) from M. tuberculosis and
estimates that 2 billion people world wide have latent control antigens. In this method whole-blood specimens
TB, while 3 million people die of the disease each year of donors is stimulated with ESAT-6 and CFP-10 antigen
over the world. and then cultured. Plasma concentration of interferon-
gamma discharged is determined with quantiFERON-
Basis of Tuberculin Test CMI. The optimum cut-off level determined by Harada
Infection with M. tuberculosis produces a delayed-type et al2 was 0.35 units/ml for both ESAT-6 and CFP-10.
hypersensitivity skin reaction to certain components of This gave the test a sensitivity of 89.0% and specificity of
the bacterium. These are contained in extracts of culture 98.1% in detecting tuberculosis infection. This test is not
filtrates and the core elements of the classic tuberculin affected by previous BCG vaccination, presence of
PPD (purified protein derivative). This material is used nontuberculous mycobacteria in the environment. As in
for skin testing for tuberculosis. Reaction in the skin to the case of clinical tests in general, the cut-off should be
tuberculin PPD begins when specialized immune cells set at a lower level when the test is applied to high
called T cells, which have been sensitized by prior prevalence situation.
infection, are recruited by the immune system to the skin Harada et al3 used this test for detecting tuberculosis
site. There they release lymphokines which are called infection among contacts of a tuberculosis patient by
chemical messengers. The induration is induced by determining the wholeblood interferon-gamma response
lymphokines through local vasodilation leading to to specific antigens. It is unaffected by BCG-caused
edema, fibrin deposition, recruitment of other types of tuberculin allergy. In the case of an outbreak, QFT greatly
inflammatory cells to the area. For the PPD test to be reduced the indication of chemoprophylaxis, from 28%
positive, the incubation period varies from 2 to 12 weeks of all the contacts solely based on tuberculin test to only
after exposure to TB. The details are discussed further in 7%. It is emphasized by Harada et al3 that this will
the chapter. provide a high possibility for wider and more accurate
297
Chapter 23 Tuberculin Test
indication of chemoprophylaxis and will be one of the TUBERCULINS

essential tools of tuberculosis control of the 21st century
The tuberculin skin test is based on the fact that infection
in Japan. Pai et al4 used this test to estimate latent
with M. tuberculosis results in sensitivity to certain
tuberculosis infection prevalence in health care workers
antigens of this organism that are also contained in the
along with the tuberculin skin test (TST) to determine
culture extracts called ‘tuberculins’. There are two main
agreement between the two. They compared their
types of tuberculin: Old tuberculin (OT) and Purified
correlation with risk factors. A large proportion of the
protein derivative (PPD). Old Tuberculin (OT) is a filtrate
health care workers were latently infected. Fifty percent
obtained from heat-sterilized concentrated broth culture
were positive by either TST or IFN-gamma assay, 31%
of tubercle bacilli. Initially, glycerinated meat broth was
were positive by both. There was high agreement between
used as the medium; synthetic media later replaced this.
TST and IFN-gamma assay and similar association
Currently this preparation is rarely used. Florence
between positive test result and risk factors. Therefore,
Seibert9 coined the term “Purified protein derivative”
they concluded that decision to select one test over the
(PPD) in 1934 for the product from heat-concentrated
other will depend upon population, purpose of testing
synthetic medium OT by precipitating the protein
and resource availability.
initially with trichloroacetic acid.7 The PPD resulting
Kang et al5 evaluated these two tests in Korean adult
from these experiments was called “SOTT” (synthetic
population and concluded that this is a better indicator
medium old tuberculin trichloroacetic acid) precipitate.
of the risk of M. tuberculosis infection than TST in a BCG
In the same year Joseph Aronson gave a detailed
vaccinated population.
description of its use and designed a “kit” for field use,
including a 1 ml glass syringes and 26 gauge platinum
HISTORY
needles.7 Later, in 1941 Seibert prepared a large batch of
In 1890, Robert Koch announced a cure for tuberculosis. PPD in which ammonium sulfate was used for
This consisted of giving patients subcutaneous doses of precipitation to obtain a highly purified preparation.10
a filtrate of heat-killed culture of tubercle bacilli. This was This material, lot 49608, was designated the standard
known as Koch’s lymph or Koch’s remedy.6 The use of tuberculin “PPD-S”, and became the International
tuberculin for the cure of tuberculosis was based on his Standard for all tuberculins.11
observations of altered response to tuberculin in Another commonly used tuberculin, PPD RT23, is a
previously infected guinea pigs. There was quick healing large batch of purified tuberculin produced by the Statens
at the site of second injection of viable organisms (Koch’s Serum Institute, Copenhagen and issued since July 1,
phenomenon). Within a year of announcement of this 1958.12 Recently in view of short supply of PPD-S, a new
therapy, it was disapproved as a cure for tuberculosis. standard has been manufactured and tested.13
However, this discovery became the most widely used The International Standard tuberculins are in the
diagnostic test ever developed. custody of the laboratory for the Biological Standards,
Von Pirquet demonstrated that if a child with Statens Serum Institute, Copenhagen, Denmark.14
tuberculosis was inoculated with a solution of old In India, currently there is shortage of PPD. The BCG
tuberculin (OT), a papule 5 to 20 mm in diameter laboratory, Guindy, has stopped manufacturing PPD
developed at the site of scarification. It took 8 days or so RT23 of 1TU with tween 80, as it has exhausted the stock
for it to disappear. This term was designated allergy. of PPD RT23.15 At present, Span Diagnostics Limited is
Bleiker, a Polish researcher named Koch’s remedy as marketing a tuberculin that has been calibrated against
‘tuberculin’ in 1891 and thus the Tuberculin test was born.7 PPD RT23 in 3 strengths: 1 TU, 5 TU, and 10 TU.16 The
Various methods of administration were tested: Pirquet use of 10TU is not recommended for use in pediatrics.
cutaneous test, the Moro percutaneous patch test, the
Mantoux intracutaneous test, and the Calmette COMPOSITION
conjunctival test.8
Two commonly used methods for the preparation of PPD
Seibert9 in 1934 described that in the culture filtrate
are ammonium sulfate and trichloroacetic acid
of tubercle bacillus, besides tuberculoprotein impurities,
precipitation. M. tuberculosis is grown in liquid medium,
other cell wall components were contained in this form
sterilized using steam at 100°C for three hours. Filtration,
of tuberculin. This was called old tuberculin (OT)
precipitation, and washing procedures give PPD higher
resulting in nonspecific reactions. Due to this
concentration of protein and polysaccharide, whereas
standardization of the dose the maintenance of potency
trichloroacetic acid preparation method results in PPD
was difficult. In 1941 Seibert and Glenn10 separated a
with higher percentage of nucleic acid.
product with predictable qualities and called it purified
The potency of PPD is expressed as Tuberculin Units
protein derivative (PPD). This is now injected intradermally
(TU) instead of International Units (IU). The standard
for tuberculin test.
298
Section 5 Diagnosis
5 Tuberculin Unit (TU) dose of PPD-S is defined as the iii. The remaining solution should not be frozen, and
delayed skin test activity contained in a 0.1 mg/0.1 ml iv. The tuberculin should be stored in a dark place as
dose of PPD-S. One TU of PPD RT23 has been defined as far as possible.
0.02 mg in 0.1 ml of phosphate buffered saline with
0.005% Tween 80 (polyoxyethylene sorbiton monocleate). IMMUNE BASIS OF TUBERCULIN REACTIVITY
The standard dose of a commercial PPD preparation is
Initial infection with tubercle bacilli is followed by the
defined as the dose of that product which is biologically
equivalent to that contained in 5 TU of PPD-S (i.e. it elicits development of allergy to tuberculoprotein approxi-
skin reactions of equivalent size + 20%).17 One TU of PPD mately after 4 to 6 weeks. This is in the form of a cell
RT23 (with Tween 80) corresponds fairly well to 5 TU of mediated, delayed hypersensitivity reaction (Type IV)
RT 19-20-21 and to 6 or 7 TU of RT 22.18 One TU of PPD (Fig. 23.1).
RT23 (with Tween 80) corresponds to 3 TU of PPD-S. The Mantoux tuberculin reaction is a classic example
Therefore, 2 TU of PPD RT23 was used for diagnosis or of delayed-type hypersensitivity (DTH). Infection with
surveys.19 However, these values are approximations, M. tuberculosis sensitizes the person to the antigenic
with the ratios likely to vary in different populations.18 components contained in tuberculin. The process of
Therefore, prior to comparison of utility of any two sensitization takes place mainly in the regional lymph
tuberculins, one must consider the abovementioned facts. nodes, as a result of which sensitized T lymphocytes enter
PPD RT23 in saline buffer containing tween 80 is the blood stream and circulate for long periods of time.
approximately twice as potent as PPD-S in phosphate The sensitization of lymphocytes usually reaches a level
buffer saline without Tween 80, if similar protein weights adequate to produce a detectable DTH response at 2 to
are used. Since reaction to RT 23 tends to be some what 10 weeks after the initial infection with M. tuberculosis.
softer in appearance and generally less severe, all tests Their subsequent restimulation with the same or a similar
with this tuberculin can be carried out at a strength of 2 antigen, such as an intracutaneous injection of tuberculin
TU. elicits a characteristic delayed hypersensitivity reaction
1 TU and 250 TU preparations contain one-fifth and with induration and erythema that peaks at 48 to 72 hours
fifty times the concentration of antigen determined to be and subsides over a period of 5 to 7 days.
equivalent to 5 TU PPD-S. 20 These have limited Histologically, the earliest phase of the reaction is seen
usefulness in the diagnosis of tuberculous infection.7 as a perivascular cuffing with mononuclear cells
Tuberculin preparations retain their potency for nearly followed by a more extensive exudation of mono- and
6 months if stored in cool (2 to 20°C) dark place. The polymorphonuclear cells. The latter soon migrate out of
optimum temperature for storage is 2 to 8°C. Opened the lesion leaving behind a predominantly mononuclear
vials of tuberculin should not be kept for more than 2 cell infiltrate consisting of lymphocytes and cells of the
days.19 They should not be frozen. When diluted, PPD is monocyte-macrophage series. When the sensitized T cells
absorbed on glass and plastic surfaces. To minimize this,
a small amount of detergent, Tween 80, is added to the
diluent for PPD and the solution is kept refrigerated in
the dark.11 The other antigens used for screening for
nontuberculous mycobacterial cervicofacial
lymphadenitis in children are from Mycobacterium kansasii,
Mycobacterium avium and Mycobacterium scrophulaceum.
In these cases optimal cut-off for a positive test is 5 mm.
Tuberculin skin testing with these antigens had a
sensitivity and specificity of 70% and 98% respectively
as reported by Lindeboom et al.20a It was recommended
by them21 that in the diagnostic analysis of cervicofacial
lymphadenitis in children without a history of TB
exposure or bacilli Calmette-Guerin vaccination,
tuberculin skin test is a valuable first step in the diagnostic
analysis.
In order to minimize the reduction in potency:
i. Tuberculin should never be transferred from one
container to another,
ii. Skin test should be given as soon as possible after
the syringe is filled, Fig. 23.1: The tuberculin response
299
come in contact with the specific antigen they secrete after injection when the induration is maximum. In some
lymphokines which in turn recruit nonsensitized individuals zero mm induration (pseudoanergy) may be
lymphocytes to the site of inflammation, retain them at recorded despite the fact that he/she has tuberculin
the site where they become activated, thus amplifying sensitivity. In such cases biopsy findings are similar to
the immune response and giving rise to the characteristic that of positive tuberculin test cases. Pseudoanergy has
type IV hypersensitivity response (Fig. 23.1). This is also been reported in HIV-seronegative hemophiliacs and in
accompanied by increased vascular permeability. There chronic obstructive pulmonary disease patients receiving
is usually a 2- to 3-fold increase in the thickness of the prednisolone. In children, this pseudoanergy can be
dermis in the classical reaction and this peaks a day later present in those who are on long-term steroid therapy
than the erythema. This increase in the volume is much because of certain diseases like nephrotic syndrome and
greater than that of infiltrating cells measured by malignancy (lymphatic leukemia). In preliminary
histometry (20-30%).21,22 Therefore, edema fluid accounts evaluation of patients with active tuberculosis, false-
for much of swelling.17,18 In fact, the usual clinical method negative results can be noted in 25% cases. Tissue
of determining tuberculin sensitivity relies more on the specimens were taken after Mantoux test in children who
secondary effect of edema rather than the cell had received BCG. Specimens were processed in the
infiltration.22 usual manner and embedded in paraffin. Then 5 µm thick
Delayed-type reactivity cannot be transferred from a sections were cut and stained with hematoxylineosin. In
sensitized to a nonsensitized individual with serum addition, 5 µm thick sections were added to polylysine
antibody. Lymphoid cells, especially the T-lymphocytes coated slides and stained with streptovodin biotin
are required for the same. 23 Hence, three major method using CD45, CD3, CD68 and CD20 antibodies.
components of the delayed hypersensitivity skin reaction In immunohistochemistry, positivity of cells were
are:24 assessed semiquantitativaly. In all cases hematoxylin-
i. Antigen recognition (afferent limb). eosin sections revealed a mononuclear cell infiltration
ii. Antigen sensitized cell reactivity (efferent limb). around the dermal vasculature and dermal adnexa. A
iii. Cutaneous inflammation. granulomatous reaction with or without necrosis was not
seen in any sample. With immunohistochemical stains
TUBERCULOSIS AND IMMUNE SYSTEM CD45+ (leukocyte common antigen) and CD3+ (a T-cell
Hegde et al25 have elaborated on the tuberculosis and antigen) cells comprised the majority of the infiltrate.
immune system. Table 23.1 summarizes the clinical CD68 positivity was also noted, although in a lower
situations described by them. percentage of cells. On the other hand CD20 (a B-cell
marker) did not stain any cells of the infiltrate.
Immunochemistry of Tuberculin Skin Test In the material, the great majority of cells were CD45+
Mycobacterium tuberculosis produces a delayed type cells, and at least 50% of these cells were CD3+ T cells. It
hypersensitivity reaction to certain antigenic components is proposed that determination of T-lymphocytes
of the organism that are contained in the extracts of dominating infiltration may be used in pseudoanergy
culture filtrates called tuberculins. Tuberculin PPD cases in which an induration is not observed. If clinical
(purified protein derivative) is isolated from a culture observation and laboratory findings are consistent with
filtrate of bacilli by protein precipitation. PPD is injected tuberculin sensitivity in a particular anergic patient, a
intradermally into the volar surface of the forearm punch biopsy from the test site can help in diagnosing
(Mantoux test). Test should be read after 48 and 72 hr pseudoanrgy cases from real anergic ones.
Table 23.1: Host responses to exposure to the tubercle bacillus

Immune status Clinical situation Tuberculin test (Mantoux)
• Activated helper and cytotoxic No clinical disease (e.g. + ve
cells CD45 RO (Memory cells) BCG vaccination)
• Normal CMI Nonactivated May or may not show –ve to +ve in 2-8 weeks
Helper cells CD45RA (Naïve cells) clinical disease
• Impaired CMI* Clinical disease –ve or diminished or +ve
• Total lack of CMI Fulminant disorders likely – ve
*CMI = cell-mediated immunity
300
Section 5 Diagnosis
Biomarkers Changes Associated with Tuberculin Skin bevel upward, into the superficial layer of the skin
Test (TST) Conversion: A Two Year-Longitudinal Follow- (intradermal). The syringe is held by the barrel only and
up in Exposed Household Contacts the plunger is not touched until the point of the needle
has been satisfactorily inserted. After injecting 0.1 ml of
A high prevalence (50-80%) of tuberculin skin test
the PPD, the finger is removed from the end of the
positivity (TST+ > 10 mm induration) has been reported
in TB endemic countries. This pool forms a huge reservoir plunger before the needle is withdrawn. The injection
for new incident MTB cases. The measurement of should raise a flat anemic wheal with pronounced pits
biomarkers in household contacts of a recently TB and a steep border. If the injection is given into the deeper
exposed cohort revealed that there was significant layer of the skin, it will affect the size of the resultant
suppression of IFN-γ, raised IL-10 and raised TNRα in tuberculin reaction and make interpretation difficult.
response to mycobacterial culture filtrate (CF) In order to reduce the discomfort of the injection,
irrespective of their TST status.25a topical anesthesia may be applied. In a recently published
Post TST conversion was associated with significant randomized study, it has been observed that topical
increase of culture filtrate induced IFN-γ, IL-10 and IL-6 lidocaine-prilocaine did not affect the TST size reaction.27
levels. CF induced IFN-γ was higher in recently infected
household contact groups. Mitogen induced cytokine Reading the Mantoux Test
secretion showed similar differences for different groups. The test should be read 48 to 72 hours after injection, as
the delayed hypersensitivity reaction is maximal at 48 to
ADMINISTRATION OF TUBERCULIN TEST 72 hours.28 An immediate hypersensitivity response is
There are two techniques of applying the tuberculin of no significance.29 The reading should be made in good
test—the intracutaneous Mantoux test and the light, with the forearm slightly flexed at the elbow. It is
percutaneous multiple-puncture skin test. The multiple- based on the presence or absence of induration which
puncture tests are cheaper and easier to administer and can be determined by either palpation or the pen
are in routine use in many developed countries. method.30 A ballpoint pen is lightly run transversely from
However, their results are not diagnostic and a Mantoux the side of the arm towards the indurated area, starting
test is needed before tuberculous infection can be approximately 4 cm away. When the border of the
diagnosed.26 In India, Mantoux test has been in popular induration is reached, a slight resistance is felt, and the
use and hence, will be the only test detailed here. pen is lifted. The procedure is repeated from the opposite
side and the distance between the two end marks is
The Mantoux Test measured in millimeters. The diameter of induration
should be measured transversely to the long axis of the
The test is performed by the intracutaneous injection of
forearm and recorded in millimeters.
0.1 ml of PPD containing 5 TU PPD-S or an equivalent
A recent study questions the reliability of health care
dose of other PPD into the volar (ventral) surface of long
workers in accurately reading a tuberculin skin test
axis of the forearm. This raises a wheal 6 to 10 mm in
diameter. It is suggested that a wheal of 7 to 8 mm is also reaction in a known tuberculin positive individual.31 In
sufficient. The injection is administered with a short this study, 93% of 107 health care professionals under-
26/27 gauge steel or platinum needle with short bevel read the tuberculin reaction. This suggests marked inter-
with a glass or plastic (disposable) tuberculin syringe.11,22 observer variability. It appears that educational strategies
It is important to note that the test should not be repeated directed toward improving the accuracy of tuberculin skin
at the same site where previous test has been done. It is test reading are needed for health care professionals at
because repeat test at the same site will have boosting effect each center.
and a larger reaction will occur which does not indicate
active disease. This boosting effect does not occur in the Interpretation of Test Results
1st week but lasts for 18 months. Hence, it is suggested The aim of the tuberculin skin test is correct identification
that when a confirmatory repeat test is necessary, it should of past infection with M. tuberculosis. In clinical practice,
be done within one week. The boosting effect will have it helps in diagnosis of tuberculosis disease in younger
disappeared if 18 months have elapsed between the first children under five years of age. Therefore, the definition
tuberculin test and the repeat test. of significant tuberculin reaction should be based on the
degree to which this definition allows a clear separation
Injection Technique between reactions resulting from infection with
The skin of the arm is lightly stretched length wise and M. tuberculosis and reactions to tuberculin that result from
the pointer of the needle is inserted length wise, with other mycobacteria and after BCG.
301
A positive test conveys that the patient has been Table 23.2: Causes of a false-negative
infected with M. tuberculosis either recently or in the past. reaction to Mantoux test
In a population, percentage of positive test will steadily
• Infections:
increase with age. Actual interpretation of tuberculin test Viral (mumps, measles, chickenpox, HIV infection)
must have distinct cut-off point for positive and negative Bacterial (recent or overwhelming tubercular infection,
results. Bigger the size of induration the more is its leprosy, brucellosis), associated fungal infection
significance in detecting disease (younger than 5 years • Faulty technique
of age). This is based on the premise that tuberculin, being • Improper storage and dilution of tuberculin
derived from M. tuberculosis, would elicit a greater • Desensitization due to heavy load of antigen as in miliary
tuberculosis and tuberculous meningitis
reaction in an individual exposed to M. tuberculosis than
• Attenuated viral vaccination (measles, mumps, polio)
to other organisms. Less than 5 mm size of induration is • Metabolic derangements (chronic renal failure)
definitely a negative test. Size below 10 mm (5-9 mm) is • Protein energy malnutrition (grade III & IV)
not definitely positive except in a child with associated • Lymphoreticular disorders
HIV/AIDS as there are so many factors such as • Lack of available circulating T lymphocytes (congenital
malnutrition, severe tuberculous disease, viral and other hypotrophy or atrophy of thymus)
infections, patient on steroid therapy, presence of • Presence of abnormally high number of T-suppressor
malignancy, etc. that can produce lesser degree of cells at the site of skin test
• Intake of corticosteroids, immunosuppressive drugs
induration.11 Therefore, it is very important to consider
• Extremes of age (newborn or elderly)
other factors in an individual for proper interpretation • Stress (surgery, burns, graft versus host disease)
of positive or negative test result. In a strongly positive • Denatured/contaminated tuberculin
test we may be dealing with active tuberculosis especially • Errors in recording
in children but many healthy adults also can have
strongly positive test. Similarly, a negative test does not
INFECTION WITH NONTUBERCULOUS MYCOBACTERIA
exclude active tuberculosis.
The reaction to tuberculin skin test is interpreted as Infection with M. avium or other members of the genus
follows: nontuberculous Mycobacterium can result in tuberculin
Size of induration with 5TU PPD-S / 1TU PPD with sensitivity. These cross-reactions occur in many parts of
RT 23 and Tween 80 the world. In principle, the larger the induration size,
<10 mm - Negative the greater the likelihood of ‘true’ infection with
10 mm - Borderline M. tuberculosis. Lindeboom et al20a has emphasized the
>10 mm - Positive role of tuberculin skin testing in the diagnosis of
Tuberculin reaction is more specific in younger age nontuberculous mycobacterial cervicofacial lymphadenitis
group, i.e. 0 to 9 years. If a child below 2 years is found in children described earlier.
to be tuberculin positive, it may be an indirect evidence
of an active tuberculous focus in the body. Use of PPD in BCG VACCINATION
high doses, i.e. 10 TU, etc. should be avoided, because,
reaction elicited is due to ‘dose response’ rather than due The effect of BCG vaccination on the subsequent Mantoux
to real infection. In every country there should exist a test is highly variable as it partly depends on the strain
national consensus and one should be careful in using of BCG used. In BCG vaccinated children, the reaction
the type and dose of PPD as per the recommendations of to tuberculin ranges from 3 to 10 mm. The presence or
the national authorities. size of postvaccination tuberculin skin test reaction does
not reliably predict the degree of protection afforded by
Causes of a False-negative Reaction BCG because it is a hypersensitivity reaction. Tuberculin
to Mantoux Test skin reactivity due to BCG vaccination wanes with time
These have been enumerated in Table 23.2. and is unlikely to persist beyond 10 years after
vaccination. Several studies have shown that at least 50%
Causes of False-positive Reaction to Mantoux Test of the children after BCG vaccination do not become
In a small number of individuals tuberculin reactions tuberculin positive and 80 to 90% of those who show
maybe due to errors in administering the test or reading weak positive test initially become negative after 2 to 3
the results; however, the more common causes of false- years of BCG vaccination. Seth et al32 have demonstrated
positive reactions are infection with nontuberculous that, there is 50 to 60% waning in the first year itself.
mycobacteria or recent vaccination with bacille Calmette- Hence, with other supportive criteria for diagnosis of
Guérin (BCG). tuberculosis, positive tuberculin test must not be ignored
302
Section 5 Diagnosis
and attributed to BCG vaccination. The following features sensitization was found in Ahmednagar, Maharashtra39
suggest infection with tuberculosis in a tuberculin where BCG is expected to be more protective. In a
positive child who has received BCG. multiple skin test survey using newer tuberculins
i. Size of the reaction >10 mm. conducted in Hanoi and Nba Trang cities of Vietnam,
ii. Household contact with a tuberculosis patient. low levels of mycobacterial sensitization with remarkable
iii. High prevalence countries regional differences were recorded.40 Similar tuberculin
iv. Long time interval between vaccination and testing has also been carried out in other countries
tuberculin testing. showing differing profiles.41 Logically, therefore, one
Al-Kassimi et al33 have described the significance of must consider the cross-reactivity profile of the
positive Mantoux reactions in BCG-vaccinated children. population and the risk of exposure of the individual
They demonstrated that tuberculin sensitivity rises more before interpreting a tuberculin test.38
steeply with age in the BCG vaccinated than the One approach to determine the extent of cross-
unvaccinated children. BCG vaccinated children display reaction may be to determine the correlation between
an increased ability to respond immunologically to reactions to PPD-S and to PPD-B (indicator of sensitivity
encounter environmental mycobacteria. In countries with to atypical mycobacteria). Some studies have shown that
low prevalence of environmental mycobacteria, this from the results of dual testing in those with medium
results in a slow but persistent rise of skin reactivity to size induration of 6 to 11 mm to 5 TU PPD-S, those
tuberculin14 more in vaccinated than unvaccinated infected with M. tuberculosis could be clearly separated
subjects. from those not so infected.42 However, similar distinction
Wang et al34 in a recent meta-analysis, showed that was not possible in the Indian setting.43
(a) BCG significantly increases the likelihood of a positive
tuberculin skin test, (b) the effect was less after 15 years,
Booster Phenomenon
and (c) reactions > 15 mm were more likely to be the On sequential tuberculin testing some persons show a
result of tuberculosis infection rather than of BCG marked increase in the size of their skin reactions that
vaccination. may not be due to recent or past tuberculous infection.
This enhancing or ‘boosting’ phenomenon has been
VARIABLES AFFECTING INTERPRETATION reported for more than four decades and was attributed
to faulty administration of the test, observer’s error,
There are many reasons (operating individually or
stability of the antigen, previous BCG vaccination, race,
together) for a false-negative Mantoux test reaction
contact with tuberculosis and recent illness or
(Table 23.2).11,24 A physician must keep them in mind
immunization.44 The increase seems to occur as the initial
when interpreting a tuberculin test reading. Most of the
test stimulates the factors that determine reaction size in
errors in administration and reading can be avoided by
the subsequent test. 11,44-47 However, most of these
careful attention. However, some situations need special
correlations are difficult to explain.44 Boosting is probably
mention in relation to the tuberculin test and are
a situation in which hypersensitivity to tuberculin has
described below:
waned so that an initial reaction to PPD is not significant
but provides the stimulus to boost the size of a reaction
Cross Reactivity to a second test, sometimes leading to tuberculin
Tuberculin reactivity due to infection with mycobacterial conversion.11,47 Sensitivity caused by one or more of the
species other than M. tuberculosis frequently complicates nontuberculous mycobacteria can also be a cause. It is
tuberculin test interpretation. 35, 36 Generally these important to determine whether or not the cause is
reactions are less than 10 mm in diameter (which is the infection with M. tuberculosis and if so, whether this
general cut-off point), but depending on the exposure of infection is of recent or past occurrence; for appropriate
the population to nontuberculous mycobacteria, some therapy of subclinical infection detected in people after
reactions can be greater.37 The reverse may also be true, a positive tuberculin test and epidemiological surveillance
i.e. some persons infected with M. tuberculosis may programs depend on its correct interpretation.44
develop reactions less than 10 mm diameter to the 5 TU The booster effect can occur as soon as a week after
dose of tuberculin.37 Stanford et al38,39 and Ly et al40 have the initial test and persist for as long as a year.20 It contributes
put forward useful information on the environmental significantly to false conversions. Alexander and Roper48
mycobacterial profile of different cities in India and reported 28% conversions while Morse et al49 reported a
Vietnam. In India, a high level of initial sensitization to 31% change in tuberculin test status. However, it occurs
mycobacteria was observed in a multiple skin test study rarely in children, increases in frequency with age and is
of school children in Agra.38 Conversely, a low level of seen more frequently in persons over 50 years of age.45
303
As yet its relationship with the progress of tuberculosis of the reaction size at times was also seen.57 Patient’s
disease and healing has not been studied. reading of their own results were also inaccurate and
Biologic variability as well as difference in adminis- unreliable. It is best to have one person, who is skilled in
tration and reading can result in change of less than 6 the procedure, to do the testing in a medical facility.
mm in 9% of subjects if tuberculin test is administered
again. Therefore, an increase of 6 mm or more should be Persistently Negative Tuberculin Reactions
considered to represent a true biologic phenomenon; this A study by Steiner et al61 identified a small number of
may be due to boosting or conversion.50 Boosting is children with culture proven tuberculosis who did not
maximal if the interval between the two tests is between have severe disease but consistently failed to react to
1 to 5 weeks.51 The boosting phenomenon is common as tuberculin for no apparent reason. Culture and biopsy
it is roughly correlated with the prevalence of initial techniques have to be relied upon for diagnosis in these
tuberculin reaction. It is, however, nonspecific as it is cases. By as early as 1968, and subsequently reinforced
associated with remote TB infection, non-tuberculosis by many studies by Seth and coworkers (AIIMS, New
mycobacterial sensitization and BCG vaccination. 50 Delhi),62 it has been established that severe malnutrition
Boosting can be differentiated from conversion based on interferes with the elicitation of DTH, i.e. Mantoux
the clinical situation (exposure in the interval between test.63-65 Hence, in spite of having tuberculosis infection
the two tests), the size of the reaction (as the size of second or disease the test can be negative.
reaction increases, the likelihood that it represent true
conversion, increases). Indications for Tuberculin Testing
In most situations, an individual whose tuberculin Table 23.3 lists the indications for tuberculin testing as
reaction changes from less than 10 mm in diameter to recommended by the American Academy of Pediatrics.
more than 10 mm in diameter and increases by 6 mm HIV infection is also an indication for tuberculin testing.20
within a period of 2 years, should be considered recently We especially recommend tuberculin testing on a priority
infected.9 In order to classify as recent convertor, the basis in children who are in contact with sputumpositive
following criteria should be met: tuberculosis cases as they are at higher risk of infection
i. The skin reaction must have increased by > 6 mm. and the disease. Sometimes tuberculosis is also found in
ii. The increase must have been from less than 10 mm patients with diseases which are likely to render them
to more than 10 mm. anergic.20
iii. The increase occurred over a time period of less than
24 months. HIV Infection and Tuberculin Test
There is paucity of data regarding tuberculin skin test
Tuberculin Reaction in Relation reactivity in HIV-infected children. It has not been shown
to Isoniazid Therapy that HIV-infected children are able to mount antigen-
specific cell-mediated immune responses that
It has been reported that isoniazid treatment of tuber- are qualitatively similar to those of age-matched
culosis in children had no significant effect on tuberculin control subjects.66 Moreover, the loss of delayed-type
sensitivity.52 Studies conducted over a period of ten years hypersensitivity responses corresponds to both clinical
concluded that isoniazid treatment did not reduce the and immunological progression to HIV-disease.
tuberculin sensitivity and that conversion rate was Tuberculin test is also indicated in HIV-seropositive
similar to patients receiving placebo therapy.53,54 It has children and in this group tuberculin negative children
been suggested that a positive tuberculin reaction in require annual testing.26,67 This is to enable timely
the isoniazid treated patient is to child’s advantage. With detection and treatment of tuberculosis in HIV-infected
the risk of endogenous disease removed by treatment, children because progression of HIV infection to disease
the patient gains cellmediated immunity which protects (AIDS) on one hand, renders the patient anergic (to
the child from future exogenous reinfections.55-57 tuberculin), on the other hand, in patients with clinical
disease (AIDS) tuberculosis presents in atypical forms
Inter-observer Bias which is difficult to diagnose. Garcia-Garcia et al68 have
demonstrated that PPD reactivity is useful to diagnose
Significant variability in performance and interpretation tuberculosis only among HIV-infected individuals with
of the Mantoux test has been observed in various CD4+ counts more than or equal to 500 cell/mm3. Among
studies.31,34,58-60 It was noted that differences in size of individuals with lower counts, lowering cut-off levels or
reactions recorded by experienced readers were as using anergy panels such as candida and tetanus toxoid
variable as those of inexperienced readers. Variability of did not permit comparable reactivity as that observed
15% in reading by the same person, extending up to 50% among HIV-infected children.
304
Section 5 Diagnosis
Table 23.3: Indications for tuberculin testing infection in a patient/ prevalence of tubercular infection
in the population and the specificity of the test in that
• Children for whom immediate skin testing is indicated
– Children with suspected tuberculosis on radiographic population.
or clinical findings Some studies suggested that stronger the reactions
– Contacts of confirmed or suspected infectious to tuberculin, greater the chances of active disease.69-71
tuberculosis cases As the test is simply a delayed-type hypersensitivity
– Children immigrating from endemic areas (Asia, reaction giving information about previous exposure to
Africa, Latin America, etc.) to nonendemic areas tubercular infection, it does not seem plausible that it
• Children who should be tested annually can accurately predict the presence of active disease.
– Children infected with HIV In a review by Udani et al71 tuberculin testing using
• Children who should be tested every 2-3 years
1TU PPD RT 23 was positive in 52.3% (19.3-73.3%) of
– Children exposed to following individuals: HIV
infected, homeless, ‘drug-addicts’, prison-inmates children with tuberculosis. The positivity was lower in
• Children who should be considered for testing at ages 4 children with severe malnutrition, disseminated
to 6 and 11 to 16 years tuberculosis, miliary tuberculosis, and tubercular
– Children (without high risk factors) residing in high meningitis. Another study reported 41% test positivity
prevalence areas (notified high tuberculosis rates) in 61 children with definite tuberculosis.72 In this study
– Children whose parents immigrated from high the sensitivity improved if 5 TU or 10 TU were used.
tuberculosis prevalence regions (countries) of the However, it is not recommended to use 10TU strength.
world In a community, tuberculin test can be used to determine
– Risk of progression to disease
the overall prevalence of a positive skin reaction. The
– Children with other medical risk factors: mal-
annual incidence and prevalence of infection helps to
nutrition, congenital or acquired immunodeficiencies,
diabetes mellitus, chronic renal failure (Underlying determine the problem of infection due to tuberculosis.
immune deficiencies would enhance the possibility Population vaccinated with BCG shows a lack of
for progression to disease; and initial Mantoux correlation between the positive reaction after vaccination
tuberculin test should be performed before initiation reported retrospectively by the subject and the current
of immunosuppressive therapy as indicated in a child) skin reaction observed by the physician. Repeat BCG in
– BCG vaccination is not a contraindication to tuberculin a population previously vaccinated results in a booster
testing effect of tuberculin in Mantoux test due to mycobacteria
– Some of the indications may not be of practical importance circulating in the general population.
in developing countries like India Nagelkerke et al73 have described that tuberculin
(Modified from: American Academy of Pediatrics, surveys of children can be used to estimate national or
Committee on Infectious Diseases; update on tuberculosis regional infection prevalence and are commonly
skin testing of children. Pediatrics 1996; 97: 282-4) and
designed as multistage surveys. It is emphasized that
pediatrics 2001; 107: e54 down loaded by Indian Council
increasing the number of selected districts is more
of Medical Research on July 2010.
efficient for increasing the precision of the estimate than
Uses increasing the number of children per district beyond
several hundred to a few thousand.
A significant reaction to 5TU of PPD-S or equivalent dose The benefits of screening for latent tuberculosis has
of other tuberculin demonstrates presence of hyper- gained importance in the wake of a large number of high-
sensitivity to tubercle bacilli. The larger the reaction, the risk categories. To name a few, concurrent infection of
greater is the probability that the responsible organism tuberculosis and HIV/AIDS, immune compromised
is M. tuberculosis. Tuberculin skin test is useful in states such as malignancies, intravenous drug abuse, end-
evaluation of children suspected of having tuberculosis stage renal disease and the children exposed to an open
in as much that a significant reaction supports the adult case. Rose74 in 2000 did a MEDLINE search to
diagnosis. determine tuberculosis risk. Tuberculin skin test
In any population, the probability that a positive skin screening and preventive therapy for 3 years old and
test represents a true infection, depends on the prevalence 30-year-old persons with positive test results was done.
of infection with M. tuberculosis. The tuberculin test has Outcome measures were life time and 10-year risk,
a specificity of approximately 99% in populations that including spread to others, life expectancy extension and
have no other mycobacterial exposures or BCG number needed to screen to prevent 1 case was 10 to 6888,
vaccination. Specificity is lower (approx. 95%) in popu- and the number needed to treat was 2 to 179. The benefits
lations where cross-reactivity with other mycobacteria of screening and preventive therapy varied widely,
is common. Therefore, the positive predictive value of a although the benefits outweigh the risks for all risk
tuberculin test depends on probability of tubercular groups.
305
Other Tests to Detect Tuberculosis Infection: 3. QFT- γ does not trigger anamnestic response (i.e.
Interferon-γγ Release Assays booster reaction with repeated testing) as does TST.
Till a few years ago, the tuberculin skin test was the only Limitations of the Test
investigation available to confirm the diagnosis of
tuberculosis infection. In the recent years, Interferon-γ 1. As with TST, the QFT- γ cannot differentiate between
Release Assays (IGRA) have been developed. These tests tuberculosis infection and disease.
measure the cell mediated response in infected 2. QFT- γ test may be less sensitive (though more specific)
individuals by the levels of interferon gamma released. than TST for tuberculosis infection.
During tuberculosis infection, T cells from the individual 3. The predictive value of the QFT- γ depends upon the
will be sensitized (via MHC proteins) to the antigens prevalence of M. tuberculosis infection in the
presented by cells of the M. tuberculosis. T cells will thus population being tested. Therefore, false-positive tests
be able to bind to foreign infecting cells, releasing will occur when the test is applied to persons from a
interferon-gamma. Interferon-gamma Release Assays low-prevalence population.
4. QFT- γ cannot be used alone to exclude tuberculosis
take advantage of this natural process in infected
disease in patients suspected of disease.
immunocompetent individuals. When antigens specific
5. It has been evaluated in response to ESAT-6 and
for a given infecting agent (often in the form of purified
CFP-10 antigen.
protein derivatives) are applied to whole-blood samples
from infected individuals, T cells sensitized to the
Performance of the Tuberculin Skin Test and
antigens will be present in the blood, and will bind to
Interferon-γγ Release Assay for Detection of
the antigen. The T cells will then release Interferon-
Tuberculosis Infection in Immunocompromised
gamma. The presence of sensitized T-cells in infected
Patients in a BCG-Vaccinated Population
individuals will result in far higher levels of IFN-γ release
than among uninfected individuals. The presence of Kim et al 75 reported that in immunocompromised
IFN-γ can then be quantified using a single step enzyme- patients, the QFT- γ may be more sensitive than the TST
linked immunosorbent assay (ELISA) using anti-IFN- γ for detection of LTBI, but it resulted in a considerable
antibodies. proportion of indeterminate results. Therefore, both tests
IGRAs differ from each other mainly with respect may maximize the efficacy of screening for LTBI in
to the technique of IFN-γ detection (enzyme linked immunocompromised patients.
immunospot; ELISPOT vs enzyme linked immunosorbent
assay; ELISA) and the samples utilized (peripheral blood Comparison of Tuberculin Skin Testing and
mononuclear cells vs whole blood). There are two T-SPOT: TB for Diagnosing Latent and Active
commercial IGRAs and both measure overnight IFN- γ Tuberculosis
responses (<24 h) to overlapping ESAT-6 and CFP-10 Simsek et al76 have evaluated the performance of T-SPOT.
peptides. The T-SPOT. TB assay (Oxford Immunotec, TB and TST for diagnosing LTBI and found that they were
Oxford, England) is an ELISPOT assay that uses comparable (54.8%) in the diagnosis of latent TB.
peripheral blood mononuclear cells and QuantiFERON- However, T-SPOT. TB was superior in terms of sensitivity
TB Gold (QFT-γ) and QuantiFERON-TB Gold In Tube (83.0%), TST detected 18 where as T-SPOT. TB test
(QFT-GIT Cellestis, Victoria, Australia) are ELISA assays detected 39 out of 47 patients with active TB. TST has
utilizing whole blood. The QFT-GIT assay has replaced more false negative results.
the QFT- γ test and also contains the TB 7.7 peptides. Recommendations for Use of IGRAs in the CDC Issues
1. The QFT-γ test offers some distinct advantages over Updated Guidelines for Testing for Tuberculosis
the TST. First, it requires only one patient encounter Infection
to draw the blood, and not two as in TST. • To assist in diagnosing infection with M. tuberculosis
2. The proteins used in the QFT- γ are absent from all tuberculin skin tests and IGRAs may be used for
bacille Calmette-Guerin (BCG) strains and from surveillance or to identify persons likely to benefit
commonly encountered nontuberculous mycobacteria from treatment.
except, M. kansasii, M. szulgai and M. marinum. This • Established protocols using FDA-approved test
should make the test more specific for M. tuberculosis formats are required for performance and interpretation
infection than the Quanti FERON-TST, both of which of IGRAs in compliance with clinical laboratory
use PPD as the antigen. This could make QFT- γ more improvement amendment standards.
attractive for use in children who have received BCG • Both the standard qualitative test interpretation and
vaccination. the quantitative assay measurements should be
306
Section 5 Diagnosis
Table 23.4: Comparison of the features of the tuberculin skin test and the interferon-g release assays
Feature Technique IGRAs
In-vitro test
Tuberculin skin test in vivo (QuantiFERON- g ELISA; T-SPOT.TB: ELISPOT
Cross reactivity with BCG Present Relatively specific for
/environmental bacteria M. tuberculosis
Results Subjective; the results are dependent For a chosen cut-off, provides
on observer and technique ‘yes/no’ answer
Needs a return visit for the Needs single visit for collection of
determination of result blood sample; test is performed in
the laboratory
Results reported as mm induration QuantiFERON: Interferon-γ units
T-SPOT.TB: Spot-forming units
Booster phenomenon (by TST) Yes Yes
Cost Low High
Other requirements Needs cold chain; safe Requires expensive lab set-up and
injection practices expertise.
reported along with the criteria used for interpretation show improved predictive value for progression to active
of the test. disease, once an individual is infected with M.
• Arrangements for IGRAs testing should be made for tuberculosis. The IGRAs have been shown to perform
collection of blood in proper tubes for performance similar to the skin test in multiple studies in children.77, 78
of the test within the required time frame. Table 23.4 compares the feature of tuberculin skin test
• Before implementing testing with IGRAs, each and the interferon γ release assays. While the IGRAs have
institution and Tuberculosis Control Program facility revolutionized the diagnosis of LTBI in low burden
should consider availability, overall cost, potential countries, the performance of IGRAs may be modulated
benefits of IGRAs and characteristics of the test by several factors in high-burden settings.79-90 In all
population in their own setting. settings, IGRAs retain specificity in those who are BCG
• Neither the tuberculin test nor the IGRAs should vaccinated or have a false-positive TST due to
typically be used to test persons at low risk for both environmental mycobacteria.
infection and progression to active tuberculosis if
infected, unless they are likely to be at increased risk HIGHLIGHTS
in the future.
• The tuberculosis skin test is also known as the
• An IGRA is preferred for testing persons from groups
tuberculin test or PPD test.
that typically have low rates of returning and to those
• The PPD test is used to determine if some one has
who have received BCG. The latter can have false- developed an immune response to the bacterium that
positive skin test. cause tuberculosis (TB).
• IGRAs or the tuberculin skin test may be used to test • The standard tuberculin test is the MANTOUX test,
recent contacts of persons with infectious which is administered by injecting 0.1 ml volume
tuberculosis. containing 1 or 5 TU (tuberculin units of) PPD into
• IGRAs or the tuberculin skin test may be used for the top layers of skin of the forearm.
periodic screening for occupational exposure. • Skin test should be read 48 to 72 hours after the
• For testing children younger than 5 years, the injection.
tuberculin test is preferred Vs the IGRAs. • The basis of the reading of the skin test is the presence
• Guidelines summarize that although substantial or absence and the amount of induration.
progress has been made in documenting the utility of • A negative test does not always mean that a person
IGRAs, additional research is needed that focuses on is free of tuberculosis
the value and limitations of IGRAs in situations of • A person after BCG vaccine may also have a positive
importance to medical care or tuberculosis control. skin reaction to the TB test.
A limitation of IGRAs is their relatively high cost and • Primary infection with M. tuberculosis is followed by
need for laboratory infrastructure. However, one would the development of cell-mediated delayed-type skin
need to demonstrate significant advantage over the TST, hypersensitivity after 4 to 6 weeks.
to justify the investment for developing countries. The • The skin test only measures the degree of
outstanding question to resolve now is whether IGRAs hypersensitivity and not immunity to tuberculosis.
Contd..
307
• A number of causes of false-positive and false- 12. Magnusson M, Bentzon MW. Preparation of purified
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infection. reference tuberculin standards. Am J Respir Crit Care
• As the presence of mycobacteria other than Med 2000;161:1167-71.
M. tuberculosis can cause same response at the test 14. World Health Organization Expert Committee on
site, there is a need for developing species-specific Biological Standardization. Fifth report. Geneva World
antigens. Health Organisation (WHO) technical report series No.
• Interferon-γ release assays are new generation in 56,1952;6.
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with the tuberculin skin test and have some remedy. Indian Pediatr 2004;41:293-4.
advantages. However, high cost and need for 16. Jani T. Tuberculin in India. Indian Pediatr 2004; 41:
expensive lab set-up and expertise limit its utility in 1185-6.
developing countries. 17. American Thoracic Society. Diagnostic standards and
classification of tuberculosis in adults and children. Am
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test. Who, when and how? Arch Intern Med tuberculin conversion in Indo-Chinese refugees. JAMA
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51. Cauther GM, Snider DE, Onorato IM. Boosting of
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32. Seth Vimlesh, Kukreja N, Sunderam KR, et al. Waning isoniazid. Am J Dis Child 1983;137:1090-2.
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35. Edward LB, Hopwood L, Palmer CE. Identifica-tion of 56. Grzybowski S, Galbraith JD, Dorken E. Chemo-
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40. Ly HM, Trach DD, Long HT, et al. Skin test 61. Steiner P, Rao M, Victoria MS, et al. Persistently negative
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69. Mehta R, Sain L, Mittal SK. A critical evaluation of BCG 80. Lewinsohn DA, Lobato MN, Jereb JA. Interferon-gamma
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72. Milburn HJ, Gibilaro J, Atkinson H, et al. High incidence 82. Bianchi L, Galli L, Moriondo M, et al. Interferon-gamma
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83. Hansted E, Andriuskeviciene A, Sakalauskas R, et al.
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75. Kim EU, Lim JE, Jung JI, et al. Performance of the 84. Kampmann B, Whittaker E, Williams A, et al. Interferon-
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76. Simesk H, Alpar S, Ucar N, et al. Comparison of evaluation of young children at high risk for tuberculosis
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T-SPOT.TB assay and tuberculin skin test for the 87. Connell TG, Ritz N, Paxton GA, et al. A three-way
evaluation of young children at high risk for tuberculosis comparison of tuberculin skin testing, QuantiFERON-TB
in a community setting. Pediatrics 2009;123:38-43. gold and T-SPOT.TB in children. PLoS One. 2008; 3: e2624.
78. Grare M, Derelle J, Dailloux M, et al. Quanti FERON(R)- 88. Okada K, Mao TE, Mori T, et al. Performance of an
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in a French pediatric hospital. Diagn Microbiol Infect Dis tuberculosis infection in children. Epidemiol Infect
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89. Dheda K, Smit RZ, Badri M, et al. T-cell interferon-gamma
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Interferon-gamma Release Assays Compared to
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print]. 59(RR-5): 1-28.
24 Newer Tuberculins:
Profile in Developing Countries
JL Stanford
THE REAGENTS antigen of the species from which they were made. Newer
tuberculins made from the same species will contain
It is now more than 110 years since Robert Koch first plenty of groups I and IV antigens, and little group II
introduced, as a potential immunotherapeutic reagents antigen.
for tuberculosis,1 which subsequently became known as
old tuberculin (OT). Later studies showed that although
Skin Test Responses and Antigens
the reagent could be very dangerous in the doses used in
treatment, minute doses were useful in epidemiology and Antigens of groups I, II and IV can all elicit positive skin
to some extent in diagnosis. Old tuberculin consisted of reactions in individuals.2,4,5 However, so far there is no
a biologically standardized dilution of medium in which evidence that the fast-grower associated, group III
tubercle bacilli had been grown, and heat killed. It had antigens play a part in skin tests. Thus to a single skin
the disadvantages of containing the nutrients required test with tuberculin (from M. tuberculosis) a person may
for bacterial growth together with the heat degraded make a positive response to antigens shared by all
substances released by live and dead tubercle bacilli. mycobacterial species, to antigens shared by slow-
When such a reagent was used for skin testing, it was growing mycobacterial species, to antigens specific to the
necessary to test the person simultaneously with a control tubercle bacillus, or to various combinations of these.
dilution of heated, uninoculated medium.
The problem of medium constituents in the reagent Differentiating the Results
was overcome by precipitating out the tuberculoprotein,
Fortunately there are two ways that help determine which
washing it, and redissolving it in a buffer solution.
of these antigen groups a response is directed towards.
However, such purified protein derivatives (PPDs) still
had the disadvantage of containing material partially
degraded by incubation in the culture medium, and
Responses to Groups of Antigens Distinguished by Size
material damaged by the heat sterilization process.
To overcome the problem of heat degradation, In the 1990s studies were carried out on Finnish school
reagents known as new tuberculins (NTs) were prepared children, in which PPDs prepared from tubercle bacilli
from organisms harvested from nonantigenic media and and from M. scrofulaceum have been compared with each
broken with ultrasound.2 The sonicate is then sterilized other and with two batches of newer tuberculins (NTs)
by centrifugation and filtration to 0.2 µm pore size, and prepared from tubercle bacilli.
diluted to 1mg of protein per ml with M/15 borate Analysis of the results indicates that, within the
buffered saline at pH 8 for storage at 4°C. Such reagents protective type of response, reactions to one group of
are then diluted to a standard skin test strength for use (2 antigens (e.g. species specific) are of small size and that
µg/ml in most cases). when the reaction is to two or more groups of antigens
(e.g. species specific and slow-grower associated), the
The Antigens in Skin Test Reagents response size is larger.
Because of their different ways of production, OTs and The Protective vs the Koch-types of Response6,7
PPDs on one hand will have different concentrations of
mycobacterial antigens than have NTs (Table 24.1). Thus, There are two qualitatively different types of response
when prepared from slow-growing mycobacteria, OTs both giving areas of induration palpable at 48 to 96 hours.
and PPDs are particularly rich in slow-grower associated, One of these is usually accompanied by slight edema and
group II antigens, 3 presumably because these are pink erythema, is not painful, but may be tender to touch.
relatively resistant to degradation. It has rather soft induration with an ill-defined edge, and
However, they also contain some common myco- may be directed to any of the groups of antigens. This
bacterial, group I antigen, and some specific, group IV type of response to tuberculin usually follows vaccination
311
Chapter 24 Newer Tuberculins: Profile in Developing Countries
Table 24.1: Relative concentrations of the groups of antigens demonstrable in sonicates of

mycobacteria known to be present in the different types of skin test preparation
Groups I II III IV
of Common Slow-grower Fast-grower* Species
antigens mycobacterial associated associated specific
Old tuberculin + ++++ – +
or
PPD tuberculin
New tuberculin ++ + – +++
* Not known to activate in skin test responses
with BCG in the United Kingdom and is thought to slowly. The difference between the two types of response
correlate with protective immunity. is thought to lie in the release of different cytokines,10,11
The second type may or may not have surrounding as well as the infiltration including different cell types.
edema, and has a zone of central purplish/brick red Thus, tumor necrosis factor (TNF) and interleukins 4 and
erythema overlying a hard and sharply demarcated area 6 (IL4 and IL6) are important mediators in Koch
of induration, which may be surrounded by a corolla of responses,6 but not in protective responses. Interleukin2
pink erythema.8 The reaction is often painful and tender (IL2), and possibly gamma interferon may be involved
to touch, the skin overlying may have small bullae, hair in both types of reaction. The protection type of response
follicles and sweat gland puncta, and sometimes may appears to be mediated by T helper lymphocytes,
ulcerate. whereas Koch responses are thought to be due to a
Responses of this type are to species specific antigens, combination of Th1 and Th2 lymphocyte activity.
occasionally to slow-grower associated antigens, and
never to common mycobacterial, group I antigens. Quadruple Skin Testing and Categorization of
Reactions of this type are expressions of immuno- Responders4,12
pathology with necrotizing elements analogous to the
Interpretation of skin test results is also helped by
Koch’s phenomenon. Thus, they are often referred to as
carrying out tests with reagents prepared from four
necrotizing or Koch responses.9
separate species of mycobacteria simultaneously. These
Though the qualitative differences are appreciable two should consist of tuberculin itself, a reagent from
around 72 hours after injection, the two reaction types another slow-growing species, and reagents from two
have different time courses. The response thought to fast-growing species (1 of which may be replaced with
correlate with protection is maximal at 48 hours and Leprosin A made from M. leprae harvested from infected
disappears within 7 days or so. That of the Koch-type is armadillos). Table 24.2 shows the antigenic contents of
maximal around 72 to 96 hours and resolves much more the four reagents and how different patterns of response
Table 24.2: Quadruple skin testing, the groups of antigens injected and the interpretation
of possible responses to them
Right arm Left arm

Scrofulin Tuberculin
Gr IV M. scrofulaceum Gr IV M. tuberculosis
Gr II slow-grower associated Gr II slow-grower associated
Gr I common mycobacterial Gr I common mycobacterial
Vaccine Flavescin
Gr IV M. vaccae Gr IV M. flavescens
Gr III fast-grower associated
Gr I common mycobacterial Gr I common mycobacterial
Interpretation of results
+ ve to all 4: Cat 1 responder to Gr I Ags
– ve to all 4: Cat 2 nonresponder: skin test suppression
+ ve to upper 2: Cat 3 responder to Gr IV Ags of both species (or Cat 4 responder to Gr II Ags—requires confirmation by
further tests with reagents of other slow growing species)
+ve to lower 2: Cat 3 responder to Gr IV Ags of both species
Gr = Group; Cat = Category; Ags = Antigens
312
Section 5 Diagnosis
to them can divide any group of people tested into Table 24.3: Example of the way in which the “True”
categories of responders. Errors due to chance percentage of a population sensitized by contact with
sensitization to the group IV, specific antigens of all four tubercle bacilli can be calculated from the categorized
species, and to chance inexperience of all four species, quadruple skin test results
can be corrected mathematically. As a rough rule of Categorization of the tested population
thumb for adults, 10 to 15% will be category 1 responders
Category 1 responders 20%
to the group I antigens in all four reagents. About the Category 2 responders 15%
same proportion will be category 2 nonresponders to any Category 3 responders 65%
of the reagents, due to a suppressor mechanism Category responders 5%
apparently preventing the release of cytokines when the
dose of antigen is small. This can usually be broken
through by repeating the tests with reagents 10 times responders to slow-grower-associated antigens.
stronger. The remaining 70 to 80% of people will mainly Therefore at least 50% of people were reacting to species
be responders there will also be a proportion of category specific antigens of M. tuberculosis. Since a similar
4 responders to group II, slow grower associated distribution is likely in categories 1 and 2, the true
antigens,13 but proof of this requires additional tests with number of people actually sensitized by contact with
reagents made from further slow-growing species. tubercle bacilli would be: 50% + 10% + 7.5% = 67.5%.
22% of the category 3 responders were recorded to
have Koch-type responses and there were none amongst
Using the System category 1 responders. Some category 2 nonresponders
may have had suppressed Koch type responses (15 × 22/
Infants are negative to all four reagents due to inex-
50 = 70). Therefore, the likely proportion of the
perience, but this changes at a rate dependent upon how
population with subclinical or latent tuberculosis would
often they meet mycobacteria in their environment, until at be 22 + 7 = 29%.
some point during childhood they acquire the adult pattern
(Fig. 24.1).14,15 The Size of Positive Response
At any age the frequency of sensitization by given
species can be roughly gauged from the category 3 With the use of OT and PPDs in determining who has
responders. The prevalence of tuberculosis disease can been infected with tubercle bacilli, or who is suitable for
then be estimated on the basis of the proportion of BCG vaccination, it has been expedient to select a
responses to tuberculin that are of Koch-type16 (Table particular cut-off size of response, above which it is
24.3). considered positive, and below it negative. Although this
has practical value, for our purposes such an approach
Example would be quite unsuitable. If immune cells infiltrate a
site where particular antigens have been injected, then
Of 75% positive tuberculin reactors, 55% were category their presence has been recognized and the response
3 responders, of whom 5% were also category 4 cannot be considered negative. In fact for our purposes,
even taking the smallest appreciable induration (usually
2 mm) underestimates the true proportion of responders
as shown by histology of needle biopsies of some zero-
induration responses.17
The actual size in mm of the response may also be
useful. To some extent this can indicate the frequency of
contact with an organism, may distinguish between a
healthy contact of leprosy patients and a person with
paucibacillary disease, and may help to distinguish
between protective and Koch-types of responses6-8
(Fig. 24.2).
Sensitization by Environmental Mycobacteria

The great majority of mycobacterial species live free in
the environment, although others are constantly being
Fig. 24.1:The development of the adult pattern of responder released into the environment by diseased persons or
categories, and the effect of vaccination with BCG animals. Thus, tuberculosis and leprosy patients
313
age and experience.18,19 There are wide differences in

percentages of positive responders amongst children of
the same age living in different places, as shown in Table
24.4. Beside from their frequency in the environment,
species differ in their skin test sensitizing ability, some
species switching off positive responses to their antigens
if they are met too frequently.20 Thus several fast-growing
species such as M. nonchromogenicum and M. vaccae rarely
induce more than 30% positivity to NTs produced from
themselves.14,15 With such species there is increasing
positivity with age until a plateau is reached, which
appears to be due to the numbers of new persons
becoming sensitized being equal to the numbers of
persons whose responses are suppressed by repeated
contact.
The mechanism by which responses are switched in
this way is probably an homeostatic one based on control
of cytokine release, which determines the presence of
induration rather than some inhibition in migration of
cells to the injection site. This is similar to that seen in
category 2 nonresponders where the antigens triggering
cytokine control appear to be of group I, rather than
Fig. 24.2: Tuberculin responses of Ethiopian school children with or group IV specificity. One would expect the lymphocytes
without BCG scars, showing those considered to have a Koch-type of
response or qualitative criteria of such a person to transform in vitro despite their lack
of skin test induration, as indeed they do. This is one of
contaminate the environment via respiratory discharges the explanations for the lack of conformity between
as droplet nuclei. lymphocyte transformation test (LTT) and skin test
Skin test reagents can be used to monitor the rate of results.
immunologically effective contact of children with Other species, including many of the slow-growers
individual mycobacterial species, and it can easily be induce increasing positivity with age until all persons
shown in non-BCG vaccinated children that an increased are positive except the category 2 nonresponders.
percentage of positive responses accompanies increasing Amongst such species are those capable of inducing
Table 24.4: Geographical differences in responses to new tuberculins for children

aged 11+ years without BCG scars
New tuberculins Tuberculin response (%)
Agra Ahmednagar Bombay Lebanon Kenya Libya
Tuberculin 82 41 67 4 23 35
Leprosin A 48 29 25 5
Kansasin 60 16 3
Marinin 89 24
Scrofulin 84 22 38 8
Gordonin 35 4 68 33
Aviumin A 75 24 62 25
Aviumin C 95 41
Vaccin 47 20 28 8 26 15
Gilvin 2 19
Nonchromogenicin 2 17 2
Flavescin 22 40
Chitin 51
Ranin 2 24 24 31
Dierhoferin 12
Rhodesin 3
Neoaurumin 35 58
Note: In many instances the batches of reagents used were the same
314
Section 5 Diagnosis
either the protective or the Koch-type of response. The Evolution of Skin Test Responses after BCG
Thus, taking M. scrofulaceum as an example, occasional Vaccination
contact produces the soft induration typical of
protective responses (such as the 25% positivity to Within 12 weeks of vaccination of tuberculin negative
scrofulin found in Iran), and frequent contact, instead (<5 mm to 2TU or its equivalent) children with a good
of suppressing the response, converts it to one of the quality BCG, more than 95% of them become positive to
Koch-type (as reflected in the 85% positivity to tuberculin (responses >5 mm). These responses directly
scrofulin found in Burma now Myanmar).6,21 This is a due to the vaccine are of small size compared with
very significant deleterious effect of the environment responses developing later, can be thought of as priming
in some situations. responses and are short-lasting in many people (half-life
about 1 year).26 They are either followed by a return to
Environmental Mycobacteria and Disease Susceptibility negativity, or are supplanted by a longer-lasting response
type following contact with tubercle bacilli in the
Since all mycobacteria share group I antigens, and these environment. Normally this is the soft induration thought
antigens are those recognized in protective immunity, to correlate with protective immunity, and has a mean
contact with any species will give some protection from size of a few mm more than that of the priming response
a challenge with any other. Thus natural protection (Fig. 24.3). Such a response may last for many years.27,28
steadily increases due to contact with environmental Fluctuating from time to time according to the experience
mycobacteria until it becomes as good as that provided of the individual.
by BCG vaccine (perhaps the explanation for the poor If, on the other hand, BCG is inadvertantly given to a
protection provided by BCG in the trial in Georgia and child who already has a Koch-type response to M.
Alabama,USA), although it may take some years to do tuberculosis or some other species, the vaccine will be
so.22,23 This naturally acquired protection seems to be followed by a larger-sized response to tuberculin of Koch-
more readily undermined by conversion to the Koch type. This may, or may not persist; it is not associated
response by excessive contact with some species as with protective immunity and may herald the
explained above, than is the protective immunity development of clinical disease.
provided by BCG vaccination (as seen in the trial of BCG
against leprosy in Burma-Myanmar).24 Once a Koch’s Assessing BCG Program
phenomenon has been induced, BCG vaccination is
ineffective, and disease susceptibility is increased. Indeed Skin tests can be used to assess BCG that has already
BCG vaccination may make things worse by further been given in several ways:
overloading the immune system to no benefit (first Tuberculin can be used alone to compare groups, one
reports of the trial of BCG against tuberculosis in South with BCG scars and the other without.2,16 Because of a
India indicated a negative protective effect of the whole series of variables such as sex,28 social class, and
vaccine).25 whether or not tuberculin testing is used to select who is
to be vaccinated, such groups are difficult to match.
Nonetheless, the reduction in the proportion of persons
SKIN TEST AND THE ASSESSMENT OF VACCINE EFFICACY producing a Koch response to tuberculin among the
vaccinated, as compared with the nonvaccinated can be a
Vaccination with BCG
useful measure (Fig. 24.2).
The effect of BCG vaccination is to lower the threshold
of immunological recognition for subsequently
encountered mycobacterial species—pathogenic and
nonpathogenic. Thus, as well as the increase in positivity
to tuberculin directly due to the group IV antigens of
tubercle bacilli in the vaccine, the rate of acquisition of
skin test positivity to other species increases after
vaccination more than can be explained by the expansion
of category 1 responders to group I antigens. This is
thought to be due to priming via responsiveness to group
I antigens leading to easier recognition of group IV Fig. 24.3: Pooled data from several studies carried out in India. The
antigens. This mechanism may be the same as that figure shows the percentages of children two years after BCG
vaccination responding to tuberculin according to the mean diameter
producing protective immunity through the rapid of induration of their responses. Equivalent results for the same age
recognition and destruction of small challenges with range of children (3 to 15 years) without BCG scars are shown for
virulent tubercle or leprosy bacilli. comparison
315
This was used to assess the efficacy of BCG Leprosin A or an analogous soluble preparation of
vaccination among school children in Shoa district of leprosy bacilli.
Ethiopia;16 it suggested: The only vaccine known to work against leprosy is
1. Level of protection of about 80%. BCG itself,36 which may be more effective against leprosy
2. Reagents prepared from any mycobacterial species then it is against tuberculosis, 37 highlighting the
can be used to assess the usefulness of BCG to some importance of group I antigens in protective immunity.
extent, but they are best used as part of a set of 4 Thus new vaccines need to compare advantageously with
reagents as discussed above.18,29 It can then be shown BCG. Considerable care is needed in making sure that
that where BCG is effective it expands category 1 of what is measured after the vaccine is not the direct, and,
responders to common mycobacterial antigen, therefore, perhaps ephemeral, effect of the vaccine, but
decreases category 2 nonresponders, and increases its long-lasting effect. This requires the follow-up skin
the category 3 responders to reagents prepared from tests to be performed at least one year, and preferably
organisms present in the environment.30 two years after the vaccine has been given. An effective
3. Studies are currently in progress to determine the vaccine should show an increasing not a decreasing level
optimum time after birth for the administration of of positivity over this timescale to Leprosin A, or an
BCG vaccine, and in part these depend on skin testing. equivalent, and should show the proportion of category
In Finland it has been shown that BCG given in the 1 responders to be at least as high as after BCG alone.38
first few weeks of life produces a significantly Without the ability to distinguish between the
different size of tuberculin response, measured years protective and Koch-types of response to tuberculin,
later, than does BCG given to a child just a few weeks which are particularly properties of the NT reagent,
older. Correlations of this with actual prevention of single tuberculin tests are of little help in assessing the
disease have still to be made (E Tala, personal efficacy of BCG against Leprosin A in this context. In
communication). fact, except in some patients with paucibacillary disease,
A number of studies have been carried out showing responses to Leprosin A are always of the protective type,
that when BCG is given at birth, only a small proportion suggesting that enhancing positivity is enhancing
of children remain tuberculin positive by the time they protective immunity. In support of this new cases of
are 5 to 6 years old,31 unless the frequency of meeting disease have been found to occur amongst the previously
tubercle bacilli is high. Subsequently, Tuberculin Leprosin A negative (reaction less than 2 mm) portion of
positivity may rise, but it is not certain whether BCG the population (Dr K Desikan, personal communication).
revaccination should be considered.28 However, additional evidence on this point would be
Seth et al have conducted a number of studies, to see very valuable.
the effect of age and nutrition on the take-up of BCG Recent studies in Maldiv have shown that responses
vaccine.22-35 It can be summarized that the take-up of BCG to NTs made from fast growing mycobacterial species
vaccine was similar when it was given to full-term and are associated with protection from both leprosy and
preterm babies who had weight appropriate for tuberculosis.39
gestation. Further, they found that children who were
given BCG at birth and later became malnourished, the NEW TUBERCULINS AND DIAGNOSIS OF
retention of cell-mediated immune response (CMIR) MYCOBACTERIAL DISEASE
tested by Mantoux test and leukocyte migration
inhibition test (LMIT) was poor in them in comparison Tuberculosis
to normal nourished children. The waning of delayed
hypersensitivity was maximum in the first year as only Unfortunately, in the diagnosis of tuberculosis among
30 to 40% of the children had positive Mantoux test. This adults the NTs offer no advantage over OTs or PPDs
positivity decreased further to 16.7% children in the age except perhaps in the ease of differentiating between
group of 3 to 6 years. response types, since the responses only differ in
proportion from those of persons infected, but without
DEVELOPMENT OF NEW VACCINES disease. Some 10 to 15% of bacteriologically confirmed
newly diagnosed cases of pulmonary disease are
The only new vaccines being tested in the field at the completely negative to tuberculin. These are not always
moment are directed primarily at preventing leprosy, the patients with most extensive disease as used to be
and it would be very useful if skin tests could be used to thought, although their prognosis for surviving the
assess their likely relative efficacy. So far, most period of chemotherapy may not be good (P Byass and T
publications on this have addressed the question of Corrah, personal communication).
obtaining the most positivity either to Lepromin (which In childhood, in the absence of a BCG scar, a strongly
is not a reagent of the type being discussing), or to positive response to tuberculin (10 mm or more to 2TU
316
Section 5 Diagnosis
or its equivalent) can be a useful indicator of infection, of the results, but the clinician is often reassured in his
although in many developing countries infection without decision not to treat a disease, which, if it were caused
disease is so common that the test becomes irrelevant. by tubercle bacilli, would require chemotherapy.
Several studies have shown that the proportion of Table 24.5 lists some of the results achieved with these
category 1 responders to skin tests are significantly reagents.
reduced amongst both tuberculosis and leprosy
patients.40,41 The same lack of ability to respond to group
Mycobacterium Ulcerans Disease
I antigens can be shown in LTTs.42
The diagnosis of this disease is correctly clinical, but skin
Leprosy testing with Burulin (prepared from M. ulcerans) can be
useful in deciding the stage of the disease,44-47 and the
Most cases of leprosy are either completely negative to
Leprosin A, or have large sized (>10 mm diameter) kind of treatment required. Treatment of a Burulin
responses to it. If quadruple testing is carried out almost negative (< 2 mm) case should include active antibacte-
all untreated multibacillary cases and half of rial therapy, or wide excision, whereas treatment of a
paucibacillary cases will be category 2 nonresponders to Burulin positive case should be more conservative with
all 4 reagents.43 Beyond this, skin testing is of little help clean dressing, debridement, and “postage stamp” skin
in diagnosis, and soluble M. leprae reagents are less grafts, etc. There is some evidence that Burulin testing
efficient in separating multibacillary from paucibacillary of healthy persons may help delineate regions where M.
disease than is Lepromin (an autoclaved suspension of ulcerans is casually encountered, and where sporadic
whole leprosy bacilli). There is a possibility that large cases of the disease might be expected.
sized responses to Leprosin A in apparently healthy
persons may herald the onset of tuberculoid disease STUDIES OF CLOSE CONTACTS OF PATIENTS WITH
(unpublished observation).
DISEASE
Cervical Lymph Node Tuberculosis Thus testing of the families of index cases may help in
disease control, although this is probably much more
In developing countries many children have this
useful in developed countries where other sources of
condition caused by M. tuberculosis itself and the
contact with mycobacterial disease are uncommon or
comments above are true for it. However, in developed rare. Nonetheless, quadruple skin testing of families in
countries, disease of this type is usually caused by other developing countries can provide useful information and
species such as Mycobacterium avium, M. intracellulare, M. insight into the delicate balance between health and
malmoense or M. scrofulaceum. Specific reagents to these disease. Relatives of tuberculosis patients who have
can be very helpful in indicating the species responsible, Koch-type responses to tuberculin should be given
and I regularly send sets of these reagents to requesting preventive chemotherapy. It may be safe not to offer such
pediatricians in the United Kingdom. Unfortunately it treatment to non and those with small responses to
is often difficult to obtain bacteriological confirmation tuberculin if there are financial constraints.
Table 24.5: Results of quadruple skin tests in children with cervical adenitis
Subjects Skin test in response (mm) with reagents

(age in years) T AA AC S Mal
AA (5) 0 12 0 28
MU (3) 4 12 15* 12
DW (8) 8 15 8 12
MQ (16) 0 3 0 8
CS (5) 0 0 5 5
MW (2) 0 6 0 10
LD (5) 0 0 12 9
LH (4) 0 8 5 0
SM (2) 0 28* 10
TS (14) 0 0 10 10
T = Tuberculin; AA = Aviumin A (M. avium); AC = Aviumin C (M. intracellulare); S = Scrofulin; Mal = Malmoensin; *M.
intracellulare grown from operative specimen
317
Contacts of Tuberculosis Patients Contacts of other Mycobacterial Diseases

Most cases of tuberculosis develop amongst persons Since none of these diseases are associated with direct
producing large sizes responses of Koch-type, to infectiousness, there is no need to examine close contacts.
tuberculin. Thus, anyone with this type of tuberculosis However, skin testing of family contacts of such patients
should be examined clinically, and sputum samples often gives evidence of infection without establishment
should be taken for acid-fast bacilli examination. Some of disease. Thus the parents of a child with M. avium
clinicians would advise prescribing a course of infection are generally very strongly skin test positive to
prophylactic antituberculosis chemotherapy, but this is Aviumin.
probably not advisable in countries where drug
resistance is common.
Children living with proven cases of pulmonary DETECTION OF RISK FACTOR
tuberculosis and who are completely negative to all four
Potential risk factors increasing the chances of developing
reagents, or have Koch responses to tuberculin should
be examined particularly carefully for signs of disease. mycobacterial diseases can also be investigated with
Such children without clinical signs of disease should be tuberculin tests, and especially with the quadruple test
selected for chest X-rays. Only if these are clear should system.
tuberculin negative children be given BCG vaccination.
Children who have the protective type of response to Infection with the Human Immunodeficiency Virus
tuberculin, especially if they respond to all four skin tests, (HIV)
are unlikely to develop disease.
This has proved to be a very important risk factor for
Contacts of Leprosy Patients tuberculosis, although this may be less evident in
Although it is often said that paucibacillary leprosy is congenital or neonatal infections. However, the risk to
not infectious, there is evidence that it can be, and this such children of BCG vaccination is still uncertain,
should not be allowed to give a false sense of security. although lack of accurate knowledge of which infant may
Most children in close contact with leprosy patients be infected makes the question somewhat academic.
rapidly acquire positivity to Leprosin A, especially if they Most doctors advise that BCG should be given according
have BCG scars. Children with large responses to to the practice in the district unless the infant is clearly
Leprosin A should be examined for patches of known to be at special risk of HIV infection.
tuberculoid disease, and children over 5 years of age who The value of skin tests in determining which HIV
remain skin test negative should be checked by slit skin infected individuals are likely to develop tuberculosis
smears for the presence of acid-fast bacilli if they have has not been assessed in a tuberculosis endemic situation,
been living with an untreated patient. although in the United States of America a positive
In a study of contacts of multibacillary leprosy, it was tuberculin test in such a person would be taken as an
found that although the eventual plateau of positivity to indication to treat. Comparative quadruple skin test
Leprosin A was the same in close and casual contacts, studies have shown that HIV seropositive persons do
the rate of acquisition of positivity during childhood was not respond to common mycobacterial antigens; thus,
much greater in the close contacts.47 Superimposed on none of them are category 1 responders.48 Category 3
this were geographical differences suggesting that responders are present early in HIV disease, but as the
frequent contact with environmental mycobacteria might CD4 count falls, these too disappear. Lymphocyte
offer some synergistic influenes on the development of transformation studies have shown that the recovery of
Leprosin A positivity. This synergism maybe related to CD4 counts with highly active antiretroviral therapy
that associated with BCG vaccination. (HAART) is not accompanied by a return of immune
Recent studies of families of leprosy patients have recognition of the common mycobacterial antigens (GM
shown differences according to whether the family case Bahr, personal communication). Thus a positive
has lepromatous or tuberculoid disease. In Tamil Nadu tuberculin reaction in an HIV seropositive person
(India) the children of such families have reacted indicates sensitization by meeting M. tuberculosis and not
differently in their responses to quadruple skin test after cross-reaction with other species. It is not yet known
vaccination. This has been further investigated in whether HIV patients can be differentiated into Koch-
Argentina, where it has been shown that family members type and protective responses to tuberculin. If they can,
consanguineous with the patient have similar responses then scarce resources for tuberculosis prevention could
whatever the type of disease. be reserved for Koch responders.
318
Section 5 Diagnosis
PREVACCINATION SKIN TESTS Using new tuberculin, take 5 mm mean diameter of

induration as the cut-off point below which give BCG if
Parasitic Disease there is no definite scar of previous vaccination. Others
Studies in Africa of patients infested with schistosomes using OT or PPD recommend a 5 mm or 10 mm cut-off
have shown them to have reduced responsiveness to point, depending on the reagent strength being
tuberculin, suggesting that such infestations maybe a risk employed. For infants below 1 year of age it is reasonable
factor for tuberculosis. Studies with quadruple skin tests not to carry out a prevaccine test, unless the child is a
in Argentina show that the same is true for patients close contact of a patient.
seropositive for Chagas’ disease, and that such patients
have specifically lost responses to group I, common Selecting Persons to be Given Vaccines Against Leprosy
mycobacterial antigens.49 This makes it highly likely that
There are several important aspects of this for which there
Chagas’ disease is a risk factor for tuberculosis and
is really no substitute for skin testing:
leprosy, both of which are endemic in the regions where
1. If the vaccine incorporates BCG, then the same
the reduvid bug abounds. These interesting findings are
constraints are needed that have been considered for
being actively expanded (O Bottasso, per-sonal
the use of this vaccine alone.
communication).
2. If the vaccine is in short supply, then its use needs to
be directed toward those most at risk.
Selecting Candidates for BCG Vaccination Against
3. There is little point in giving a novel vaccine to
Tuberculosis persons who already have evidence of good
This is one of the major uses of the tuberculin test, and protective immunity.
there is no doubt that if it can be afforded, and if it does 4. Since these vaccines are still within the period of
not lead to loss of individuals by their failing to turn up their assessment of efficacy, a prevaccination test is
for the test to be read and the vaccine to be given, then it needed for later comparative purposes. However,
is to be recommended. The advantages of prevaccination these advantages depend on the availability of a
tuberculin tests are several: reagent like Leprosin A containing both group I
1. Persons likely to already have tuberculosis can be antigens and the specific group IV antigens of the
identified, examined and treated, without the leprosy bacillus. The quadruple skin test system
complication of superimposed vaccination. allows us to determine to which of these antigen
2. Those with large responses to tuberculin do not groups a tested individual is responding. Table 24.6
receive a further dose of M. tuberculosis antigens, and illustrates the use of Leprosin A in the assessment
perhaps precipitate disease. of a potential improvement on BCG as a leprosy
3. Many of those likely to have severe reactions to BCG, vaccine. This consists of the addition of 107 killed
or complications following it can be identified by their Mycobacterium vaccae per dose of BCG, following
large tuberculin responses and should not be vaccinated. which an increased recognition of Leprosin A is seen,
In some places BCG has obtained a bad name among in comparison with BCG alone, in close contacts of
the population because of numerous postvaccination multibacillary disease. Table 24.6 also shows the
complications which could have been avoided. effect on Leprosin A positivity of vaccinating with
Table 24.6: Studies of vaccines in close contacts of multibacillary leprosy patients. Leprosin A results obtained before,
and 1 to 2 years after, (I) vaccination with BCG alone or in combination with 107 killed M. vaccae, (II) vaccination with 108
killed M. vaccae alone results from Tamil Nadu and Vietnam
(I) BCG alone BCG + M. vaccae

Initial result 0/64 0/88
p < 0.00001 p < 0.00001
1-2 years result 30/64 (47%) p < 0.003 62/88 (70%)
(II) Tamil Nadu Vietnam
Children with scars of previous BCG
Initial result 4/32 (13%) 5/39 (13%)
p < 0.001 p < 0.0001
1-2 years result 22/32 (69%) 18/29 (62%)
Children Tuberculin positive, but without BCG scars
Initial result 0/18 (0%) 7/33 (21%)
p < 0.002 p < 0.0001
1-2 years result 8/18 (44 %) 16/21 (76%)
319
10 8
killed M. vaccae alone, in persons in whom one By the qualitative evaluation of reactions, two
might wish not to use BCG. variants of a positive response to some reagents can be
recognized of different immunological significance. One
Skin Testing in the Assessment of Immunotherapy is thought to be a correlate of protective immunity, and
the other the mechanism of immunopathology.
It is just 110 years since Koch advocated immunotherapy The system of skin testing with reagents prepared
in the treatment of tuberculosis,1 as mentioned in the first from four different species allows the recognition of four
sentence of this paper. The problems of treatment of both
categories of responders to mycobacterial antigens. By
tuberculosis and leprosy, and the failure of worldwide
such quadruple tests the immunologic anomalies of the
control of these diseases, have led to a modern reconsi-
major mycobacterioses, and the processes by which
deration of the immunotherapeutic approach. A
immunity or susceptibility to them are developed have
combination of the bacterial killing power of modern
been partly elucidated.
chemotherapeutics together with the correction of
Practical uses of the tests include selection of persons
immune mechanisms to eradicate persisters in
for BCG vaccination and assessment of its efficacy, the
tuberculosis and to alleviate reactions in leprosy is an
development of new vaccines, 30 new methods of
attractive proposition. It combines savings in cost with
immunotherapy,50, 51and the discovery of the etiology of
reductions in treatment time and better compliance with
some idiopathic disease. Stanford et al52 have described
therapy.
the importance of common mycobacterial antigens in the
treatment of disease.
Assessment of Immunotherapy for Tuberculosis
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25 Laboratory Diagnosis of Mycobacterial
(Tuberculosis) Infection in Children
25.1 CONVENTIONAL METHODS
Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
THE DIAGNOSTIC CHALLENGES and a positive TST. Consequently, in endemic settings,

the diagnosis of childhood tuberculosis depends mainly
Children with tuberculosis usually have paucibacillary
on clinical features and the subjective interpretation of
disease and contribute little to disease transmission
within the community. Consequently the treatment of the CXR. 16,17
children with tuberculosis is often not considered a Sputum smear-positive TB is rarely present in
priority by tuberculosis control program. However, children. Although this reduces their risk of actively
children carry a huge tuberculosis disease burden, spreading the disease, it makes it more challenging to
particularly in endemic areas.1,2 Accurate information on establish a definitive diagnosis. In contrast to adults,
the global distribution of the childhood tuberculosis where the sensitivity of sputum culture approximates 80
epidemic is scarce,3 but of the estimated 8.3 million new to 90%, young children are unable to expectorate,
cases of tuberculosis reported globally in 2000,8,84,019 alternative specimens such as gastric aspirates or induced
(11%) were children. 2 The extent of the childhood sputum are difficult to collect and culture yields are low
tuberculosis burden is well recognized, but not well (widely reported as 30-40%).18,19 Traditionally, three
quantified in many endemic areas.4–6 Another common fasting gastric aspirate samples are collected on three
misconception is that children develop mild forms of consecutive mornings, requiring hospitalization of the
tuberculosis and that severe disease manifestations are child and, frequently, the caregiver.
the exception. However, almost 15% of all pediatric Novel culture methods have been developed in an
deaths have been reported to be caused by tuberculosis attempt to circumvent the slow turnaround times, poor
in some Indian hospitals.7
sensitivity and cost of conventional automated liquid
The absence of a practical gold standard test
broth systems. The most feasible alternative to date has
complicates the diagnosis of childhood tuberculosis.8,9
been the microscopic observation drug susceptibility
Sputum microscopy, often the only diagnostic test
assay (MODS), which uses an inverted light microscope
available in endemic areas, is positive in 10 to 15% of
to rapidly detect ‘spindle and cord formation’ in selective
children with probable tuberculosis, and culture yields
broth culture that is indicative of mycobacterial growth.20
are also low (30–40%).10,11 For this reason, alternative
Phage amplification assays that use bacteriophages to
strategies were developed to diagnose tuberculosis in
detect the presence of live M. tuberculosis have been less
children with sputum smear-negative disease. In
successful.21
nonendemic areas, the triad of (1) known contact with an
There is abundant literature utilizing commercial and
adult index case, (2) a positive tuberculin skin test (TST)
in-house polymerase chain reaction (PCR) for the
as evidence of latent tuberculosis infection (LTBI), and
diagnosis of mycobacterial infection in sputum and body
(3) suggestive signs on chest X-ray (CXR) is used in clinical
fluids such as cerebral spinal fluid, but results in the
practice.12 Also International Standards for Tuberculosis
literature are highly variable and have not been well
Care recommends this approach;13 however, the accuracy
validated in children.21 Recent reviews and meta-analyses
of the triad is greatly reduced in endemic areas, where
of PCR in TB meningitis, pleuritis and sputum smear-
most of the population acquire M. tuberculosis infection
negative pulmonary TB have demonstrated poor
during childhood and where transmission is not restricted
sensitivity.22 PCR may play an invaluable role in offering
to the household. 14,15 This limits the diagnostic
rapid species identification and detection of drug
contribution of both documented household exposure
323
Chapter 25 Laboratory Diagnosis of Mycobacterial (Tuberculosis) Infection in Children
resistance in patient with smear-positive TB. 20 The diameter is raised. Mantoux positivity is based on the
application in patients with sputum smear-negative or size of induration and epidemiological risk factors. The
extra-pulmonary TB requires further evaluation, and use Centers for Disease Control (CDC) and the American
in low-income countries remains limited due to cost Association of Pediatrics (AAP) recommend specific
constraints. interpretations of skin reactions (Table 25.1.1). 25,26
T-cell assays that measure interferon-gamma released Children in the highest risk category (e.g. had contact
by lymphocytes in peripheral blood, after exposure to with an index case, are infected with HIV, or have clinical
M. tuberculosis specific antigens, have been hailed as evidence of TB) are considered infected with M.
reliable TB tests. Two commercial tests are available: T- tuberculosis if the Mantoux test result is indurated at least
5 mm. For children with moderate risk factors, a reactive
SPOT® . TB (Oxford Immunotec, Oxford, UK) and
diameter 10 mm or more is considered a positive result.
QuantiFERON ®-TB Gold (Cellestis, Carnegie, VIC,
Fifteen millimeters of induration or greater is considered
Australia). However, study results are highly variable,
to be positive for any child, including those children with
and experience in children remains limited. Current
low risk. A negative TST does not necessarily exclude
consensus is that these tests are unable to distinguish
infection with M. tuberculosis. A decreased response to
latent infection (a third of the world population is latently
TST may be caused due to a number of factors including
infected) from active disease and adds little to the
concurrent illnesses or infections, along with active TB.
traditional tuberculin skin test (TST). These tests are also
Nearly about 25% of people with active TB are found to
too expensive and complex for routine use in low-income
be nonreactive to 5 TU of tuberculin.27 It is likely that
countries.20,21,23,24
these individuals have suppressed immune responses
and may convert to a negative skin test after several
TUBERCULIN SKIN TEST (MANTOUX TEST) months of anti-TB medication.28 In addition, if a child
Tuberculin skin test (TST) has been the standard was exposed to M. tuberculosis within a month of
diagnostic tests for M. tuberculosis infection in the last implanting a skin test, it may be too early to elicit a
100 years. Today the Mantoux test uses 1, 2 and five delayed hypersensitivity reaction, as it can take up to
tuberculin units of purified protein derivative (PPD). A 3 months for tuberculin reactivity to become apparent.
delayed hypersensitivity reaction appears in infected The false negative rate has been increased by the failure
individuals at 48 to 72 hours when tuberculin is injected to administer the PPD intradermally and the complexity
properly and a wheal of fluid measuring 6 to 10 mm in in reading the indurated reactions.
Table 25.1.1: Definitions of positive tuberculin skin test (TST) results in infants, children, and adolescents
Induration >5 mm:
1. Children in close contact with known or suspected contagious people with tuberculosis disease.
2. Children suspected to have tuberculosis disease:
• Findings on chest radiograph consistent with active or previous tuberculosis disease
• Clinical evidence of tuberculosis disease†
3. Children receiving immunosuppressive therapy‡ or with immunosuppressive conditions, including HIV infection.
Induration >10 mm:
Children at increased risk of disseminated tuberculosis disease:
• Children younger than 4 years of age
• Children with other medical conditions, including Hodgkin’s disease, lymphoma, diabetes mellitus, chronic renal
failure, or malnutrition
Children with increased exposure to tuberculosis disease:
• Children born in high-prevalence regions of the world
• Children frequently exposed to adults who are HIV infected, homeless, users of illicit drugs, residents of nursing
homes, incarcerated or institutionalized, or migrant farm workers
• Children who travel to high-prevalence regions of the world.
Induration >15 mm
Children 4 years of age or older without any risk factors.
†
Evidence by physical examination or laboratory assessment that would include tuberculosis in the working differential
diagnosis (e.g. meningitis).
‡
Including immunosuppressive doses of corticosteroids.
Reproduced with permission from the American Academy of Pediatrics.26
324
Section 5 Diagnosis
RADIOLOGY-BASED APPROACHES adequate specimen for culture. Efforts are to be made to

obtain specimens from any body cavity in which the
The diagnosis of TB in endemic areas depends organism may reside before starting antimicrobials. In
predominantly on the subjective interpretation of the addition, several specimens should be sent for evaluation
chest X-ray (CXR). Despite its many limitations, the CXR to increase the chances of capturing the bacilli. Possible
remains the most practical and helpful test in everyday microscopy and culture sites include the following: whole
practice. It usually provides an accurate diagnosis, at least blood, bone marrow (in miliary disease), biopsy
in HIV-uninfected children with suspicious symptoms, specimens (i.e. lymph node or bone), cerebrospinal fluid,
if evaluated by an experienced clinician.29 The most sterile fluids (i.e. pleural), first morning urine, and
sensitive tool currently available to detect hilar bronchoalveolar lavage fluid. Sterile leak-proof containers
adenopathy and/or early cavitations is High-resolution without fixative agents should be used for collection and
computed tomography.30 This technique (if available) has quickly transported to the laboratory where examination
definite application in rare problem cases, but the natural should be performed on the day of receipt. If brief storage
history of disease demonstrates that particular caution is necessary, specimens other than blood should be
is required when interpreting the relevance of these refrigerated to inhibit the growth of contaminating
findings29 as a limited degree of hilar adenopathy is microorganisms. General guidelines for collection of
common following recent primary infection. These signs various types of specimens are listed in Table 25.1.2.
are usually transient and not indicative of disease in the Different types of collected specimens including
absence of symptoms. Therefore, it is important to gastric aspirates, induced sputum, bronchoalveolar
evaluate the presence of other clinical signs and lavage or specimen collected using the string test have
symptoms, and not to base a diagnosis of TB solely on been used for confirmation of pulmonary TB. Whichever
the radiographic findings. technique is used, at least three specimens are evaluated
to ensure recovery of low numbers of mycobacteria. On
FINE NEEDLE ASPIRATION CYTOLOGY (FNAC) arrival in the laboratory, most specimens are
homogenized with a mucolytic agent and decon-
FNAC has been less widely utilized in pediatrics as a taminated before inoculation to culture media to inhibit
diagnostic modality. However, in developing countries the normal flora. The stain and culture yield from three
with a high burden of infectious diseases such as TB and properly obtained gastric aspirates, was found to be
HIV, FNAC can be of remarkable value in confirming higher than from bronchoalveolar lavage by Abadco and
the diagnosis of mycobacterial infection, permitting early Steiner32 and Somu et al.33 Collection of gastric content
appropriate therapy as well as a means to obtain is best performed after a child has fasted for at least 8
specimens for histopathology culture, bacterial species hours and is still in bed. A silastic nasogastric tube is
determination and sensitivity testing.31 FNAC is a simple usually used to perform aspiration, which is inserted
and minimally invasive technique that can be performed before the child had taken anything by mouth. When
at the bedside, and is well tolerated by children. Most aspiration of gastric secretions is unsuccessful, sterile
aspirates in children taken are from cervical and axiliary
lymph nodes that are easily accessible. If the procedures
are performed correctly, with a small gauge needle (22- Table 25.1.2: Specimen for examination and
23 G or smaller), complications such as a small hematoma diagnostic studies
are rare. In developing countries where TB is endemic Specimen Procedure
and specimens for bacteriological diagnosis are difficult, Aspirates, fluids Sterile syringe, container, or direct
if not impossible, to obtain from children, FNAC provides inoculation to culture media
the means for accurate diagnosis in a significant Bone marrow Direct inoculation to broth culture
percentage of children with mycobacterial infection. This media designed for mycobacterial
is particularly important in countries with a high HIV blood cultures or ISOLATOR tube/
rate, as well as increasing rates of multidrug resistant Myco F lytic bottle (BACTEC)
(MDR) and extremely drug resistant (XDR) TB. FNAC Bronchial washings Sterile container
can be performed as an out-patient procedure and is a Gastric lavage Obtain when patient awakes 50 mL
gastric aspirate in sterile container
cost-effective diagnostic modality procedure.
with 100 mg of sodium carbonate
Sputum Exudates from lungs by a productive
CONVENTIONAL LAB DIAGNOSIS cough (not saliva), sterile container
Stool Clean container
Specimen Collection and Transport Tissues, biopsy Sterile container
specimens
In children, TB is often paucibacillary and extra-
Urine First morning void, do not pool
pulmonary and it is therefore challenging to obtain ]
325
distilled water can be instilled and aspirated. If gastric inadequate, while if the rate is less than 3%, it is too
aspiration is performed under these conditions, M. harsh.
tuberculosis will be recovered in up to 50% of children A number of methods for the digestion and
with TB disease.34 Nonhospitalized children can also decontamination of the specimens are available: The most
undergo gastric aspiration for Acid-fast bacilli (AFB) commonly used and widely preferred reagent is sodium
staining and culture, but the yield is found to be lower.35 hydroxide (NaOH), usually in combination with
Induced sputum in older children is easily performed N-acetyl-L-cysteine (NALC). While NaOH alone is
in an outpatient setting, which is an advantage over the effective as both a mucolytic and decontaminating agent,
hospitalization required when obtaining specimens via final concentration of 2% or greater are often required
gastric lavage. Excess oral flora should be removed by for maximum efficacy. Following digestion/deconta-
rinsing the oral cavity of the child with water before mination, the specimen is centrifuged to sediment the
collecting induced sputum. Infection control measures mycobacteria. The relative centrifugal force (RCF)
to be taken to reduce exposure to other patients and staff. applied to the sample must be monitored closely.
The collection of a single hypertonic-saline induced Extreme care must be taken to prevent contamination
sputum specimen reportedly provides the same yield as with other specimen during specimen processing.
three gastric aspirate specimens.36 Unfortunately, the
safety and feasibility of this technique has not been Biosafety Pertinent to Mycobacteriology
studied outside the hospital setting. In addition, induced
coughing may pose a transmission risk to healthcare The single most important piece of laboratory equipment
workers, and also to other children, if the procedure is in a mycobacteriology laboratory is a well-maintained
not performed in a separate, well-ventilated room and/ properly functioning biological safety cabinet (BSC).
or equipment is not adequately sterilized. It also requires Although Class I or Class II BSCs can be used in the
the administration of a bronchodilator by nebulization to mycobacteriology laboratory, most laboratories employ
prevent bronchospasm. a class II BSC, which is a vertical, laminar-flow BSC
The string test which is a novel approach has recently that blows HEPA-filtered air over the work area.
been evaluated for its ability to retrieve M. tuberculosis Technologists should be trained in operating and
from sputum smear-negative adults infected with HIV.37 cleaning the cabinet and in organizing the work surface,
A gelatin capsule that adheres to gastric contents over a so the air circulation is not compromised. Technologist
couple of hours is swallowed and then pulled back up should also be conscious of the airflow in a BSL-3
for investigation. In a recent study the string test was laboratory and have a method to verify that the air
shown to be well tolerated in children over 4 years of pressure is lower than the adjacent areas. In addition,
age, yet there were no positive TB cultures detected periodic checks on the airflow should be performed and
the airflow should be tested and recertified at least yearly
within this small study.38
by trained personnel. After the completion of work UV
lights should be turned on for a minimum of one hour.
Specimen Processing
Centrifugation of a specimen suspected of containing
Specimens derived from normally sterile body sites, such mycobacteria must be done in an aerosol-proof
as aspirated body fluids, blood, bone marrow, and tissue centrifuge, the carrier should be opened, and the tubes
(grind in sterile 0.85% saline), should be inoculated removed in a BSC at a BSL-3 laboratory.
directly to culture media. Digestion and decontamination A BSC should be used to prepare and dry the AFB
is needed for specimens contaminated with normal flora smears from concentrated and liquefied specimens.
microorganisms before inoculating to culture media. This Despite it being fixed, organisms on the dried and heated
step will help to prevent the overgrowth of more rapidly slide can still be viable but aerosolizaton is less of a
growing microbes, and also digest the mucin that may concern. Manipulations of viable cultures done for
bind any mycobacteria present, inhibiting their recovery. identification or susceptibility testing should be
The goal, however, is to inhibit the normal flora but not performed in a BSC at a BSL-3 laboratory. All manipu-
the hardier mycobacteria. It is important for the lations with cultures or specimens should be done with
laboratory to monitor the overall rate of the specimen protecting garments, gloved hands, and face protection.
contamination. The goal is not to reduce this rate to zero, For the mycobacteriology laboratory, the minimum level
since that would indicate too many mycobacteria are of respiratory protection is an aspirator that contains a
being lost in the decontamination process; instead it is to National Institute of Occupational Safety and Health
be expected that under normal circumstances, between (NIOSH)- certified N Series filter with a 95% efficiency
2 to 5% of specimens will be overgrown by normal rating (N-95). Procedures for spills in the myco-
flora. If overtime contamination rates are more than bacteriology laboratory should address spills and the
5%, the decontamination technique employed is likely disinfectant should be applied. After atleast 20 minutes
326
Section 5 Diagnosis
of contact time, the items can be removed for transport

to an autoclave.
AFB Microscopy
Microscopic examination of acid-fast-stained smears is
one of the easiest, most inexpensive and rapid method
for demonstrating the presence of mycobacteria in clinical
specimens and cultures. AFB smear continues to be the
backbone of TB diagnosis under the RNTCP (Revised
National TB Control Program) in India. Although the
technique is more than 100 years old and it is grossly
inadequate, as it has low and variable sensitivity and
cannot identify drug-resistant/ MDR-TB strains. HIV
Fig. 25.1.2: ZN stain: bacteria are stained bright red against blue
coinfection complicates the clinical presentation and background (For color version see Plate 6)
diagnosis of active TB and further limits the sensitivity
of AFB sputum smear. Fluid and solid specimens which
have been liquefied can easily be stained. Stains used in positive control smear ensures the staining capability of
the process, penetrate the bacilli’s cell wall. Once applied, the stain solutions and the negative control smear
the stain is difficult to remove even when mineral acids confirms presence or absence of contaminants.
are applied to it, and hence, comes the name “acid fast.” Reporting Smear Results (Table 25.1.3):
1. A slide with no acid-fast bacilli visible in 100 fields is
Ziehl-Neelsen Stain reported “No AFB seen”.
Fuchsin-stained smears are examined with a Brightfield 2. Slides positive for AFB must be examined by at least
microscope under oil immersion field (Fig. 25.1.1). AFB two technicians before the result is reported.
appears as red and rod-shaped filaments. Ziehl-Neelsen 3. If the slide is positive, fewer fields need to be
staining is the most common technique used to identify examined and a count can be reported according to
AFB in which the bright red stained bacteria stand out the smear evaluation table as follows:
clearly against a blue background (Fig. 25.1.2). Another
method is the Kinyoun method, in which the bacteria Fluorescence Stain
are stained bright red and stand out clearly against a AFB can also be visualized by fluorescence microscopy
green background. The slide is examined by making three using specific fluorescent dyes, such as auramine and
parallel sweeps along the length of the smear, or rhodamine. Fluorescence-stained AFB smears have
alternatively, by making nine parallel sweeps across the similar morphology and will fluorescent yellow when
width (as per the following diagram). This procedure examined with a fluorescent microscope (Fig. 25.1.3). In
allows up to 100 fields per slide to be viewed. a systematic review of 45 studies comparing the two
The positive and negative ZN QC smears from each methods found that fluorescence microscopy yielded an
batch of smears stained should be examined first. The average increase in sensitivity of 10%, without loss of
specificity. 39 Thus fluorescence microscopy has
advantages over light microscopy for detection of
pulmonary TB. However, the equipment cost for
fluorescence microscopy are high, so its utility has been
limited to regions that can afford it.
All mycobacteria exhibit various degrees of acid
fastness so microscopy alone cannot be used to determine
Table 25.1.3: AFB smears grading

Carbol fuchsin 1000X Report
0 No AFB seen
1-9/100 F Report exact count
10-99/100 F 1+
1-10/F 2+
Fig. 25.1.1: Recommended method for examining acid-fast
>10/F 3+
stained smears
327
and agar-based media. Lowenstein-Jensen (LJ) is an egg-

based media and most commonly used globally. To
suppress the growth of contaminating bacteria and fungi,
the LJ contains malachite green, thus LJ is used for both
detection and susceptibility testing. In resource-
challenged countries LJ is often the only media used,
while in the USA it is used in conjunction with liquid
media.
It is easier to observe colony morphology and
enumerate colonies on agar-based media Middlebrook
7H10 and 7H11. Middlebrook 7H11 is better than LJ at
establishing resistant M. tuberculosis isolates. The average
time for M. tuberculosis detection on LJ and Middlebrook
7H11 media is 4 and 3 weeks, respectively. Physiologic
tests are performed to identify mycobacterial species,
Fig. 25.1.3: Fluorescence-stained AFB smear—bacteria after a colony appears on the culture. Such tests include
fluorescent yellow (For color version see Plate 6)
pigment inspection, microscopy examination for
recording, colony morphology, and biochemical tests.
the individual species of mycobacteria including Use of chromatography for the analysis of fatty acids
M. tuberculosis. Despite this, staining has significant extracted from the mycobacterial cell wall is a more
advantages because it remains the most rapid technique reliable method for identifying mycobacteria. Molecular
and is of significant value in identifying the most methods used to speciate mycobacterium include the use
infectious patients for hospital and community infection of gene probes in hybridization assays, amplification with
control. The number of microorganisms seen on the subsequent DNA sequencing, or restriction fragment
microscopic examination of the stained smears reflects length polymorphism analysis.
the burden of bacterial infection. The sensitivity of
positive sputum smear examination indicates a Liquid-Based Culture Systems
concentration of at least 104 bacteria/mL. 39 Higher
grading of results (1_ to 3_) indicates greater concentra- Liquid media supports growth of the M. tuberculosis
tion of bacteria. Environmental contamination, which complex better than solid media with an increased
usually involves only a few organisms, rarely results in recovery of positive cultures,44 even in cases in which a
a positive smear examination. child was started on anti-TB medication before obtaining
Given the paucibacillary nature of pediatric TB, most cultures.45 An important advantage of the liquid media
children are smear-negative. Less than 10 to 15% of over the solid one is the shorter time taken for detection
children with proven TB will have a sputum or gastric of positive cultures. Isolation and susceptibility testing
aspirate stain positive for AFB.40 The rates of positive of M. tuberculosis in liquid media can be reported on an
smears from other specimen sources are even lower.41 average of 2 and 4 weeks, respectively.46 The average
Adolescents, however, often develop adult type disease time for recovery of smear-positive specimens is only 8
and have higher bacteriological yield. 42 Further, days compared with 18 days taken by solid conventional
microscopy evaluation in low-income settings is often media.47 Because of the significant increase in the positive
performed on unconcentrated sputum and the sensitivity culture rates and the timesaving, the CDC has
of this method for detecting mycobacteria is limited. recommended the use of commercially available liquid
media for detection as well as for drug susceptibility
testing of M. tuberculosis in the USA.48 The first broth-
Traditional Culture Methods
based mycobacterial detection system was the BACTEC
Culture is more sensitive than microscopy and can detect 460, which uses modified Middlebrook broth and a novel
as few as 10 to 100 bacteria/mL of specimen43 but is radiometric detection scheme. Mycobacterial growth can
positive in less than 50% of children with active disease. be periodically ascertained by the liberation of 14CO2 as
There are two major forms of media which are routinely metabolized by the mycobacteria and detected by the
used in mycobacteriology laboratories, solid and liquid BACTEC instrument. Most recently, a nonradiometric
media. The main advantage of solid media is that it allows liquid culture system has been developed to minimize
the determination of characteristic features of colonial the handling and disposal of radioactive waste.44
morphology, growth rate, and pigment production, The Mycobacterial Growth Indicator Tube (MGIT;
which can yield significant preliminary information. The Becton Dickinson, Baltimore, MD) is supplemented with
two types of solid media commonly used are egg-based enriched growth media and antibiotics and processes all
328
Section 5 Diagnosis
types of clinical specimens other than blood and urine; is determined on the basis of growth (or metabolic)
however, a recent study in India found high sensitivity inhibition induced by the drug by means of (1)
when using concentrated urine specimens. 49 The macroscopic observation of growth in drug-free and
automated MGIT system has slightly superior sensitivity drug-containing media; (2) detection or measurement of
and reduced turnaround time compared with the metabolic activity or products ( 3) lysis with
conventional LJ culture.50 There is a manual MGIT system mycobacteriophage; and (4) detection of genetic
that allows anti-TB drug susceptibility testing. Tubes are mutations using molecular techniques.
placed on a 365-nm UV transluminator and are examined A direct test uses the processed clinical specimen for
for fluorescence. However, the high cost of even the susceptibility testing, whereas the indirect method uses
manual MGIT system and laboratory infrastructure the primary isolate culture for testing. Conventional or
required remain major limitations in resource-challenged rapid techniques can be used to perform both direct and
regions. indirect tests. Conventional techniques involve
It is customary to use at least two types of media to inoculating the microorganisms to a solid medium that
maximize the recovery of M. tuberculosis: liquid media contains a known concentration of the test drug. The
to assure rapid results and solid media to examine clinical proportion method is the most commonly used
morphology (which is not possible in liquid media). conventional techniques in the USA. Dilutions of the
Moreover, using solid media provides a backup in case inoculum are made so that growth on control media
of any kind of contamination occurring in the liquid results in the production of a number of colonies that is
media.45 counted and compared to the number of colonies that
Because mycobacteremia and miliary TB occur more grow on the drug containing media. Thus, the proportion
often in children with TB than adults, it is always of organisms resistant to a drug can be measured and
important to obtain blood cultures in children with expressed as a percentage of the total population. If more
suspected TB disease. The ISOLATOR tube (Wampole than 1% of the test population is resistant to the drug
Laboratories, Princeton, NJ) provides a unique approach being tested, it is established that resistance to that drug
to the recovery of mycobacteria, which tend to circulate has developed. Results usually take about 3 weeks by
intracellularly. Saponin is used to lyses leukocytes the conventional method. In contrast, BACTEC
releasing any intracellular microbes in the ISOLATOR susceptibility results are usually available in as little as 4
system. After centrifugation, the sediment can be used to 6 days after inoculation and provide results with a
to inoculate a variety of mycobacterial media. BD high degree of correlation to the proportion method.
(BACTEC) also has Myco/F lytic bottles for mycobacteria Newer techniques including the microscopic
blood culture. observation drug susceptibility (MODS) and the phage
based assays enable laboratories, particularly those in
Susceptibility Testing resource-limited regions where the incidence of MDR-TB
The incidence of multidrug-resistance (MDR) TB, defined is the highest, to have access to modern drug susceptibility
as resistance to both isoniazid and rifampin, has increased methods. The luciferase reporter mycobacte-riophage is
in many parts of the world. As children have lower rates reported to be a rapid method that is highly accurate,51
of TB isolation, MDR-TB is often initially identified but its specificity may vary.52 The MODS technique is a
exclusively in the adult index case. liquid-based methodology that also enables rapid (within
The unique mechanisms by which mycob-acteria 10 days) detection of drug resistance.53,54
acquire drug resistance are chromosomal alternations
such as mutations or deletions. These chromosomal Quality Control
alterations affect either the drug target itself or the
bacterial enzymes activating the prodrug. In the United Quality control (QC) is an important integral part of
States, drug susceptibility is performed on all initial laboratory testing. Laboratory should establish a protocol
isolates and on any isolate from patients with persistent of all the aspects of quality control testing. The frequency
positive cultures or relapse of clinical symptoms. In of the QC testing depends upon the workload in a
addition to the immediate benefit in planning a laboratory, type of media used, and laboratory-
therapeutic regimen, drug susceptibility information is established policies. All QC procedures should be written
valuable for public health. Understanding resistance and results of QC testing documented in the laboratory
patterns in a particular region provides strategic policy records. In case there is a situation of unsatisfactory
advantage for the treatment and control of TB. performances, corrective measures should be taken and
There are a variety of methods to determine the their outcome should be documented.
susceptibility of M. tuberculosis to anti-TB drugs. From a • AFB smear: With each run, and whenever new
technical perspective point of view, drug susceptibility reagents are introduced, a known positive and known
329
negative smear is read. It is preferable to use actual hence the glucose levels are usually not as low as that
sediment from clinical specimens to prepare these observed in other bacterial infections. The chronic nature
controls, but if that is not available, a suspension of of TB infection also causes a lymphocytic predominance
M. gordonae for the positive and E.coli for the negative in CSF and pleural fluid.
control can be used.
• Culture media: Records of batch numbers and expiry Antibody-based Assay
date of all media and reagents should be documented.
QC records of commercial media may be obtained from A number of serologic tests for TB have been developed
the manufacturer and should be kept in the file. Quality recently using a variety of antigens to detect certain
control should be carried out both on culture media antibodies in the blood. As of yet, none of these tests have
and reagents. shown adequate accuracy due to great heterogeneity of
• The following three mycobacterial cultures are humoral responses in patients with TB and cross-
recommended for quality control testing. reactivity with other mycobacterial species. Therefore,
– M. tuberculosis H37Ra ATCC 25177 no serological test has been widely implemented in
– M. kansasii ATCC 12478 clinical care.60 A particular problem in pediatrics is that
– M. fortuitum ATCC 6841 children tend to have lower antibody titers than adults.61
• Susceptibility testing: Quality control of Mycobacterial A recent comparison of seven serologic tests for active
tuberculosis culture (MTBC) susceptibility testing TB in adults found poor to moderate sensitivity ranging
should include an isolate that is completely from 16 to 57% and variable specificity of 62 to 100%.62
susceptible to the antimicrobial agents being tested. Higher accuracy can be achieved by a combination of
The strain M. tuberculosis H37Rv (ATCC 27294) is well two serological tests, that is, sensitivity 66% and
suited for use as a “pan-susceptible” control organism specificity 86%.62
and its performance is well documented. Various antigens, such as antigen 85A, antigen 85B,
Alternatively, M. tuberculosis H37Ra, which is 38-kDa protein, alpha-crystallin (16 kDa), and 19-kDa
believed to be avirulent could be used. Quality control lipoprotein, have been recognized to have significant
testing using M. tuberculosis H37Rv (ATCC 27294) diagnostic value. It has been found that specific antibody
should be performed once each week when patient profiles vary according to the stage of TB disease. Only a
isolate is tested. few published studies report on antibody detection in
primary infection, a condition that predominantly occurs
IMMUNE-BASED DIAGNOSIS in children. Scientists examined serologic response to
only two antigens, the 30 kDa and 16 kDa, in 26 children
Fluid Chemistry—ADA with biologically proven or suspected active TB and
found a sensitivity of 84% and 73% for the 30- and 16-
Adenosine deaminase (ADA) is an enzyme found at the kDa antigens, respectively.63 A study performed in India
cell surface of lymphocytes and macrophages. It catalyzes with the 38-kDa IgG antibody was found to be positive
the conversion of adenosine to inosine and is generally in 37% of children with pulmonary TB, 86% of children
elevated in regions of active lymphocyte proliferation. with TB lymphadenitis, and 27% of controls (who may
Several studies have consistently shown high ADA levels have been latently infected).64 It is believed that in the
in the pleural, peritoneal, and cerebrospinal fluids in case future serologic assays will contain various specific
of patients infected with M. tuberculosis55-58 in the antigens to evaluate the humoral immune response to
respective anatomic cavities. One meta-analysis found
M. tuberculosis during different stages of infection.
that ADA levels over 36 to 40 IU/L had a sensitivity of
100% and specificity of 97%.58 A study in adults with
Antigen-based Assay
meningitis found an ADA level above 5 U/L in the CSF
had a 81% sensitivity in culture-confirmed TB meningitis Antigen detection has the potential to overcome some of
and 86% specificity in the non-TB meningitis group.59 the well-recognized problems with antibody detection
Giusti colorimetric method based on simple reaction to assays, especially in populations infected with HIV.
form ammonia is usually used to determine ADA. Since Attempts have been made to detect M. tuberculosis
ADA determination is a fast, inexpensive, and antigens directly in body fluids. Assays using serum or
discriminating test, effusions and CSF should be urine may have particular application in extrapulmonary
analyzed when working up a patient with active TB. disease, which tends to occur more often in children or
A common finding in M. tuberculosis infected fluid is people coinfected with HIV and TB. Recent development
a low-glucose and high-protein level secondary to the of monoclonal antibodies to target proteins and
leukocytes recruited to the site of infection. The doubling glycolipids such as lipoarabinomannan(LAM), a heat-
time of mycobacteria is much slower than other bacteria; stable high-molecular-weight glycolipid present in the
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Section 5 Diagnosis
cell wall of mycobacteria, has proved to be an important conclusive evidence on which to base formal
achievement in the detection of level of M. tuberculosis. recommendations.
Several groups have demonstrated elevated LAM levels The sensitivity and specificity of IGRAs cannot be
in the sputum,65 serum,65 and urine66,67 of TB patients. calculated with certainty mainly due to lack of a gold
Recently a large study in Ethiopia found a urine LAM- standard test to detect latent tuberculosis infection (LTBI).
ELISA was slightly more sensitive than smear Recently, the US Centers for Disease Control and
microscopy (74% versus 69%) in culture-proven TB Prevention recommended that the QFT-G assay could
patients.66 A urine test called LAM-ELISA was first be used in place of the TST for all indications, including
developed by a US company, Chemogen and screening of children.68 However, there are limited data
subsequently by Inverness Medical Innovations
on the performance of the QFTG assay in children. A
(Waltham, MA, USA), which marketed the test as
recent study from Italy raised concerns about the
Clearview TB ELISA.
diagnostic accuracy of the QFT-G assay in young
children, as indeterminate results were recorded in 32%
Interferon-γγ Release Assays: (IGRAs)
of children, 5 years of age. 69 An Australian study
A new generation of immune-based rapid blood tests for substantiated this observation by reporting that 17% of
the diagnosis of LTBI, called IGRAs, offers particular the QFT-G assays yielded indeterminate results in
advantages over the century-old TST. The basis of these children, and the concordance between QFT-G and the
tests is host response to M. tuberculosis infection, by TST was poor (k = 0.3).70 By contrast, a study among
measuring the IFN-g produced by T-cell responses to M. hospitalized children in rural India showed strong
tuberculosis -specific antigens called early secreted agreement (k = 0.73) between the TST and QFT-G In Tube,
antigenic target 6 (ESAT-6) and culture filtrate protein
but data were inadequate to estimate sensitivity among
10. These antigens are encoded by the region of
confirmed tuberculosis cases.71
difference_1 (RD-1), a segment of the genome specific
Evidence for the ELISPOT assay indicate that it is a
for M. tuberculosis and absent in BCG and most species
of NTM, therefore being more specific to M. tuberculosis more sensitive marker of M. tuberculosis infection than
than tuberculin (PPD). Two assays are currently available the TST, as reflected by better correlation with the degree
as commercial kits and have recently been approved by of exposure following a school tuberculosis outbreak in
the US Food and Drug Administration (FDA). First the the UK.72 Improved sensitivity was also shown in HIV-
QuantiFERON-TB Gold® assay (Cellestis, Carnegie, infected children diagnosed with tuberculosis and in
Australia) which is based on Whole-Blood Enzyme- those with malnutrition, although the improved
Linked Immunosorbent Assay (ELISA). The latest and performance in malnourished children was not
the most preferred version of this assay, the substantiated after correction for the HIV status of the
QuantiFERON-TB Gold In-tube® (QFT), includes an child.73 Despite its superior sensitivity, a study from
additional M. tuberculosis specific antigen TB 7.7. Second South Africa reported that ELISPOT responses to ESAT-
is the T-Spot.TB® (T-Spot) test (Oxford Immunotec, 6 and CFP-10 were detectable in only two-thirds of
Abingdon, UK) which is based on the ex vivo overnight children with a clinical diagnosis of tuberculosis and in
enzyme-linked immunospot assay. The T-Spot 83% with culture-confirmed disease. 74 In a recent
enumerates individual T-cells producing IFN-g after household contact study conducted on Gambian
antigenic stimulation, while the QFT measures the level children, the ELISPOT assay was slightly less sensitive
of IFN-g in the supernatant of the stimulated whole than the TST in detecting M. tuberculosis infection and
blood. Both the QFT and the T-Spot have an internal
neither test was confounded by prior BCG vaccination.75
positive control (a mitogen) that elicits robust IFN-g
In a head-to-head comparison between the Quanti
responses in immunocompetent people. The mitogen
FERON-TB Gold and TSPOT.TB assays, T-SPOT.TB gave
provides information regarding the validity of the assays
in a subject with questionable immune status, such as considerably less indeterminate results, particularly in
HIV-infected individuals or very young children. The T- high-risk groups such as immunocompromised adults
SPOT.TB is licensed for use in Europe, Canada and other and young children.69 Although the agreement between
countries, but has been still awaiting US FDA approval. the various T-cell assays and TST results are fairly high,
The use of T-cell assays in children is currently limited the interpretation of discordant results remain
by high cost, the relatively large volume of blood (4-5 problematic.
ml) required, the non-availability of adequate laboratory Overall, it appears that T-cell assays are good at
infrastructure to perform enzyme-linked immunospot detecting M. tuberculosis infection, but in the absence of
(ELISPOT) assays in particular, and the absence of symptoms or radiological signs, novel T-cell assays, like
331
the TST, fail to make the crucial distinction between LTBI detect rifampicin resistance in sputum specimens. The
and active disease. The main application of these assays is in FASTPlaque-TB kits are currently not FDA approved,
nonendemic areas, where disease elimination is a realistic but are CE marked for use in Europe. No information
target. The aim of this target would be the screening of groups exists on its utility in the diagnosis of childhood
with known or expected tuberculosis exposure to identify and tuberculosis. The FASTPlaque-TB Response assay detects
treat everyone with LTBI. In tuberculosis-endemic areas rifampicin resistance, a reliable marker of multi-drug
where transmission is poorly controlled, tuberculosis resistant disease, with a fair degree of accuracy in adults,
especially when used on culture isolates.84
exposure and infection are extremely common and the
The microscopic observation drug susceptibility assay
benefit of preventive treatment is reduced by the high
(MODS) is a novel assay that uses an inverted light
likelihood of reinfection. However, the provision of
microscope and Middlebrook 7H9 broth culture to
preventive treatment remains a high priority in rapidly detect mycobacterial growth. Early growth of M.
individuals who are at high risk of progressing to active tuberculosis is visualized as ‘‘strings and tangles’’ of
disease after infection, such as young and/or bacterial cells in the broth medium, which may contain
immunocompromised children. In tuberculosis-endemic antimicrobial drugs for susceptibility testing. In a recent
areas, the superior ability of the ELISPOT assay to detect study from Peru, MODS detected 94% of 1908 positive
M. tuberculosis infection in high risk groups, 76,77 sputum cultures, whereas conventional LJ culture
particularly in children infected with HIV, in whom the detected only 87%.85 MODS also had a shorter time to
TST performs poorly,78 seems to offer particular value. culture positivity (average of 8 days) compared with
In this group, where the diagnostic dilemma is most Lowenstein– Jensen culture. Although MODS are a
pronounced, a sensitive test for M. tuberculosis infection promising and inexpensive tool, limited information
may also provide supportive evidence to establish or exists on its utility in children. The potential of a gas
refute a diagnosis of active tuberculosis. Formal sensor array electronic ‘‘nose’’; E-Nose to detect different
recommendations on the use of T-cells assay for children Mycobacterium species in the headspaces of cultures and
from tuberculosis endemic areas require further research sputum samples is another innovative approach that is
to take place.80, 81 currently in development. The array uses 14 sensors to
profile a ‘‘smell’’ by assessing the change in each sensor’s
NOVEL CULTURE SYSTEMS AND DETECTION electrical properties when exposed to a specific odor
METHODS mixture. In an initial study using spiked sputa and
sputum samples from patients with culture-confirmed
Major limitations of traditional culture methods are slow
tuberculosis and those without tuberculosis, after
turnaround times, suboptimal sensitivity, and the
training of the neural network, the E-Nose correctly
excessive cost of using automated liquid broth systems.
predicted 89% of culture-positive patients with a
TK Medium (Salubris, Cambridge, Massachusetts, USA)
specificity of 91%.86 Further applications of this test,
is a novel colorimetric system that indicates growth of
including its potential value in the diagnosis of child
mycobacteria and allows for early positive identification,
tuberculosis, are under investigation.
before visible bacterial colonies appear.81 It also allows
susceptibility testing for drug resistance, and can allow
DIAGNOSIS OF TB IN HIV INFECTED CHILDREN
for differentiation between M. tuberculosis and NTM.
Although TK Medium promises to be a practical, low- The diagnosis of TB in HIV infected children is
cost and simple test, published evidence is limited and complicated by the reduced sensitivity of immunological
the test is currently not FDA-approved.82 Also no data diagnostic techniques such as the TST and gamma-
exist on its value in the diagnosis of childhood interferon assays. There is also greater clinical need to
tuberculosis. make a firm diagnosis, and a wider range of alternative
Bacteriophage-based tests use bacteriophages to infect pathological processes to consider. The use of a 5-mm
live M. tuberculosis and detect the presence of cut-off for a positive Mantoux test is recommended.
mycobacteria using either phage amplification or the Gamma-interferon assays may be preferable to the TST
detection of light.83,84 In general, phage assays have a turn in this population,87 but a negative test cannot exclude
around time of 2 to 3 days, and require a laboratory tubercular disease. On biological grounds it would be
infrastructure similar to that required for performing reasonable to assume that smear, culture and possibly
cultures. Commercial kits are available for phage NAD (Nucleic acid detection) assays would have a
amplification assay like the FASTPlaque-TB (Biotec greater diagnostic role in HIV infected children due to
Laboratories, Ipswich, Suffolk, UK) assay that can be used an increased bacillary load. However, yields from smear
directly on sputum specimens for diagnosis, and a and culture have not always been higher in HIV positive
variant, the FASTPlaque-TB Response kit, is designed to children.88 Also, firm data regarding the performance of
332
Section 5 Diagnosis
NAD assays in this setting are lacking. Positive NAD active TB, as the paucibacillary nature of pediatric
assays may lend support to the diagnosis, particularly TB limits the rates of positive AFB smear and culture.
the commercial assays which have better specificity. The gold standard remains solid traditional culture,
Bronchoscopy may be worthwhile, if the diagnosis and it is recommended to perform the liquid-based
remains unclear even after ‘first-line’ investigations such culture in conjunction with solid agar to decrease
as gastric aspirates and induced sputa have been the time to detection.
performed. Since TB may be rapidly progressive in HIV • In TB-endemic settings, limited access to diagnostic
positive children, empirical therapy may be required services often results in substantial diagnostic delay
more commonly than in immunocompetent children. and patients often received a diagnosis after as many
as 3 to 6 months of being symptomatic. This delay
HIGHLIGHTS fuels disease transmission and increases severity of
• Many promising advances have been made in the disease when it is finally diagnosed. A suitable TB
development of novel tools to diagnose tuberculosis diagnostic would need to be sensitive, simple, have
in adults, but none of these tests are capable enough a rapid turnaround time, and be able to detect MDR-
to replace microscopy or culture. Few of these novel TB. Such a test would combine these features in a
approaches have been tested in children, the group simple point-of-care format that could replace
in which the diagnostic dilemma is most microscopy and culture in the first clinic visit. In
pronounced. At present, the use of adequately general, assays based on the immunological
validated symptom-based diagnostic approaches responses to M. tuberculosis are preferred to the
and improved access to chest radiography and current bacteriologic methods of TB diagnosis
antituberculosis treatment seem to offer the most because they do not depend on the detection of
immediate benefit to children in tuberculosis- mycobacteria and exposure risk is minimized.
endemic countries with limited resources. • Till date many promising advances have been made
• IGRAs in the diagnosis of TB, still there is no test that is
– Improved sensitivity and specificity offered by highly accurate in children, also none of the tests
new IGRAs may assist tuberculosis eradication developed so far are currently in a position to replace
efforts in nonendemic countries and the diagnosis microscopy or culture in TB-endemic regions.
of M. tuberculosis infection in high-risk individuals. • There is a great need for innovative and novel assays
– IGRAs appear to be sensitive in children over 2 to be tested in children, a population most
years of age, and unlike the TST, are specific for M. vulnerable to severe disease. The pathophysiologic
tuberculosis. In conjunction with clinical and response to M. tuberculosis in young children is
radiologic findings, both these tests are also used to different from that observed in adults, hence these
aid in the diagnosis of active TB. distinctions should be considered as future
– An effort should be made to obtain several diagnostic tests are developed and evaluated in
specimen samples in any child being evaluated for clinical trials.
25.2 MOLECULAR DIAGNOSTIC METHODS
S Kumar, Bansidhar Tarai, Nimrat Bawa, Sarman Singh, Ashok Rattan
INTRODUCTION two-thirds of the cases in the South-East Asia Region.

This makes India the highest TB burden country in the
Tuberculosis (TB), caused by Mycobacterium tuberculosis, world.3, 4
is an old and serious infectious disease in humans, and it TB remains one of the major causes of death in India.
is still a major public health problem worldwide.1, 2 It is Early diagnosis, together with adequate therapy and
estimated that nearly 1 billion people will be newly prevention measures against further transmission are
infected with TB between 2000 and 2020 and, essential for TB control. Traditional smear microscopy
furthermore, two hundred million people will develop and culture-based routine diagnostics in M. tuberculosis
disease and 35 million will die from TB within this period. are commonly used in clinical Mycobacteriology
In India 1.8 million tuberculosis cases occur annually, laboratories. However, traditional methods are
accounting for one-fifth of the world’s new TB cases and inadequate for the effective control of TB due to the fact
333
that they are time-consuming, cumbersome and high due to amplicon cross-contamination of specimens. To
concentrations of bacteria must be present in the sample minimize the risk of specimen-to-specimen contamin-
to be detected. A rapid, sensitive, and accurate diagnostic ation, a physical separation of processes, equipment, and
tool for detection of M. tuberculosis in clinical specimens reagents is recommended. Four different work areas are
is essential for the successful diagnosis of TB patients. suggested, including a reagent preparation area to
Over the last few years, new molecular methods have prepare PCR master mix, a sample processing area where
been introduced, including PCR-Restriction Fragment procedures, including nucleic acid extraction, occurs, a
Length Polymorphism, real-time PCR, DNA sequencing, target loading area where the specimen is added to the
DNA strip assays as mycobacterial diagnostic tools, PCR master mix in the reaction vessel, and an
leading to considerable improvement of both speed and amplification area where thermocycling and probe
accuracy of identification. detection occurs.11 The reagent preparation area should
The prevalence of TB is further complicated by the be kept free of all patient specimens and DNA extracts.
appearance of strains with multidrug resistance (MDR) Protocols for the sample preparation area should
in almost 3% of all newly diagnosed patients.5 The minimize the number of tubes that are simultaneously
conventional phenotypic methods for assessing drug open. Each of the work areas should contain dedicated
resistance are slow and in order to avoid delays in both working materials, reagents, and pipetting devices.
therapy and prevention of MDR transmission, various Reagents should be prepared and aliquoted into single
genotypic methods based on line probe assays, DNA use or small volumes. This ensures ease of use and less
sequencing or real-time PCR, have been proposed for chance of contamination. All working surfaces should
detection of the mutations associated with resistance to be cleaned before and after use, preferably with a reagent
anti-tuberculosis drugs. The molecular methods used in that destroys nucleic acid such as a 5% bleach solution.
Mycobacterial diagnostics and their diagnostic usefulness Gloves should be changed frequently, at least before
in a modern clinical Mycobacteriology laboratory is beginning each of the separate tasks required in a
reviewed. dedicated work area and should always be changed if
moving from one work area to another work area. The
Direct Detection of Mycobacteria in Clinical use of aerosol-resistant pipette tips and pipette tips long
Specimens: In-house PCR for Detection of enough to prevent specimen contact with the pipetter
Mycobacteria from Clinical Specimens aids in the prevention of specimen contamination.12
Enzyme contamination control systems such as uracil-
In the last decade, nucleic acid amplification-based N-glycosylase can be incorporated into the real-time PCR
techniques have become accessible to the clinical master mix as an added safeguard to sterilize amplified
mycobacteriology laboratory. PCR protocols amplifying product that may be carried over to subsequent batches
a large variety of chromosomal DNA have concentrated of tests.13
on detection of both genus-specific and M. tuberculosis Over the last few years, real-time PCR systems have
complex-specific DNA regions. The insertion element IS been increasingly used in routine mycobacteriology
6110 and the 16S rDNA are the most common targets laboratories. The technique allows real-time monitoring
used. Other regions used for amplification include the of a DNA amplification reaction by measuring an
rpoB gene encoding the β-subunit of the RNA accumulating uorescence signal. Real-time PCR provided
polymerase, the gene coding for the 32 kD protein, the improved sensitivity and specificity, reducing
recA gene, the hsp65 gene, the dnaJ gene, the sodA gene turnaround time and avoiding the use of ethidium
and the 16S-23S rRNA internal transcriber spacer.6-8 bromide-stained gels. Different real-time instruments are
In research laboratories, nucleic acid amplification now available in the market.
tests (NAATs) are very sensitive and detect as few as 10 Real-time PCR detection technology has been widely
bacilli. These tests are highly sensitive in clinical samples evaluated. The majority of real-time PCR methods
and studies have shown that sensitivity and specificity reported to date for mycobacteria focus on detection of
are ranging as high as 90 to 100%. NAATs may be tested the M. tuberculosis complex. Several publications address
on any specimen thought to contain bacilli (blood, urine, the detection of Mycobacteria at the genus level. The risk
cerebrospinal fluid (CSF)) but there is even less sensitivity of contamination is considerably less with real-time PCR
reported in nonrespiratory samples. Sensitivity is compared to conventional PCR, but it still can occur.
improved when multiple samples are tested, because not Specimen-to-specimen contamination has become a
all samples necessarily contain detectable nucleic acid.9,10 greater challenge than amplified product contamination.
Most of in-house PCR procedures achieve a sensitivity The most obvious situation where specimen-to-specimen
never matched by commercial systems but are often contamination can occur is with the transfer of specimen
burdened by the high incidence of false positive results to the PCR vessel or to the DNA extraction tube.14,15
334
Section 5 Diagnosis
COMMERCIALLY AVAILABLE ASSAYS integrated in the Cobas instrument. Without further

handling, the amplification product will be automatically
Amplicor MTB Test transferred into the detection station where the
chromogenic reaction is developed and read. The
The Amplicor MTB Test (Roche Molecular Systems,
turnaround time is 6-7 hours. The method is approved
Basel, Switzerland) relies on standard PCR. A 584 bp
by the Food and Drug Administration of United State of
fragment of the 16S ribosomal RNA gene, comprising a
America (US FDA) for testing smear-positive respiratory
species-specific region flanked by genus-specific
samples. It includes an internal control, composed of
sequences, is amplified using biotinylated primers. In the
synthetic DNA characterized by identical annealing
master mix, an unusual combination of nucleotides is
sequences as the mycobac-terial target; when this is not
present— as an adjunct to adenine, guanidine and
amplified, it signals the presence of inhibitors. The
cytosine, uracil is used in place of thymine. As a
detection of M. tuberculosis complex DNA can also be
consequence, the amplification product differs from the
carried out without the Cobas instrument, using a manual
target DNA in that it contains uracil instead of thymine.
kit that, however, does not include an internal control.
This device is part of a contamination-control system
Other Amplicor kits are available for detection of M.
based on the use of uracil-N-glycosylase, an enzyme that
avium and M. intracellulare DNA in clinical samples. From
fragments DNA wherever uracil is present. The enzyme,
the literature review, specificity is close to 100% while
added to the samples before amplification, destroys any
sensitivity ranges from 90 to 100% in smear-positive
amplicon resulting from previous amplifications without
samples and from 50 to 95.9% in smear-negative ones.17
damaging the uracil-free target DNA. Because of the
genus-specific nature of the annealing regions, 16S
ribosomal DNA belonging to any Mycobacterial species Amplified MTD
is amplified by this PCR. The use, in the revealing phase, Amplified M. tuberculosis Direct Test (AMTD), developed
of magnetic beads coated with M. tuberculosis complex- by GenProbe (San Diego, CA, USA), is an isothermal
specific probes allows the removal, by washing, of any (42°C) transcriptase-mediated amplification system. A
other DNA. The detection of the specific amplification M. tuberculosis complex-specific region of the 16S
product is performed by adding an avidin-enzyme ribosomal RNA gene produces double-stranded
conjugate and a chromogenic substrate.16 ribosomal DNA, due to the combined action of reverse
The amplification and detection steps are carried out transcriptase and ribonuclease. In turn, RNA polymerase
automatically by the Cobas Amplicor instrument (Fig. catalyzes the synthesis of multiple stretches of ribosomal
25.2.1). Once the sample extraction has been performed RNA from the ribosomal DNA synthesized before. A new
by heating (95°C), the tube is placed in the thermal cycler cycle starts when the newly produced ribosomal RNA
undergoes further transcription by reverse transcriptase.
The sensitivity of the method is increased by the presence,
in each bacterium, of a high number of 16S ribosomal
RNA target molecules (about 2,000) compared to only
one copy of 16S ribosomal DNA. Another advantage of
the amplification from RNA relies on the low stability of
such a molecule; this minimizes both the risk of
contamination and the incidence of false-positive results
due to the persistency of stable nucleic acids (DNA) in
the host organism, even after the complete eradication
of the infection. The detection of amplification products
relies on hybridization with a specific, single-strand DNA
probe labeled with a chemilumin-escent molecule
(Hybridization Protection Assay). The whole process is
performed manually, starting with the extraction by
means of sonication, continuing with the addition of
different reagents until the final reading with the
luminometer. Thermal cyclers are not needed and the
whole amplification step is carried out on a heating block
at 42°C. The turnaround time is 2.5 hours. No internal
control is provided in the kit to monitor the presence of
inhibitors. The method is approved by the US FDA for
Fig. 25.2.1: Cobas Amplicor Instrument testing smear-positive and smear-negative respiratory
335
samples. The overall sensitivity for respiratory specimens M. avium, M. intracellulare and M. kansasii. The literature
was found in the range between 90.9% and 95.2% and reports a rate of sensitivity ranging from 98.5 to 100%
the specificity between 97.6% and 100%.18,19 for smear-positive samples and very variable (0.33-100%)
for smear-negative ones.20,21
BD ProbeTec ET
The BD ProbeTec ET (Becton Dickinson, Sparks, MD) Genotype Mycobacteria Direct Assay
uses DNA polymerase and isothermal strand It is for detection of M. tuberculosis complex and four
displacement amplification to produce multiple copies atypical mycobacteria (Hain Lifescience, Nehren,
of IS6110, an insertion element unique to M. tuberculosis Germany). This novel assay is based on the nucleic acid
complex. The rationale of strand displacement sequence-based amplification (NASBA) applied to DNA
amplification is extremely complex; what is presented strip technology. According to the manufacturer, the
here is an extreme simplification. In the initial phase assay has three steps. The first step consists of isolation
(target amplification), amplification is started by two of 23S rRNA, the second step includes amplification of
pairs of primers complementary to contiguous sequences RNA by NASBA method, and the third step involves the
delimiting the target. The elongation of the upstream reverse hybridization of the amplified products on
primer, also named bumper, determines the membrane strips using an automated system. The assay
displacement of the simulta-neously elongating has the ability for simultaneous detection of M. avium,
downstream primer and finally releases the produced M. intracellulare, M. kansasii, M. malmoense and MTBC.
amplicon. A restriction site, present in the downstream Isolation of highly specific RNA is achieved by the use
primer, will also be present in the released amplicon. In of the “magnetic bead capturing” method. This assay is
the exponential amplification phase, a new primer useful, reliable and rapid, with sensitivity and specificity
anneals to the amplicon and, following digestion by the of 92% and 100%, respectively.22
restriction enzyme, the upstream fragment acts as
bumper and displaces the downstream fragment. Real- LCx MTBC Assay (Abbott Laboratories, Diagnostic
time detection is based on the energy transfer technology. Division, Chicago, USA)
A hair-pin-shaped probe, complementary to IS6110, is
marked by two fluorescent molecules, one of which, the The assay uses the ligase chain reaction for amplification
donor, is quenched by the other, the acceptor; of a target sequence within the chromosomal gene that
furthermore, it presents a restriction site in the sequence codes for protein antigen b, which is specific for members
between the two markers. Once its free end has of the MTBC. The overall sensitivity and specificity of
hybridized with the amplification product, the probe the assay was 74% and 98%, respectively. For smear-
undergoes elongation before being displaced by a primer positive samples the sensitivity reached 100%, but for
annealed upstream to the same amplicon. The elongation smear-negative it was only 57%. In a multicenter
makes the probe able to bind a new primer which, while evaluation of Amplicor and LCx, the sensitivity of both
elongating, stretches out the “hair-pin” and moves the methods was significantly better when only respiratory
acceptor away from the donor. The nicking of the specimens were considered (78% and 88%, respectively).
restriction site by a proper enzyme further separates When nonrespiratory samples were used, the sensitivity
donor and acceptor and allows the first to free a was reduced to 59% for Amlicor and 65% for LCx.23,24
fluorescence signal. Some manipulation is required In conclusion, it should be noted that, although the
before introduction of the sample into the automatic traditional methods for diagnosis of tuberculosis, such
instrument; each sample is first inactivated at 105°C, and as microscopy and culture, cannot be replaced by direct
then sonicated to extract the DNA, transferred into a amplification tests, these assays provide a major
priming well at 72.5°C, and subsequently into an improvement in terms of speed. They could be used for
amplification well at 54°C. In the BD ProbeTec ET rapid confirmation in patients with smear-positive
instrument, the microplate containing the samples and samples. In smear-negative patients, the amplification
the amplification reagents is incubated at 52.5°C and the tests are recommended only when suspicion for TB is
fluorescence emitted is continuously monitored. A high and always in relation to clinical data. For
thermal cycler is not required. The turnaround time is extrapulmonary specimens, the use of the amplification
3.5 to 4 hours. An internal control is present, characterized methods is advocated, since rapid and accurate
by the same annealing sequences as the mycobacterial laboratory diagnosis is critical (e.g. tuberculous
target. In case of amplification failure, this control alerts meningitis). The specificities of amplification methods
for the presence of inhibitors. are very high, whereas, the sensitivities vary greatly.
The system is not yet approved by the US FDA. Kits Multiple specimens from the same patient, proper
are also available for the amplification of nucleic acids of decontamination procedures, improved extraction
336
Section 5 Diagnosis
methods and use of internal controls decrease the are added to the broken mycobacterial cells, to form a
frequency of false-negative results. stable DNA-RNA complex. Following separation of the
labeled complex from unhybridized DNA, the
IDENTIFICATION OF MYCOBACTERIAL SPECIES FROM hybridization is detected by light emission in a
CULTURE BY MOLECULAR METHODS luminometer. The AccuProbe can be used for both solid
and liquid cultures. The method is easy to perform and
For many decades, the identification of mycobacterial only a sonicator and luminometer are required as
isolates was performed on the basis of biochemical equipment. The method has been widely evaluated with
reactions and phenotypic characteristics, which are time- good results. The AccuProbe kits are rapid, highly
consuming and often give ambiguous results. The sensitive and specific. The procedure can be completed
molecular methods for mycobacterial identification are in less than two hours.28
now providing rapid and accurate results. Several
methodologies have been used. Line Probe Technology (hybridization in strips)
PCR-based Sequencing The line probe technology includes PCR (with
biotinylated primers), reverse hybridization with
This methodology is considered the “gold” standard for different specific DNA probes, immobilized in parallel
identification of mycobacteria. Initially, a PCR lines on a strip and colorimetric detection in an
amplification takes place followed by sequencing of the automated instrument. The banding pattern is indicative
amplicons in an automatic sequencer. The identification of the species of the isolate. The turnaround time is
of an unknown strain is completed by comparison of the approximately five hours. Two systems of line probe
nucleotide sequence with a library of known sequences. assay are commercially available: (a) the Inno LiPA
The databases for this purpose are available in the Mycobacteria v2 and (b) the GenoType Mycobacterium:
internet. Such databases are the GenBank, the Ribosomal
Differentiation of Medical Microsystems database Inno LiPA Mycobacteria v2, (Innogenetics, Ghent,
(RIDOM) and that of the European Molecular Biology Belgium)
Laboratory (EMBL). Several target genes have been used
for the procedure but the most common is the 16S rRNA This assay is based on the amplification of the
gene.25 This gene has been widely sequenced because it mycobacterial spacer region 16S-23S rRNA for the
contains both highly conserved and variable regions. It simultaneous identification, in just one strip test, of
consists of more than 1500 bp but usually the first 500 bp the 17 most frequently isolated mycobacterial species:
are adequate for identification of a common M. tuberculosis complex, M. avium, M. intracellulare, M.
mycobacterium species. As previously mentioned, other scrofulaceum, M. kansasii, M. xenopi, M. chelonae, M. gordonae,
important target genes are those encoding for the 65-kDa M. fortuitum complex, M. malmoense, M. genavense, M.
heat shock protein, the 32 kDa protein, the 16S-23S rRNA simiae, M. smegmatis, M. haemophilum, M. marinum/M.
internal transcribed spacer (ITS) and the recA gene. The ulcerans and M. celatum. Moreover, it has the ability
MicroSeq System (Applied Biosystems, CA) is a to discriminate subgroups within M. kansasii and M.
commercial 16S ribosomal DNA sequencing system. chelonae on the same strip. Mixed populations are easily
Evaluations of the MicroSeq System for routine use were identified. The overall sensitivity and specificity was
performed by and with good results. The system offers 100% and 94.4%, respectively. The probes specific for M.
the ability to mycobacteriology laboratories to identify fortuitum complex, for M. avium-intracellulare-scrofulaceum
many of the recently described mycobacteria.26,27 group and for M. intracellulare type 2 cross-reacted with
several mycobacteria rarely isolated from clinical
DNA probe Technology specimens.29
The DNA probe technology for identification of bacteria GenoType Mycobacterium (Hain Lifescience, Nehren,
is one of the most successful molecular methods. The Germany)
AccuProbe (Gen-Probe, San Diego, CA, USA) is the assay
based on this technology that is used by the majority of The procedure includes a multiplex PCR, followed by
clinical mycobacterial laboratories worldwide. It has the reverse hybridization and line probe technology. There
ability to identify a series of clinically important are three kits: (a) the GenoType MTBC for distinguishing
mycobacteria. These are M. tuberculosis complex, M. avium members of the M. tuberculosis complex, and (b) the
complex, M. avium, M. kansasii, and M. gordonae. The DNA GenoType Mycobacterium CM (Common Mycobacteria),
probes are single-stranded DNA oligonucleotides labeled and GenoType Mycobacterium AS (Additional Species)
with acridinum ester that are complementary to the for NTM. The GenoType MTBC is based on the gyrB gene
target, which is the rRNA. After sonication, the probes polymorphism. The AS and CM assays use 23S rDNA as
337
their target, thus the amplicon generated in the CM assay target, its hybridization and reading on the chip requires
can be used for the AS assay without the need to perform approximately two hours. It allows the identification of
a second PCR. The combined use of CM and AS can a large number of strains in one reaction. Sequences of
distinguish almost 30 different NTM including the regions from the 16S rRNA and rpoB loci had been
following species: M. avium, M. chelonae, M. abscessus, M. developed. Unique hybridization patterns allowed for
the identification of mycobacterium species and the RMP-
fortuitum, M. gordonae, M. intracellulare, M. scrofulaceum,
resistant alleles. A great disadvantage is, however, the
M. interjectum, M. kansasii, M. malmoense, M. marinum,
current high cost of the required equipment.34
M. ulcerans, M. peregrinum, M. xenopi, M. simiae, M.
mucogenicum, M. goodii, M. celatum, M. smegmatis, M.
MOLECULAR METHODS FOR DETECTING DRUG
genovense, M. lentiavum, M. heckeshornense, M. szulgai,
M. phlei, M. hemophilum, M. gastri, M. asiaticum and M.
RESISTANCE IN MYCOBACTERIAL STRAINS
shimoidei. The GenoType assays are rapid, easy-to- The emergence of strains of M. tuberculosis that are
perform and easy-to-interpret. They have allowed clinical resistant to antimicrobial agents is a global problem.
mycobacteriology laboratories to detect infrequent MDR-TB strains are generally defined as resistant to at
mycobacterial species, without the need of sophisticated least isoniazid (INH) and rifampin (RIF). Drug resistance
techniques. The sensitivity and the specificity compared develops either due to infection with a resistant strain,
with 16S rRNA gene sequencing were 97.9% and 92.4% or as a result of inadequate treatment such as when a
patient is exposed to a single drug, or because of selective
for CM and 99.3% and 99.4% for AS, respectively.30,31
drug intake, poor compliance, use of inappropriate non-
standardized treatment regimens, irregular drug supply,
PRA Method (Polymerase Chain Reaction and
poor drug quality, or rarely erratic absorption of
Restriction Enzyme Analysis for Identification of
medications. Knowledge of the susceptibility pattern of
Mycobacteria from Culture)
the isolate is crucial for successful therapy.35
Telenti et al. (1993) developed a rapid method, based on Existence of MDR-TB strains poses a serious threat
the amplification of the gene encoding the 65-kDa heat to TB control programs in many countries. As per the
shock protein, followed by restriction-fragment-length estimates from the State representative drug resistance
polymorphism, using two restriction enzymes BstEII and surveillance (DRS) survey in Gujarat and various district
HaeIII. Isolates from both solid and liquid cultures can level DRS studies, the prevalence of MDR-TB in new
be used. The fragments of the restriction enzyme smear-positive pulmonary TB (PTB) cases is 1.1 to 5.3%
digestion are analyzed by agarose gel electrophoresis and and 12 to 17% amongst smear-positive previously treated
compared. The test can be completed within a day. It is a PTB cases. These data from India on MDR-TB had been
cost-effective and reliable assay that can be used by low- collected from referral centers and institutions, and did
not reflect the overall status of drug resistance problem
budget laboratories as well.32
in India. Prevalence of drug resistant tuberculosis varies
considerably throughout the world and particularly in
Pyrosequencing
India. The reasons for this variation in different studies
Pyrosequencing™ (Biotage, Uppsala, Sweden) were poor study design, inadequate laboratory support
technology is a novel method of nucleic acid sequencing- and reporting systems.36
by-synthesis that is based on the detection of released The detection of resistant M. tuberculosis strains is
pyrophosphate (PPi) during DNA synthesis. The cascade generally performed by phenotypic assays, which require
of enzymatic reactions generates visible light. The the isolate to be cultured in the presence of the different
generated light is proportional to the number of drugs. Despite the use of new liquid medium cultures
incorporated nucleotides. The method is optimal for (BACTEC TB-460 (Becton Dikinson, Sparks, MD),
determining short sequences (typically 20-30 bases of a BACTEC MGIT 960, or Bact/Allert 3D (bioMerieux,
DNA) rapidly and in a semi-automated format.33 Durham, NC)]), the isolation of M. tuberculosis is still time
consuming (i.e. 1-2 weeks) and leads to delays in
DNA Microarrays (DNA chips) obtaining susceptibility patterns. Rapid methods to detect
The method is based on hybridization of fluorescently resistance are necessary to optimize antituberculous
labeled PCR amplicons of an unknown strain to a DNA treatment and avoid the transmission of resistant strains.
array, containing nucleotide probes for 16S ribosomal Several molecular methods to detect resistance mutations
RNA gene. The hybridization pattern and intensity is in M. tuberculosis have been described as the molecular
determined by scanning the chip using laser confocal basis of resistance to anti-TB drugs is becoming more
fluorescence microscopy. The process of generating the clearer.
338
Section 5 Diagnosis
Resistance to anti-tuberculosis drugs is primarily due R4b: His526Asp, R5: Ser531Leu. All the probes are
to mutations in a series of genes. The most frequently immobilized on a nitrocellulose strip. A M. tuberculosis
found mutations in RMP resistant isolates (96%) are isolate is considered susceptible to RMP, if all the wild
mutations in an 81-bp segment of the rpoB gene that type probes give a positive signal and all the probes for
encodes the β-subunit of RNA polymerase. In 75 to 85% resistance are negative. The absence of hybridization of
of INH resistant M. tuberculosis strains there are mutations one or more of the S probes is indicative of a mutation
in two genes, katG encoding catalase-peroxidase and that may be identified by one of the R probes. Inno-LiPA
inhA that takes part in fatty acid elongation. Mutations Rif TB to be a reliable, simple and informative tool with
in the embB gene, which plays a role in the synthesis of absolute correlation (100%) between its results and those
lipoarabinomanan and arabinogalactam, are connected obtained by the classic susceptibility testing, and the M.
with ethambutol resistance. More than 70% of tuberculosis probe to be completely specific. Although the
pyrazinamide resistance is due to mutations in the pncA assay is recommended for use only on isolates where the
gene, which encodes for pyrazinamidase that converts amount of DNA is large, it can be used directly on clinical
pyrazinamide to its active form. Mutations in the 16S specimens after modifications of the protocol (nested
rRNA gene or the rpsL gene that encodes for the PCR). Studies evaluating the line probe assay directly to
ribosomal protein 12S cause approximately 65 to 75% of clinical samples are limited. Inno LiPA assay provides a
resistance to streptomycin. Molecular assays have the rapid and reliable detection of RMP resistance in 78.3%
ability to detect these mutations and reveal the of clinical specimens, compared to Bactec 460 and to rpoB
underlying resistance mechanism within hours.37-40 gene sequencing.41,42
GenoType MTBDR plus (Hain Lifescience, Germany).
PCR-DNA Sequencing This assay offers the simultaneous identification of M.
tuberculosis complex and detection of the most common
Among the many techniques used to identify drug resistance mutations in rpoB (RMP resistance), katG and
resistance-associated mutations, automated DNA inhA gene (INH resistance). This assay is the newer
sequencing of PCR products has been the most widely version of the GenoType MTBDR assay, which did not
applied. This is considered as the reference method for have the ability to detect INH resistance, caused by
detection of drug resistance mutations. One important mutation in inhA. The previous and the new version of
advantage of sequence-based approaches is that the the assay could correctly identify rifampicin-resistance
resulting data are virtually unambiguous because a in 98.7% of the cases, when compared to conventional
resistance-associated mutation is either present or absent. susceptibility testing. Furthermore, the new GenoType
Initially, the region that is most frequently associated with MTBDR plus achieved better sensitivity for INH
resistance mutations is amplified. Then, the amplicons resistance (92% vs. 88.0% of the previous version).
are sequenced in order to determine the presence or GenoType MTBDR plus is a reliable tool for the detection
absence of a specific mutation. The expensive equipment of INH and RMP resistance either in strains or directly
and the expertize needed are probably the most serious in smear positive specimens.43,44
drawbacks of the method.
Hybridization on DNA Chips
Hybridization-based Techniques
The DNA microarrays can also be used for rapid
Line Probe Technology detection of mutations responsible for drug resistance.
It can simultaneously detect different drug resistant
There are two commercially available assays: the Inno-
LiPA Rifotuberculosis (Inno-LiPA RFTB; Innogenetics, mutations of M. tuberculosis. The DNA chip technology
Belgium) and the GenoType MTBDR plus, (HAIN, seems to be the most promising method for future
Lifescience; Nehren, Germany). These assays use probes investigation on drug resistance. A drug resistance
specific only for the M. tuberculosis complex and detection DNA chip (CombiChip Mycobacteria, Geneln,
additionally for the detection of the mutations responsible Pusan, South Korea) is avialable for identifying mutations
for drug resistance. associated with resistance to INH and RMP (katG, inhA
Inno-LiPA RifTB (Innogenetics, Ghent, Belgium). The and rpoB genes). It is an oligonucleotide microchip
kit contains 10 oligonucleotide probes: one specific for coupled to PCR for the detection of mutations. The results
M. tuberculosis complex, five wild type probes (S1-S5), were compared to DNA sequencing and culture based
and four probes (R) for the detection of the most frequent drug susceptibility tests. The CombiChip detected all
mutations that cause resistance to RMP. More than 95% RMP resistant isolates by screening 7 codons in the rpoB
of the RMP-resistant strains have mutations within an hot spot region and it correctly identified 84.1% of INH
81-bp hot spot region (codons 507-533) of the rpoB gene. resistant isolates by screening the katG codon 315 and
The R probes used are: R2: Asp516Val, R4: His526Tyr, inhA.45
339
PCR-SSCP (single-strand-conformationpoly-morphisms) HIGHLIGHTS

SSCP is based on the conformational distortion that a • Laboratory diagnostic tests for TB have evolved
nucleotide substitution can cause in a single strand DNA rapidly as new technology has been introduced and
fragment. This conformational change leads to an provide unprecedented opportunities for the rapid,
electrophoretic mobility different to that of the wild-type sensitive and specific diagnosis of M. tuberculosis
single-strand fragment. The procedure involves itself in clinical samples and the status of its drug
amplification of a DNA fragment including the region sensitivity.
of interest by PCR, denaturation and running of this • Some of the molecular tests have now been
fragment in a polyacrylamide gel together with a incorporated into routine laboratory usage allowing
denaturated wild-type reference sample. Mobility shifts the physicians to more rapidly initiate proper drug
in the clinical sample indicate presence of mutation. regimens.
This method has 100% specificity for RMP and INH • Due to certain limitations in these molecular tests,
resistance and sensitivity for RMP 96% and for INH 87%, however, conventional tests such as those based on
microscopy and culture should be applied in parallel
using four genetic regions (rpoB, katG, inhA, ahpC,). A
with any new molecular tests for diagnosis of TB.
nested PCR- linked SSCP analysis is also used directly
• In addition, particular emphasis should be applied
on sputum samples, to detect M. tuberculosis and
to quality control and quality assurance programs
determine RMP susceptibility. In this study, the target in clinical laboratories which employ any new
was a 157 bp portion of rpoB gene, which has been widely diagnostic approaches.
used for PCR-SSCP. The results were concordant with
those of conventional drug susceptibility testing and
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26 Imaging of Tuberculosis in Children
Ashu Seith Bhalla, A Kumar, AK Gupta, S Mukhopadhyaya
Tuberculosis continues to be a major health problem all tuberculosis is caused by reactivation of latent foci of
over the world, especially in developing countries. The infection implanted during primary tuberculosis. Earlier,
incidence of tuberculosis has risen steadily since 1985, primary tuberculosis was considered a disease of
despite a preexisting decrease of its frequency due to children. A significant change has occurred in the pattern,
effective chemotherapy. This is related to the occurrence as primary tuberculosis is being encountered in adult
of AIDS epidemic, together with increasing prevalence of population with more frequency. Primary tuberculosis
multidrug resistant TB. In all cases, pulmonary tuberculosis is an air borne infection, resulting from inhalation of
remains a common disease. Pediatric cases are particularly mycobacterial aerosol. It consists of a small focal
important epidemiologically because each usually parenchymal infiltrate or consolidation, with lymphatic
represents a new infection rather than reactivation of prior spread to mediastinal and hilar nodes, known as the
disease. Indeed it is said that, “Children with primary Ghon’s complex. It usually heals, but may progress to
tuberculosis are the reservoir from which future cases will progressive pulmonary tuberculosis in 5-10% of patients
emerge.” 1, 1a with primary TB, involving multiple lobes and more
Pathologically, in tuberculosis two processes are in extensive lesions. Primary tuberculosis usually shows
play: caseationdestructive and dangerous and the other lympho-hematogenous spread, while post primary pre-
sclerosis- conservative and healing. The ultimate result dominantly shows endobronchial spread. Endobronchial
in a given case depends upon the capabili-ties of the body spread results from cavitation of the tuberculous
to restrict and limit the growth of the bacilli. Hence a consolidation or rupture of necrotic lymph nodes into
widespectrum of tuberculous lesions are encountered the bronchi. Hematogenous spread may also occur.
radiographically. In this article, imaging of the Congenital TB is an unusual entity resulting from
tuberculous lesions affecting different organ systems of hematogenous spread across the placenta or fetal
children is discussed. ingestion of infected amniotic fluid.4
PULMONARY TUBERCULOSIS IMAGING MODALITIES

Lungs are the most common and usually the first site of
involvement in tuberculosis. Bacterio-logical confirmation Plain Radiographs
of pulmonary tuberculosis in pediatric age group is A patient suspected of pulmonary tuberculosis is evaluated
difficult. The lung lesions do not cavitate as frequently as by a posteroanterior (PA) chest roentgenograph. Mostly a
in adults. Sputum collection is difficult. Gastric contents PA view is adequate for diagnosis and subsequent follow-
with swallowed organisms show positive-smear in about up. Lateral view is indicated to evaluate lesions not well
5% and positive culture in about 40% children. Less than seen in PA view.
50 percent of children with tuberculosis are diagnosed
without bacteriological confirmation.2
Ultrasound (US)
Imaging plays an important role in pediatric pulmonary
tuberculosis. The patients who are exposed to tuberculous While chest radiography is the primary imaging modality
infection for the first time have pathological, clinical and in evaluation of chest diseases, US may be helpful in
roentgenological features different from those who have evaluation of persistent or unusual areas of increased
reactivation of previous disease or superinfection.3 But there opacity in the peripheral lung, pleural abnormalities, and
are overlap of findings in these two groups. mediastinal widening. In tuberculosis, US is particularly
The radiographic findings can be divided into primary useful in follow-up of patients with pleural effusion/
and post primary or reactivation forms. Primary empyema. US also helps guided interventions such as
tuberculosis represents the initial infection with M. empyema drainage and mediastinal nodes sampling,
tuberculosis in an unsensitized host. Postprimary when large.5
345
Chapter 26 Imaging of Tuberculosis in Children
Computerized Tomography (CT) IMAGING FINDINGS

Computerized tomography (CT) can give important The disease may be described under the following
information in deciding presence and nature of headings:9
lymphadenopathy, diagnosis and extent of bronchiectasis, 1. Pulmonary primary complex (PPC)
pleural and chest wall lesions. Contrast enhanced CT • Parenchymal involvement
(CECT) may detect a number of abnormalities which are • Nodal involvement
not visible on chest radiographs. Several times, CT may • Parenchymal and nodal involvement
be the only modality to detect them, thus, aiding in making • Airway involvement
a confident diagnosis of tuberculosis.6, 7 CT is hence useful • Mild pleural involvement
in patients who are symptomatic Mantoux positive (SMP) 2. Progressive primary disease (PPD)
with normal chest X-ray. It also helps in assessing disease • Consolidation
activity in equivocal cases. • Collapse
• A study at All India Institute of Medical Sciences • Collapse with consolidation
(AIIMS), New Delhi, India over 3 years (2003-06) was • Cavitation
conducted to evaluate the role of CT in chest • Significant pleural involvement
tuberculosis in children. A total of 91 patients with • Bronchopneumonic spread
clinical and laboratory evidence, or chest radiograph, • Miliary spread
suggestive of pulmonary tuberculosis were studied. 3. Post primary lesion (PPL)
All these patients underwent chest radiography and • Calcification
CECT of the chest and were given antitubercular • Fibrosis
treatment (ATT) for 6 months. Out of these 91 patients, 4. Symptomatic Mantoux positive (SMP)
46 were lost to follow-up. Rest of the 45 patients Over the past 30 years patients attending the Pediatric
underwent repeat CECT within 30 days of completion Tuberculosis Clinic of All India Institute of Medical
of ATT. Chest radiographs were normal in 8 patients Sciences (AIIMS), New Delhi, were assessed
in the pre-treatment phase, in whom the disease was roentgenologically under these four broad heads. There
diagnosed on CECT. Even, in those patients, with were 2,677 patients of pulmonary tuberculosis, among
whom 50% were in PPC, 13% in PPD, 16% PPL, and 21%
abnormal radiographs, CT revealed additional
in SMP group.9
findings and hence, helped in making a specific
diagnosis. After 6 months of ATT, chest radiographs
were normal in 4 patients, where as CECT still showed Pulmonary Primary Complex (PPC)
enlarged nodes. CT also detected complications, like Primary tuberculosis of the chest usually affects one or
empyema in 5 patients, and other complications in 9 more of the four structures, i.e. pulmo-nary parenchyma,
patients.8 lymph nodes, tracheobron-chial tree and pleura.2
The main concern with use of CT is the exposure of
children to ionizing radiation, especially as repeat studies Parenchymal Involvement
maybe required on follow-up. All CT studies should hence
use specific pediatric protocols to minimize the radiation The typical roentgen appearance is that of an airspace
dose. consolidation of variable size, usually unifocal,
homogenous, ill-defined margins except when it abuts a
fissure (Figs 26.1A and B). It is often indistinguishable
Magnetic Resonance Imaging (MRI)
from typical bacterial pneumonia. In tuberculous
MRI is not routinely used in evaluation of the lungs due consolidation and in PPC there is lack of systemic toxicity,
to low proton density of lungs, physiological motion and presence of significant number of associated lymph-
extensive air-tissue interfaces; all resulting in poor signal. adenopathy and failure to respond to antibacterial
It has however, found utility in evaluation of therapy. Cavitation and endobronchial spread of disease
mediastinum as an alternative to CT, being associated is rare in children with uncomplicated primary
with no risk of radition exposures. However, its cost, long tuberculosis.10-13 There is no consensus as to the most
examination times and need for patient cooperation are common site of paren-chymal involvement in primary
still limiting factors. MRI maybe used in older children tuberculosis, different series documenting upper lobe10,
and young adults for initial and follow-up evaluation of lower lobes14,15, no regional predominance16 and equal
suspected mediastinal nodes. involvement of upper and lower lung zones13. For
346
Section 5 Diagnosis
paratracheal and less commonly, the subcarinal region.

When associated with parenchymal lesion, the nodes of
the same side are involved. Although typically unilateral
and right sided, bilateral adenopathy may occur in up to
31% cases.13,22 A recent study has reported the subcarinal
region as the most frequently involved site seen in 90 of
92 pateients.7 Adenopathy may be the sole radiographic
manifestation of primary tuberculosis. Adenopathy alone
is a finding that decreases in frequency with age,22 being
encountered in up to 49% of children aged 0 to 3 years,13
in 9% children age 4 to 15 years,23 and only rarely in
adults24,25 (Figs 26.2A and B).
CT in Evaluation of Lymphadenopathy
Contrast enhanced CT scan can show the nature of an
enlarged lymph node. Tuberculous nodes larger than
2 cm in diameter usually show central areas of
multifocal relative low density with rim enhancement
of irregular thick wall. With CT-histologic correlation,
excised nodes exhibiting this pattern of enhancement
have been found to contain complete central necrosis
in association with a highly vascular, inflam-matory,
capsular and perinodal reaction.26, 27 Other findings in
Figs 26.1A and B: Pulmonary primary complex: Chest radiograph (A)

and chest CT (B) shows an ill-defined consolidation involving the left
upper lobe, abutting the major fissure
practical purpose, primary tuberculosis can cause

consolidation of any lobe.17 Persistent mass like lesion
or tuberculoma is uncommon in children. In the series
by Seth et al9 at Pediatric Tuberculosis Clinic, All India
Institute of Medical Sciences New Delhi (AIIMS), 39%
patients of PPC group had only parenchymal
involvement. As in lymphadenopathy, CT is superior to
plain X-rays in demonstrating the parenchymal changes.
Consolidation is seen as a homogeneous soft tissue
attenuation lesion with air bronchogram or areas of
breakdown within. Parenchymal changes are better
appreciated on high resolution CT (HRCT).18 CT is
superior to MRI in the demonstration of lung
parenchymal changes.
Lymph Node Involvement

Lymphadenopathy is a common feature of primary
tuberculosis and is seen in up to 96% of children.6,13,19 It
Figs 26.2A and B: Pulmonary primary complex: Chest radiograph (A)
is the radiologic hallmark of disease in children.20-23 and contrast enhanced chest CT (B) show enlarged right paratracheal
Enlarged lymph nodes are usually in the hila, the right and right hilar adenopathy, which appears heterogeneous on CT
347
tuberculous nodes being varying degree of homogenous by subcarinal, pretracheal, precarinal and right hilar
enhancement, large central low density with uniform nodes, with largest nodes found in the prevascular,
thin rim- enhancement with preserved or obliterated subcarinal, and paratracheal location. The enhancement
perinodal fat.28 Androkinou et al7 describe ‘ghost-like’ pattern was most commonly homogenous, followed by
ring enhancement in a group of matted nodes as the inhomo-genous and peripheral rim like pattern. A
common pattern of enhancement rather than discreet combination of these patterns was also seen in a
rim-enhancement of single large nodes. Necrosis with significant portion of patients. Majority of the nodes were
rim enhancement is not a usual finding in lymphoma conglomerate and had obscured perinodal fat.
but reported in various fungal diseases and malignant Calcification was also found in a few patients without any
nodes undergoing central necrosis2 (Figs 26.3A to D). prior treatment.8 Mediastinal and hilar nodes are equally
Calcification is uncommon and seen in 10 to 21% well demonstrated on MRI. Focal necrosis is seen as areas
children with tuberculosis and is never present in of increased signal intensity on T2- weighted images.18
children less than 6 months of age.7,29 Figures 26.4A and In the Pediatric Tuberculosis Clinic of AIIMS, 29%
B show lymph node calcification on CT. Figure 26.4B children of PPC group had both parenchymal as well as
shows noncontrast and shows 26.4C Figure 26.4C shows nodal involvement (Fig. 26.5).9
contrast enhanced CT scan of two different patients
showing calcification in the paratracheal nodes. In the Airway Involvement
study of 91 patients, nodal involvement was the most
common abnormality (96.7%).8 The most frequent nodal Thirty percent patients of primary tuberculosis in Weber’s
groups to be involved were paratracheal (84%), followed series 10 showed atelectasis caused by tuberculous
Figs 26.3A to D: CT scout (A), contrast enhanced chest CT (B) and abdomen (C) reveal enlarged right paratracheal lymph nodes which show
classical central necrosis and rim-enhancement. Enlarged and matted left axillary, periportal, peripancreatic nodes are also present. Lung window
(D) reveals left upper lobe consolidation
348
Section 5 Diagnosis
Fig. 26.5: Pulmonary primary complex: Chest radiograph reveals

right midzone parenchymal lesion and right paratracheal adenopathy
tracheobronchial disease. Atelectasis in primary

tuberculosis typically affects anterior segment of upper
lobe or medial segment of middle lobe due to
compression by lymph node enlargement. In the AIIMS
series8 31 of 91 about 34% children showed airway
involvement. However, some of these cases showed
features of PPD.
Pleural Involvement
Pleural involvement in the form of effusion is not very
common in primary tuberculosis. Weber et al10 observed
pleural effusion in 10% of their pediatric patients. Mostly,
effusion is mild to moderate in quantity and usually
associated with parenchymal lesion. In the AIIMS series,9
pleural effusion was very uncommon in PPC, and if
present was very mild in quantity.
Progressive Primary Disease (PPD)

A primary lesion may disseminate through tracheo-
bronchial tree resulting in bronchopneu-monic spread
or may erode into a vascular channel causing miliary
dissemination into lungs and in many other organs.
Progressive primary disease is the result of
progression or reactivation of the primary disease. This
includes large consolidation, atelectasis, a combination
of consolidation and atelectasis and cavitating lesions.
In AIIMS series 9 of 2,677 patients, 13% were in the
PPD group. At times after initial good response to
treatment, the typical picture of primary tuberculosis
becomes confusing by the continuing progression or
reinfection of the disease. Patients may report for
Figs 26.4A to C: (A) Lymph node calcification, Noncontrast (B) and
contrast enhanced (C) CT scans of two different patients showing treatment first time at this stage and it becomes
calcification in paratracheal nodes difficult to ascertain whether this is PPC or PPD.
349
Parenchymal Involvement
Consolidation in PPD is usually heterogenous, poorly
marginated with predilection of involvement of apical or
posterior segments of upper lobe or superior segment of
lower lobe.3, 19 Often more than one pulmonary segment is
involved.14 Segmental consolidation if not adequately
treated results in lobar or complete lung involvement.
Consolidation of PPD has propensity for cavitation in some
cases (Figs 26.6 and 26.7A to C).
Untreated consolidation may lead to collapse.
Endobronchial tuberculosis or pressure on bron-chus by
enlarged lymph nodes may lead to collapse. If not treated
actively and adequately, the collapse may become
irreversible (Fig. 26.8). On HRCT bronchial compression
by enlarged nodes as well as endobronchial involvement
is well detailed. Acute tracheobronchial tuberculosis
manifests on HRCT as irregular or smooth bronchial wall
thickening associated with luminal narrowing.30 One of
the most striking feature of juvenile pulmonary
tuberculosis is the absence of proliferative apical
tuberculosis before onset of adolescence.31
Consolidation may be associated with collapse of the
same lobe or different lobes of the lung (Fig. 26.9).
Lobar or segmental consolidation may progress and
breakdown into necrotic areas when some of the content
is drained via bronchus, a cavity is formed (Fig. 26.10).
Cavities are more frequently multiple and typically
within area of consolidation. The cavity wall is initially
thick and irregular, then progressively becomes thin with
healing. This progression is well demonstratrated on
HRCT.26 In the AIIMS series9 of PPD there were only 1%
cavitating lesions (Fig. 26.11).
Figs 26.7A to C: Progressive primary disease: Chest radiograph (A)

shows a large area of heterogeneous consolidation involving right upper
lobe. Multiple cavitary lesions are seen in right lower lobe. CT scan (B
Fig. 26.6: Progressive primary disease: Chest radiograph shows and C) reveals cavitation in the upper lobe lesion and bilateral lower
massive right side consolidation lobe cavities
350
Section 5 Diagnosis
Fig 26.8: Collapse of left lower lobe seen as a triangular opacity

through cardiac shadow in the chest radiograph
Fig. 26.10: Progressive primary disease: Chest radiograph showing

consolidation with cavitation in left lower lobe, with adjoining multiple
air-space nodules
Fig. 26.9: Progressive primary disease: Chest radiograph showing Fig. 26.11: Progressive primary disease: CT scan showing a thick-
consolidation and cavitation involving left upper lobe, with volume loss walled cavity with surrounding consolidation with collapse in the right
of the lobe upper lobe
Pleural Involvement become loculated, causing a tuberculous empyema

(Figs 26.13A and B). In chronic tuberculous empyema, CT
Tuberculous infection of the pleura is more com-mon in shows right sided pyopneumothorax, a focal fluid
adults and teenagers than in children19 but may occur collection with pleural thickening with or without
from infancy to old age. With appropriate therapy pleural extrapleural fat proliferation. As a consequence of post
effusion carries the best prognosis of all types of primary tuberculosis, pleural disease can result in
tuberculosis and is least likely to subsequent bronchopleural fistula due to rupture of a cavity or
complication. Usually pleural effusion in PPD is secondary to empyema. CT may demonstrate directly
moderate to large in quantity, unilateral, free flowing and the communication between the pleural space and
with or without lung lesion (Fig. 26.12). It commonly bronchial tree or lung parenchyma in these patients. At
develops on the same side as the site of initial tuberculous times, the effusion may not clear completely and leaves
infection. Primary pleural effusion tends to clear residual encysted sac of thick pleura with or without
completely or results merely in obliteration of the residual fluid in it. Fibrothorax with diffuse pleural
costophrenic angle. Tuberculous pleurisy, however, may thickening with calcification, but without pleural effusion
351
and was seen in 3% of children with PPD. In the

subsequent study with CT, however, pleural lesions were
seen in 18 of 91 patients. Majority (n = 9) of them had
only pleural thickening, 4 had pleural effusion while 5
showed CT feature of empyema.8
Tuberculous Bronchopneumonia
When a tuberculous necrotic parenchymal lesion
extends locally and erodes into the tracheobronchial
lumen, there may be wide dissemination through the
bronchial tree to ipsilateral or bilateral lung
parenchyma. Such endobronchial spread results in
formation of multiple foci of alveolar shadows very
suggestive of bronchogenic spread. The disease process
Fig. 26.12: Chest radiograph shows massive right sided may extend through surrounding airspaces leading to
free pleural effusion acute confluent air space pneumonia. The lesions usually
occur in clusters and vary widely in size. Usually the open
cavity or consolidation in remote areas gives clue to the
primary site of dissemination (Figs 26.14A and B).
Bronchopneumonic spread is better appreciated on CT
Figs 26.13A and B: (A) Right sided loculated pleural effusion seen in
chest radiograph (B) Empyema CT scan of another patient with right
sided pyopneumothorax
on CT, suggests inactivity.30 Loculated fluid may be Figs 26.14A and B: Bronchopneumonic spread: (A) Chest radiograph
mistaken for pneumonia or round consolidations. reveals extensive bronchopneumonic tuberculosis with consolidation
In AIIMS series with chest radiographs9 pleural in left lower lobe of right lung. (B) After adequate therapy there is diffuse
healed calcified foci in right lung and a large calcified node in left
effusion was most commonly seen in school going age, paratracheal region
352
Section 5 Diagnosis
particularly HRCT compared to plain radiographs. The Miliary Tuberculosis

appearance is widespread, bilateral but not always
symmetrical fluffy densities (alveolar nodules) (Figs A primary lesion may erode into a vascular channel
26.15A to C). Early lesions are seen as small, ill-defined causing miliary dissemination into the lungs and many
centrilobular nodules with branching (tree-in-bud organs. In the early stage of miliary dissemination chest
appearance). This sign results from the impaction of roentgenogram may be normal. The interval between
bronchioles with exudates and when present is dissemination of bacilli and development of
indicative of active disease. roentgenographically discernible disease is probably 6
weeks or more. When these lesions increase in size they
are tiny, discrete pinpoint opacities evenly distributed
throughout both lungs with some basal predominance,
reflecting gravity induced more blood flow to the base.
HRCT is sensitive to the depiction of even early changes
in miliary tuberculosis (Figs 26.16A and B). Initially, they
are about 1 mm in diameter and may reach 3 to 5 mm size
if adequate therapy is not given. The lesions may become
confluent presenting a “snow storm” appearance.3
Associated lymph adenopathy is seen in 95% of the
children as compared to 12% in adults.32 Affected nodes
are mostly on the right side in paratracheal region.
The primary site of dissemination is not always
recognized on a chest X-ray. With adequate therapy
roentgenographic clearance is usually compelete without
any residue and clearance may be extremely rapid.
In AIIMS series, only 3% children had bronchopneu-
monic and miliary tuberculosis.9
Figs 26.15A to C: Progressive primary disease: (A) Chest radiograph

reveals mediastinal widening with multiple, bilateral pulmonary nodules.
(B) Chest CT shows extensive necrotic mediastinal adenopathy. (C)
Lung fields on CT reveal extensive brochopneumonic spread with Figs 26.16A and B: Miliary spread: Chest radiograph (A) and (B) HRCT
consolidation in the right lower lobe show bilateral, diffuse, tiny, discrete, pinpoint opacities
353
Post-Primary Lesion (PPL) FOLLOW-UP

This group includes patients with parenchymal or nodal At AIIMS, in collaboration with Pediatric Department a
calcification and/or fibrotic lesions. In AIIMS series of routine of serial radiological evaluation of children with
2677 patient, 9 16% patients were in this group. pulmonary tuberculosis is followed. The first X-ray is
Lymph node enlargement may be massive; in a series taken at presentation/diagnosis of tuberculosis. Repeat
of 15 children of primary tuberculosis by Giammona et X-ray is taken after 3 months of therapy, then every 3
al23 with hilar and mediastinal lymphadenopathy, 10 months in first year and every 6 months in the second
children, all 5 years or younger had massive nodal year. After this the patient is kept under surveillance and
enlargement. in case of development of signs and symptoms, he is
In this series9 of 1350 patients in PPC group, 32% assessed again clinically and radiologically. CECT is a
children had only nodal involvement. useful tool after chest radiograph, not only for the
diagnosis, but also for monitoring the response to ATT.8
Symptomatic Mantoux Positive Group (SMP) However because it entails significantly greater radiation
exposure, its routine use cannot be advocated. MRI can
This group forms 21% of the cases. These are children be used in older children with nodal disease.
who are symptomatic, have positive Mantoux test and
normal chest X-ray. They comprise 21% of the total cases
Imaging Follow-Up
of pulmonary tuberculosis in the Pediatric TB clinic.9 CT
scan of chest in 10 patients of SMP group revealed The parenchymal and nodal lesions may regress till there
lymphadenopathy not appreciated on a chest is complete clearance, calcification or fibrosis. The
X-ray. One report comparing the findings of radiographs, majority of children with PPC on follow-up show no
showing that up to 60% of children with normal roentgen sign of the initial lesion, the sole evidence of
radiographs had lymphadenopathy on CT.6 A normal disease being a positive Mantoux test. Calcification of
chest radiograph can hence be misleading.6, 7 paren-chymal or nodal lesion is not very common in PPC.
In the series of Weber et al10 children with adequate
PREDICTION OF ACTIVITY OF TUBERCULOUS LESION follow-up, calcification was seen in 17% of the
parenchymal and 36% of nodal lesions. Thirty two
A radiologist or a clinician should never be dogmatic percent of children showed residual parenchymal
about assessment of activity of a tuber-culous lesion on scarring. Decrease in the size of enlarged lymph nodes
a single radiograph. There may be a typical exudative usually, parallel resolution of parenchymal lesion. Some
lesion on X-ray but repeated gastric lavage for AFB are children who had atelectasis in active stage of the disease,
negative. The lesion may remain unchanged for a long have residual dilated and distorted bronchial tree or
time. On the other hand a typical fibrotic lesion may have bronchiectasis.
active granulomatous lesion. A static lesion for a long Bronchiectasis in PPD can develop by two mechanisms:
time (6 months or more) may indicate inactivity. CT can (i) destruction and fibrosis of lung parenchyma resulting
help predict the disease activity on the basis of specific in retraction and irreversible bronchial dilatation,
findings in nodes and parenchyma. These features can and (ii) cicatricial bronchostenosis secondary to localized
therefore be used to monitor response on imaging. HRCT endobronchial infection resulting in obstructive
has a definite role in prediction of activity of parenchymal pneumonitis and distal bronchiectasis.3 CT plays important
lesions. The presence of thick-walled cavities, role in the diagnosis and evaluation of extent of bron-
consolidation and centilobular nodules indicate active chiectasis, thereby helping in surgical excision (Figs 26.17A
disease. Whereas, thin-walled cavities, fibrotic bands and and B).
well defined nodules are seen in inactive disease. CT
picture can, however, be equivocal and clinical Family Survey
correlation in this regard is imperative.8 Evaluation of
All children with pulmonary tuberculosis should have
activity in nodes is difficult, though presence of low
family survey to detect asymptomatic contact positive
attenuation areas has been suggested as a sign of activity.
cases. Chest radiograph should be taken for all adults
However, this sign is of limited reliability as and children. Mantoux test should be done for those
enhancement patterns of the nodes can be quite variable below 12 years. Any family member with suspicious
as discussed previously.30 lesion in chest radiography should be further investigated
In the CT study of AIIMS 8 node enhancement and treated. In AIIMS series in the Pediatric TB clinic
(homogeneous or inhomogeneous), conglomeration and there was positive family history in about 30% of children
obscuration of fat were found as indicators of disease with pulmonary tuberculosis.9 Radiological screening of
activity in nodes. adult contacts, taking a child with PPC as an index case,
354
Section 5 Diagnosis
Figs 26.18A and B: CT guided trucut biopsy from partially calcified

right paratracheal node, using posterior approach and co-axial
technique. Histopathology revealed active disease
Figs 22.17A and B: (A) Collapse of left lower lobe with bronchiectasis
location of the lesion. Rarely, presence of massive or
seen in chest radiograph (B) Chest CT scan reveals loss of volume of
left lower lobe with cystic bronchiectasis, mediastinal shift to the left moderate hemoptysis may necessitate need for
and herniation of right lung into left hemithorax bronchial artery embolization, especially in those with
extensive parenchymal involvement.
showed active pulmonary lesions in 4 to 5% of those
INTRACRANIAL TUBERCULOSIS (33-39)
screened. Hence it is advocated rightly in Revised
National Tuberculosis Control Program (RNTCP) in It is almost always secondary to hematogenous
India that children of a pulmonary tuberculosis put on dissemination from a primary focus elsewhere, usually in
DOTS must be screened for tuberculosis. the lungs. Rarely, it may also result from direct spread
from calvarial or middle ear infection. On the basis of
Interventions in Thoracic TB location it is described as either meningeal or parenchymal.
Depending on the type, however, it is classified as diffuse
Both diagnosic and therapeutic image guided
meningeal (TBM); tuberculomas, tuberculous abscess and
interventions may be required in thoracic TB
focal cerebritis.
occasionally. These include FNAC or trucut biopsy of
mediastinal nodes in equivocal cases.(Figs 26.18A and
Tuberculous Meningitis (TBM)
B). Image guided drainage of pleural collections may
be performed, especially in loculated effusions (Figs It is a common clinical problem in India. The diagnosis
26.19A and B). Similarly large mediastinal (pre or of tubercular meningitis is based on clinical suspicion
paravertebral) abscesses can also be drained. These and CSF examination for biochemical analysis, AFB and
may be ultrasound or CT guided depending on the polymerase chain reaction. Imaging has a role in
355
Fig. 26.20: Axial CECT image shows extensive enhancing exudates

in the basal cisterns
Figs 26.19A and B: CT guided drainage of loculated empyema with

malecot catheter
corroborating the diagnosis and is especially useful for

assessing complications including hydrocephalus and
infarcts.
Pathological lesions observed on CT/MRI scan of
head are: exudates in the basal cisterns; hydrocephalus,
infarct, associated tuberculoma or cerebritis.
On a noncontrast CT, exudates are visible as either
isoattenuating or minimally hyper-attenuating which has Fig. 26.21: TBM: Localized exudate in left sylvian fissure only on CT
been described as the most specific sign of TBM. 33
Following intravenous contrast administration, however, Hydrocephalus, although a sequelae of basal exudates,
there is intense enhancement (Fig. 26.20). The abnormal may be the first manifestation on CT. It is a very common
meningeal enhancement or enhancing exudates are finding and is usually of the communicating type due to
usually seen in the basal cisterns including suprasellar blockage at the level of cistterns. Associated periventricular
cistern and cisterns around the brainstem and in the ooze suggests high pressure hydrocephalus (Fig. 26.23)
sylvian fissures. 34,35 Enhancement may extend over which is more commonly seen when it is a non-
cerebral and cerebellar hemispheres. The enhancement communicating hydrocephalus.
seen is usually thick, continuous with ill-defined edges or Infarcts due to basal arteritis are an important and
nodular differentiating it from normal vascular not an uncommon finding. Basal ganglia infarcts due to
enhancement. We have observed a good correlation the involvement of medial striate and thalamoperforating
between the degree of exudates and the clinical outcome. arteries in the basal exudates is a very characteristic
At times exudates may be localized to only one cistern infarct location for TBM (Fig. 26.24). However, infarcts
(Fig. 26.21). On follow-up scan (Fig. 26.22) calcification is may also occur in the adjoining areas of localized
the sequelae. meningeal or cisternal enhancement.33
356
Section 5 Diagnosis
Fig. 26.22: TBM: Healed calcified exudates in the suprasellar Fig. 26.24: Axial CT image of the same patient as in Figure 26.23
cisterns on follow-up NCCT performed 4 days later, shows a left basal ganglia infarct
Fig. 26.23: Axial CT shows hydrocephalus with periventricular ooze Fig. 26.25: Axial CECT shows multiple ring enhancing lesions in bilateral
in a patient with tubercular meningitis temporal lobes with perilesional edema consistent with multiple
tuberculomas
Late sequelae of TBM include atrophy, meningeal On noncontrast CT (NCCT), tuberculomas have a low
calcifications and focal infarcts. Contrast enhanced MRI or minimal high attenuation. After intravenous contrast,
is more sensitive than CT for detecting subtle meningeal they enhance either homogenously or in a ring fashion
enhancement. However, because of its high cost it is
(Fig. 26.25) with a smooth or a lobulated margin.36 They
reserved for problem solving cases when the CT findings have been described as immature (small discs and rings
are equivocal. Moreover, CT is almost equally sensitive with massive edema) and mature form (large rings or
as MRI to detect the major complications.
lobu-lated masses with lesser edema). Tuberculoma
cannot be reliably differentiated on CT from granuloma
Intracranial Tuberculomas due to other infectious diseases like neurocysticercosis,
It may occur either alone or in association with TBM, fungal and even pyogenic infection. Radiological features
may be single or multiple, latter being more common. which favor a tuberculoma over an neurocysticercus are
357
larger size (2 cm), thicker walls, intense perilesional edema, without raised choline.38 Magnetisation transfer images
hyperdensity on plain scan, conglomeration and adjacent have been shown to be more sensitive than T2 weighted
meningeal enhancement. (Fig. 26.26) With specific images in detecting small tuberculomas (Figs 26.28A and
treatment, surrounding edema diminishes and disappears B).39
first before reduction in the size of the tuberculoma takes
place which may either disappear totally or calcify (Fig. Tuberculous Abscess
26.27).
It is a rare presentation of intracranial tuber-culosis. CT
Magnetic Resonance Imaging (MRI) of Intracranial morphology is similar to pyogenic abscess, i.e. thin
Tuberculoma enhancing wall with low density center (Figs 26.29A to
C).
MRI appearance depends on whether the A noncaseating tuberculoma with ring enhan-cement
tuberculoma is noncaseating, caseating with a solid is differentiated from a tuberculous abscess by noting
center or caseating with a liquid centre.37 The signal the attenuation values of the center of the lesion which
characteristics are shown in Table 26.1. Based on these will be similar to normal brain in the former and low in
signal intensity characteristics it may be helpful to
the latter. MR spectroscopy of a tubercular abscess also
differentiate it from neurocysticercosis.
shows lactate and lipid peaks without any amino acid
Advanced MR imaging techniques including
peak which helps in differentiating it from pyogenic
spectroscopy and magnetization transfer imaging have
also been shown to be helpful in differentiating abscess.
tuberculomas from other lesions. Tuberculomas on MR Abscess may not respond to chemotherapy and then
spectroscopy characteristi-cally show lipid peak with or surgical intervention would be required.
Fig. 26.26: Tuberculomas. Axial CECT shows large (>2 cm) sized Fig. 26.27: Postgradolinium MRI scan shows in enhancement
conglomerate lesions in right temporo-occipital region with extensive with a solid center
perilesional edema
Table 26.1: MRI features of intracranial tuberculoma
Types of tuberculoma T1WI T2WI Postgadolinium
Noncaseating Hypointense Hyperintense Homogeneous enhancement

Caseating with Hypo-to Iso- to hypointense Rim enhancement rim (Fig. 21.27)*
solid center isointense with hypointense rim
Caseating with Centrally Centrally Rim enhancement
liquid center hypointense hyperintense with
hypointense rim
*Surrounding edema will be hypointense of T1W1 and hyperintense on T2W1
358
Section 5 Diagnosis
Figs 26.28A and B: Tuberculoma. T2-weighted axial MRI image (A) shows a ring lesion with hypointense walls and
iso to hypointense center. The lesion shows peripheral enhancement on post contrast T1-weighted axial image (B)
Figs 26.29A to C: Tuberculous abscess. T2-weighted axial (A) and post contrast T1-weighted axial (B) MRI images show a
large thick walled peripheral enhancing lesion with hypointense wall and hyperintense centre on T2 with marked perilesional
edema in the right cerebellar hemisphere. The MR spectroscopy (C) from the lesion shows significantly elevated lipid peak
Focal Cerebritis This long time interval probably accounts for the
small number of children with genito-urinary
It is usually associated with TBM. Focal edema with gyral tuberculosis. Nowadays, it is seen in children almost
enhancement without an evident abscess or tuberculoma exclusively with miliary disease.
in the same region points to the diagnosis of focal It is suggested that: (i) all children (and adults) with a
cerebritis. history of pulmonary tuberculosis should have a periodic
urine culture for acid-fast-bacilli, and (ii) tuberculosis should
URINARY TRACT TUBERCULOSIS 40-46 always be suspected in all children with chronic or recurrent
Symptomatic tuberculosis affecting the urinary tract urinary tract infections which do not respond to the usual
occurs only rarely below the age of 20 years because there antibacterial medications. A high clinical index of suspicion
is a time lag of 2 to 20 years (average 8 years) between is required to diagnose these cases at an early stage. Majority
the initial pulmonary infection and the diagnosis of of urinary tract tuberculous cases are secondary to
secondary genitourinary tuberculosis. pulmonary tuberculosis.
359
Imaging caliectasis (Fig. 26.31) where-as complete stricture

of it will cut-off the cavity from the collecting system
Imaging plays a vital role in the overall management resulting in a tuberculous abscess (Fig. 26.32).
of these patients. One must remember that imaging v. Stricture at the inferior margin of the renal pelvis
can only suggest imaging ‘is compatible with results in its cephalic retraction producing the so-
disease’ but diagnosis is always by urinary culture called “hike-up-pelvis”.
for M. tuberculosis. vi. Advanced disease results in diffuse fibrosis and the
kidney becomes nonfunctional, the so-called
Plain X-rays “autonephrectomy”. Amorphous calcification may
They are valuable and might show the following features: be seen within this kidney. This stage is usually seen
i. Calcification in the genitourinary tract areas is a late only in adults.
feature and is, therefore, seen mostly in adults.
Characteristic features are lobar calcification, and
putty-like appearance of the calcification.
ii. Other tuberculous lesions, e.g. evidence of vertebral
tuberculosis, mesenteric or retro-peritoneal lymph
node calcification or adrenal calcification.
iii. Chest X-rays positive for tuberculosis either active
or healed sequelae. In the overall group of
genitourinary tuberculosis (including adults) less
than 50% of patients are reported to have chest
abnormality indicative of tuberculosis.
Intravenous Urography (IVU)

This remains the key investigation for the radiological
diagnosis of early urinary tract tuberculosis. The newer
imaging modalities like ultrasonography, computed
tomography and magnetic resonance imaging do not
have the spatial resolution capable of demonstrating the
early, fine erosive changes affecting the uroepithelium.
Following findings may be seen on IVU.
Fig. 26.30: IVU: Tuberculous kidney-note irregular, fuzzy outline in a
cavity and a noncommunicating focal mass around which superior calyx
Kidney is draping
i. In the earliest stage granuloma is localized to the

glomerular arterioles and IVU will be normal at this
stage although urine is positive for AFB.
ii. Spread of infection to medulla results in papillary
ulceration which produces the earliest changes
detectable radiologically. These are seen as poor
definition of minor calyx/calyces or “moth-eaten
calyx”. At this stage, clinically patients have either
minimal or nonspecific symptoms and therefore IVU
is usually not done and hence, these lesions are
rarely detected.
iii. In the next stage, papillary granulomas caseate, and
rupture into a collecting system, thereby, forming
a small commu-nicating cavity-single or multiple,
but usually unilateral. On IVU these are seen as
round areas with irregular shaggy walls and are
outlined by contrast at its periphery (Fig. 26.30).
iv. Infection now spreads to the uroepithelium where
fibrotic reaction is initiated. Stenosis of the Fig. 26.31: IVU: Tuberculous kidney-amputation of superior calyx
infundibulum results in proximal dilatation and with caliectasis of middle calyx
360
Section 5 Diagnosis
Urinary Bladder
Mucosal irregularity occurs at an early stage but small,
contracted bladder with reduced capacity results at a later
stage.
CT Scanning
It can readily demonstrate type and distribution of
calcification, morphological changes like scars,
hydronephrosis, caliectasis, nature of dilated system (Figs
26.34 and 26.35); functional status of the kidney and lastly
extrarenal spread of infection. CT, therefore, is a very useful
imaging tool.
Fig. 26.32: IVU: Tuberculous kidney-large tuberculous cavity filled

with contrast
Ureters
Ureteric involvement is almost always asso-ciated with
ipsilateral kidney disease. On IVP one or more of the
following may be seen:
i. Stricture at single or usually multiple sites with
dilatation in between resulting in a “beaded”
appearance (Fig. 26.33).
ii. Stricture extending over several centimeters which
is a characteristic feature of tuberculous involvement.
iii. “Pipe stem ureter” occurs in advanced, end-stage
disease in adults due to the extensive mural fibrosis.
Even ureteric wall calcification may be present. Fig. 26.34: CECT in same patient as in Figure 21.30, contrast filled
iv. Vesicoureteric junction involvement produces either renal pelvis is seen separate from noncommunicating tuberculous
a stricture or patulous opening. abscesses visible as low attenuating masses
Fig. 26.33: IVP: Tuberculous ureteritis-producing ‘beaded’ Fig. 26.35: CT in tuberculous kidney: NECT: Note calcified
appearance mesenteric nodes and low attenuating focal areas in right kidney
361
Ultrasound
It can provide only part of the information avail-able on
CT. Sonography, however, is useful as a screening
modality and for carrying out inter-vention procedures,
e.g. guided aspiration of a focal mass lesion in a kidney
or nephrostomy.
ABDOMINAL TUBERCULOSIS47-51
It is not as common in children as in adults. Four clinical
presentations of abdominal tuberculosis are:
1. Gastrointestinal
2. Adenopathy
3. Peritoneal
4. Visceral
Gastrointestinal Tuberculosis
It is usually secondary to either ingestion of infected
Fig. 26.36: Plain X-ray Fig. 26.37: Barium swallow study:
sputum, infected milk or to hemato-genous spread from
abdomen, anteroposterior Esophageal tuberculosis with a
a primary focus in the lungs. Clinical complaints include view: Extensive mesenteric fistulous communication with
fever, anorexia, pain abdomen, abdominal distension and retroperitoneal calcified bronchus
and weight loss. nodes
Plain X-ray Findings in Abdominal TB affect the colon, either alone or in association with ileocecal
disease.
i. Intestinal obstruction
ii. Calcified mesenteric/retroperitoneal lymph nodes
CT Scanning
(Fig. 26.36)
iii. Enteroliths—usually seen in adults Circumferential wall thickening or more typi-cally an
iv. A positive chest X-ray for tuberculosis asymmetric thickening of the ileocecal valve, medial wall
v. Associated tuberculous lesion, e.g. verteb-ral of the cecum and terminal ileum along with pericecal
tuberculosis, psoas abscess which may even be regional lymphadenopathy is highly suggestive of
calcified.
Barium Study
Barium study is the single most important investigation
to demonstrate the presence and extent of tubercular
pathology affecting the gastrointestinal tract. Although
the mural and extramural disease may be detected with
ultra-sound or CT but definite mucosal evaluation is
possible only with a good barium study.
Very rarely, tuberculous mediastinal nodes may
secondarily involve the esophagus producing narrowing
with resultant dysphagia. More uncommon in this age
group is the formation of a fistula between esophagus and
tracheobronchial tree (Fig. 26.37). Classically, the ileocecal
area is commonly involved (Fig. 26.38) which in later stages
would produce a shrunken cecum and proximal ascending
colon which are also pulled-up resulting in an alteration in
the angle of entry of terminal ileum which is also dilated.
Ulcerations/strictures in one or more areas of small bowel,
sparing the ileocecal area, are also not unknown. These
Fig. 26.38: Barium study classical ileocecal tuberculosis extending to
result in proximal dilatation and delay in clearance of small involve right colon also. Marked dilatation of terminal small bowel is
bowel contrast. Uncommonly, tuberculous process may seen
362
Section 5 Diagnosis
ileocecal tuberculosis on CT. Ultrasonography may also iii. Omental masses (‘caking’).
demonstrate bowel wall thickening as a hypo-echoic halo. iv. ‘Stellate’ mesentery.
v. ‘Sliced bread’ appearance on sonography.
Abdominal Adenopathy vi. Low density masses surrounded by thick solid rims.
In addition, abdominal adenopathy is com-monly
It is a very common presentation of abdominal seen either as low density masses or with a multilocular
tuberculosis either alone or along with other pathological appearance.
abnormalities. Although it is a nonspecific finding, the
clues indicating tuberculous etiology are:
Visceral Tuberculosis
i. Tendency for involvement of mesenteric and
peripancreatic lymph nodes Liver, spleen and rarely pancreas may be involved with
ii. On a contrast enhanced CT, demonstration of low disseminated disease. There is usually only
density centers with enhancing peripheral rim hepatomegaly or splenomegaly but uncommonly focal
(which may even give it a multilocular appearance). masses may also be visible. Following healing, multiple
calcific foci may be seen in the liver and splenic
Peritoneal Tuberculosis (Fig. 26.39) parenchyma indicative of residual sequelae.
It is an uncommon presentation of abdominal
OSTEOARTICULAR TUBERCULOSIS52-56
tuberculosis. Etiopathological mechanism is believed to
be rupture of mesenteric lymph nodes seeded from a Overall incidence of tuberculosis of bones and joints is
primary pulmonary lesion via. hematogenous route. approximately 4% among patients with all types of
Clinically there is pain, distension and fever. Although tuberculosis. Osteoarticular tuber-culosis is always
three forms of peritoneal tuberculosis have been described: secondary to primary focus elsewhere, usually in the chest.
‘wet-ascitic’ type, ‘dry-plastic’ type and ‘fibrotic-fixed’ Mode of spread is usually by hematogenous
type, but there may be considerable overlap in the imaging dissemination.
features. The spectrum of findings in peritoneal
tuberculosis as a whole are as follows: Tuberculous Osteitis/Osteomyelitis
i. Ascitic fluid of high density (25-45 HU on CT) which
reflects the exudative nature, with multiple fine Involvement of Long Bones of Extremities
delicate septations and incomplete mobile fibrin
Typically metaphyses are the common sites of affection
strands seen on sonography only.
usually around the hip, knee and ankle joints. On X-ray:
ii. A disorganized appearance of soft tissue densities,
(i) focal destructive lesion with poorly defined edges and
loculated ascitic fluid and matted bowel loops
regional osteoporosis is usually present (Fig. 26.40), (ii)
forming a poorly defined mass.
Fig. 26.39: Barium meal and follow through study: Peritoneal Fig. 26.40: X-ray, lower limb: Large oval destructive lesion in tibial
tuberculosis: Bowel loops show ‘tacking’ indicative of adhesions diaphysis with varying degress of sclerosis around it
363
infection may spread to rest of the bone and/or to the

neigh-boring joint. Transphyseal spread of infection is
an important feature of tuberculosis differen-tiating it
from pyogenic osteomyelitis, (iii) at times, predominant
proliferative reaction produces dense sclerotic lesion.
Tuberculosis of Short Bones of Hands and Feet

(Tuberculous Dactylitis)
Involvement of these bones is considered a disease of
childhood. It is known by the name of spina ventosa due
to the cystic, ballooned out appearance of the involved
bone (Fig. 26.41). Radiographically: (i) soft tissue
swelling, often large in size and fusiform in shape, is a
common finding; (ii) periostitis indicates the earliest
involvement of bone; this periosteal sheath at a later stage Fig. 26.42: X-ray, chest: Tuberculosis involving multiple ribs. Note
may be very thick enveloping the cystic lesion, (iii) with irregularity, undulation of inferior margin of lower right ribs
destruction of underlying bone a cyst-like cavity appears
with expansion of medullary space, (iv) sequestrum may
be formed. It is important to remember that these bone Usually, these lesions have no evidence of new bone
changes indicate chronic osteomyelitis and may be formation. Ribs may be involved either by hematogenous
produced by many other pathological conditions, e.g. route or by contiguous involvement from a vertebral
fungal osteomyelitis. lesion.
Tuberculosis of Ribs Multifocal Tuberculosis (Cystic Tuberculosis)

Clinically it may present with or without palp-able soft Multiple bone involvement by tuberculous pathology is
tissue swelling due to the cold abscess. On X-ray three more common in adolescents females rather than in
types of lesions are seen: children. In the long bones lesions are usually diaphyseal
i. Expanding, cyst like lesion— entirely within the rib. rather than metaphyseal in location. X-ray appearance
ii. Destruction of lower margin of rib (Fig. 26.42). is similar to the solitary lesions described earlier with a
iii. Complete destruction as seen in metastatic tendency to form “cyst-like” lesions (Figs 26.43A and B),
malignancy. i.e. lesions are radiolucent, well- defined, round or oval
in shape with variable amounts of sclerosis. Lesions may
also be solitary rather than multifocal.
Tuberculous Arthritis
It has an insidious onset. Typically it is a mono-articular
disease with preference for weight bearing joints.
Infection may initially involve either the synovium or
the bone. Radiological findings are nonspecific and at an
early stage include joint effusion with soft tissue edema
with normal appearing bones. Later, significant peri-arti-
cular osteopenia and at a still later stage characteristic
marginal erosions appear. Perio-steal reaction and
sclerosis are not the usual features of tuberculous
arthritis. Later the joint space decreases. The triad of juxta-
articular osteoporosis, marginal bony erosions and
gradual narrowing of joint space is termed Phemister’s
triad and is characteristic of tuberculous arthritis.
Synovial involvement in young patients leads to
chronic hyperemia, hypertrophy of epiphyseal centers
and an early epiphyseal fusion with resultant leg-length
Fig. 26.41: X-ray, hand: ‘Spina-ventosa’: first and fifth metacarpals are discrepancy. This is similar to that seen in hemophilics
involve in disease process, with expansion, periosteal reaction in the
latter
or juvenile rheumatoid arthritis.
364
Section 5 Diagnosis
Fig. 26.44: Tuberculosis of hip joint ankylosis of hip joint with suggestion
of intrapelvic abscess as reflected by bladder displacement
Tuberculosis of Sacroiliac (SI) Joint

It has a characteristic appearance: (i) in the early stage—
haziness and loss of definition of joint margins occur; (ii)
later, the articular surface is eroded (iii) following healing,
sclerosis with decreased joint space occurs; but (iv) if the
disease progresses then destruction and later ankylosis
result.
Tuberculosis of the Spine: Tuberculous Spondylitis

(Pott’s Disease)
It may manifest during early stages of primary
pulmonary infection or years later after the primary
infection has subsided. Either a single (uncommon) or
multiple vertebrae may be affected and in the latter
instance involvement may be contiguous or at multiple
levels. It is more common in the thoracic and lumbar
Figs 26.43A and B: Multifocal tuberculosis (A) X-ray forearm bones spine. Bone lesions may either be destructive or
show extensive lytic lesions involving both forearm bones. (B) X-ray proliferative (sclerotic). Primarily tuberculosis commonly
anteroposterior view of pelvis shows lytic lesion in left iliac bone
involves the body of a vertebra and rarely its appendages.
The X-ray appearances are:
i. Destructive changes usually appear first in the upper
Tuberculosis of Hip Joint and lower margins of the vertebral bodies
(commonly in the anterior part of the body). Usually
It is the most common lesion after spinal involvement
the destructive focus is associated with sclerosis at
and shows the following features:
the periphery. Tuberculous focus completely
i. Earliest change is atrophy of muscular tissue and
localized within the vertebral body may be difficult
bones about the joint seen as decreased soft tissue
to differentiate from lesions of pyogenic or fungal
mass and rarefaction of bones.
infections.
ii. Joint space usually decreases but it may increase if
ii. Next, the intervertebral space is narrowed or
effusion develops. In the later instance fat planes
obliterated due to the contiguous spread of infection.
about the joint are displaced laterally.
iii. Compression-collapse of vertebra ensues with
iii. Bony contours become hazy and indistinct.
formation of gibbus (Fig. 26.45) and paraspinal
iv. In the late stage (Fig. 26.44) joint destruction, bony
abscess (Fig. 26.46). The combi-nation of vertebral
ankylosis and interference with growth occurs.
body destruction, decreased disc space and
365
Role of CT and MRI in Tuberculous Spondylitis

Both CT and MRI are highly sensitive, providing much more
information than plain radiographs, information, which is
not only important for clinical management but also for
follow-up of the patient. CT is comparatively ‘cheaper’,
faster especially with helical CT and is the preferred
modality for assessment of osteomyelitis, sequestrum and
for interventional procedures. MRI has higher contrast
resolution, multiplanar imaging capability, ability to detect
marrow infiltration and ready assessment of extradural
disease but it lacks the excellent bony details possible with
CT.
CT of Vertebral Tuberculosis
Bone destruction with fragmentation is the most common
type of lesion. Bone fragments may extend into the
paravertebral soft tissue mass or into the spinal canal.
Fig. 26.45: X-ray, vertebrae: Tuberculosis of the vertebra collapse of Associated soft tissue masses (Figs 26.47A and B) may
vertebral body, decreased disc space and gibbus formation extend much beyond the site of destruction, they may
calcify and after intravenous contrast may show
enhancement either diffuse or typical of an abscess, i.e.
rim enhancement. Disc narrowing and multilevel
involvement are also readily visualized on CT. After
successful treatment the vertebral bone density increases
and the size of paravertebral soft tissue masses decreases.
Fig. 26.46: X-ray, vertebrae: Spinal tuberculosis: bilateral paraspinal

abscess in an anteroposterior spine X-ray
formation of paravertebral abscess is highly

suggestive of tuberculosis in Indian settings though
some other conditions can also produce similar
picture.
iv. Paraspinal abscesses may later calcify.
v. Paraspinal abscess may run along the anterior
surfaces of vertebrae and may cause erosion of
multiple contiguous vertebrae.
vi. Rarely, osteoblastic changes may predomi-nate.
Figs 26.47A and B: Para- and prevertebral abscess (A) Plain X-ray
vii. In late stage—fused vertebrae, kyphosis and and barium swallow (B) CT: shows large abscess as well as underlying
osteoporosis occur. bony changes
366
Section 5 Diagnosis
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27 Pathologic Spectrum
Sandeep R Mathur, Kusum Verma
PATHOLOGIC SPECTRUM OF Granuloma

It is a compact (organized) collection of mature
Tuberculosis has continued to be a major cause of mononuclear phagocytes (macrophages and/or
morbidity and mortality in children all over the world, epithelioid cells) which may or may not be accompanied
especially in the developing countries.1 In recent years, by accessory features such as necrosis or the infiltration
worldwide resurgence of pediatric tuberculosis is being of other inflammatory leukocytes.2 Granulomas can be
witnessed due to many factors like HIV epidemic, necrotizing, nonnecrotizing or a combination of both.
emergence of drug resistance and inadequate public Necrotizing granulomas: Granulomas of this type most
health infrastructure in developing countries. However, commonly occur in tuberculosis, but may also be seen in
the disease is often underdiagnosed, misdiag-nosed or fungal infections, Wegener’s granulomatosis, rheumatoid
even overtreated because of presence of nonspecific arthritis, and even sometimes in sarcoidosis.
clinical manifestations and diagnostic problems. Delay Nonnecrotizing granulomas: These are typically seen in
in diagnosis of tuberculosis leads to prolonged morbidity noninfectious conditions like sarcoidosis, berylliosis,
and mortality. foreign body reactions, drug reactions, hypersensitivity
Tuberculosis can involve any organ in the body pneumonitis, tuberculoid leprosy and Crohn’s disease.
although lung, lymph nodes and meninges are the Presence of nonnecrotizing granulomas does not rule out
common sites of involvement in children. Disease may tuberculosis.
be a manifestation of primary infection or reinfection. Immune granulomas: These occur as a result of immune
Hallmark of tuberculosis is a granulomatous inflammation. T-cell mediated reactions. Immune granulomas, the
However, granulomas can be seen in a number of prototype of which is tuberculosis, generally show a
nontuberculous conditions and it is thus important to prominent lymphocytic component.
have a clear understanding of the term “granuloma” and Nonimmune granulomas: They occur as a response to a
their different types. persistent, nondegradable organism or product. These
Fig. 27.1: A typical epithelioid cell granuloma seen in histologic section Fig. 27.2: Epithelioid cells with elongated slipper shaped, vesicular
comprising of epithelioid cells, lymphocytes, Langhans giant cell and nuclei seen in a FNAC smear (For color version see Plate 7)
necrosis (For color version see Plate 7)
369
Chapter 27 Pathologic Spectrum
Tuberculous lesions can also be broadly classified

as exudative and proliferative lesions. Exudative
lesions (soft granulomas), comprise of polymorphs,
lymphocytes, macrophages and epithelioid cells
arranged loosely, with an insignificant fibroblastic
response. Acid fast bacilli (AFB) are easier to find in
such lesions. Proliferative lesions (hard granulomas) have
a more organized collection of epithelioid histiocytes,
with lymphocytic rimming, fibrosis, and more
Langhans giant cells. AFBs are more difficult to
demonstrate in these lesions. Ultimately the entire
granuloma or necrotic focus undergoes fibrosis,
calcification or even necrosis.
It is not always possible to pinpoint the exact etiology
of a granulomatous lesion on histology. An accurate or
definitive diagnosis of tuberculosis would perhaps only
Fig. 27.3: Confluent granulomas in histologic sections showing
large areas of necrosis (For color version see Plate 7) be possible in the event of demonstration of acid-fast
bacilli using special stain. In endemic areas presences of
usually lack the lymphocytic response and show necrotizing epithelioid cell granulomas with or without
prominent numbers of foreign body type of giant cells. giant cells, even in the absence of acid fast bacilli are
Epithelioid cell granulomas: These are organized highly suggestive of tuberculosis. A histological
collection of epithelioid macrophages surrounded by a diagnosis of tuberculosis is often made in the presence
collar of mononuclear cells, mainly lymphocytes and of this morphological scenario, if the clinical picture is
rarely plasma cells (Fig. 27.1). Epithelioid cells are not contradictory. In all other situations a definitive
modified macrophages with elongated slipper shaped, diagnosis of tuberculosis would perhaps not be possible,
vesicular nuclei and abundant pale eosinophilic although it is well known that the commonest cause of
cytoplasm with ill-defined margins (Fig. 27.2). Epithelioid granulomatous inflammation in our country is still
cells may fuse to form giant cells. tuberculosis and other causes of granulomatous
inflammation like sarcoidosis, etc. are rare in the pediatric
Granulomas in Tuberculosis age group.
Epithelioid cell granulomas are classically seen in
tuberculosis. Two types of giant cells are encountered in Pathologic Diagnosis
tuberculosis, the Langhans giant cells (Fig. 27.1) where Various samples helpful in rendering histopathologic/
nuclei are arranged in a horse-shoe pattern at the cytologic diagnosis of pulmonary or extrapulmonary
periphery of the cytoplasm and the foreign-body type of tuberculosis in pediatric age group are as given in the
giant cell where nuclei do not show any specific pattern Table 27.1.
of arrangement. In histological sections the granulomas
may appear discrete or they may appear to coalesce
Cytological Criteria for Diagnosis of Tuberculosis
forming “confluent granulomas”. Presence of necrosis
is commonly seen in the center of these granulomas when Histologic diagnosis of tuberculosis is based on
it is called as “necrotizing granulomatous inflam-mation” granuloma as detailed earlier. A cytologic diagnosis of
(Fig. 27.3). tuberculosis can be rendered on FNAC from various
The term “caseous”, meaning cheese-like has often body sites or a number of cytologic specimens like
been loosely applied to the structure-less necrosis seen bronchoalveolar lavage, pleural fluid, pericardial fluid,
in tuberculosis, although this is strictly a terminology for cerebrospinal fluid, etc. A definitive diagnosis on FNAC
the naked eye/gross appearance of necrosis encountered specimens is by identification of epithelioid cell
in tuberculosis. The caseous necrosis results from the granulomas, necrosis and AFB. However, a spectrum of
exuberant killing of infected macrophages presenting morphological changes are seen in FNAC smears of
mycobacterial antigen by Mycobacterium tuberculosis tuberculous lesions. These may be classified into five
specific cytotoxic T lymphocytes along with the damage groups according to the combination of each of the
to surrounding tissues by the hydrolytic proteases and morphologic features4 (Figs 27.4 to 27.8).
lipases released by activated macrophages and other Group I—epithelioid granulomas with necrosis with or
dying host cells. 3 Presence of confluent necrotizing without giant cells.
epithelioid cell granulomas is the hallmark of tuberculosis. Group II—epithelioid cell granulomas only.
370
Section 5 Diagnosis
Table 27.1: Samples helpful for histopathologic or cytologic diagnosis of pulmonary

or extrapulmonary tuberculosis in pediatric age group
Site of lesion Histopathologic assessment Microbiologic assessment Cytopathologic
(culture) assessment
Pulmonary • Transbronchial lung biopsy • Sputum (induced) • Bronchoalveolar lavage
• Transthoracic lung biopsy • Gastric lavage • Transbronchial FNAC«
• Transbronchial aspirate
• Bronchoalveolar lavage • Transthoracic FNAC
Lymph node • Biopsy • Biopsy • FNAC
• FNAC
CNS • Biopsy • Biopsy • CSF
• CSF • Guided FNAC
• Squash cytology
Pleura/pericardium/ • Biopsy • Biopsy • Effusion cytology
peritoneum • Effusion fluid
GIT • Endoscopic biopsy • Biopsy • FNAC (in case of a mass)
Liver • Biopsy • Biopsy • FNAC

• FNAC
Genitourinary • Biopsy • Biopsy • FNAC
• FNAC • Urine cytology
Bone and joint • Biopsy • Biopsy • FNAC
• FNAC
Cold-abscess - • FNAC • FNAC
• FNAC: fine needle aspiration cytology
Group III—granular necrotic material only.

Group IV—acute inflammatory exudate with focal
granulomas.
Group V—acute inflammatory exudate only.
A morphological diagnosis of tuberculosis can only
be confidently rendered in group I smears, i.e. cases
showing epithelioid cell granulomas with necrosis. These
account for approximately 60 to 70% of cases. In all other
combination of morphological patterns, a definitive
diagnosis of tuberculosis can only be made in the event of
demonstration of AFB in the smears using special stains.
Fig. 27.5A: Smear showing epithelioid cell granulomas only (group

II) as seen on Papanicolaou stain (For color version see Plate 7)
Fig. 27.4: FNAC smear depicting classical picture of epithelioid cell Fig. 27.5B: Epithelioid cell granulomas as seen in May-Grunwald
granuloma with necrosis (group I) (For color version see Plate 7) Giemsa stained preparation (For color version see Plate 7)
371
Fig. 27.6: FNAC smears may at times yield only necrotic material Fig. 27.7: Smear showing an acute inflammatory exudate
(group III) (For color version see Plate 8) with granuloma (group IV) (For color version see Plate 8)
Table 27.2: Cytomorphological spectrum and AFB

positivity in FNAC smears of tuberculous lesions
Cytologic Authors Positivity
% Spectrum (ZN stain)
• Group I
Necrosis and Bezabih et al5 61.9
granulomas Kumar et al6 14.3
Das et al7 31.9
Prasoon8 19.1
• Group II
Epithelioid cell Bezabih et al5 20.0
granulomas Prasoon8 01.9
• Group III
Necrosis only Bezabih et al5 69.7
Kumar et al6 26.2
Das et al7 36.6
Radhika et al9 17.8
Fig. 27.8: Aspirates in tuberculosis may at times yield an acute
inflammatory exudate only (group V) (For color version see Plate 8) • Group IV
Acute inflam- Kumar et al6 47.5
matory exudate
with focal
Table 27.2 summarizes the cytomorphological spectrums granulomas
and the AFB positivity in smears from tuberculous • Group V
lesions.5-10 Acute inflam- Kumar et al6 35.8
Smears may at times reveal only an acute inflammatory matory exudate
exudate and be misinterpreted as a pyogenic abscess if only
special stains for AFB are not performed. This is especially • All Cases Bezabih et al5 59.4
Handa U10 37.4
relevant in AIDS and other immunosuppressed
Radhika et al9 23.6
conditions. A meticulous search for acid fast bacilli is very Kumar et al6 33.5
important in all such smears.
Cytomorphologic diagnosis is difficult in exfoliative
cytology specimens like sputum, bronchoalveolar lavage, Demonstration of Acid Fast Bacilli
urine, etc. Epithelioid cell collections forming ill-defined As per the new guidelines in the Consensus Statement
granulomas are rarely encountered. Tubercular pleural on Childhood Tuberculosis published by the Working
and peritoneal effusions are exudative in nature and Group on Tuberculosis, Indian Academy of Pediatrics,
show large numbers of lymphocytes with paucity of every attempt must be made to demonstrate acid fast
mesothelial cells. This appearance is, however, not bacilli before arriving at a diagnosis of tuberculosis.11
diagnostic as maybe seen in viral infections also. Some studies have reported as high as 33% bacteriological
372
Section 5 Diagnosis
Fig. 27.9A: Smear from neck swelling in an immunocompromised Fig. 27.9B: AFB stained smear of the same patient showing
patient showing numerous foamy macrophages in a necrotic background macrophages packed with tubercle bacilli (For color version see
(For color version see Plate 8) Plate 8)
positivity even in primary disease such as hilar Mycobacterial Culture of Biopsy on FNA Material
adenopathy.12, 13
Material for culture studies can be conveniently collected
Acid-fastness is regarded as the hallmark of
at the same setting as the FNAC procedure and is very
mycobacteria. It is due to the ability to form stable
useful in situation of multidrug resistant tuberculosis
mycolate complexes with certain aryl methane dyes like
(MDR-TB) to determine drug sensitivity. Because of
carbol-fuchsin, crystal violet, auramine-rhodamine,
the delay (4 to 6 weeks) in growing mycobacteria,
which are not removed even by rinsing with 95% ethanol
culture studies are generally restricted to situations of
plus hydrochloric acid. The bacilli appear red with carbol- drug resistant forms of tuberculosis. Nataraj
fuchsin (ZN stain), purple with crystal violet and exhibit et al16 isolated mycobacteria on culture of FNA material
yellow-green fluorescence under ultraviolet light (AR in 82.6% of cases where tuberculosis was also diagnosed
stain). ZN stain and AR stains can be used to demonstrate cytomorphologically. In addition they picked up
AFB in both FNAC smears as well as tissue sections. But mycobacteria in 28 cases on culture which were
the detection rate of AFB positivity in tissue sections is undetected on cytological screening. Radhika et al9
much lower than that observed in smears possibly as a reported an overall rate of isolation of mycobacteria on
result of the damage to mycobacterial cell wall during culture from FNA material as 35%, while their overall
the rigorous processing of tissue. Fluorescent microscopy AFB positivity in smears was 23.58%. Atypical myco-
with auramine-rhodamine stain is superior to ZN stain bacteria can also be readily identified on culture. The
when the bacterial load is low as the AFB are readily BACTEK system utilizes radiolabelled compounds in
seen as yellowish-green beaded rod-like structures liquid media and radiometrically detects release of CO2
against a dark background. The overall AFB positivity is by the growing AFB. This may reduce the average
lower using ZN stain alone and higher positivity rates reporting time to 1 to 2 weeks as opposed to 6 to 8 weeks
are reported using a combination of ZN and AR stains. with conventional culture.
AFB positivity is also higher in group IV and V (Table
27.2) where a diagnosis of tuberculosis on morphology Polymerase Chain Reaction in Diagnosis of Tuberculosis
alone would be impossible. Three consecutive specimens
Molecular diagnostic methods like polymerase chain
of gastric aspirate obtained in the early morning by a
reaction (PCR), uses amplification of the DNA sequences
nasogastric tube are useful to detect AFB in children.14,15
of mycobacteria to detect tuberculosis. This is especially
In the context of atypical mycobacterial infection in
useful in problem situations where the bacillary load is
immunocompromised host a peculiar pattern may be
low or it is difficult to detect evidence of tuberculosis on
seen. The smear or section shows numerous foamy
morphology or special stains.
macrophages with pale blue cytoplasm in a necrotic back-
Gong et al17 performed nested PCR for diagnosis of
ground (Fig. 27.9A). ZN staining will demonstrate
tuberculosis in material obtained by FNAC of tuberculous
numerous AFB inside these macrophages (Fig. 23.9B).
lymphadenitis and compared it with conventional ZN
Conversely when such a picture is encountered in
staining. They reported 77.8% detection rate with PCR as
sections or smears, the clinician must be cautioned to compared to 39.7% by ZN staining and concluded that
investigate the patient for an immunocompromised state PCR is more sensitive for detection of Mycobacterium
and also perform culture studies. tuberculosis in FNAC than ZN stain. Baeck et al18 reported
373
a detection rate of 76.4% using PCR on material obtained addition to causing compression and atelactasis, an
by FNAC of cervical tubercular lymphadenitis. In a pilot inflamed caseous lymph node erodes through a bronchus
study by Singh et al19 the sensitivity of PCR on tissues and transmits infection to the lung parenchyma.
from biopsies (68%) was not significantly higher when Commonest site is the anterior segment of the upper lobe
compared to that on material obtained by FNAC (55%). or the medial segment of the middle lobe.22
Shankar et al20 used PCR in the rapid diagnosis of TB
meningitis and found it to be far more sensitive than ELISA Progressive Pulmonary Tuberculosis
and conventional culture.
The primary focus at times may enlarge with the
One of the important drawbacks of PCR is the false
development of a large caseous center. Although rare, it is
positivity due to contaminants from the environment.
a serious complication resulting in development of a thin
PCR may serve as a useful adjunct but not a replacement
walled cavity with a large caseous center and numerous
for the conventional methods for a reliable diagnosis of
tubercle bacilli. This cyst may rupture into adjacent
tuberculosis.
bronchus or pleural cavity leading to intrapulmonary
dissemination or pyopneumothorax. Significant signs and
SPECTRUM OF MORPHOLOGIC CHANGES
symptoms usually accompany this lesion.
Pulmonary Tuberculosis
Chronic Pulmonary Disease
Primary Pulmonary Tuberculosis
It is similar to the adult or reactivation type of
Lung is the portal of entry of tubercular bacilli in 95% of tuberculosis. This presumably is thought to be due to
cases in children. An incubation period of around 4 to 8 the endogenous reactivation of previous site of
weeks is required between the time the bacilli enter the tuberculous infection. This form of tuberculosis is
body and the development of cutaneous hypersensitivity. extremely uncommon in children. It is more common in
Around this time there maybe a febrile reaction and the children who acquire the initial infection after 7 years of
primary complex may become visible on chest X-ray. age.23 Common sites are the original parenchymal focus,
Primary complex, also termed as Ghon’s complex is the regional lymph nodes or the apical seeding (Simon’s
constituted by a parenchymal, often subpleural focus of focus). This form usually remains localized to the lungs.
consolidation (Ghon’s focus), the draining lymphatics,
and the enlarged draining in hilar lymph nodes. The hilar Lymphohematogenous Dissemination
lymph nodes are generally much larger than the or Early Generalization
parenchymal lesion and are seen in vast majority of
children with primary tuberculosis.21 The parenchymal It appears that in all cases there is early lympho-
portion of the primary complex undergoes caseous hematogenous dissemination from the caseous center of
the primary complex.24,25 This hematogenous dissemin-
necrosis and encapsulation and most often heals by
ation may or may not be symptomatic depending upon
fibrosis and calcification. In the event of intensive
the quantity of the organisms. Many organs may thus be
caseation, the center of the lesion may liquify and empty
seeded during this process, and may be the source of
into associated bronchus leaving a residual cavity or there
reactivation tuberculosis.26
may be spread of bacilli from the primary focus via the
blood stream and lymphatics to other foci. The liver,
spleen, lung apices, meninges, lymph nodes, peritoneum Miliary Tuberculosis
and bones are the common sites of dissemination. These This form of tuberculosis arises when very large number
metastatic foci maybe clinically asymptomatic or maybe of bacilli are released into the blood stream, resulting in
the origin of both extrapulmonary tuberculosis and simultaneous disease in multiple organs. It is more
reactivation tuberculosis later in some children. common in infants and younger children.26,27 This may
Tubercular bacilli may remain viable for decades in occur as a result of erosion of the wall of blood vessel
the hilar lymph nodes even after development of fibrosis by a caseous focus. Malnutrition, malignancy or
and calcification in the nodes. At times the hilar and immunosuppressed status may predispose to this
paratracheal lymph nodes may enlarge and cause external condition.
compression of the regional bronchus, leading to either Hepatosplenomegaly and generalized lymphaden-
hyperinflation (partial obstruction) or atelactasis opathy occur in 20 to 30% of cases. Although chest X-ray
(complete obstruction) of the lung segment. Epituberculosis may be normal initially, they show numerous tubercles
or collapseconsolidation or segmental tuberculosis is the over a course of 3 to 4 weeks in majority of cases. Miliary
radiologic term used to describe the combination of tubercles maybe seen in organs like kidney, intestine,
pneumonia and atelactasis which results when in fallopian tubes, epididymis, prostate, adrenals, bone,
374
Section 5 Diagnosis
meninges, brain, lymph nodes, etc. Cutaneous BCG Adenitis

papulonecrotic tuberculids may appear in crops. Culture
In children receiving BCG vaccination the usual reaction
confirmation is more difficult and a liver or bonemarrow
is that of induration followed by ulceration and regional
biopsy maybe needed for diagnosis.28
lymphadenopathy, with healing of all these lesions in
Classical findings include, multiple, 1 to 2 mm sized,
due course of time. At times lymphadenopathy may
discrete nodules, grayish on cut surface. Some of the
persist and needs to be distinguished from tuberculosis.
older lesions may have a caseous appearance on cut
Gupta et al 32 found that granulomas in a reactive
surface. Microscopically they resemble the classical
background are rare in BCG adenitis as compared to
granulomatous lesion of tuberculosis, with or without
tuberculosis. AFB positivity (76.8%) was found to be more
caseous necrosis.
common in BCG adenitis, when compared to tuberculous
lymphadenitis. In a recent study the incidence of BCG
Extrapulmonary Tuberculosis
adenitis was found to be 0.1% in children vaccinated.33
This is a consequence of the reactivation of the foci that
were seeded during lymphohematogenous dissemination Pleural Tuberculosis
of the tubercle bacilli. Tuberculous lymphadenitis is the
This is categorized as an extrapulmonary form of
most common form of extrapulmonary tuberculosis in
tuberculosis. Pleural effusion is very uncommon in
children followed by tuberculous meningitis. Skeletal,
children less than 6 years of age and is encountered in 2 to
abdominal and genitourinary tract tuberculosis are very
38% of children with pulmonary disease. It may be the
uncommon in children and adolescent.29
only radiologic manifestation of primary pulmonary
tuberculosis in 38 to 63% of cases.21 Few reports have
Lymph Node Tuberculosis (Scrofula)
emphasized upon the utility of pleural fluid adenosine
This is the commonest form of extrapulmonary tuberculosis. deaminase (ADA) levels in the diagnosis of tuber-
It is estimated that up to 22% of children with persistent culosis.34,35 In one study the sensitivity of this test for
cervical lymphadenopathy and no obvious local factor may values >40 U/L approached 90%.36 Utility of pleural fluid
have tuberculous adenitis.30 They commonly present as interferon γ levels for diagnosis of tuberculosis has also
painless lymphadenopathy, most often in the cervical region been demonstrated in some studies. 37 Tubercular
although other lymph node groups may also be affected. effusions classically show a marked preponderance of
Tonsillar and submandibular group of lymph nodes are lymphocytes on cytological examination. Acid fast stains
the commonest superficial lymph nodes affected, usually fail to demonstrate the bacilli and culture
possibly as a result of spread from the tonsils. However, positivity rates are also low. Hence the diagnosis of tuber-
it is now believed that it may also be due to extension culous pleural effusion maybe difficult to make.
from paratracheal lymph nodes. The hilar and
paratracheal group of lymph nodes are always involved Pericardial Tuberculosis
in primary pulmonary tuberculosis or in cases of
This is reported to occur in 0.4 to 4% of tuberculosis cases
reactivation of previous infection. In adolescent and
in children.38 The pericarditis is initially serofibrinous or
young adults the onset of lymphadenopathy may herald
hemorrhagic and with continued fibrosis it leads to
the reactivation of tuberculous infection. The lymph
constrictive pericarditis. The pericardial fluid shows a
nodes may be multiple, discrete to begin with and later
preponderance of lymphocytes. Culture studies or biopsy
become matted together as a result of periadenitis. The
are more useful as the AFB stains on pericardial effusions
consistency may vary from firm to soft or cystic
generally fail to demons-trate tubercle bacilli.39
depending upon the presence of necrosis and abscess
formation. The lymph nodes forming an abscess can
Liver and Spleen
perforate the deep fascia and present as a fluctuant
subcutaneous swelling (collar-stud abscess). Lymph node They are often involved during the initial lymphohem-
abscess may burst giving rise to discharging sinus and atogenous spread but this involvement is generally
ulcer formation. Jones and Campbell have described 5 asymptomatic. The reported incidence of hepatic
stages of lymph node tuberculosis.31 granulomas in Indian studies has ranged from 1.6 to
Stage 1—enlarged, firm, mobile, discreet nodes 10.4%.40 Approximately 12% of patients showed presence
Stage 2—large, rubbery nodes, fixed to surrounding of hepatic granulomas in a study of pediatric tuberculosis.41
tissues due to periadenitis Nonspecific changes like Kupffer cell hyperplasia, fatty
Stage 3—central softening due to abscess formation infiltration and focal cell necrosis have also been reported
Stage 4—collar-stud abscess formation in patients with tuberculosis. Bharathi et al reported a
Stage 5—sinus tract formation. case of hepatic tuberculoma in an eight-year-old girl
375
which simulated a liver tumor clinically and as well as Chronic tubercular epididymoorchitis is most
on imaging.42 commonly tubercular in etiology. The infection is either
as a result of retrograde spread from an infected seminal
Skeletal Tuberculosis vesicle along the vas deferens, or may be blood borne.
The disease begins as a tender nodule and as the disease
Clinically significant bone and joint lesions of progresses more nodules appear. The entire epididymis
tuberculosis usually appear after 1 year of primary becomes beaded in nature due to presence of submucosal
infection.43 The bones most commonly affected are the tubercles. Rarely the epididymo-orchitis may present as
thoracic and lumbar vertebrae and the weight bearing a cold abscess in the lower and posterior aspect of the
joints like hip and knee along with small bones of hand scrotum or as a discharging sinus. A FNAC can be very
and feet. Necrosis of the vertebral bodies, which are useful to obtain material for diagnosis. The kidneys must
affected most often, leads to spread through the be investigated for involvement by tuberculosis in cases
intervertebral discs to involve adjacent vertebrae and of tubercular epididymo-orchitis.
even soft tissues causing paravertebral and parapharyn-
geal abscesses. The upper extremities and bones like the Central Nervous System Tuberculosis
skull and clavicle are rarely involved.44 Children may be
more prone to skeletal tuberculosis because of the rich The tubercle bacilli can infect the central nervous system
vascularity of the growing bones.45 The infection reaches in many ways manifesting as tubercular meningitis,48,49
the site commonly by blood from a focus of active visceral serous meningitis,50 tubercular brain abscess, tuberculoma
disease. The lesion usually starts as an endarteritis in the or spinal leptomeningitis.51 The caseous foci located at
metaphysial region of long bones. 45 It may also be the superficial cortex or meninges (Rich focus),
affected by direct extension via lymphatics from a discharge tubercle bacilli into the subarachnoid space.52
pretracheal or paravertebral lymph node. Destruction of A thick gelatinous exudate forms around the pia-
bones may even lead to spread to adjacent joint spaces. arachnoid. The exudate has a predilection for the base
of the brain, hence the III, VI, VII cranial nerves and the
Necrosis of bone gives rise to the sequestrum. The new
optic chiasma are commonly involved. Vasculitis
bone formation resulting from extension of lesion
affecting the vessels entrapped in this exudate leads to
through cortex with elevation of periosteum gives rise
periarteritis and endarteritis, causing vascular
to the involucrum.
thrombosis and infarction of the region supplied by
these vessels. Branches of the middle cerebral artery,
Genitourinary Tuberculosis
especially the perforating vessels to the basal ganglia
The kidneys are usually infected due to hematogenous are commonly affected.
spread from a pulmonary focus of infection. Although
the renal tubercular granulomas are localized initially in Tubercular Meningitis
the cortex, the preferred site of involvement is the renal
It is more common in children less than 4 years of age,
medulla. Damage to vessels may lead to papillary
occurring usually within 3 to 6 months of initial infection.
necrosis. Tuberculous pyonephrosis may ensue as a result
The cerebrospinal fluid (CSF) shows pleocytosis with
of spread to the renal pelvis. Spread of infection outside
preponderance of polymorphs in the early stage and later
the renal capsule may give rise to a mass lesion dominated by lymphocytes. The protein level is markedly
mimicking a neoplasm. Long standing pulmonary elevated, while the glucose is in the range of 20 to 40
tuberculosis can give rise to renal amyloidosis. 46 mg/dl.
Interstitial fibrosis, membranous glomerulonephritis, On gross examination a fibrinous or gelati-nous
focal lymphoid aggregates and cloudy swelling of the exudate is seen, more often at the base of the brain and
renal tubular epithelial cells are some of the microscopic encasing the cranial nerves. Discrete gray-white granules
changes described in kidneys of patients with pulmonary may also be seen scattered over the leptomeninges. There
tuberculosis.47 Infection may spread down into the is also evidence of border-zone encephalitis due to
bladder giving rise to mucosal and mural granulomatous impingement of meningeal exudate on the brain
lesions and scarring leading to a small capacity bladder parenchyma. Microscopically there is an admixture of
(thimble bladder). Ureteric strictures and segmental lymphocytes, plasma cells and macrophages, with
dilatation may be seen as a result of ureteric involvement presence of epithelioid cell granulomas, caseous necrosis
leading to obstruction or reflux. and giant cells in florid cases. A fibrous adhesive
Associated renal tuberculosis is detected in most cases arachnoiditis may be seen in long standing cases. The
of seminal vesicle and prostatic tuberculosis, although brain underlying the exudate usually shows edema,
involvement of these organs is uncommon in the perivascular inflammatory infiltrate and micro-glial
pediatric population. reaction.
376
Section 5 Diagnosis
Hydrocephalus may occur because of blockage of the the intestinal mucosa via ingested sputum. The bacilli
CSF flow by the thick inflammatory exudate, along with are carried by macrophages to the submucosa where they
interference to the absorption by the pachinion bodies. evoke granulomatous inflammation followed by caseous
Ventriculitis may be seen due to involvement of the necrosis and spread of inflammatory process. Endarteritis
ependy-mal lining and choroid plexus. of the vessels supplying mucosa in the affected intestinal
segment leads to ischemia and ulceration of the mucosa.58
Tuberculomas The mesenteric lymph nodes may become enlarged
because of spread of inflammation along the lymphatics.
These are well circumscribed intraparenchymal lesions, The mesenteric lymph nodes may also undergo caseous
which may measure a few centimeters in diameter. They necrosis and become matted.
may clinically mimic a brain tumor.53,54 Tuberculomas Grossly intestinal tuberculosis can appear as
are more often infratentorial in children as compared to ulcerative, hypertrophic or ulcerohypertrophic. In the
adults. Long standing lesions may appear calcified. ulcerative form, the intestinal mucosa reveals superficial,
Microscopically they show the typical tuberculous transversely oriented, and circumferential ulcers with
granulomatous inflammation. undermined edges. The underlying intestinal wall is
indurated. Small tubercles maybe present on the serosal
Tubercular Brain Abscess aspect. The ulcerohypertrophic type has a combination
It is generally lacking; the usual granulomas and giant cells of features. There are superficial ulcers as well as marked
leading to misdiagnosis of pyogenic abscess. The pus is, thickening of the bowel wall. The mesenteric lymph
however, rich in acid-fast bacilli. nodes may appear markedly enlarged giving rise to an
appearance termed as tabes mesenterica. Colonic
Peritoneal Tuberculosis tuberculosis may show marked mucosal granularity
similar in appearance to other chronic inflammatory
Tubercular peritonitis can result from primary intestinal bowel diseases. Microscopically these lesions show
focus, enlarged mesenteric nodes, tubercular pyosalpinx, characteristic granulomatous inflammation with or
or due to blood-borne infection from pulmonary without necrosis. Older lesions show transmural
tuberculosis, usually the miliary form.55 The peritonitis involvement by granulomatous process, while in early
may have an ascitic form, where the peritoneum and lesions these are restricted to the mucosa and Peyer’s
omentum are studded with tubercles along with a straw patches. Fibrosis maybe seen in older lesions and
colored peritoneal fluid collection. The peritoneal fluid sometimes only extensive areas of hyalinization are seen
is rich in lymphocytes.56 Acid fast bacilli are very difficult in the intestine whereas the draining lymph nodes show
to demonstrate, although culture may at times be features of granulomatous inflammation.
positive.56 The fibrous or plastic form of peritonitis is
characterized by dense adhesions between coils of Tuberculosis of the Eye and Middle Ear
intestine which become matted and distended. These
patients may present with subacute or acute intestinal The conjunctiva and cornea are the areas involved in this
obstruction. Dinler et al57 found laparoscopy and uncommon form of childhood tuberculosis. Conjunctiva
peritoneal biopsy as the most reliable and safe methods may serve rarely as the site of primary infection with
for the diagnosis of tuberculous peritonitis. According enlargement of the submandibular and cervical lymph
to them, tuberculous peritonitis should be clinically nodes. Phlyctenular conjunctivitis represents a hyper-
suspected in all patients with slowly progressive sensitivity phenomenon to childhood tuberculosis.
abdominal distension, particularly when it is Choroids tubercles have also been described in children
accompanied by fever and pain.57 with miliary tuberculosis.59
The middle ear is an uncommon site of primary focus
Intestinal Tuberculosis and may be seen in area of eustachean tube of neonates,
who have aspirated infected amniotic fluid. The
Primary gastrointestinal tuberculosis is uncommon, preauricular lymph node is usually involved when it
unlike in the past when there was a higher prevalence of is a primary focus.
Mycobacterium bovis infection due to use of unpasteurized
milk. Intestinal infection occurs by direct ingestion of Congenital and Perinatal Tuberculosis
bacilli, hematogenous, lymphatic spread or rarely by
direct extension of disease from neighboring organs. The newborn can be infected via the placenta or the
Commonest sites of involvement are the ileum, ileocecal amniotic fluid.60,61 Transplacental spread occurs via the
region and rarely the colon, duodenum, jejunum, umbilical vein from an infected mother. In such cases
appendix, stomach, esophagus or ano-rectum. In patients the liver is enlarged with enlarged lymph nodes at the
with pulmonary tuberculosis, the tubercle bacilli reach portahepatis with or without evidence of miliary disease.
377
Congenital infection can also occur due to ingestion of 4. Verma K, Kapila K. Aspiration cytology for diagnosis of
infected amniotic fluid, in utero or at the time of delivery. tuberculosis- perspectives in India. Indian J Pediatr
2002;69:S39-43.
It can also occur due to inhalation from infected mother,
5. Bezabih M, Mariam DW, Selassie SG. Fine needle
attendants, etc. widespread involvement of lungs, hilar aspiration cytology of suspected tuberculous
and mediastinal lymph nodes without associated hepatic lymphadenitis. Cytopathology 2002;13:284-90.
lesions indicate aspiration of infected amniotic fluid. 6. Kumar N, Tiwari MC, Verma K. AFB staining in
Demonstration of tubercle bacilli in gastric washings, cytodiagnosis of tuberculosis without classical features:
middle ear fluid, endotracheal aspirate and lymph node, A comparison of Ziehl-Neelsen and Fluorescent methods.
lung or skin biopsy is essential for diagnosis. Congenital Cytopathology 1998; 9:208-14.
7. Das DK, Bambhani S, Pant JN, et al. Superficial and deep
tuberculosis is characterized by a nonreactive response.
seated tuberculous lesions: Fine needle aspiration
Multiple primary foci and miliary spread are commonly cytology diagnosis of 574 cases. Diagn Cytopathol
seen. The regional lymph nodes show marked caseous 1992;8:211-5.
necrosis and many bacilli. Granuloma and giant cell 8. Prasoon D. Acid fast bacilli in fine needle aspiration smears
formation is rare. Neonatal infection is most often from tuberculous lymphnodes. Where to look for them
due to inhalation of tubercle bacilli from an infected Acta Cytol 2000;44:297-300.
mother.62 9. Radhika S, Gupta SK, Chakrabarti A, et al. Role of culture
for mycobacteria in fine needle aspiration in diagnosis
of tuberculous lymphadenitis. Diagn Cytopathol
Tuberculosis in Adolescents
1989;5:260-2.
This may represent an initial infection during adolescent 10. Handa U, Palta A, Mohan H, et al. Fine needle aspiration
age or a reactivation or exacerbation of infection acquired diagnosis of tuberculous lymphadenitis. Trop Doct
during early life.63 In both sexes there is an increased 2002;32:147-9.
11. Amdekar YK. Consensus statement on childhood
risk of acquiring active tuberculosis at the time of
tuberculosis working group on tuberculosis, Indian
adolescent growth spurt. A primary infection acquired
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to a primary infection acquired during early infancy. et al. Value of bronchoalveolar lavage and gastric lavage
Most often they develop classical primary complex which in the diagnosis of pulmonary tuberculosis in children.
is asymptomatic. It may occasionally progress to cavitary Tuber Lung Dis 1995;76:295-9.
disease or chronic pulmonary tuberculosis. 13. Singh M, Moosa NV, Kumar L, et al. Role of gastric lavage
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HIGHLIGHTS Pediatr 2000;37:947-51.
• Concept of granuloma and its types 14. Abadco DL, Steiner P. Gastric lavage is better than
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• Samples for pathologic diagnosis of tuberculosis Infect Dis J 1992;11:735-8.
• Cytologic criteria for diagnosis of tuberculosis 15. Vallejo J, Ong LT, Starke JR. Clinical features, diagnosis
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• Role of culture and PCR 1994;94:1-7.
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28 New Approaches to
TB Diagnosis in Children
Ben J Marais, Daphne Ling, Madhukar Pai
INTRODUCTION Standards for TB care made the same recommendation.3

Most national TB guidelines still regard the TST and chest
Globally, there is increasing awareness that children radiograph (CXR) as prerequisite screening tests to
suffer from severe tuberculosis (TB)-related morbidity exclude active disease in child TB contacts, which serves
and mortality in TB endemic countries. The World Health as a huge barrier to access preventive therapy in resource
Organization (WHO) published its first guidance for limited settings. It has been recognized that symptom-
national TB programs on the management of TB in based screening may have considerable value to improve
children in 2006,1 and the Global Drug Facility (GDF) has access to preventive therapy in settings where even the
made child friendly drug formulations available to most basic tests are not readily available.4 The WHO
deserving poor countries since 2008. However, these guidelines promote symptom-based screening in these
positive developments focus more attention on the settings (Figure 28.1).1 In settings where the TST is used
tenacious problem of establishing an accurate TB for screening purposes it is important to be conscious of
diagnosis in children, particularly in settings with limited
the multiple reasons for a false negative result, including
resources that carry the brunt of the disease burden. This
awareness that TST conversion may be delayed for up to
chapter introduces important disease concepts, discuss
three months after exposure. In fact, the contribution
new approaches to contact screening and TB in children,
and outlines the new diagnostic tools in the pipeline. made by the TST in routine TB contact screening is
Robert Koch (1843-1910) identified Mycobacterium extremely limited, since infection can only be excluded
tuberculosis as the biological agent causing TB in 1882.
However, it was soon recognized that although M.
tuberculosis is a necessary cause for the development of
active TB it is not a sufficient cause, since many perfectly
healthy people are infected with the organism; as
indicated by a positive tuberculin skin test (TST).2 It is
estimated that up to a third of the world’s population is
infected with
M. tuberculosis of whom only a small fraction (less than
10%) will progress to active disease over a lifetime. It
remains an intriguing and largely unexplained
observation that only a small minority of immune
competent people infected with M. tuberculosis ever
progress to active disease. This explains why the
diagnostic challenge is more pronounced in TB endemic
countries where TB infection is exceedingly common;
thereby increasing the need to accurately differentiate TB
infection from active disease, and the need to develop a
test that can identify those at risk for progressing from
latent infection to active TB.
#
Isoniazid 5/mg/kg daily for 6 months
SCREENING CHILD CONTACTS FOR ACTIVE DISEASE $
Unless the child is HIV-infected (in which case isoniazid 5/mg/kg daily for 6
months is indicated)
Current WHO guidelines advise that all children under
Adapted from: WHO Guidance for National Tuberculosis Programmes on the
five years of age in close contact with a sputum smear- Management of Tuberculosis in Children. WHO, Geneva, Switzerland. WHO/
positive index case should be actively traced, screened HTM/TB/2006.371
for TB and provided preventive chemotherapy once Fig. 28.1: Suggested approach (WHO 2006) to contact management
active TB has been ruled-out. 1 The International when chest X-ray and tuberculin skin testing are not readily available.
381
Chapter 28 New Approaches to TB Diagnosis in Children
in non-anergic children ≥ three months after exposure It is important to understand differences in the
occurred. Therefore, the decision to initiate preventive rationale that motivates discrepant approaches in low-
therapy is not influenced by the TST result following burden countries with adequate resources where TB
documented exposure (Fig. 28.1). eradication is an achievable goal and TB endemic areas
The WHO guidelines indicate that any “close contact” with limited resources where the primary aim is to reduce
with a sputum-smear positive source case is important, even TB associated morbidity and mortality and to achieve
if this occurs outside the household. The main factors epidemic control (limit transmission). In non-endemic
areas, the provision of preventive chemotherapy to
influencing the risk of infection in “close contacts” are the
everyone with documented TB infection is justified to
infectiousness of the source case, as well as the proximity
assist TB eradication, since resource constraints are not a
and duration of contact. However, the guidelines fail to
major consideration and eradicating the pool of latent TB
address the frequency with which children in settings where infection is important to prevent future reactivation
TB/HIV coinfection is common are exposed to adults with disease, which is the most common cause of adult disease.
sputum smear-negative pulmonary TB and the In TB endemic areas, the converse is true. Resources are
transmission risk that this exposure poses. It seems prudent highly constrained, and careful priority setting is essential.
to also consider intimate contact with a primary caregiver Due to ongoing transmission, re-infection is common,
who has sputum smear-negative pulmonary TB (diagnosed which makes it impossible to eradicate the pool of latent
on culture or CXR) as a significant exposure risk. In addition infection before adequate epidemic control is achieved.
to children <5 years of age, WHO guidelines also state that In these settings, re-infection rather than re-activation
HIV-infected (immune compromised) children should be seems to be the major cause of adult disease and therefore,
regarded as high-risk contacts that require preventive
the primary aim is to limit ongoing transmission which
therapy, irrespective of their age. The problem is that in
sustains the epidemic. In addition, everything possible
most TB endemic areas health systems are already
should be done to protect the most vulnerable subgroups
overburdened with the provision of curative treatment to
following documented exposure and/or infection in an
patients with active TB and are reluctant and/or unable to
perform contact screening and provide preventive therapy attempt to limit TB associated morbidity and mortality.
to large numbers of children. In these settings, it is of
particular importance to focus preventive therapy Interferon-Gamma Release Assays (IGRA’s)
interventions on those children who are at greatest risk to
These novel T-cell assays measure interferon-gamma
progress to active disease following documented TB
(IFN-gamma) released after stimulation by M. tuberculosis
exposure and/or infection.
specific antigens. Two assays are currently available as
Figure 28.2 presents a simplified screening approach
commercial kits; the T-SPOT.TB® [Oxford Immunotec,
that takes these considerations into account.
Adapted from: Marais BJ, Pai M. New Approaches and emerging technologies in the diagnosis of childhood tuberculosis. Paediatr Respir Rev 2007;8:124-33
Fig. 28.2: Proposed algorithm to screen children with documented exposure to a confirmed TB index case in resource-limited settings.
382
Section 5 Diagnosis
Oxford, UK] and the QuantiFERON®-TB Gold® In Tube • IGRAs cannot be recommended routinely for use in
assay [Cellestis Limited, Victoria, Australia]. In general children younger than five years of age or for
these tests are regarded as more specific and potentially immunocompromised children of any age because of
more sensitive than the traditional TST.5,6 However, a lack of published data about their utility with these
although the US Centres for Disease Control and groups.
Prevention (CDC) recommend the routine use of these • Indeterminate IGRA results do not exclude
assays in children there is little evidence to support this tuberculosis infection and should not be used to make
recommendation.6 Pediatric studies remain limited and clinical decisions.
results inconsistent, with no clear evidence of benefit from
studies conducted in TB endemic areas such as India.7 In APPROACHES TO CONFIRM ACTIVE DISEASE
the absence of symptoms or radiologic signs, T-cell assays
Establishing a definitive diagnosis of childhood TB
like the TST, fail to make the crucial distinction between
remains a major challenge. Sputum smear-microscopy is
latent TB infection (LTBI) and active disease. A possible
positive in less than 10 to 15% of children with TB, and
application of these assays may be the screening of high
culture yields are generally low (30-40%),8 although it may
risk groups (close contacts and HIV-infected children)
be considerably higher in children with advanced disease.9
to help guide the provision of preventive therapy, but
In low-burden countries the triad of; 1) known contact with
meticulous documentation of TB exposure is likely to be
an infectious source case, 2) a positive TST, and 3) a
more effective. As with the TST, there are multiple causes
suggestive CXR is frequently used to establish a diagnosis
of indeterminate or false negative results and test
of childhood TB.9 This provides a reasonably accurate
conversion occurs a few weeks (probably around 4-8
diagnosis in non-endemic settings, but it has limited value
weeks) after primary infection. Following documented
in endemic areas where exposure to, and/or infection with
TB exposure, the first priority remains the provision of
M. tuberculosis, is common and often undocumented. The
preventive therapy to high risk contacts irrespective of
diagnosis of TB in children is further complicated by the
the IGRA (or TST) result.
great diversity of disease manifestations, which
If these assays are shown to be more predictive of
necessitates accurate disease classification at least for
active TB than the TST then their application may expand.
research purposes. 10-11 Seth et al12 has described a
Currently the inclusion of additional antigens is explored
clinicoimmunological spectrum of childhood tuberculosis
to assist the distinction between LTBI, incipient disease
which can be used to grade the severity of the infection
and active disease. There is also the opportunity to
and disease. Table 28.1 summarizes traditional and novel
improve the existing TST by replacing the non-specific
diagnostic approaches, their potential application and the
antigens currently used [purified protein derivative
perceived problems and/or benefits of each.
(PPD)] with M. tuberculosis specific antigens, similar to
those used in IGRA’s. This should result in a more specific
Symptom-Based Approaches
skin test that may be a feasible and more cost-effective
alternative for developing countries. Due to the diagnostic limitations mentioned and the
In 2009, the American Academy of Pediatrics (AAP) difficulty of obtaining a CXR in TB endemic areas with
Red Book (http://aapredbook. aappublications.org/) limited resources, a variety of clinical scoring systems
concluded that “neither an IGRA nor the TST can be have been developed to diagnose active TB. A critical
considered a “gold standard” for diagnosis of LTBI.” The review of these scoring systems concluded that they are
new AAP Red Book recommendations for use of IGRAs severely limited by the absence of standard symptom
in children are as follows: definitions and inadequate validation. 13 Accurate
• For immunocompetent children five years of age and symptom definition is important to differentiate TB from
older, IGRAs can be used in place of a TST to confirm other common conditions, as poorly defined symptoms
cases of tuberculosis or cases of LTBI and likely will (such as a cough of >3 weeks duration) have poor
yield fewer false-positive test results. discriminatory power.14 However, the diagnostic use of
• Children with a positive result from an IGRA should well-defined symptoms with a persistent, non-remitting
be considered infected with M tuberculosis complex. character holds definite promise in low-risk children
A negative IGRA result cannot universally be (immune competent children >3 years) in whom TB is
interpreted as absence of infection. usually a slowly progressive disease. 15 The most helpful
• Because of their higher specificity and lack of cross- symptoms include; 1) persistent, non-remittent coughing
reaction with BCG, IGRAs may be useful in children or wheezing, 2) documented failure to thrive despite food
who have received BCG vaccine. IGRAs may be useful supplementation (food scarcity is not a concern) and 3)
to determine whether a BCG-immunized child with fatigue or reduced playfulness; clinical follow-up is also
a reactive TST more likely has LTBI or has a false- a valuable diagnostic tool, particularly in children who
positive TST reaction caused by the BCG. are at low risk of rapid disease progression.16
383
Table 28.1: Traditional and novel diagnostic approaches; potential application and perceived problems
and/or benefits
Traditional diagnostic Application Problems/ Benefits Validation

approaches
TB culture using solid Bacteriologic Slow turn around time; too Accepted gold standard
or liquid broth media confirmation of active TB expensive for most poor
countries; poor sensitivity in
children
Chest radiography Diagnosis of probable Rarely available in endemic Marked inter and intra
active TB areas with limited resources; observer variability;
accurate disease classification reliable in expert hands
important and in presence of
suspicious symptoms
Symptom-based Diagnosis of probable Poor symptom definition Not well validated
approaches active TB
Tuberculin skin test Diagnosis of Rarely available in endemic Various cut-offs advised
(TST) M. tuberculosis infection areas with limited resources; in different settings
does not differentiate latent
TB infection (LTBI) from
active disease; not sensitive in
immune compromised
children; simple to use and
less expensive than blood-
based tests
Novel diagnostic Application Problems/Benefits Validation
approaches
Organism-based
Colorimetric culture Bacteriologic Simple and feasible, limited Not well validated in
systems (e.g. TK- confirmation of active TB resources required; potential children
Medium) for contamination in field
conditions
Phage-based tests Diagnosis of probable Requires laboratory Not well validated in
(e.g. FASTPlaque-TB) active TB, and detection of infrastructure; performs children but evidence
rifampin resistance relatively poorly when used from adults suggests
on clinical specimens poov performance
Microscopic Diagnosis of probable Simple and feasible, limited Not well validated in
observation drug active TB, and detection of resources required children but evidence
susceptibility assay drug resistance from adults suggests
promise
PCR-based tests Diagnosis of probable - Rarely available in endemic - Extensively evaluated,
active TB, and detection of areas but evidence not in
rifampin resistance - Sensitivity tends to be poor favor of widespread use
in paucibacillary TB
- Specificity a concern in
endemic areas, where LTBI is
common
- Requires adequate quality
Antigen-based control systems Not well validated but
assays Simple, point of care testing; evidence from adults
LAM detection assay Diagnosis of probable limited clinical data on shows inconsistent per-
active TB accuracy formance
Contd....
384
Section 5 Diagnosis
Contd....
Novel diagnostic Application Problems/Benefits Validation
approaches
Immune-based Simple, point of care testing, Not well validated in
Antibody-based Diagnosis of probable variable accuracy and children but evidence
assays active TB difficulty in distinguishing form adults not in favor
LTBI from active TB of routine use
Simple, point of care testing, Not sufficiently
MPB64 skin test Diagnosis of probable require a second visit to read validated
active TB the result No studies in children
Limited data in children, Not well validated in
T-cell assays Diagnosis of LTBI inability to differentiate LTBI young children; evidence
from active TB; blood volume is not consistent and no
required (3-5ml); expensive; strong evidence that
may have particular relevance IGRAs are superior to
in high-risk children, where TST in high-incidence
LTBI treatment is warranted countries.
Symptom-based Limited resources required; Additional validation

Symptom-based Screening child contacts of should improve access to preferable
screening adult TB cases preventive chemotherapy for
asymptomatic high-risk
contacts in endemic areas
Limited resources required; Additional validation
Refined symptom- Diagnosis of probable should improve access to preferable
based diagnosis active TB chemotherapy in resource-
limited settings; poor
performance in HIV-infected
children
Abbreviations: LAM - lipoarabinomannan; LTBI - latent tuberculosis infection; TB - tuberculosis; TST - tuberculin skin test
Adapted from: Marais BJ, Pai M. Recent advances in the diagnosis of childhood tuberculosis. Arch Dis Child 2007; 92: 446-452.
Current evidence on various TB tests is available at: http://www.tbevidence.org/
The most common extrathoracic manifestation of TB adenopathy and/or early cavitation. However, although
in children is cervical lymphadenitis. A simple clinical HRCT has definite application in rare problem cases, the
algorithm that identify children with a persistent (>4 natural history of disease demonstrates that particular
weeks) cervical mass of ≥ 2x2 cm, without a visible local caution is required when interpreting the relevance of these
cause or response to first-line antibiotics, has shown findings, since a limited degree of hilar adenopathy is
excellent diagnostic accuracy in a TB endemic area. common following recent primary infection and not
However, establishing a definitive tissue and/or culture necessarily indicative of disease in the absence of symptoms.
9
diagnosis remains preferable and this can be done in a Therefore, it is important to evaluate the presence of other
minimally invasive fashion using fine needle aspiration clinical signs and symptoms in conjunction with the CXR,
biopsy (FNAB). and not to base a TB diagnosis solely on the radiographic
findings.
Radiology-Based Approaches
Immune-Based Approaches
In everyday clinical practice, the diagnosis of TB in endemic
areas depends predominantly on the subjective Immune-based diagnosis is complicated by the wide
interpretation of the CXR. Despite its many limitations the clinical disease spectrum (ranging from subclinical latent
CXR remains the single most helpful test and usually infection to various manifestations of active disease) and
provides a fairly accurate diagnosis, at least in HIV- other factors that influence the immune response such as
uninfected children, if evaluated by an experienced BCG vaccination, exposure to environmental non-
clinician.9 High-resolution computed tomography (HRCT) tuberculous mycobacteria (NTM) and HIV co-infection;
is the most sensitive tool currently available to detect hilar all of which are particularly prevalent in TB-endemic
385
areas.5 No serological assay is currently accurate enough and possible increased bacteriological yield with the
to replace microscopy and culture. A recent systematic addition of a nutrient broth to standard liquid media
review showed that currently available serological, using automated systems.20 Further research is required
antibody-based tests have highly variable sensitivity and to identify optimal growth conditions that can be coupled
specificity.17 However, various serological tests are to a variety of detection systems. Thin layer agar (TLA)
marketed as diagnostic tests despite the absence of and nitrate reductase assay (NRA) are other non-
evidence, particularly in TB endemic countries where commercial, but promising approaches.
regulatory control is less well established.17 The use of Other innovative organism-based approaches include
novel T-cell assays have been discussed and like the TST, the detection of TB-specific antigens such as
current IGRAs fail to differentiate TB infection from active lipoarabinomannan (LAM) in sputum and/or urine.
disease. Identifying novel ways to differentiate LTBI from Initial field trials demonstrated sub-optimal sensitivity,
active TB and finding the correct application for these tools although improved sensitivity was achieved in HIV-
in TB-endemic areas remain top priorities for future infected adults and those with disseminated disease. No
research.6 results from pediatric studies have been reported to date.
Another innovative approach measures the immune The phage amplification assay utilizes bacteriophages to
response (delayed type hypersensitivity response similar infect live M. tuberculosis and is commercially available
to the TST) to transdermal application of the MPB64 as FASTPlaque-TB; a variant (FASTPlaque-TB Response®)
antigen.5 In initial pilot studies, the MPB64 skin patch was designed for the rapid detection of rifampicin (RMP)
test successfully distinguished active TB from LTBI, but resistance. The phage assay has a turn-around time of
results from more extensive field trials and information only 2 to 3 days, but is less sensitive than traditional
of its ability to detect active TB in children are eagerly culture methods and no information exists on its utility
awaited. in children.5 The test has proven ability to rapidly
differentiate between rifampicin susceptible and
Organism-Based Approaches potential multidrug resistant (MDR) cases, but has been
superseded by polymerase chain reaction (PCR)-based
A positive culture is regarded as the “gold standard test”
tests.5 Recent field studies of FASTPlaque-TB tests has
to establish a definitive diagnosis of TB in a symptomatic
raised concern about contamination and false-positive
child. However, it is limited by sub-optimal sensitivity,
results.
slow turn-around times, excessive cost (automated liquid
Nucleic acid amplification tests (NAAT’s) amplify
broth systems) and the fact that organisms may be
regions specific to the M. tuberculosis complex. These tests
isolated from non-diseased (asymptomatic) children
have shown highly variable results and limited utility in
shortly after primary infection; during the initial period
children to date. As demonstrated in several meta-
of organism multiplication. This is rarely a problem in
analyses (available at www.tbevidence.org), existing
clinical practice where children present with symptoms
NAAT’s have high specificity, but modest and variable
suspicious of TB, but it may be a major confounder in
sensitivity, especially in smear-negative and extra-
studies where asymptomatic children are routine
pulmonary TB. Several newer NAATs have been
cultured for TB following documented TB exposure.9 It
developed recently, including the loop-mediated
is important to point out that adolescent children (>10
isothermal amplification [LAMP] (Eiken Chemical Co.
yrs of age) frequently develop sputum smear-positive
Ltd., Tokyo, Japan), a simplified manual NAAT designed
disease that may be diagnosed using traditional
for peripheral laboratory facilities, and the Xpert® MTB/
methods.9 Novel culture-based approaches include
RIF assay (Cepheid, Sunnyvale, Calif, USA), a fully
simple colorimetric and microcolony methods with
automated NAAT platform that can detect TB as well as
reduced turn-around times, but their accuracy and
rifampin resistance. These tests have shown promise in
robustness in field conditions have not been confirmed.5
early studies, although published evidence is still limited,
The Microscopic Observation Drug Susceptibility
especially in children.
(MODS) assay uses an inverted light microscope to
rapidly detect mycobacterial growth in liquid growth Specimen Collection Methods in Children
media. It is an inexpensive method that has demonstrated
Collecting an adequate specimen presents a significant
excellent performance under field conditions (both in
challenge, particularly in small children who are unable
adults and children)18-19 being more sensitive than
to expectorate. In young children (<8 years of age), the
automated liquid media systems. Unfortunately the test
routine specimens collected are two to three fasting gastric
is not widely available at present, while it remains highly aspirates. However, the collection of 2 to 3 fasting, early
operator dependent and labor intensive. A recent morning gastric aspirate specimens is cumbersome and
pediatric study demonstrated reduced times to detection usually requires hospitalization. In an initial
386
Section 5 Diagnosis
study, the collection of a single hypertonic-saline induced is precisely the age-group that suffers the greatest burden
sputum specimen provided the same yield as three gastric of disease. Fine needle aspiration biopsy (FNAB), is a
aspirate specimens,21 but subsequent studies have not been robust and simple technique that provides a rapid and
able to substantiate this observation.22 However, induced definitive diagnosis. In a comparative study FNAB
sputum seems at least as good as a gastric aspirate sample specimens provided superior yields compared to
and can be done as an outpatient procedure; the value/ standard respiratory specimens in child TB suspects with
risk of the technique is currently being tested in a primary a palpable lymph node mass. 24 The use of a small 23-
health care clinic setting. The string test is an innovative
gauge needle is well-tolerated and associated with
collection method that has been used with great success
minimal side-effects; the technique can be performed as
to retrieve M. tuberculosis from sputum smear-negative
an outpatient procedure by well-trained doctors or
HIV-infected adults, demonstrating superior sensitivity
compared to induced sputum.23 A major limitation at nurses.25 Table 28.2 provides a summary of various
present is the inability of young children (<5 years of specimen collection methods and the perceived problems
age) to swallow the string containing capsule, while this and/or benefits of each.
Table 28.2: Specimen collection methods; perceived problems and/or benefits
Specimen collection Problems/ Benefits Potential clinical application

method
Sputum Not feasible in very young children; Routine sample to be collected in
Assistance and supervision may children >7yrs of age (all children who
improve the quality of the specimen can produce a good quality specimen)
Induced sputum Increased yield compared to gastric To be considered in the hospital setting
aspirate; No age restriction; Specialized on an in- or out-patient basis
technique, which requires nebulization
and suction facilities; Use outside
hospital setting not studied; Potential
transmission risk
Gastric aspirate Difficult and invasive procedure; Not Routine sample to be collected in
easily performed on an outpatient basis; hospitalized who cannot produce a
Requires prolonged fasting;Sample good quality sputum specimen
collection advised on 3 consecutive days
Nasopharyngeal Less invasive than gastric aspirate; No To be considered in primary health care
aspiration fasting required;Comparable yield to clinics or on an outpatient basis
gastric aspirate
String test Less invasive than gastric aspirate; Potential to become the routine sample
Tolerated well in children >4 years; collected in children who can swallow
Bacteriologic yield and feasibility the capsule, but cannot produce a good
requires further investigation quality sputum specimen
Bronchoalveolar Extremely invasive Only for use in patients who are
lavage intubated or who require diagnostic
bronchoscopy
Urine/Stool Not invasive; Excretion of M. tuberculosis To be considered with novel sensitive
well documented bacteriologic or antigen-based tests
Blood/Bone marrow Good sample sources to consider in the To be considered for the confirmation
case of probable disseminated TB of probable disseminated TB in
hospitalized patients
Cerebrospinal fluid Fairly invasive; bacteriologic yield low To be considered if signs of tuberculous
(CSF) meningitis
Fine needle Minimally invasive using a fine 23G Procedure of choice in children with
aspiration biopsy needle; excellent bacteriologic yield, superficial lymphadenopathy
(FNAB) minimal side-effects
Adapted from: Marais BJ. Pai M. Specimen collection methods in the diagnosis of childhood tuberculosis. Indian J Med Microbiol
2006; 24: 249-251
387
From World Health Organization & Stop TB Partnership. New laboratory diagnostic tools for tuberculosis control. World Health Organization, Geneva, 2008
Fig. 28.3: Summary of new technologies by the Retooling Task Force and Stop TB Partnership’s New Diagnostics Working Group
Section 5 Diagnosis
Courtesy: Stop TB Partnership’s New Diagnostics Working Group

Find = Foundation for Innovative new diagnostic
TDR = Tropical disease research.
Fig. 28.4 New website resource for “Evidence-based TB Diagnosis” (www.tbevidence.org)
388
389
HIV-infection the TST is positive in the minority of HIV-infected

children with bacteriologically confirmed TB despite
HIV-related immune compromise is one of the main risk
using a reduced induration size cut-off of ³5 mm.
factors that increases the vulnerability to develop active TB
• Chronic pulmonary symptoms from other HIV-
following infection. Since children get TB where adult source
related conditions are common and failure to thrive
cases spread the infection, both HIV-infected and uninfected
is a typical feature of both TB and HIV, which greatly
children experience high rates of TB exposure in HIV-
reduces the specificity of symptom-based diagnostic
endemic areas where the TB epidemic is poorly controlled.
approaches. Rapid disease progression may also
Among HIV-infected children, TB is a major cause of
occur, thereby reducing the sensitivity of diagnostic
morbidity and mortality and is often under-diagnosed in
approaches that focus on persistent, non-remitting
resource-limited settings. However, unlike the situation with
symptoms.
adults in many HIV-endemic areas, the majority of child TB
• CXR interpretation is complicated by HIV-related
cases remain HIV-uninfected, since relatively few children
comorbidity such as bacterial pneumonia,
become infected in areas with adequate prevention of mother
lymphocytic interstitial pneumonitis (LIP),
to child transmission (PMTCT) programs. Very young
bronchiectasis, pulmonary Kaposi sarcoma (KS) and
children are highly vulnerable to develop TB following
the atypical presentation of TB in immune
documented exposure, irrespective of their HIV-status.
compromised children.
The diagnostic challenge is greatly pronounced in HIV-
infected children due to a number of factors:26
Expanding TB Diagnostics Pipeline and Current Evidence
• HIV-infected adult patients are more likely to
have sputum smear-negative pulmonary TB. The new diagnostics pipeline for TB is rapidly expanding.
Although not in accordance with current In 2008, the Stop TB Partnership’s Retooling Task Force
international guidelines, it seems prudent to provide (RTF) and New Diagnostics Working Group (NDWG)
preventive therapy to high risk contacts who are in produced a detailed brochure on the diagnostics pipeline,
intimate contact such as the children of the source mainly to provide guidance to National TB Programs
case. (NTPs), and for funding the technical agencies that may
• The TST and IGRA’s have reduced sensitivity in wish to support the development, evaluation or
HIV-infected children. Although test sensitivity is implementation of new tools. Figure 28.3
influenced by the degree of immune compromise, shows the pipeline, where the tools are stratified as “WHO-
In nonendemic areas where the risk of reinfection is low and where TB eradication is an achievable goal, it would be desirable to provide
preventive treatment to all individuals with documented TB infection
Adapted from: Marais BJ, Gie RP, Schaaf HS et.al. Childhood pulmonary tuberculosis – Old wisdom and new challenges. Am J Resp Crit
Care Med 2006;173:1078-90
Fig. 28. 5: Algorithm to guide the diagnosis and management of children with suspected pulmonary TB
390
Section 5 Diagnosis
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• If the child is exposed or infected and active TB has Tuberculosis in Children. Seth Vimlesh Kabra SK (eds),
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indicated? Ltd 2006; 95-105.
• If the child has active TB, what is the appropriate 13. Hesseling AC, Schaaf HS, Gie RP, et al. A critical review
treatment regimen? of diagnostic approaches used in the diagnosis of
• Evidence based diagnosis of tuberculosis has been childhood tuberculosis. Int J Tuberc Lung Dis
discussed. 2002;6:1038-45.
14. Marais BJ, Obihara CC, Gie RP, et. al. The prevalence of
symptoms associated with pulmonary tuberculosis in the
ACKNOWLEDGMENTS average child from a high-burden community. Arch Dis
This book chapter draws heavily on several previous Child 2005;90:1166-70.
review papers, including those published in Indian J Med 15. Marais BJ, Gie RP, Obihara CC, et. al. Well-defined
symptoms have improved value in the diagnosis of
Microbiol 2006; 24: 249-51; Arch Dis Child 2007; 92: 446-
childhood pulmonary tuberculosis. Arch Dis Child
52; Pediatr Respir Rev 2007; 8: 124-33; Semin Respir Crit
2005:90:1162-5.
Care Med. 2008;29(5):560-8; and PLoS Med. 2008 Jul 16. Marais BJ, Gie RP, Schaaf HS, et al. A refined symptom-
22;5(7):e156. Adapted tables and figures have been based approach to diagnose pulmonary tuberculosis in
acknowledged with due credit. children. Pediatrics 2006.118:e1350-9.
391
17. Steingart KR, Henry M, Laal S, et al. A systematic review 24. Wright CA, Hesseling AC, Warren RW, et al. Fine needle
of commercial serological antibody detection tests for the aspiration biopsy – a first line diagnostic procedure in
diagnosis of extrapulmonary tuberculosis. Thorax pediatric tuberculosis suspects with peripheral
2007;83: 705-12. lymphadenopathy. Int J Tuberc Lung Dis 2009; In press.
18. Moore DAJ, Evans CAW, Gilman RH, et al. Microscopic- 25. Wright CA, Warren RW, Marais BJ. Fine needle
observation drug-susceptibility assay for the diagnosis aspiration biopsy: an undervalued diagnostic modality
of TB. N Engl J Med 2006;355:1539-50. in pediatric mycobacterial disease. Int J Tuberc Lung Dis
19. Oberhelman RA, Soto-Castellares G, Caviedes L, et al. 2009; In press.
Improved recovery of Mycobacterium tuberculosis from 26. Marais BJ, Graham SM, Cotton MF, et al. Diagnostic and
management challenges of childhood TB in the era of HIV.
children using the microscopic observation and drug
J Infect Dis 2007;196:S76-85.
susceptibility method. Pediatrics 2006;118:e100-6.
27. Perkins MD, Cunningham J. Facing the crisis: improving
20. Brittle EW, Marais BJ, Hesseling AC, et al. Improved
the diagnosis of tuberculosis in the HIV era. J Infect Dis
mycobacterial yield and reduced time-to-detection in
2007;196:S15-27.
pediatric samples using a nutrient broth growth 28. Pai M, O’Brien R. New diagnostics for latent and active
supplement. J Clin Microbiol 2009;47:1287-9. tuberculosis: state of the art and future prospects. Semin
21. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus Respir Crit Care Med 2008; 29:560-8.
gastric lavage for microbiological confirmation of 29. Pai M, Ramsay A, O’Brien R. Evidence-based
pulmonary tuberculosis in infants and young children: tuberculosis diagnosis. PLoS Med 2008;5:e156./
a prospective study. Lancet 2005;365:130-4. www.plosmedicine.rog
22. Hatherill M, Hawkridge T, Zar HJ, et al. Induced sputum
or gastric lavage for community-based diagnosis of SUGGESTED READING
childhood pulmonary tuberculosis? Arch Dis Child
2009;94:195-201. Ichhpujani RL, Agarwal SP, Chauhan LS. Diagnostic needs
and status of new diagnostic tools for tuberculosis in TB book,
23. Vargas D, Garcia L, Gilman RH, et al. Diagnosis of
by TB Division of Ministry of Health and Family Welfare,
sputum-scarce HIV-associated pulmonary tuberculosis in
Government of India. Chapter 18. 2008;165-78.
Lima, Peru. Lancet 2005;365:150-2.
SECTION 6
MANAGEMENT
• Principles of Therapy
• Antituberculosis Drugs: First-line Agents
• Antituberculosis Drugs: Second-line and
Newer Agents
• Antituberculosis Drugs: Pharmacokinetics
• Pharmacogenetics of Tuberculosis
• Management of Tuberculosis
• Consensus Statement on Childhood Tuberculosis,
2010 IAP Working Group on Tuberculosis
• Drug-resistant Tuberculosis in Children
– Drug-resistant Tuberculosis
– Multidrug-resistant Tuberculosis
• Organization of Pediatric Tuberculosis and
HIV Clinic
29 Principles of Therapy
Standard medical therapy of tuberculosis for decades was in children have been described by her based on
focused on rest, the sanatorium, a good climate and a clinicoimmunologic profile. These should be followed.3,3a
proper diet. This continued for some time even after the
discovery of the tubercle bacillus by Koch and MICROBIOLOGICAL PRINCIPLES
establishment of infective etiology of tuberculosis. The
first principle of the modern treatment of tuberculosis is Mycobacterial Population
the recognition of the primacy of drug treatment over all Mycobacteria exist in any diseased site in four distinct
other forms of therapy. This was established in the 1940s but mutually interchangeable population group. Not all
with the discovery of effective antituberculosis drugs work equally well on all bacillary sub-population.
chemotherapeutic agents. The principles of chemo- It is customary to discuss antituberculosis drugs in terms
therapy of tuberculosis in the era of short-course of their effect on these different population of
treatment regimens were developed when isoniazid mycobacteria.
(INH), para-aminosalicylic acid (PAS), and streptomycin
became available. When drugs like pyrazinamide, Group I
ethambutol and most importantly rifampicin were
Rapidly multiplying organisms in extracellular
introduced with the better understanding of their
environment of pulmonary cavities. They multiply
mechanisms of action, came the concept of short-course
rapidly due to the presence of a neutral pH and an
chemotherapy. There has been redefining of the
abundance of oxygen. They are killed by isoniazid
principles of tuberculosis in adults and lately in children.
followed by rifampicin (RIF), pyrazinamide (PZA) and
It was the laboratory and field work of seminal figures
streptomycin (SM) and less so by bacteriostatic drugs,
such as Fox 1 and Mitchison 2 of the Tuberculosis
Elimination Bureau of the British Medical Research such as ethambutol (EMB), para-aminosalicylic acid
Association working in conjunction with colleagues in (PAS) and thiacetazone (THA).
East Africa and India, that lead to the development of
Group II
modern principles of chemotherapy.
The aim of therapy in tuberculosis is to cure; cure all Intermittently multiplying organisms (semi-dormant) in
patients with disease at various sites, of varying severity relatively hypoxic or acid environ-ment of solid caseous
and resistance pattern. Patients who may have received material. They are specifically acted upon by rifampicin
treatment before, with variable compliance pose further which has the property of being able to act very soon
problems. With the current regimens of treatment of after the multiplication of bacilli starts. This drug has its
tuberculosis, available at low cost, if not free for all, there action only when the bacteria are multiplying.
should be minimal relapses, and side effects. Thus the
aims can be summarized as follows: (i) Cure patients with Group III
minimal interference with their living, in shortest possible
Occasionally dividing organisms (dormant) in the
time, whether the pretreatment organisms are susceptible
activated macrophages. These mycobacteria are
or resistant to the drugs; (ii) Prevent death from active
specifically acted upon by pyrazinamide and much less
disease or its late effects; (iii) Avoid relapse; (iv) Prevent
by other drugs.
emergence of acquired drug resistance and (v) Protect
the community from infection. To add to this, Seth3,3a
Group IV
recommends that the children should be tackled
simultaneously both for prevention and treatment of the Drug resistant mutants. Pyrazinamide (PZA) and
disease, using proper regimens with clear case definitions isoniazid (INH) are the main drugs which help in the
which may differ from adults. Different case definitions prevention of emergence of drug resistant mutants.
396
Section 6 Management
Table 29.1 grades the activity of antituberculosis in Mycobacterium tuberculosis develops by mutation.
drugs on the various groups of myco-bacteria existing Infection by organisms which are resistant to drugs prior
at disease site. to exposure leads to primary resistance. Such naturally
resistant organisms are present within large populations
Population Load of M. tuberculosis. All known genes that encode for drug
The second major biological determinant of the success resistance are located on a chromosome, transfer of
of antituberculosis chemotherapy is the size and type of resistance between organisms does not occur. The
the bacillary population within the host. Patients with estimated frequency of these naturally drug resistant
cavities or extensive infiltrates have large bacterial organisms is about 10–6 but varies among drugs, with
population whereas patients with infection (reactive skin streptomycin it is 10–5, with isoniazid 10–6, rifampicin
test) but no disease have a small bacterial population load. 10–8 and pyrazinamide 10–8. The natural occurrence of
In adults, there are studies which indicate the bacterial resistance to one drug is independent of resistance to
load in relation to the extent of lesion in pulmonary any other drug. The chance that an organism is naturally
tuberculosis, e.g. X-ray positive but sputum negative, resistant to both INH and RIF is of the order of 10.14
both sputum and chest X-ray positive. In the former, the Because populations of this size do not occur in patients,
bacillary load will be less as compared to the latter. In the chances that organisms naturally resistant to two
children this has not been worked out and hence, no drugs exist in a patient are almost negligible. However,
literature is available. As a corollary to this Seth3,3a has acquired resistance to these two drugs referred to as
described a clinicoradioimmunological spectrum as (i)
Asymptomatic Mantoux positive (ASMP); (ii) Symptomatic
Table 29.2: Population of bacilli within a host (adult)
Mantoux positive (SMP); (iii) Pulmonary primary
Parameter Cavity Closed Macro-
complex (PPC); (iv) Progressive primary disease (PPD);
caseous phages
(v) Bronchopneumonia; (vi) Pleural effusion; (vii) Post
Population 107-109 104-105 104-105
primary lesion PPL having calcification or fibrosis; (viii)
size
Miliary types of lesion and (ix) Extrapulmonary form of Metabolism and – slow/ slow
tuberculosis are lymphadenitis, osteoarticular and active replication intermittent
meningeal tuberculosis. The most common being pH Neutral/ Neutral Acid
tubercular lymphadenitis. Bronchopneumonia will have Alkaline
a larger load of bacilli in comparison to ASMP, SMP and Most effective H, R, S R, H Z, R, H
PPC. The miliary and meningeal are dissemination drug
complications of PPC. Table 29.2 gives the size of bacterial
load in adults and other host and pathogen Table 29.3 shows the size of bacillary load in children.
characteristics. The early bactericidal activity 4 of
antituberculosis drugs is the most important factor for Table 29.3: Size of bacillary load (children)
their efficacy in the treatment, particularly of pulmonary Parameter Bacillary Drug resistant
tuberculosis. load mutants
Cavity 109 ++
Resistance
Positive Mantoux 103-104 Rare
The other microbiological principle in the chemotherapy Pulmonary
of tuberculosis is of innate resistance to drugs. Resistance primary complex 104-105 +
Table 29.1: Activity of antituberculosis drugs on different bacterial population

Bacterial population
Agent Active* Semi dormant* Dormant** Resistant ***
(extracellular) (caseous ) (intracellular) (mutants)
Isoniazid +++ ++ + +++
Rifampicin +++ +++ ++ +++
Pyrazinamide* - - +++ -
Streptomycin +++ - - ++
Ethambutol** ++ - ++ ++
* Bactericidal action , ** Sterilizing action, *** Prevention of emergence of resistance
* Bactericidal drug active against intracellular organisms
** Bacteriostatic drug active against both intracellular and extracellular organisms
397
Chapter 29 Principles of Therapy
multidrug resistance (MDT-TB) has become a problem Disease in children is a direct consequence of the
of significance. This laboratory evidence was provided primary infection and they typically have closed caseous
by the work of Fox1 and Canetti.5 This formed the basis lesion with relatively few mycobacteria. Since the
for understanding the principle that multi-agent likelihood of developing resistance to any antimicrobial
chemotherapy is required for the treatment of active drug depends primarily upon the size of the bacillary
tuberculosis. This was further proved when initial population, resistance that emerges during therapy, i.e.
studies, in which, streptomycin alone was used to treat secondary drug resistance, is rare in children. Most
active pulmonary tuberculosis had significant treatment resistance encountered is primary resistance, i.e. infection
failures and high relapse rates. The relapses were by develops by an already resistant organism.4
organism resistant to streptomycin.6
If a patient with extensive pulmonary tuberculosis is Pharmacological Principles
given a single medication, the subpopulation of bacilli The aim of treatment with antituberculosis drugs is to
susceptible to that drug will be eliminated but the cure the individual patient and to prevent the emergence
subpopulation of bacilli resistant to this drug have the of drug-resistant organisms. This is achieved by: (1)
opportunity to multiply and become the dominant strain. Rapid reduction of the organism load; (2) Ensuring
The patient after temporary improvement, will suffer a effective eradication of dormant and intermittently
relapse and that will be drug resistant. Also, if all the metabolizing (persistent) bacilli; and (3) Achieving this
organisms have initial (primary) resistance to a drug and with minimal adverse effects for the child.8-12
the patient is treated with that plus one other drug, he/ Mitchison2 described antituberculosis drugs in terms
she will be getting only one effective drug. This results of their activity, in three areas: (i) Early bactericidal
in relapse with tuberculosis that is resistant to both drugs activity; (ii) Sterilizing activity and (iii) Prevention of
(secondary resistance). The phenomenon of drug drug resistance. This is depicted in Table 29.4.
resistant mutants and bacterial population size explains
why poor patient compliance can lead to rapid Early Bactericidal Activity
development of drug resistance.
Hence, the following points should be kept in mind It is the ability of the drug to reduce the number of bacilli
during the initial part of therapy.4 INH is the most potent
while introducing antituberculosis chemotherapy for the
bactericidal agent.
prevention of emergence of resistance:7
• Monotherapy is the most potent stimulus for
development of resistance and has a substantial
Sterilizing Activity
chance for relapse, and, therefore, should be avoided. It is the ability of a drug to kill semidormant bacteria
• Achieve rapid reduction of bacterial load and is measured by the speed with which the last few
• Initial therapy should begin before sensitivity data viable bacteria are killed.13 Rifampicin and pyrazinamide
are available, but should be based on the prevailing are the most potent sterilizing agents.
sensitivity pattern of isolates in the community. Each of the first-line drugs makes a specific
• Never add a single drug to a failing regime. contribution during different periods of drug action.
• Compliance with drugs is a major determinant of the Immediate effect in first 2-3 days include killing of fast-
success of therapy. growing extracellular bacilli,14 mainly by the excellent
The major biological determinant of success of bactericidal activity of isoniazid (INH). 15 In the
antituberculosis drugs is the size of the bacillary
population in the host. Adults with cavities or extensive Table 29.4: Relative activities of antituberculosis medications
infiltrates have large bacillary load and many naturally Early bactericidal Preventing Sterilizing Status
resistant organisms are present. For such patients, at least activity drug activity of
three antituberculosis drugs must be used to affect a cure. resistance activity
Conversely, in patients with infection (skin test positive) In vitro In vivo
but no disease, the bacillary population is small and drug • INH INH INH RIF High
RIF RIF PZA
resistant organisms are few or nonexistent. For such
SM
patients, theoretically, two drugs can be used. For • EBM EMB SM INH
example, in a child who is otherwise asymptomatic, but PZA RIF EMB SM
found to be a recent Mantoux conver-ter due to the THA EMB
exposure to a contact in the family, the type of bacilli • THA SM
will be similar to that of the source case. In such a child, PAS PZA
X-ray chest and Mantoux test must be done and child THA
treated accordingly. Details are discussed elsewhere. PAS PZA THA Low
398
subsequent phase that lasts for 4 to 8 weeks, extracellular administered in the initial weeks of therapy with
bacilli that are growing slowly are killed, this action is isoniazid and para-aminosalicylic acid, the failure rate
more dependent on physiological state of the bacilli and evaluated by bacteriological conversion at 6 months was
less by the bactericidal activity of the drug. During this much lower. After rifampicin emerged as the most
period, the bactericidal activity of rifampicin (RMP) is effective antituberculosis medication, the most effective
important and pyrazinamide (PZA) contributes by killing and modern short-course regimen were formulated.
extracellular bacilli that persist in acidic areas of
inflammation.16 During maintenance phase of treatment Effective Anti-TB Drug Treatment—Properly Applied
that lasts for 4-6 months, persistent intracellular bacilli Short-course Chemotherapy
are eradicated mainly by rifampicin, although INH will
continue to offer protection against the development of It is known for over 100 years that M. tuberculosis causes
resistance and may assist with organism eradication, TB and effective anti-TB drugs are available for nearly
especially in fibrocaseous tissue with poor drug 50 years. Yet the world’s TB problem is now bigger than
penetration.17 Host immunity plays an important role ever, why? The problem is not the lack of an effective
throughout, but is of particular importance to effect treatment. Properly applied short-course chemotherapy
organism eradication and prevent disease relapse, as (SCC) fulfills the above aims of anti-TB drug treatment.
indicated by the high relapse rate in HIV-infected The problem is how to apply SCC properly. The answer
children.17 is a properly managed TB control program.
Prevention of Drug Resistance Standardized TB Treatment Regimens

Drugs that are highly active in the prevention of drug There are many different possible anti-TB treatment
resistance, suppress the growth of the entire bacterial regimens. The World Health Organization (WHO) and
population to prevent the emergence of mutants resistant the International Union Against Tuberculosis and Lung
to another drug. Isoniazid and rifampicin have the Disease (IUATLD) recommend standardized TB
highest activity in preventing the emergence of drug treatment regimens. The regimens are affordable. The
resistance, followed by streptomycin and ethambutol. World Bank recognizes short-course chemotherapy
The activity of pyrazinamide in this area is poor. (SCC) as one of the most cost-effective health
interventions.
Development of the Concept of
Two Phase Chemotherapy Short-Course Therapy
Bactericidal drugs ensure rapid reduction of the organism It was realized that long-term therapy of 18 to 24 months
load, which improves clinical symptoms, limits disease though effective was expensive and leads to
progression, terminates transmission, and prevents the noncompliance on the part of the patient. This led to field
emergence of drug resistance. Sterilizing drugs ensure trials of several short-course regimens. The British
the effective eradication of dormant and intermittently Medical Research Council and its collaborators through
metabolizing (persistent) bacilli, thus preventing disease field trials provided useful insight into formulation of
relapse. These principles provide the rationale behind effective short-course chemotherapy and also provided
the intensive and continuation phases of current framework for future investigation. 9-11 These trials
antituberculosis treatment regimens.18 established that:
Soon after the development of the principle of i. RIF containing regimes could allow effec-tive short-
multidrug therapy for active infection came the course therapy of active, smear-positive, cavitary
theoretical notion that an initial intensive phase of disease.19-21
therapy with more than two drugs followed by a ii. Inclusion of at least two bactericidal drugs is
continuous phase during which fewer drugs could be necessary in short-course chemotherapy.
given, would be more effective in achieving good iii. Relapses in short-course tend to occur within the
outcome. The justification for this was based on the notion first year after completion of therapy.
that larger numbers of organisms contain greater number iv. Multidrug therapy can be given with minimal
of bacilli that may be resistant to initial agents, so that by toxicity.
adding several agents at once in the initial phase more v. Relapses occurring after short-course, multi-agent
effective killing could be achieved. therapy were almost always caused by organisms
In 1960s several studies provided strong evidence for that retain their original sensitivity pattern, i.e.
the concept of initial intensive phase using multiple multi-agents are effective in prevention of
drugs. 4 It was found that when streptomycin was emergence of drug resistance.
399
Shortest-Course Therapy to problems not only for the individual but for the
Several trials in the 1980s by British Medical Research community at large since it is a contagious disease.
Council, tried to shorten the duration of therapy to even Moreover, it leads to selections of drug-resistant strains
less than 6 months by using more effective drugs in the of mycobacteria.
In response to the problem of noncomp-liance, a
initial intensive phase.21 The general consensus that
variety of solutions have been propo-sed, including
emerged was that regimens shorter than 6 months were
programs of directly observed therapy under which
likely to be associated with significant relapse rates even
patients receive incentives to complete their treatment
if most active agents were used.
while being supervised.31-33 Further, the use of fixed dose
combination may enhance patient adherence
Intermittent Treatment and may reduce the risk of inappropriate monotherapy.
Researchers noticed that the major cause of treatment For this reason, the use of such fixed dose combinations
failure, relapse and the emergence of drug resistance was is encouraged.34
the nonadherence to therapy by the patient. Two methods
to address these problems were studied: HIV TB Coinfection
i. Supervised therapy Infection with HIV and tuberculosis is a major challenge
ii. Intermittent therapy. due to drug interaction. WHO recommendations advise
Supervised therapy involves watching the patient starting ART once ATT is established (after a period of
swallow each dose of medication. This was found to be 2-8 weeks) for all WHO clinical stage 4 HIV-infected
an effective way to address nonadherence. To make it children and stage 3 children with advanced or severe
more-effective, intermittent (2 to 3 times/week) rather immunosuppression; for children in WHO clinical stage
than daily therapy was tried. 22 It was found that 3 with mild or no immuno-suppression, ART may be
efficiency of INH did not change significantly as interval deferred until 6 months till ATT are completed.35 There
of dosage was increased from daily to every 4 days. are reports suggesting benefits of early addition of
Moreover, ethambutol and rifampicin were found to be antiretroviral drugs with ATT. 36,37 There is need to
actually more effective when given intermittently. identify precise time when ART can be introduced with
Intermittent regimens have proved to be effective and ATT.
no more toxic than daily regimens.23 Based on these
principles, directly observed therapy strategy have been Disease Principles Specific to Pediatrics
developed. Intermittent regimens have been documented Children with tuberculosis typically have closed caseous
to be as effective as daily regimen in the pediatric lesions and thus the bacillary load is less. As already
population.24-27 There are no randomized controlled trials discussed, the likelihood of developing drug resistance
comparing thrice weekly regimen with daily treatment. during therapy is less and most commonly encountered
A meta- analysis of twice weekly regimen with that of resistance in children is infection with already resistant
daily regimen has concluded that twice weekly organism acquired from an adult.
intermittent short-course therapy is less likely to cure Children have higher propensity than adults to
tuberculosis in children as compared to daily therapy. develop extrapulmonary forms of tubercu-losis,
There is a need for better quality randomized controlled particularly disseminated disease and meningitis. It is
trials for assessing efficacy of alternate schedule for important that antituberculosis drugs used in children
intermittent therapy for childhood tuberculosis.28 Thrice penetrate a variety of tissues and fluids, specially the
weekly intermittent therapy has been used in children meninges.
under DOTS. 29,30 Indian Academy of Pediatrics The pharmacokinetics of antituberculosis drugs differ
recommend use of supervised thrice weekly intermittent in children and adults. In general, children tolerate larger
therapy till new data are available. doses per kilogram of body weight and have less side
effects than adults. It is unclear whether the higher serum
Socioeconomic Principles concentration of antituberculosis drugs, achie-ved in
children provide a therapeutic advantage. In general,
The major determinant of the outcome of treatment is children with more severe forms of tuberculosis, or those
patient adherence to the drug regimens. The length of with malnutrition, expe-rience more significant
treatment programs, adverse effects of drugs, hepatotoxic effects than less severely ill children treated
symptomatic improve-ment of the patient before they with same dosage per kilogram.
complete therapy and the cost of therapy make Antituberculosis formulations for children should
compliance with antituberculosis chemotherapy difficult avoid the usage of suspensions or crushing of tablets as
even in the best of circumstances. Noncompliance leads it leads to inadequate absorption.
400
Case Definitions in Children children under five years in the family of an adult with
There is necessity of making case definitions in children. sputum-positive PTB or severe sputum –ve PTB.
DOTS has been described in details about children Till this date, the contact survey for children under
elsewhere. However, there is no mention of separate case five years is only on paper, and in the program, it is hardly
definitions. In Chapter 9 on pulmonary tuberculosis, we being followed. PPD of the desired strength, i.e. 1TU with
have analyzed our data from the Pediatric TB clinic and Tween 80 is now available for the children in the program.
categorized it as per WHO classification used in DOTS. Some pediatricians are using Span PPD of 5TU strength.
For children, case definitions as described in the earlier This is also not a bad practical solution as an interim
part of chapter based on the clinico-immunoradiological arrangement because a sizable population of preschool
profile by Seth3,3a should be followed. Case definitions children under five years have associated grade
are necessary for two purposes: II and III malnutrition. Seth in Chapter 8 on
i. To determine treatment clinicoimmunological profile has demonstrated that
ii. For recording and reporting. delayed type hypersensitivity is better elicited with 5TU
of PPD particularly in malnourished children.
Why do case definitions determine treatment?
The other basic investigation is radiology, or good
The reasons are:
X-ray chest of the child. Pediatricians would not compro
i. To identify priority cases.
mise if at least these two tests are not made available in
ii. To make the most cost-effective use of resources (by
the program situations, otherwise making a committee
targeting resources on priority cases).
iii. To minimize side-effects for patients, (by using the involving few so called renowned pediatricians
most intensive regimens only for certain cases). (members of Indian Academy of Pediatrics) is futile.
Now, there is ample literature that childhood contacts
What determines case definitions? are potential sources for transmission of the TB disease.
There are four determinants: Merely treating adults will not control tuberculosis. For
i. Site of TB diagnosing tuberculosis in children, also under RNTCP,
ii. Result of sputum-smear status (Adole-scence age described elsewhere, specific guidelines have been laid
period) down. Again, as has been happening in the past, scoring
iii. Previous TB treatment system for diagnosis are being given as a soother.
iv. Severity of TB. However, these are far from satisfac-tory, though can also
Always ask a “new” TB patient if he or she has ever had TB be tried along as a supple-ment but not as a substitute to
treatment before. tuberculin test and X-ray chest. In DOTS, now it is very
Case definition by previous treatment. Seth et al (Chapter rightly emphasized to involve medical colleges and
9) has proposed under this, when to continue the same practitioners including pediatricians for better coverage
regimen, when to reassess the patient and restart either of this valuable section. However, the ground reality is
the same regimen or new, depending upon the type of that pediatricians will not be satisfied for diagnosis of
tuberculosis. This is dependent upon for how long the tuberculosis, based on the scoring system which is being
child has taken treatment. recommended to start with alone. Tuberculin test *(PPD
In DOTS or otherwise, all the child patients must be of 5TU strength) is being used not only by private
given due importance to the treatment/management of practitioners, and pediatricians, but also by pediatric
Fig. 29.1: Case definitions in tuberculosis

401
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• The aim is to the sterilize the tuberculosis lesions, at
10. World Health Organization. Treatment of tuberculosis:
various sites in the body, to prevent spread of disease Guidelines for national programs. 3rd edn. Geneva,
both local as well as hematogenous from primary Switzerland: World Health Organization; 2003. WHO/
infection. CDS/TB/2003.313.
• Single drug therapy for active tuberculosis results in 11. Blumberg HM, Burman WJ, Chaisson RE, et al. American
a substantial relapse rate and development of isolates Thoracic Society, Centers for Disease Control and
resistant to the initial agent. Prevention, Infectious Diseases Society. Treatment of
tuberculosis. Am J Respir Crit Care Med 2003;167:603-
• Patients should receive an initial intensive phase of
62.
treatment with at least 3 to 4 drugs, followed by 2 12. European Respiratory Society Task Force. Tuberculosis
drugs for 4 to 6 months. management in Europe: Recommendations of a Task
• Never add a single drug to a failing regimen. Force of the European Respiratory Society, the World
• Short-course, intermittent therapy is the most Health Organisation and the International Union against
effective and least costly approach to treatment that Tuberculosis and Lung Disease—Europe Region. Eur
now exists. Respir J 1999;14:978-92.
13. Grosset J. The sterilizing value of rifampicin and
• An appropriate combination of drugs prescribed in
pyrazinamide in experimental short-course
correct dosage should be ensured. chemotherapy. Tubercle 1978;59:287-97.
• Compliance with therapy is the major issue in 14. Mitchison DA. Role of individual drugs in the
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• Case definitions defined by Seth3 should be followed. 2000;4:796-806.
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15. Mitchison DA. The diagnosis and therapy of tuberculosis 27. Te Water Naude JM, Donald PR, et al. Twice weekly vs
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Pulmonary Tuberculosis: Old Wisdom and New 30. Sharma S, Sarin R, Khalid UK, et al. The DOTS strategy
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1998;37:433-6.
30 Antituberculosis Drugs:
First-line Agents
INTRODUCTION strategies like change in diet, residence, climate or

employment. These methods have had varied results and
Despite the availability of effective treatment for over fifty probably might have provided benefit to some patients
years, tuberculosis continues to pose a serious threat to by increasing their cellular immune response. Paraamino
global health with nearly a million new cases every year. salicylic acid (PAS) was the first antituber-culosis drug
DOTS has been expanded all over India. To sustain DOTS, and was also the first effective agent administered to a
Global TB Drug Facility (GDF) has been developed by TB patient, antedating the introduction of streptomycin
the Global partnership (STOP.TB) to address these issues. by one month.1 Streptomycin was discovered by Albert
The aim being to increase and secure access to high quality Schatz a graduate student of the famed Dr. Waksman’s
TB drugs. GDF was launched on 24 March in 2001 with laboratory who was a pioneer in the field of soil
the financial help from the government of Canada. microbiology.2 Streptomycin was a powerful, clinically
Further details of the GDF are available on the website at proven antituberculosis drug, but by the end of 1940s it
http://www.STOPTb.org/GDF/. The GDF’s primary became apparent that the clinical usefulness of streptomycin
support mechanism is in the form of grant’s in kind of was being severely curtailed by the emergence of drug
first-line TB drugs. The quantity of drugs provided is resistance. PAS was the first agent available that
calculated on the basis of the number of additional effectively prevented the emergence of streptomycin
patients to be treated in accordance with a national DOTS resistance when the two drugs were given concurrently.
expansion plan. The lessons learnt through the GDF could Isoniazid (INH) first became available in 1952. Treatment
increase access to medicines for disease other than TB, of this dreaded disease evolved so much that in a decade
specially HIV/AIDS. The lessons include the need to: from 1944 to 1954 the prognosis of an individual with
1. Link demand, supply and monitoring, to facilitate tuberculosis changed from a dismal outlook to the
increased access while ensuring rational use. expectation of complete cure. By this time it was apparent
2. Establish a ‘virtual organization’ through a partnership that if streptomycin, isoniazid and PAS were taken for a
of agencies. sufficient period of time, it virtually ensured control of
3. Use product packaging as a means to simplify the disease except for the most virulent forms of
logistics, promote rational use by health workers, and tuberculosis. Even after the introduction of chemotherapy,
enhance patient acceptability and compliance. traditional approaches such as those outlined above were
GDF provides a standardized catalog of TB drugs. still thought to play a role in treatment. It was not until
It ensures supply of fixed-dose combination (FDC) after several controlled studies provided evidence to the
tablets in the package of individual patient. Four and contrary that the primacy of drug therapy was undeniably
two drug FDCs are the core products provided by established.
the GDF. This strategy promotes patient acceptance As we have moved into the 21st century, it appears
and adherence to treatment. that newer antituberculosis drugs will arise from four
4. Use grant of drug to catalyse improvement in the new categories: (i) New use of old drugs; (ii) New
quality of health services provision. delivery of old drugs; (iii) New drugs within old classes;
5. Establish a disease funding base. (iv) Newer classes of drugs. 3 Old drugs such as
The TB drugs supplied are carefully selected with a clofazimine and its analogs, rifamycins, the macrolides,
view to improve the success of treatment. Procurement aminoglyco-sides, quinolones and perhaps vitamin D
of drugs through international mechanisms has not only may find a way into better regimens. New therapy may
reduced the price but has increased the reliability of the also arise from new uses of current antituberculosis
supplies. drugs. New drugs are being developed in the rifamycin,
Centuries of human suffering and deaths from fluoroquinolone and nitroimidazole families. Several
tuberculosis led to widespread efforts to interrupt the immune amplifiers such as gamma interferon,
devastating effects of the disease. Treatment methods interleukin-2 and 12 have undergone pilot testing.3
varied from bizarre exotic methods to very simple Counter-acting adhesion molecules are being tested for
404
several infectious diseases. With the unraveling of the Table 30.3: Other drugs potentially useful in multidrug-
tuberculosis genome, attacking enzymes unique to M. resistant tuberculosis
tuberculosis is easier and allows us to hit elements in both
Newer drugs
a metabolic pathway and its alternate pathway.4
Diarylquinoline
R207910
CLASSIFICATION OF DRUGS TMC 207
Nitroimidazopyran
Traditionally, antituberculosis drugs have been classified PA-824
as first-line drugs having superior efficacy with acceptable Nitro-dihydroimidazo-oxazole
toxicity and second-line drugs either having less efficacy, OPC 67683
greater toxicity or both.5,6 Antituberculosis drugs vary Macrolides
according to bactericidal action and their effect in different Telithromycin
bacterial populations. All the first-line agents are Oxazolidinones
Linezolid
bactericidal except ethambutol. This drug also becomes
PNU-100480
bactericidal in higher plasma concent-ration. The drugs AZ 5847
are classified as shown in Tables 30.1 to 30.4. Diamine
SQ109
Ring substituted imidazoles and other agents
Table 30.1: Classification of antituberculosis drugs Levamisole
First line drugs Second line drugs Thalidomide
Pentoxyfylline
Broad spectrum Narrow spectrum
Interleukin-12 (IL-12)
Isoniazid Fluoroquinolones Amikacin Interferon-α (INF- α)
Rifampicin Ciprofloxacin Capreomycin Imiquimod
Pyrazinamide Ofloxacin Kanamycin Inhibitors of transforming growth factor
Ethambutol Levofloxacin Viomycin (TGB-β) Transfer factor
Streptomycin Moxifloxacin Ethionamide
Gatifloxacin Prothionamide
Table 30.4: Classification of currently used antituberculosis
Rifamycins +Thiacetazone drugs (WHO, 2006)*
(other than
Rifampicin) Group 1 - First-line oral anti-TB drugs
Rifapentine *Para-amino - Isoniazid
salicylic acid - Rifampicin
Rifabutin - Ethambutol
- Pyrazimamide
Macrolides
Group 2 - Injectable anti-TB drugs
Clarithromycin
- Streptomycin
Azithromycin
- Kanamycin
Cycloserine
- Amikacin
* not used, + practically not being used. - Capreomycin
- Viomycin
The other drugs potentially useful for the treatment of Group 3 - Fluoroquinolones
multidrug-resistant tuberculosis are given in Tables 30.2 - Ciprofloxacin
and 30.3. - Ofloxacin
- Levofloxacin
- Moxifloxacin
Table 30.2: Classification of antituberculosis drugs - Gatifloxacin
Group 4 - Oral bacteriostatic second-line anti-TB
Tuberculocidal Tuberculostatic drugs
+
Isoniazid , Rifampicin Ethambutol* (except in - Ethionamide
Streptomycin, Amikacin inflamed meninges), - Prothionamide
Pyrazinamide Thiacetazone, - Cycloserine
Ethionamide - Terizidone
- Para-aminosalicylic acid
Capreomycin, Paraamino salicylic acid - Thiacetazone
Quinolones, Rifamycins Cycloserine* *World Health Organization. Guidelines for the programmatic
+ Bacteriostatic for resting bacilli management of drug resistant tuberculosis. WHO/HTM/TB
* Becomes bactericidal in higher concentrations 2006.361. Geneva, World Health Organization, 2006.
405
Chapter 30 Antituberculosis Drugs: First-line Agents
It has become customary to discuss anti-tuberculosis high EBA is still reached at doses that would usually be
drugs in terms of their effect on different physiologic used in clinical practice. 9b The rapid reduction in
populations of mycobacteria: infectiousness seen in TB patients is due to the use of
• Rapidly multiplying organisms in extra-cellular isoniazid.
environment of pulmonary cavities.
• Intermittently multiplying organisms (semidormant) Sterilizing Activity
in relatively hypoxic or acid environment of solid
Sterilizing activity is defined as the ability to remove so
caseous material.
called “persisters” once the large bulk of rapidly growing
• Occasionally dividing organisms (dormant) in the
organisms has been killed. There are two major
activated macrophages.
components of chemotherapy of tuberculosis.10 If there
• Drug resistant mutants.
is inability to destroy rapidly growing bacilli located
WHO has classified the drugs in four groups Table
largely extracellularly, failure of treatment results.
30.4.
However, if there is inability to eradicate the persisters,
Antituberculosis drugs vary in their ability to kill
the largely intracellular bacilli, relapse occurs subsequent
actively metabolizing extracellular population (bactericidal
to treatment completion.
action), their action on semidormant bacilli (sterilizing
Persisters are those bacilli that have a lower metabolic
action) and in prevention of emergence of resistant strains
activity. These replicate much more slowly than bacilli
(Table 30.5).
found in cavity linings. It was postulated that the efficacy
Mitchison7 has proposed three prerequisites for an
of rifampicin as a sterilizing agent was due to its activity
antituberculosis drug; (i) Early bactericidal activity; (ii)
on persisters.11 Rifampicin and pyrazinamide have the
Sterilizing activity and (iii) Ability to prevent emergence
highest sterilizing activity followed by isoniazid, while
of resistance to the companion drug.
streptomycin, thiacetazone and ethambutol have weak
sterilizing activity.
Early Bactericidal Activity
The early bactericidal activity (EBA) of an antituberculosis Ability to Prevent Emergence of Resistance to the
agent is arbitrarily defined as the decrease during the Companion Drug
first 2 days of treatment in log10 colony forming units. Prevention of the emergence of drug resistance is defined
(Cfu) of M. tuberculosis in the sputum of pulmonary as the ability of a drug to prevent selection of mutants
tuberculosis patients. These patients have smear-positive resistant to the companion drug. Rifampicin has the
TB. Isoniazid has the highest early bactericidal activity.8,9 highest activity to prevent emergence of resistance
It reflects an agents ability to kill metabolically active against isoni-azid, followed by ethambutol and streptomycin
organisms present in the walls of tuberculosis cavities. while pyrazinamide and thiacetazone have very low
While rifampicin and pyrazinamide provide almost all activity (Table 30.5).
of the bactericidal activity, isoniazid is bactericidal only
during the first two days and thereafter prevents the Isoniazid (INH)
emergence of drug resistance.9a Although the EBA of
isoniazid is significantly enhanced by n-acetyltransferase- Isonicotinic acid hydrazide (INH) was intro-duced in
2 (NAT 2) genotype, even in individuals who are clinical practice in 1952.12 It is selectively effective against
homozygous fast (ff) acetylators of isoniazid; a relatively M. tuberculosis and is nearly a perfect chemotherapeutic
Table 30.5: Activity of some important antituberculosis drugs on different bacterial populations
Agent Bacterial Populations

*Active * Semidormant ** Dormant *** Resistant
(Extracellular) (Caseous) (Caseous) (Mutants)
Isoniazid +++ ++ + +++
Rifampicin +++ +++ ++ +++
Pyrazinamide α _ _ +++ _
Streptomycin +++ – – ++
Ethambutol β ++ – ++ +++
*-Bactericidal action ** Sterilizing action
*** - Prevention of emergence of resistance
α – Bactericidal drug active against intracellular organisms
β – Bacteriostatic/bactericidal against both intracellular and extracellular organisms
406
agent owing to its marked bactericidal and sterilizing Postulated modes of action include inhibition of mycolic
action, good oral absorption, relative safety and low cost.1 acid synthesis, depletion of NAD (nicotine adenine
dinucleotide) caused by the incorporation of derivatives
Antibacterial Activity of INH into NAD. INH is neither taken up, nor has any
effect on mycolic acid sythesis in the resistant organisms.
Isoniazid is only active against mycobacteria and is the Further, there is correlation between resistance and
most widely used of the antituberculosis agents. In many loss of catalase-peroxidase activity. 30,31 Isoniazid-
respects it is an ideal agent-bactericidal, relatively easily resistance strains could be sensitized to the drug by
administered, and inexpensive. The effect of isoniazid is transformation with the M. tuber-culosis katG – encoded
mainly against M. tuberculosis complex. Among the catalase-peroxidase.33,34 Deletions and missence mutations
various non-tuberculous atypical mycobacteria, only M. within katG gene are common in isoniazid-resistant clinical
kansasii is usually susceptible to isoniazid. Isoniazid is isolates of M. tuberculosis.35,36
bacteriostatic for “resting” bacilli but is bactericidal for Based on these observations, currently iso-niazid is
rapidly dividing bacilli. The minimal tuberculostatic classified as a prodrug which requires katG gene product
concentra-tion is 0.025 to 0.05 µg/ml in broth and 0.1 to for activation by the catalase,29,37 targeting the last steps
0.2 µg/ml in agar plates.13-15 Of all the antituber-culosis in mycolic acidsynthesis.38 Although the exact mechanism
drugs, isoniazid has the most potent early bactericidal is not very clear the general mechanism of action is as
activity.8,16-18 The addition of other antituberculosis drugs given in Figure 30.1.
will not increase the early bactericidal activity.16 The
rapid reduction of infectiousness following initiation of
Mechanism of Resistance
chemo-therapy is most likely due to the bactericidal
activity of isoniazid.19-21 Mutations in several genes (katG, inhA, ahpC, kasA and
The modern short-course chemotherapy aims at rapid ndh) have been identified which confer resistance to M.
bactericidal and sterilizing action. Combination chemo- tuberculosis. Two important mutations are located on the
therapy is employed because of the usual presence of katG gene,33 and the inhA gene.39 The inhA gene which is
spontaneously resistant mutants to one drug, improper considered as the primary drug target is generally
chemotherapy leads to acquired drug resistance. The associated with low level of resistance. It is responsible
frequency of natural resistance in a sample of wild type for approximately 25 percent of clinical isolates that
mycobacteria is 3.5 × 10 –6 for INH, 3.8 × 10 –6 for demonstrate resistance. Susceptibility to isoniazid is
streptomycin, 3.1 × 10–8 for rifampicin and, 0.5 × 10–4 for dependent on the presence of the catalase-peroxidase
ethambutol.1,22 Children usually do not depict primary enzyme encoded by the katG gene. 36,40 Catalase-
resistance to antituberculosis drugs unless the source case is peroxidase is responsible for transforming the prodrug
suffering with resistant bacilli. INH (pharmacologically ‘inactive-INH’) to its activated
state (‘activated-INH’). Mutations in kat G gene render
Mechanism of Action catalase-peroxidase inactive, which, in turn fails to
activate the prodrug INH. This causes high-level
The acid fastness of the mycobacterium is lost shortly isoniazid resistance to M. tuberculosis. The ahpC gene
after treatment with isoniazid.23 Primarily isoniazid has
been shown to inhibit the biosynthesis of mycolic acids.24
There is a direct correlation between isoniazid uptake,
viability and mycolic acid biosynthesis.25,26 Isoniazid has
an inhibitory effect on the synthesis of saturated fatty
acids greater than 26 carbons and the synthesis of
monounsaturated long chain fatty acids in vivo.27,28
Isoniazid acts on the enzymatic steps (catalase-peroxidase
system) in the elongation of fatty acids, and the
biosynthesis of the very long fatty acid chains of mycolic
acids.29 Antimicrobial activity of INH has high levels of
selectivity for mycobacteria due to the unique mycolic
acids in their cell walls.
Catalase and peroxidase processed by a number of
mycobacteria play a critical role in INH sensitivity.30-32
These enzymes actively transport INH into the cells and
convert it into active metabolite. INH enters the organism
by diffusion and oxygen dependent active transport.
Under anerobic conditions the rate of uptake is reduced. Fig. 30.1: Proposed site of action of isoniazid
407
encodes the alkyl hydroperoxide reductase, and its

absence leads to isoniazid resistance.41 Approximately
60 to 70 percent of isoniazid resistant strains carry
mutations in one of the several genes involved in its
activation from prodrug (katG and possibly ahpC) or in
the drug target (inhA). Still, the mechanism of resistance
for one-third of isoniazid-resistance strains remains to
be elucidated. The maximum proportion of isoniazid-
resistant mutants able to grow during isoniazid
monotherapy of an isoniazid-susceptible strain is
estimated to be approximately 1 in 10.6,42-44
Pharmacokinetics
Following oral administration, INH is rapidly and
completely absorbed. Aluminium containing antacids Fig. 30.2: Major pathway for isoniazid metabolism
and food decrease the absorption from the gastrointestinal
tract.45 Therefore, it is best given on empty stomach. Peak
plasma concen-tration of 3 to 5 µg/ml which is 60 to 100
times the MIC of the drug (0.05 µg/ml), is achieved in 1
to 2 hrs after an oral dose of 5 mg/kg/day. However, in
children the peak ranges from 16 to 20 µg/ml probably
due to a greater dosage of INH per unit of body weight.46
A study by Seth and Rao47 have demonstrated that with
the use of INH in the dosage of 10 mg/kg orally, peak
levels of 90 to 160 times of MIC were achieved. Therefore,
administration of higher dosages in children is not
justified.
After absorption, INH diffuses in all body cells and
fluids. Concentration in CSF is about 20 percent of that
in plasma, or maybe similar to plasma when meninges
are inflamed.48 The infected tissues, phagocytes, and
caseous material retain the drug for a longer time and in
higher concentrations.49 Although the drug readily
crosses the placenta and is secreted in breast milk, yet no Fig. 30.3: Pathway for isoniazid metabolism
fetal or neonatal risks are involved.50,51
INH is metabolized in liver by both acetylation and the formation of INH derived hydrazine and decreased
oxidation via the hepatic P-450 mixed oxidase drug- hepatocellular damage.52 Significant effect on hepatic
detoxifying cytochrome systems, the major metabolites microsomal cyto-chrome P-450 IAI/2 and cytochrome
being acetyl isoniazid and isonicotinic acid. None of these P-450 2E1 activities suggest that their isozymes maybe
metabolites has any biological activity (Figs 30.2 and 30.3).2 involved in the mechanism of the toxicity. After the initial
The rate of acetylation of INH is genetically controlled. peak concentration which is similar in both slow and fast
Acetyl transferase is predominantly found in the liver acetylators, the steady state plasma concentration in the
and the small intestine. In certain ethnic groups the rate latter is less than half of that in the former.3 The plasma
of rapid inactiva-tion is high. Thus, the Japanese, Koreans half-life (t ½) in adult slow acetylators is 2.5 to 3 times
and particularly the Eskimos have a prevalence of rapid more as compared to the fast acetylators.53 Since it is the
inactivation ranging from 50 to 95 percent.2 In South peak level of the drug which is more important than the
Indian population it is as low as about 5 percent. INH sustained inhibitory concentration, the entire daily dose
metabolite hydrazine plays an important role in the given in both fast and slow acetylator types is not
hepatoxicity. Metabolism of INH leads to the production different. However, in intermittent dosing regimens
of hydrazine via both direct and indirect pathways. In (once weekly), controlled trials have shown that rapid
both cases, the activity of an INH amidase is required to acetylators fare worse than slow acetylators as the drug
hydrolyze an amide base. In experimental studies, levels fall below the therapeutic concentration towards
pretreatment with the amidase inhibitor (bis-p-nitrophenyl the end of the week.54 INH-induced hepatotoxicity is
phosphate), 30 minutes before injection of INH, inhibited suggested to be dependent on the acetylation phenotype.
408
In 1975, Mitchell et al55 in their retrospective clinical study only 7.5 percent of children.71
showed that 86 percent of rapid acetylators had INH- The incidence of hepatotoxicity in short-course
induced hepatitis. On the basis of a parallel animal study, regimens and other regimens containing both INH and
that liver toxicity was ascribed to increased exposure in rifampicin is reported to be approximately 4 times more
rapid acetylators to a potent acylating agent formed by than that of regimens containing INH alone.72,73 A study
microsomal activation of monoacetyl hydrazine. Sub- in adult patients taking INH and rifampicin revealed
sequently, doubts were cast on the supposed risk of hepatotoxicity in 5 percent of those given daily regimen
hepatotoxicity among rapid acetylators by the demon- against 0 to 0.1 percent in those receiving thrice weekly
stration that monoacetyl hydrazine is polymorphically regimen.74 The appearance of jaundice is earlier when
acetylated in man.56 both drugs are used together as compared to INH alone.
According to another school of thought, the hepato- The increased toxicity is suggested to be due to
toxicity is more common in slow acetylators.57-59 The toxic accelerated INH oxidation by rifampicin. However,
moiety according to these workers is a product of Girling75 on the basis of his studies concluded that risk
oxidative metabolism (isoniazid hydrazine) rather than of hepatitis did not increase with addition of rifampicin
of acetylation. In children acetylation phenotype plays to INH therapy. Study by O’Brien et al76 using 10 mg /
little or no role60,61 as only 3 to 10 percent of children kg of INH and 15 mg/kg rifampicin demonstrated
while on INH therapy experience transient elevation of hepatitis in only 3.3 percent of patients should hepatotoxicity
liver transaminases, a rate much lower than in adults.62,63 occur, it is observed generally with in the initial 2-3
Seth et al64 have reported comparable levels of hepatic months of therapy. A study conducted in adults
enzymes in slow and rapid acetylators in children. In a measuring the INH metabolites in urine after adminis-
large population based study, there was no significant tration of both drugs showed insignificant changes
difference in the incidence of INH-induced hepatotoxicity in the rate of hydrolysis.24 A large number of clinical
by host acetylation rate status.65 studies in 2500 adult patients in East Africa, Hong Kong
INH is excreted in urine chiefly as metabolites within and Singapore using both drugs showed incidence of
twenty four hours of oral administration. Since only a jaundice in only 1 percent of cases. This is similar to that
small portion of active drug is excreted in urine, mild encountered prior to the introduction of rifampicin.76-78
impairment of renal function does not necessitate the Hence, use of both the drugs together did not increase
dosage adjustment; however, in slow acetylators with the risk of hepatotoxicity.
severe renal damage, the doses need to be halved.66
Treatment of Hepatotoxicity
Adverse Effects
It has been observed that clinical and laboratory features
The total incidence of adverse effects is reported as 5.4 suggestive of hepatotoxicity maybe because of concomitant
percent.66,67 These include skin rash (2%), fever (1.2%), viral hepatitis rather than due to antituberculosis
jaundice (0.6%) and peripheral neuritis (0.2%). Urticaria drugs.79,80
and other hypersensitivity reactions occur in 1.2 percent When the levels of transaminase (AST, ALT) enzymes
of cases. Hypersensitivity reactions, peripheral neuritis, increase by 3 to 5 times of normal, temporary cessation
and the rare side effects related to CNS seen in adults, of both drugs is recommended.81 With clinically evident
are very rarely noticed in children. hepatotoxicity, all drugs should be stopped and
combination of ethambutol and streptomycin be given,
Hepatotoxicity till the liver functions are restored to normal. Seth82 has
recommended that rifampicin should be started in the
It is reported to occur in 15 percent of adult patients,
dose of 5 mg/kg when transaminases have decreased to
however, in children the incidence is much lower (3-10%)
with serious jaundice occurring in only 0.6 percent of levels less than twice the normal while continuing
the cases.67 Hepatotoxicity is age related, and is more streptomycin and ethambutol. AST, ALT should be
likely to occur in adolescents, in patients with severe estimated every week, if they are normal after a week,
forms of the disease such as miliary tuberculosis and rifampicin dose can be increased to 10 mg/kg and then
meningitis.68,69 It is also associated with severe malnutrition. INH is reintroduced. At this stage, if the patient is having
For most children hepatotoxicity can be monitored using serious type of tuberculosis such as TBM, miliary or
clinical symptoms and signs. The routine biochemical osteoarticular tuberculosis, pyrazinamide can be added
monitoring is not necessary when therapeutic dose of 5 in the dose of 20 mg/kg with monitoring of AST and
mg/kg/day is being used. Hepatotoxicity is noticed ALT. The drugs can be continued even if the enzyme
when higher doses are used (higher than 10 mg/kg/ levels are twice the normal. There is a need to stop INH
day).57,70 Use of INH for chemopro-phylaxis even at 10 or pyrazinamide if the liver enzyme levels rise to more
mg/kg/day resulted in elevation of transaminases in than four times the normal. Regular monitoring of liver
409
functions is necessary with the altered treatment. Diagnosis

Adjustment of doses maybe required as hepatotoxicity
Severe isoniazid poisoning is characterized by the
is dose related. INH should not be used more than 5 mg/
presence of repetitive convulsions not responsive to usual
kg/day, even in the case of tuberculous meningitis in
treatment and metabolic acidosis. Measurement of INH
daily regimen and 10 mg/kg in intermittent regimens.
serum levels are not useful for the clinical management
of INH overdose.
Peripheral Neuritis
It is attributed to drug-induced pyridoxine deficiency and Chronic Toxicity
is probably due to enhanced excretion of pyridoxine.2
Hepatitis, peripheral neuropathy and hemolytic
Peripheral neuropathy is common in adults and is dose
anemia are manifestation of chronic toxicity. It produces
and age dependent. Children are however, less prone to
nausea, vomiting, restlessness, fever, toxic hepatitis, and
have pyridoxine deficiency.83 In younger children,
hemolytic anemia may be observed. At times psychosis
pyridoxine levels maybe decreased, but clinical signs are
may occur.
not apparent. Thus they rarely require the prophylactic
administration of pyridoxine, except those having Management
deficiency symptoms before therapy or have tuberculous
meningitis. Dose of pyridoxine is 5 to 10 mg/day in Acute Toxicity
children. It is also advisable to give pyridoxine with
Patients with INH overdose should always be admitted
isoniazid to women during pregnancy and to persons
to an emergency or intensive care unit. Treatment is as
who have a seizure disorder.
follows:
Central Nervous System—Side Effects Supportive Measures
INH may precipitate epilepsy, cerebellar ataxia, optic
• Control of convulsions by short-acting barbiturate
neuritis and rarely psychotic changes in adults. These (thiopental) or benzodiazepines (diazepam).
reactions have responded to pyridoxine administration. • Protection of airway (intubation) and maintenance of
In a study by Sanfeliu et al84 done in Canada, hydrazine adequate ventilation (artificial ventilation) if
was found to be the metabolite with the highest necessary.
neurotoxicity in mouse studies. INH also interferes with • Correction of hypotension by plasma expanders and/
niacin metabolism to a significant extent and or dopamine.
can cause neurological symptoms. Pellagra has been • Rehydration and correction of metabolic acidosis
produced due to exacerbation of niacin deficiency by INH (sodium bicarbonate) and electrolyte abnormalities.
in undernourished individuals.84 Recently, Dompeling
et al85 have reported diplopia and strabismus, convergence Antidote
mimicking symptoms of tuberculous meningitis as side
effects of INH.85 Convulsions should be treated with intravenous
pyridoxine (Approximately 1g of pyridoxine for each
ACUTE TOXICITY OF ISONIAZID gram of INH ingestion).
Main Risks and Target Organs Elimination

CNS is the target organ of INH acute toxicity. It induces Gastric lavage and oral activated charcoal are indicated
generalized convulsions, coma, metabolic acidosis. Death with in 3 to 4 hours following ingestion. Ensure adequate
may occur from acute respiratory failure or hypotension. diuresis. The usefulness of forced diuresis is not
Toxicity appears after 0.5 to 4 hours following ingestion. established. Hemodialysis may be considered in patients
Symptoms may include. unresponsive to supportive treatment, anticonvulsants
• Slurred speech, hallucinations, coma and intravenous pyridoxine.
• Generalized convulsions, status epilepticus
• Respiratory failure, hypotension. Contraindications
• Severe metabolic acidosis, fever Known severe adverse reactions or hypersensitivity due
• Rhabdomyolysis to the drug. Previous hepatitis with INH. INH should
• Gastrointestinal symptoms (nausea, vomiting) are not be used in acute liver disease. INH may precipitate
frequent prior to the onset of convulsions. porphyria.
410
Caution Therapeutic Status

Convulsions may be precipitated in patients with Isoniazid is the most important drug for treating all types
epilepsy. of tuberculous infections. It is mostly used in combination
with other drugs preferably even in preventive therapy.
Miscellaneous Daily dose is 5 mg/ kg/day and in intermittent regimens
it is to be given in a dose of 10 to 15 mg/kg thrice or
Dryness of mouth, epigastric distress, methemoglobi- twice a week.
nemia, tinnitus and urinary retention are rare side effects.
Patients with subclinical pyridoxine deficiency may show RIFAMPICIN (RIFAMPIN)
anemia, rash and symptoms of neuropathy.
Rifampicin is a semisynthetic derivative of rifamycin B
A drug-induced syndrome resembling lupus erythe-
and is derived from Streptomyces mediterranei. 116
matosus (drug-induced lupus) has been reported.86 Toxic
Rifampicin is a potent broad spectrum antibiotic effective
dose may cause coma, seizures, acidosis and hyper- against mycobacteria, staphylococci, streptococci,
glycemia. meningococci, clostridia and coliform organisms. Its
Isoniazid crosses the placenta, but no significant potent bactericidal and sterilizing activity against the
teratogenic effects have been reported even when used tubercle bacillus and suitability for oral administration
during the first four months of pregnancy.86a has made it a key drug for the treatment of tuberculosis.
Rifampicin has succeeded in reducing the duration of
Pregnancy and Breastfeeding treatment of tuberculosis from the former standard of 18
to 24 months to 6 to 9 months. Rifampicin is the most
Isoniazid is distributed into breast milk. An estimated
potent antituberculosis drug in converting positive
0.75 to 2.3 percent of the daily adult dose could be sputum cultures to negative. This characteristic ability
ingested by the nursing infant. Problems in nursing of sterilization has been attributed to rifampicin’s ability
newborns have not been documented and breastfeeding to affect dormant organisms.117 The minimum inhibitory
should not be discouraged. However, because isoniazid concentration of rifampicin in vitro is 0.005 to 0.02 µg/
concentrations are so low in breast milk, breastfeeding ml. The majority of other strains of mycobacteria are also
cannot be relied upon for adequate tuberculosis sensitive but to the higher concentration of the drug.
prophylaxis or therapy for nursing infants.12 Primary drug resistance to rifampicin may occur in
less than 1 percent of cases which necessitates its
Drug Interactions administration with other drugs.118,119
Isoniazid is an inhibitor of oxidative and demethylation Mechanism of Action
metabolism, and also other cytochrome P-450 dependent
microsomal pathways.87 It is also a monoamine and Rifampicin inhibits DNA-dependent RNA polymerase
diamine oxidase inhibitor.88 Certain types of cheese rich leading to suppression of initiation of chain formation in
in monoamines may lead to hypersensitivity reactions.89 RNA synthesis. The β subunit of polymerase which is
involved in binding to DNA and initiation of RNA chain
Effect of isoniazid are potentiated by para-
has been shown to have specific binding sites for the drug.
aminosalicylic acid,90 insulin,91 carbamazepine92 and
As a result the initiation of RNA transcription is blocked
theophylline.93 Effects of isoniazid are opposed by pred- but the elongation is unaffected. Rifampicin resistance
nisolone94 and ketoconazole.95 Isoniazid potentiates the occurs usually by a single mutation in the gene that
effects of a large number of drugs. The acetaminophen specifies α subunit of RNA polymerase.10 It is bactericidal
hepatotoxicity is increased by isoniazid.96,97 The action for both intracellular and extracellular bacilli.
of antiepileptics such as phenobarbitone, diphenylhydan-
toin, 98-100 carbamazepine, 101-104 ethosuximide105 and Mechanism of Resistance
valproic acid are enhanced.106-108 The interaction of iso-
Mutations in the rpoB gene of M. tuberculosis are
niazid and antileptics increase the serum concentration
responsible for most resistance,120 and have been found
of both drugs. When these drugs are given concomitantly in more than 97 percent isolates.121,122 Micro-organisms,
the serum levels of antiepileptics should be monitored including mycobacteria, may develop resistance to
and the antiepileptic doses decreased if necessary. The rifampicin rapidly in vitro as a one-step process, and one
effects of diazepam109 and triazolam,110 haloperidol111 of every 107 to 108 tubercular bacilli is resistant to the
and tricyclic antidepressants112,113 are potentiated by iso- drug. Mutations reduce binding of rifampicin to its target
niazid. The anticoagulant action of warfarin114 and the polymerase of the mycobacterium therapy evading its
action of antineoplastic agent vincristine115 are enhanced. killing action. The maximum proportion of rifampicin-
411
resistant mutants able to grow during rifampicin ml was reached nine hours after drug ingestion in normal
monotherapy of an isoniazid-susceptible strain is subjects.132 The mean half-life in children after initial dose
estimated to be 1 to 108 approximately.123 Tuberculosis is 2.9 hours but shortens to 2.5 hours on repeated dosing
caused by rifampicin-resistant mycobacteria has been because of its hepatic enzyme inducing action.133 The
described in patients who had not received prior half-life is increased by hepatic dysfunction and may be
chemotherapy but this is very rare. decreased in slow INH-inactivator-patients concurrently
receiving INH.
Pharmacokinetics Rifampicin is metabolized in liver by deacetylation
and undergoes enterohepatic circulation. The metabolite
After oral administration of rifampicin on an empty
retains full antibacterial activity. Approximately 60
stomach, the absorption is rapid and practically
percent of the drug and metabolites are excreted in feces.
complete. 124 Seth et al 125-127 carried out detailed
Less than 30 percent of a dose is excreted in urine as
pharmacokinetic studies of rifampicin in different types
metabolites or as unaltered drug. Therefore, adjustment
of tuberculosis under different drug regimens. Serum
of dosage is necessary in hepatic dysfunction, but not
half-life of rifampicin ranged from 3.03 to 3.81 hours,
required in cases of renal insufficiency.134
whereas Cmax ranged from 3.38 to 3.88 ug/ml. Further, a
sustained serum concentration much above the MIC
Adverse Effects
of rifampicin was maintained even 24 hours after
administration of a single 12 mg/kg dose of the drug. When given in therapeutic doses, rifampicin is well
The mean t½ of rifampicin in children after initial dose is tolerated and causes adverse effects in less than 4 percent
2.9 hours but shortens to 2.5 hours on repeated dosing of patients. Common side effects are related to
because of its hepatic enzyme inducing action. Further, gastrointestinal tract (GIT) and include nausea, vomiting
when rifampicin was given in a dose of 10 mg/kg/day (1.5%), epigastric discomfort and diarrhea. Skin rash
to children suffering from pulmonary primary complex, (0.8%) and fever (0.5%) may also occur with its use in
adequate serum levels of drug could be achieved that adults.81 The incidence is more with higher doses and
were 50 times of MIC; and drug was found to be clinically with intermittent therapy. These side effects are
effective. Food interferes with the absorption of uncommon in children.
rifampicin and results in a low plasma level and hence it In general, adverse effects are divided in two broad
is advisable to give it atleast half an hour before categories which include direct toxicity (GIT, liver) and
breakfast. 128 Further, it has been shown that the immune-mediated toxicity, autoimmune manifestations,
pharmacokinetics is influenced by meals 129,130 but skin reactions etc.12
depends upon the type of constituents of food.131
Carbohydrates and proteins seem to have virtually no Hepatotoxicity
influence, while a fatty meal reduces serum concentration
The incidence of hepatotoxicity is greater when higher
considerably.131 The major differences in pharmacokinetics
doses are used (> 15 mg / kg). Only 0.6 percent of patients
following a meal include a reduced total amount
on rifampicin may develop jaundice. Patients with pre-
absorbed (area under the curve) and delayed achievement
existing liver disease are at increased risk. Many patients
of peak serum levels.132 It gives orange-red color to urine,
who develop slight elevation of serum transaminases
sweat, feces, saliva and tears.
may not show symptoms despite continuous therapy,
Rifampicin is highly lipid soluble and penetrates well
therefore, discontinuation of therapy is not necessary.
into most of the tissues and is present in effective
Concurrent administration of INH may sometimes cause
concentration in all the organs and body fluids including
serious but reversible hepatitis.134 It is usually associated
CSF. Rifampicin also reaches the caseous foci, phagocytes
with excessive doses of INH.134 In children, however, if
and crosses the placenta. Breast milk, fat tissue, cavity
the doses of INH and rifampicin are not exceeded beyond
linings of lung, parenchyma and kidney achieve higher
5 mg/kg and 10 to 12 mg/kg respectively, toxic hepatitis
tissue concentration of drug than the serum levels132 but
is rare as mentioned earlier.
well above the minimum inhibitory concentrations are
achieved in pyogenic bone lesions and the pleura. Critical
Autoimmune Reactions
concentration close to the minimum inhibitory concen-
tration were measured in caseum and cerebrospinal fluid The immune-mediated reactions appear to be related to
in meningitis. In comparative studies, mean peak the development of immune system recognition of
rifampicin concentrations in the cerebrospinal fluid of epitopes of rifampicin. Interrupted or intermittent
patients with tuberculous meningitis of 2.4 µg/ml were administration of rifampicin favours the development
obtained 6 hours after administration of 600 mg of immune system recognition. Adverse reactions
rifampicin, while a delayed mean peak of only 0.81 µg/ associated with intermittent rifampicin include the flu
412
like syndrome and syndromes associated with to concentrate. Immunosuppression especially,

thrombocytopenia and purpura which are indications depression of T-cell mediated immunity, has been
for stoppage of the drug.2 reported, however, its clinical significance is not
High dose intermittent therapy or reinstitution of known.138 The biliary excretion of bilirubin is reduced in
rifampicin therapy after a drug free interval (either as a the initial period of treatment raising the serum levels,
part of a regimen or poor compliance) may lead to many however, it decreases after 2 to 3 weeks. The drug causes
side effects that are due to the presence of rifampicin red discoloration of urine, tears and sputum which is
antibodies in the circulation.135 In patients on once weekly harmless and serves as a check for drug compliance. Two
regimen of 25 mg/kg or more, influenza like syndrome case reports show menstrual disturbances and
consisting of malaise, headache, fever and myalgias Addisonian crisis with its use.139,140 Theoretically, since
maybe seen in 50 percent; some of them may experience rifampicin crosses placenta and its teratogenicity is not
shortness of breath and wheezing also. It is advisable to known, it is best to avoid rifampicin during pregnancy.
restart the therapy within 3 weeks of its stoppage in However, practically and paradoxically, the multidrug
reduced dosage in order to avoid hypersensitivity regimen of isoniazid, rifampicin and ethambutol is
reaction due to the persistence of circulating antibodies.75 considered safe during pregnancy.
With the use of 12 mg/kg dose, both in continuous and Limb defects have been observed in foetuses of
intermittent therapy in children, these reactions are not mothers taking rifampicin,140a but Snider et al140b failed
seen. to detect increased incidence of teratogenicity among
Other autoimmune reactions include respiratory shock mothers taking rifampicin during pregnancy. Presently,
syndromes, acute hemolytic anemias and acute renal rifampicin is considered to be an essential component
failure. In case of acute hemolytic anemia or acute renal of antituberculosis treatment during pregnancy.140a,140c
failure, rifampicin should never be given again. Renal
failure is fortunately extremely rare and almost always Drug Interactions
results in complete recovery of renal function.1,7
Owing to its reported characteristic of being a powerful
inducer of hepatic drug metabolizing enzymes,
Cutaneous Syndrome cytochrome P systems: CYP1A2, 2C9, 2C19 and 3A4,
Flushing, itching with or without rash on face and scalp, rifampicin accelerates the metabolism and decrease the
and sometimes watering of eyes occur within 2 to 3 hours half-life of drugs including glucocorticoids, oral
after a dose of rifampicin. These symptoms subside with contraceptives, propranolol, metoprolol, quinidine,
symptomatic treatment.135 These are also rare in children. digoxin, ketoconazole, fluconazole, cyclosporin, theo-
phylline, barbiturates, clofazimine, sulfonylureas, oral
Rare Hypersensitivity Reactions anticoagulants and digitalis.141
Appropriate increase in the dose of these drugs is
These may occur with intermittent therapy and include required to compensate for the increased metabolism. A
eosinophilia, acute hemolytic anemia, and acute renal study from Chennai (Madras) showed enhanced renal
failure. Thrombocytopenia, which is closely related to excretion of uric acid in patients receiving rifampicin and
the presence of circulating IgG and IgM antibodies, is pyrazinamide.142
also reported. All these reactions are indications for
discontinuation of rifampicin therapy.136 Therapeutic Status
Poisoning Rifampicin is a bactericidal and rapidly sterilizing drug
useful in pulmonary and extrapulmonary tuberculosis.
Poisoning due to overdosage of rifampicin results in the It is an important ingredient for all regimens used because
development of the so called red man syndrome which of its effectiveness, safety and oral administration. In
maybe fatal.137 The skin and subsequently the sclera children it is used in doses of 10 mg/kg in daily dosage
become reddish orange in color. Nausea, vomiting, regimens and in 12 to 15 mg/kg in intermittent dosage
abdominal pain and convulsions have been observed in schedules. It is never used alone in the treatment of
the few cases of overdosage described. Treatment is tuberculosis because of rapid development of resistance.
essentially supportive and often needs gastric lavage.
STREPTOMYCIN
Miscellaneous Side Effects Streptomycin belongs to the aminoglycoside group of
Side effects related to CNS are rare and include headache, antibiotics and was the clinically effective drug which
fatigue, drowsiness, dizziness, ataxia, generalized became available a little after PAS for the treatment of
numbness, muscular weakness, confusion and inability tuberculosis in 1947.
413
Antibacterial Activity to be reduced. Deep intra-muscular injections will

prevent the discomfort of tender indurated masses at the
Streptomycin is a bactericidal drug with MIC as low as injection sites which will occur if the drug is injected into
0.4 µg/ml. Most of the strains of M. tuberculosis are the subcutaneous tissues.2 The excretion of streptomycin
sensitive to 10 µg/ml. M. kansasii is frequently sensitive, is exclusively renal, by glomenular filtration.
but other non-tuberculous mycobacteria are infrequently
susceptible. Its use has become limited because of its Adverse Effects
toxicity, need for large doses that cannot be administered
orally but only parenterally, and rapid emergence of drug Ototoxicity
resistant isolates.2,6 In addition, owing to its action
entirely on rapidly growing extracellular bacilli it Ototoxicity is the major toxic effect and is dose related.
is unsuitable for sterilization of the lesion. In children Symptoms of vestibular toxicity such as vomiting,
it needs to be used only in severe forms of tuberculosis tinnitus and vertigo are more common than hearing loss,
such as meningitis, miliary and osteoarticular tuber- which, if occurs, is permanent. The dosage should be
culosis for its action on the extracellular organisms. reduced in patients with renal insufficiency. It should
not be given during pregnancy and to a child with ear
disease.81 Streptomycin induced ototoxicity has been
Mechanism of Action
reported irrespective of period of gestation, therefore,
Streptomycin reacts with 30S-subunit of bacterial streptomycin should not be used during pregnancy. A
ribosome thereby distorting the ribosome and preventing patient on streptomycin treatment should undergo
normal interaction between codon of mRNA and frequent monitoring of vestibular functions.
anticodon of tRNA, leading to miscoding of protein
synthesis. Leakage of low molecular weight substances Renal Toxicity
from the cells in vitro is suggestive of its action on cell wall
Less severe renal toxicity than with other aminoglycosides
also.143
is known to occur with streptomycin.146 However, it
should be avoided in very young children and in patients
Mechanism of Resistance with renal insufficiency. If necessary, it should be used
Bacterial resistance is due to the development of in latter situation with half the loading dose. It is probable
ribosomes which are unable to bind to the antibiotics. that certain diuretics particularly loop diuretics may
Resistance to streptomycin results for a limited number potentiate its toxicity.147,148
of missence mutations in the rrs gene (16S rRNA) or in
rpsL gene (ribosomal protein S12).144 The maximum Neuromuscular Blockade
proportion of streptomycin resistant mutants able to In man, neuromuscular blockade is reported to occur
grow during streptomycin monotherapy of an isoniazid after intrapleural or intraperitoneal instillation of large
susceptible strain is approximately 1 in 10. 8,43 The doses.149 However, it may also follow intramuscular
incidence of resistance increases with its longer duration administrations. Most episodes of acute muscular
of therapy, hence not suitable beyond initial 2-4 months paralysis and apnea occur during anesthesia or with
of therapy. other neuro-muscular blocking agents administered
simultaneously. Magnesium may potentiate the risk of
Pharmacokinetics
neuromuscular blockade while intravenous use of
Streptomycin is poorly absorbed from the gastrointestinal calcium can overcome this toxic effect. Myasthenics are
tract. The salient features regarding the absorption of at particular risk of neuromuscular blockade and the drug
aminoglycosides are that they need to be given must be preferably avoided in this group.
intravenously or intramuscularly145. Because of their size
and cationic charge, they do not cross most biological Miscellaneous
membranes.2 The peak plasma concentration of 25 to 40
Peripheral neuritis, optic nerve dysfunction and
µg/ml after intramuscular injection of 0.7 to 1 g dose is
occasional hypersensitivity reactions characterized by
achieved within 30 to 90 minutes.4 Streptomycin is poorly
skin rash, urticaria, fever and anaphylaxis are also
distributed to extracellular fluids and CSF.2,45 However,
reported.76
high concentrations are found in renal cortex, endolymph
and perilymph of the inner ear. Diffusion to pleural and
synovial fluids is slow but concentration equals the
Drug Interactions
plasma concentration are achieved after repeated doses. Ototoxicity of streptomycin is increased by furosemide147
Plasma half-life is about 2 to 3 hours which is prolonged and ethacrynic acid.148 Further, like other aminoglycosides
in patients with renal insufficiency, where the dose has streptomycin has a neuromuscular blocking effect which
414
may lead to prolonged respiratory depression following Mechanism of Resistance

co-administration with curare-like drugs, such as
pancuronium,149 succinyl-choline or tubocurarine150 Mutations in pncA, a gene encoding pyrazinamidase,
or non-depolarizing relaxants such as diallyl- cause resistance to pyrazinamide.158,159 Resistance against
nortroxiferine.151 pyrazinamide appears to develop very fast, if given as a
single effective agent.160
Therapeutic Status
Pharmacokinetics
Since more effective and less toxic antituberculosis drugs
have become available, the use of streptomycin has Pyrazinamide is well absorbed orally. After on oral intake
decreased. In tuberculous meningitis and in regimens of 1500 mg of the drug, a peak level of 25 to 30 µg/ml is
with 5 drugs to treat resistant cases the drug is still used achieved after one to one and a half hour.161 It is widely
with good results. The recommended dose is 15 to 20 distributed in body tissues and fluids, and has one of the
mg/kg/day to be given intramuscularly. Because of best penetrations into CSF among the antituberculosis
difficulties associated with parenteral therapy and its drugs.162,163 Plasma half-life of the drug is 12 to 24 hours
potential toxicity, streptomycin needs to be reserved for which lends itself to once daily dosing.6 It is metabolized
serious and resistant cases requiring supervised therapy. in liver with about four percent of pyrazinamide excreted
These drugs cross the placenta and use of streptomycin unchanged in urine and about 30 percent as pyrazinoic
is contraindicated during pregnancy as it is associated acid.164 It is only slightly influenced by ingestion of
with an increased incidence of fetal malformations as antacids, but with a fatty meal Tmax is delayed and Cmax
compared with controls. Damage of the eighth cranial slightly lowered, although these effects are unlikely to
nerve is the most frequent associated complication. bear clinical relevance.165 Absorption of pyrazinamide
is not influenced by food intake.
PYRAZINAMIDE
Like INH, pyrazinamide is a prodrug and a nicotinic acid Adverse Effects
derivative. Studies in the early 1950s abandoned its use
due to hepatotoxic effect seen in 15 percent of the patients.
Hepatitis
However, it was later found that larger doses (50 mg/ Hepatitis is commonly associated with the use of high
kg/ day) used for a longer period was the causative doses (40 to 45 mg / kg) of pyrazinamide. Studies
factor. Hence, until 1970s pyrazinamide was used as a conducted with therapeutic doses of 30 to 35 mg/kg in
second line agent.12 In doses of 20 to 35 mg /kg/day it daily regimen or 45 mg/kg in thrice a week regimen did
was no longer a hepatotoxic drug and does not add to not report hepatitis.67 A study from India did not show
liver toxicity caused by INH and rifampicin. 75 hepatotoxicity in children treated with 30 mg/kg/day
Pyrazinamide is bactericidal with MIC of 12.5 µg/ml, dose of pyrazinamide.166 However, Kumar and Seth167
against intracellular population of mycobacteria only at reported rise in both SGOT and SGPT without evident
an acidic pH. jaundice in children with pulmonary primary complex.
Mechanism of Action Gouty Arthralgia
Pyrazinamide is only active against M. tuberculosis, the
The metabolite of pyrazinamide, pyrazinoic acid, is
other mycobacteria such as M. bovis are naturally
suggested to interfere with excretion of uric acid by
resistant.152 Pyrazinamide is believed to be most effective
decreasing its tubular secretion leading to increased urate
at an acidic pH.153 It acts specifically on dormant
concentration in serum and clinical manifestations of
intracellular organisms but is not active against rapidly
gout.83 It affects both small and large joints and mainly
and intracellularly growing M. tuberculosis. 154,155
Pyrazinamide appears to exerts its effect after getting involves the shoulder, knee and the finger joints.2 This
converted into pyrazinoic acid inside the monocytes at side effect is more common with daily regimen and
acidic pH.156 It is only the accumulation of pyrazinoic symptomatic treatment with aspirin is usually sufficient
acid through the action of amidase, pyrazinamidase by without discontinuation of the therapy. Rarely
susceptible M. tuberculosis which leads to its intracellular allopurinol might be needed. Although classical gout is
bactericidal action.157 For the susceptibility to pyrazinamide, not seen, polyarthralgia which is related to elevated
presence of both a functional pyrazinamidase and serum uric acid levels is a common side effect.2
pyrazinamide transport system into M. tuberculosis have
been postulated as the prerequisites. The exact target is Miscellaneous Effects
not known, however, the NAD metabolic pathway has Nausea, vomiting, photosensitivity and thrombocytopenia
been postulated as one of the potential targets. are the rare side effects.
415
Drug Interactions Antibacterial Activity

Allopurinol, increases plasma concentrations of Most of the strains of M. tuberculosis and M. kansasii as
pyrazinoic acid which is directly responsible for the well as a number of strains of M. avium complex are
inhibition of renal urate secretion. 168 Therefore, sensitive to ethambutol172 but the sensitivities of other
pyrazinamide induced arthralgias are unresponsive to nontuberculous organisms are variable, and has no effect
allopurinol. Further, pyrazinamide might antagonize the on other bacteria. Ethambutol suppresses the growth of
action of drugs that have a uricosuric effect such as acetyl- most isoniazid and streptomycin resistant tubercle bacilli.
salicylic acid, ascorbic acid, probenecid, and iodine It may have bactericidal effect when given in the higher
containing radiocontrast offering preparations.169,170 dosage used in intermittent therapy.
Ethambutol is bactericidal on both extracellular and
Therapeutic Status intracellular tubercle bacilli.173 The MIC of ethambutol
for M. tuberculosis is from 0.95 to 7.5 µg/ml in broth and
Due to faster sputum conversion rate, pyrazinamide is 19 to 7.5 µg/ml on agar.13
an essential ingredient of six-months treatment regimen Ethambutol is less active than INH and rifampicin,
administered usually in the first 2 months of therapy and however, it suppresses the growth of all INH and
sometimes for a total period of 6 months, with the other streptomycin sensitive as well as resistant mycobacteria.
two or three drugs. As recommended by World Health
Organization (WHO) and International Union Against Mechanism of Action
Tuberculosis and Lung Disease (IUATLD), pyrazinamide
can be safely used in pregnancy.170a If pyrazinamide is Ethambutol specifically inhibits the biosynthesis of the
not included in the initial treatment regimen the mycobacterial cell wall by inhibiting the biosynthesis of
minimum duration of treatment is nine months. Benefits arabinogalactan, the major polysaccharide of the
of the use of pyrazinamidy in HIV-positive pregnant mycobacterial cell wall. It inhibits the polymerization of
women out weigh the undermined potential risks to the cell wall arabinogalactan and of lipoarabinomannan.174
fetus. Pyrazinamide is the third most important drug in Ethambutol indirectly inhibits mycolic acid synthesis, by
the treatment of tuberculosis.22 blocking arabinosyl transferases and thus limiting the
The relapse rate with pyrazinamide is very low availability of arabinan for mycolic acids to attach to,175
because of its unique property of killing the dormant and triggers a series of changes in the lipid metabolism
of mycobacteria, resulting in disaggregation of bacterial
mycobacterial population. However, it is ineffective in
clumps into smaller clusters.173 Ethambutol is suggested
preventing drug resistance. Due to its excellent
to break the ‘exclusion barrier’, located in the M. avium
penetration into the CSF, it is the most useful
cell wall and thus significantly enables the activity of
antituberculosis agent for treating tuberculous meningitis.
other antituberculosis drugs, both intracellularly and
Doses up to 30 mg/kg/day are well tolerated by children
extracellularly.175 It suppresses the growth of both INH-
without any side effects. Safe use of pyraminamide
and streptomycin-resistant tubercle bacilli.
during pregnancy is recommended by many European
countries and international agencies like International
Mechanism of Resistance
Union Against Tuberculosis and Lung Disease (IUATLD)
however, its use during pregnancy is not recommended Bacterial resistance to ethambutol develops in vivo via
in USA. It is because of lack of safety studies (terato- single amino acid changes in the embA gene when
genecity) in the USA population. ethambutol is given alone or in the absence of another
effective agent.176 The proportion of ethambutol resistant
mutants able to grow during ethambutol monotherapy
ETHAMBUTOL
of an isoniazid-susceptible strain is estimated to be 1 in
Ethambutol is a synthetic compound, with a selective 108 tubercle bacilli.43 Resistance to ethambutol develops
bacteriostatic action against rapidly growing cells of all very slowly in vitro.
strains of mycobacteria. Ethambutol has become an
important companion drug in place of PAS or Pharmacokinetics
thiacetazone in present day regimens.171 Ethambutol was Ethambutol is rapidly and almost completely absorbed
discovered as a new antituberculosis agent in 1961. Its in (75 to 80%) from the gastrointestinal tract following oral
vitro concentrations of 1-4 µg/ml inhibited the growth administration. Serum concentration is maximal at about
of M. tuberculosis H37 RV. In the heavy dose used (60- 2 to 4 hours.177,178 Following doses of 50 mg/kg body
100 mg/kg/day body weight) it resulted in toxic weight and 25 mg/kg body weight daily, serum
amblyopia. However, these ocular disturbance improved concentrations achieved were 10 µg/ml and 5 µg/ml
after stoppage of medicine. respectively. Serum concentrations were proportional to
416
the dose. Less than 10 percent of the dose administrated Ocular Toxicity
was present in the serum after 24 hours and there was,
Ocular toxicity is the most important adverse drug event
little, if any evidence that ethambutol accumulates in the
of ethambutol, first reported in 1962.186 Subsequently a
tissues. From 90 to 94 percent of the administered drug
large number of publications have reported this
having been recovered from the urine and feces178 and
toxicity.185,187-195 It has been suggested that binding of
there was no evidence of accumu-lation of the drug over
ethambutol to zinc or copper maybe responsible for the
more than 3 months. Within 6 hours, 28 percent of an
ocular toxicity.196,197 Two types of optic neuropathy, have
oral dose was excreted in urine.177 A recent study in
been reported for ethambutol.197,198 The most important
children using more sophisticated methodology 179 is the noninflammatory axial fiber disease involving
confirmed the initial observation that within 24 hours central fibers of the optic nerve, commonly known as
three fourths of an ingested dose of ethambutol is retrobulbar neuritis. Those with periaxial toxicity have a
excreted unchanged in the urine; up to 15 percent is defect in the peripheral isopters of their field of vision,
excreted in the form of two metabolites, an aldehyde and with little or no decrease in visual acuity and normal
a dicarboxylic acid derivative. Renal clearance of redgreen color discrimination. The optic disc and fundus
ethambutol is approximately 7 ml. min–1 kg–1; thus it is are usually normal in both types of toxicity.
evident that the drug is excreted by tubular secretion in Retrobulbar neuritis can be unilateral or bilateral,
addition to glomerular filtration. About 20 percent of the manifested first as decreased visual acuity, then red-
drug is excreted unchanged in feces. The Tmax tends to green color blindness, central scotomata, sometimes loss
be somewhat delayed in comparison to other drugs of peripheral vision (gun barrel vision) occurring as early
(between 2 to 4 hours) and after a meal a lower Cmax is as the 3rd week of treatment.199 The severity of visual
found than when fasting (4.5 µg/ml vs 3.8 µg/ml after a difficulty depends on the duration of ethambutol therapy
dose of 25 mg/kg). With the exception of central nervous beyond the time the decreased visual activity first
system, the tissue distribution of ethambutol has been manifests. These symptoms are usually reversible on
good and the concentration higher than those in the discontinuation of the therapy. 200 Usually, time to
serum or plasma has been found in several studies in recovery of visual impairment after withdrawl of
patients.180 It has poor penetration in uninflammed ethambutol is proportional to the severity of impairment
meninges, however, good concentration is achieved in which in turn, is related to the duration of ethambutol
CSF in patients with tuberculous meningitis. Renal failure therapy. The color blindness may persist longer.
decreases body clearance and increases serum half-life, Continuation of therapy despite these symptoms may
hence dose adjustment in such patients is mandatory. lead to permanent blindness.
High fat meals alter the pharmacokinetics of ethambutol Seth et al185 have shown that children above the age
somewhat but probably not importantly enough.179 The of 3 years are not at greater risk for developing
concomitant concentration of ethambutol in abscess (pus) ethambutol induced optic damage as compared to adults.
was found to be considerably less than in concomitant They studied visual evoked responses (VERs) in 47
serum in two studies.181,182 children aged 3 to 13 years with tuberculosis, treated with
Zhu et al179 have found the serum concentration in ethambutol (20 mg/kg/day) as a part of the antitubercular
children to be lower than that found in adults following regimen. VERs were recorded by monocular whole field
similar doses of ethambutol. Schmid et al184 used stimulation, the stimulus being provided by a black and
ethambutol in 2634 children in a dose of 20 mg/kg and white checker-board pattern reversed every 560 m/sec
increased this by 5 mg / kg in children aged <3 years and recorded before the commencement, 2, 4, 6, 9 and
and decreased it by 5 mg/kg in patients aged >11 years. 12 months of therapy and between 3 to 6 months after
stopping the drug. In the first 6 months of therapy the
By taking into account the serum concentrations of
mean values of latency of VER ranged from 92.8 to
ethambutol, they could avoid toxicity and achieve
101.3m/sec in the 3 to <6 years age group and 88.5 to
therapeutic concentration in majority of children, without
100.3m/sec in children 6 to 13 years of age. Between 6 to
experiencing any toxic damage, including eye, when
12 months of therapy, the mean values of latency were
regular evaluation of eyes was done.
between 93.3 to 101.5m/sec in the 3 to <6 years age group
and 96.0 to 101.5m/sec in the older group. Between 3 to 6
Adverse Effects
months after stopping therapy the means of latency
When used in therapeutic doses (15 mg/kg/day) the ranged from 92 to 96m/sec. The differences were not
incidence of adverse effects is only 2 percent.83 The major statistically significant at any point of time (Fig. 30.4).
side effects pertain to eye when high dose of the drug is Similarly when amplitude was measured in the same two
used with the incidence of 5 percent at 25 mg/kg and 15 age groups (3 to <6 and 6 to 13 years), it was comparable
percent at 50 mg/kg dose (dose effect relationship). (Fig. 30.5). It is necessary to monitor the vision before
417
regimens. It is a good substitute for PAS and thiacetazone

owing to its low toxicity in therapeutic doses and better
acceptance by the patients.203 In very young children (<3
years) its use has not been recommended.203 However,
as reported by Seth et al185 it does not cause retrobulbar
neuritis in children above 3 years of age in the dose of 20
mg/kg/day and therefore, it is not likely that ethambutol
will cause ocular damage in younger children (< 3 years)
as well. The difficulty of having cooperation from
children younger than 3 years can be overcome by doing
the test for ocular toxicity under general anesthesia.
Ethambutol is usually recommended even in the
intensive phase as a companion drug with INH,
rifampicin, streptomycin and pyraz-inamide even in very
Fig. 30.4: Effect of ethambutol therapy on latency of VER in
children aged 3 to 6 years and 6 to 13 years young children with TBM and other serious forms of
tuberculosis such as tuberculous bronchopneumonia,
consolidation and disseminated disease.
Thiacetazone
Thiacetazone is the cheapest antituberculosis drug.2 It is
a bacteriostatic drug with poor antituberculous activity
and is one of the oldest known antituberculosis agents,
discovered in Germany by Domagk and collaborators at
the Bayer laboratories in 1946. The use of thiacetazone
has decreased owing to its frequent side effects and low
potency. The renewed interest in the drug appeared after
it was used in East Africa in various pilot studies to
establish its optimum dosage. 204,205 Following these
reports, the WHO expert committee on tuberculosis in
its ninth report included it amongst the main drugs. In
combination with INH in a dose of 150 mg/day (2 mg/
Fig. 30.5: Effect of ethambutol therapy on the amplitude of VER in kg) thiacetazone was widely used in developing
children aged 3 to 6 years and 6 to 13 years
countries due to its low cost. It has been emphasized that
the drug is well tolerated in some communities and not
and during the treatment. Renal insufficiency causes an
in other. An observation made in a comparison of
increase in the serum concentration of the drug, thereby
tubercle bacilli isolated from India and in the United
causing an increased frequency of ocular toxicity.201
Kingdom showed that Indian strains were considerably
Dosage adjustment in patients with renal failure is
less susceptible to thiacetazone than the strains from
necessary.
United Kingdom206 and this geographic variation was
subsequently confirmed.207-210 The susceptibility of
Other Side Effects
strains may vary even within the same country.211 The
These include pruritus, joint pains, gastrointestinal response varies with immune status of the patient.212
upsets, malaise, headache, mental confusion, and Children, however, seem to tolerate thiacetazone very
disorientation, while peripheral neuritis occurs in some well, rarely exfoliative dermatitis may occur.
patients. Anaphylaxis is rarely seen after its admini-
stration.199 Urate excretion is reduced in 50 percent of Mechanism of Action and Pharmacokinetics
the patients but symptoms due to hyperuricemia are rare.
The mechanism of action of thiacetazone is not
The untoward effect is possibly enhanced by INH and
clearly understood213 although it has been shown that
pyridoxine. There is a case report of thrombocytopenia
thiacetazone forms copper complex salts and it has been
noticed on the 6th day of therapy with ethambutol.202
postulated that these might represent the effective
compound.214 It is well absorbed when given orally. The
Therapeutic Status
peak serum concentration is achieved in 4 hours (range 2 to
The drug is used as a companion drug with INH and 6 hours) after ingestion, with half-life of 12 hours. It is
rifampicin in various short-course and long term excreted in urine in unchanged form within 24 hours.215-217
418
Adverse Effects for pediatric use, for children require lesser dosage of
both isoniazid and thiacetazone.
Major side effects are hepatic and mucocutaneous. The pharmacokinetics parameters and important
Hepatitis, exfoliative dermatitis, skin rashes and adverse effects and contraindication of individual drugs
stomatitis are the side effects to be looked for. Rarely and doses in continuous and intermittent regimens are
Stevens-Johnson syndrome has been reported.2 An ICMR given in Tables 30.6 to 30.9.
study from India reported jaundice in 4 cases, exfoliative
dermatitis in 6 and stomatitis with skin rashes in 7 cases
Fixed–Dose Drug Combination for Treatment of
out of 640 adult patients put on thiacetazone.211 Nunn et
al218 administered thiacetazone (5 mg/kg) along with
Tuberculosis
usual dose of INH. In their study 1000 children, only one Antituberculosis therapy (ATT) with multiple anti-
child developed exfoliative dermatitis who recovered microbials administered individually or as fixed dose
with symptomatic management and withdrawal of the combinations (FDC) is the key to the control of
drug. Thiacetazone is contraindicated in patients with tuberculosis. Mathew219 has emphacized arguments in
HIV infection. In one recent report, 22 of 111 HIV positive favour of FDC include better patient compliance,
patients developed cutaneous hypersensitivity reactions simplification of prescriptions, easier management of
that ranged from a maculopapular rash to toxic drug supply, reduced cost of the program and less chance
epidermal necrolysis. Three of the 5 patients died.218 of developing resistance.
Disadvantage is that the bioavailability of rifampicin
Miscellaneous in FDC may be reduced owing to chemical reaction with
Nausea, vomiting, diarrhea, dizziness, vertigo, tinnitus, isoniazid in the acidic gastric pH. Further pyrazinamide
ataxia, and even deafness maybe seen in some patients. and ethambutol catalyze this reaction. Using FDC with
Signs of bone marrow depression have been noted rarely. poor availability of rifampicin bioavailability can make
therapy inadequate and potential increased drug
Drug Interaction resistance. A multinational study reported poor
bioavailability of rifampicin twice as common with FDC
A cross resistance between ethionamide and thiacetazone in various ATT preparation from different countries
is reported. including India.
The other arguments against FDC are: (i) Younger
Therapeutic Status children may receive slightly higher dose than required;
In combination with INH, thiacetazone is being used in (ii) Development of side effects may necessitate
Africa, Latin America and Asia. It is economical, effective omission/modification of the entire combination and (iii)
and makes practical regimen in patients who cannot be FDC may be more expensive than individual components
supervised frequently. The availability of single tablet in terms of cost per tablet.
containing both INH and thiacetazone (300 mg + 150 mg For these reasons although FDC are considered the
respectively) has helped in improving compliance. international standard for the treatment of tuberculosis,
However, this combination preparation has limited value WHO cautions that only preparations with proven
Table 30.6: Pharmacokinetic parameters of individual drugs
Drugs Dose Peak serum Urine Vd Normal Anuria Protein Excreted

(mg/kg) conc # conc # (L / kg) half-life half-life bound unchanged
(µg / ml) (µg / ml) t ½ (h) t ½ (h) (%) (%)
Isoniazid 5 3-5 Low 0.6 0.5-1.5+ Same Low <25
Rifampicin 10-12 (600)* 7 10-17 1 2-5 Same 60-90 <20
Streptomycin 20-30 (750-1000) 25-40 200-400 0.25 2.5 50-100 30 90-95
Pyrazinamide 25-30 (1000)* 45-60 60-100 ? 12-24 >24 ? >20?
Ethambutol 15-25 5 High 1.5 3-4 18-20 20-30 60-80
Thiacetazone 3-5 ? ? ? 12 2-3 ? 33
# Conc. = concentration, + and ++ t half-life in rapid and slow acetylators respectively, ? Not known, Vd= volume of distribution
* Figures in parentheses is the maximum dose (mg)
419
Table 30.7: Adverse effects of antituberculosis drugs
Drug Gastro- Hepatic Renal Neurological Others

intestinal
Isoniazid Rare Yes Rare Peripheral Hypersensitive reactions,
(age related) neuritis may precipitate epilepsy.
Interaction with metabolism
of phenytoin sodium
Rifampicin Yes Yes Rare No Skin rash. Orange color of

more with (immune- urine and saliva,
intermittent mechanism) immunosuppression,
therapy pancytopenia, chills
fever, arthralgia and drug
interaction with other drugs
Streptomycin No No Yes 8th nerve Hypersensitivity (rash,

(mild) damage urticaria fever, anaphylaxis),
neuromuscular blockade,
dose related
peripheral neuritis
Ethambutol No No No Optic neuritis Hyperuricemia , rash ,

(dose related) pruritus, disorientation,
joint pain, headache ,
hypersensitive reactions
Pyrazinamide Yes Yes No No Hyperuricemia, photo-

sensitivity, fever dysuria,
malaise, arthralgia, and
rarely thrombocytopenia
Thiacetazone Yes Yes No No Exfoliative dermatitis, rarely

vertigo, tinnitus, ataxia
Table 30.8: Drug dosage recommended for children and adults

Daily regimens Intermittent regimens
Drug
Daily dose Maximum Twice weekly dose Maximum
(mg/kg) daily (mg/kg) daily
Children Adults dose (mg) Children Adults dose (mg)
Isoniazid 5 (Po) 5 300 10 15 900
Rifampicin 10 (Po) 10 600 15 10 600
Streptomycin 15-20 (IM) 15 1000 25-30 25-30 1000
Pyrazinamide 25 (Po) 15–30 2000 25-30 50-70 _
Ethambutol 15 (Po) 15–25 2500 _ _ _
Thiacetazone 2 (Po) 4 150 _ _ _
Po= Per oral route IM = Intramuscular
bioavailability should be used. In children though some isoniazid, rifampicin and pyrazinamide in the dispersible
preparations are available but a large number of studies tablet and syrup form.
on bioavailability have not been done. Seth et al (Chapter Mathew has reviewed literature and that summarized
32) have done a few studies on FDC syrup of isoniazid current based evidence does not support the presumed
and rifampicin and the combination with three drugs superiority of FDC over separate administration.
420
Table 30.9: Contraindications for antituberculosis drugs • Ethambutol is less active that INH and rifampicin,
however, it suppresses the growth of all INH and,
Isoniazid streptomycin sensitive and resistant mycobacteria.
• Known hypersensitivity to isoniazid
Children from 3 to 13 years given ethambutol 20
• Active hepatic disease
mg/kg/day as part of anti TB regimen, are not at
Rifampicin greater risk of developing ethambutolinduced optic
• Hypersensitivity to Rifampicins
damage as compared to adults.
• Hepatic dysfunction
• Role of streptomycin in the treatment of TB is
Pyrazinamide limited. In view of its toxicity and rapid emergence
• Known hypersensitivity to pyrazinamide
of resistance, in children it needs to be used only in
• Severe hepatic impairment
severe forms of tuberculosis such as meningitis,
• Gout
miliary and osteoarticular tuberculosis for its action
Streptomycin
on extracellular organisms.
• Hypersensitivity
• Although thiacetazone is the cheapest anti-
• Auditory nerve impairment
• Myasthenia gravis tuberculosis drug, its use has decreased owning to
• Pregnancy its fatal though rare dermal side effects and low
potency. The Indian strains are considerably less
Ethambutol
• Hypersensitivity susceptible than in UK strain and Africa, hence not
• Pre-existing optic neuritis used in India. Thiacetazone is contraindicated in
• Patients with creatinine clearance of less than patients with HIV infection and the toxic reactions
50 ml/min range from cutaneous hypersensitivity reactions to
toxic epidermal necrolysis.
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Second-line and Newer Agents
INTRODUCTION cases in India and showed 17.2 % MDR-TB among this

group.
The robustness of the available well-balanced chemo-
Before proceeding to the individual drug, (Table 31.1)
therapeutic regimens in the treatment of various forms
enumerates all the antituberculosis drugs as classified
of tuberculosis and the considerable investment in terms
by WHO.
of time and cost to develop and assess the efficacy of
new drugs have precluded the development of new anti-
SECOND-LINE AGENTS
tuberculosis drugs in the last two decades. Further, the
decline in tuberculosis in developed countries and the The existing regimens, prescribed in the Revised
inability of developing countries to purchase expensive National Tuberculosis Control Program (RNTCP) of the
drugs had resulted in only a low priority being given to Government of India, are found to be robust in the
development of new antituberculosis drugs. However, treatment of patients with no initial resistance or having
now because of the increasing incidence of tuberculosis resistance to either H or S but extemely poor in the
in HIV infected individuals, appearance of multidrug treatment of patients with initial resistance to R as
resistant tubercle bacilli and the anticipated further confirmed by Mathew et al3 and Mitchison.4 It is also
increase in the incidence of rifampicin (R) resistant known that resistance to R is always accompanied by
strains, there is increasing interest in the development resistance to other antituberculosis drugs. In particular,
of newer agents in the developed countries. In India, the it has been noted that the prognosis in cases with initial
situation is quite grim as indicated by a report from the resistance to HR or SHR is poor irrespective of the
Tuberculosis Research Centre (TRC), Chennai.1 Of 3357 regimen prescribed even when they contain 4 or 5 drugs
smear-positive pulmonary tuberculosis patients initiated including ethambutol (E). This makes it virtually
on antitubercular treatment in North Arcot district of important to search for newer classes of drugs with
Tamil Nadu state between April 1986 and March 1988, antitubercular activity especially against drugresistant
2306 (69%) were put on short-course chemotherapy (SCC) M. tuberculosis.
and 1051 (31%) on standard chemotherapy (non SCC), At present, there are a few classes of drugs which
43 and 35% respectively completed 80% or more of their show promise in the treatment of resistant tuberculosis
treatment. Overall mortality was 28%. Of the remaining, and they include thiomides, fluoroquinolones, such as
31% had active disease and were excreting bacilli with
ciprofloxacin, ofloxacin, lomefloxacin, gatifloxacin, moxi-
65% of the cultures being resistant to isoniazid (H) and
floxacin and sparfloxacin, the newer rifamycin deriva-
12% to rifampicin. Combined resistance to H and R was
tives such as rifabutin (ansamycin) and rifapentine
seen in 6% and to streptomycin (S) and H in 19%.
combination drugs of betalactams with betalactamase
H resistance was significantly higher in those who had
inhibitors such as sulbacin, augmentin and timentin,
been prescribed standard regimens and R resistance was
tuberactinomycin (tuberactin with viomycin), amino-
seen even in those who had not received the drug. In
glycosides such as amikacin and capreomycin, and newer
Gujarat, among the institutionalized patients, an
macrolides such as clarithromycin, azithromycin and
alarming increase in acquired R resistance from 2.8% in
some new drugs.
1980 to 37.3% in 1986 with 95% of the patients being
resistant to S, H or both was reported by Trivedi and
Thioamides
Desai.2 Among several reports documented from India,
the above cited ones reflect the ground reality of the Following the discovery of the pyridine containing
condition of tuberculosis patients in the community and isoniazid, numerous pyridine derivatives were tested,
in the specialized institutions. Behera2a in a review article and the activity of thioisonicotinamide against
about the drug resistance pattern all over the world, M. tuberculosis was found by several groups. 5,6
reported that the new figures from Gujarat state, India Ethionamide was introduced by the group of Liberman
are the first reliable source of data on previously treated et al.7-8 Prothionamide is essentially similar to ethionamide
428
Table 31.1: Antituberculosis drugs grouped by World Health Organization
Group Drugs
• Group 1 Isoniazid, rifampicin, ethambutol,
First-line oral agents pyrazinamide
• Group 2 Aminoglycosides:
Injectable agents – Streptomycin, kanamycin, amikacin
Polypeptides:
– Capreomycin, viomycin, enviomycin
• Group 3 Ofloxacin, levofloxacin, moxifloxacin,
Fluoroquinolones gatifloxacin
• Group 4: Oral bacteriostatic agents Thiomides:
– ethionamide
– prothionamide
– Cycloserine, PAS; Thiacetazone.
• Group 5: Agents with unclear – Rifabutin
efficacy : Not recommended for – Clofazimine
routine use. – Amoxycillin with clavulanic acid
– Macrolides: Clarithromycin, Azithromycin
– Linezolid.
PAS = Paraaminosalicylic acid
in its antibacterial effects and is generally considered to Pharmacological Properties

be less unpleasant to take and hence less likely to replace
the latter.2 Pharmacodynamics
Ethionamide is bacteriostatic against M. tuberculosis at
Antibacterial Activity and Mechanism of Action therapeutic concentrations, but may be bactericidal at
higher concentration. It is also active against M. kansasii,
Ethionamide is active against M. tuberculosis and to a M. leprae and some strains of M. avium complex. With
lesser extent against other mycobacteria.8 Like isoniazid, monotherapy, drug resistance develops rapidly.
ethionamide is also an inactive prodrug, and is activated
by a mycobacterial redux system. Ethionamide is
Pharmacokinetics
converted to a sulfoxide and thence to 2-ethyl- Ethionamide is completely absorbed following oral
administration. With single dose of oral administration
4- aminopyridine. Although these products are not toxic
of ethionamide, Cmax is 2409 ng/ml (30.2%, the
to mycobacteria, it is believed that a closely related
corresponding value for (AUCo-inf) is 9161 ng (23.6%)
and transient intermediate is the active antibiotic. The
and AUCo-68941 nghr/ml (24.2%). The median range
mechanism of action of ethionamide is, like isoniazid, at
value of Tmax is 0.75 (0.17-3.00) hours. Adenine
the level of synthesis of mycolic acids and consequent
dinucleotide (NAD) are tight binding inhibitors of M.
impairment of cell wall synthesis, 8 but lacks cross tuberculosis. The crystal structures are inhibitors of M.
resistance as it is active against resistant mutants of tuberculosis and M. leprae. These inhibited organisms
INH. Thus, an additional site of action is suggested. complexes provide the molecular details of target-drug
Ethionamide is a bacteriostatic drug at concentration interactions. Knowledge of the precise structure and
ranging from 0.6 to 2.5 µg/ml. Resistance can develop mechanisms of action of these drugs provides insights
rapidly in vitro. into designing new drugs that can overcome resistance
Table 31.2 gives the pharmacokinetic parameter of
Ethionamide ethionamide.
Absorption Plasma protein binding is approximately 30% and the
volume of distribution is 80 liters. Ethionamide
Ethionamide is essentially completely absorbed following undergoes extensive hepatic metabolism into several
oral administration and is not subjected to any appreciable different metabolites, with only 1 of a given dose excreted
first pass metabolism. The tablet may be administered unchanged in urine. Ethionamide-sulfoxide is the major
without regard to the timing of meals. metabolite, which has antibacterial activity. The plasma
half-life is approximately 2 to 3 hours.
429
Chapter 31 Antituberculosis Drugs: Second-line and Newer Agents
Table 31.2: Mean ± SD pharmacokinetic parameters of be divided. It is a crystaline, non-hygroscopic compound

ethionamide following single-dose administration of 250 with a faint moderate to sulfide odor.
mg film coated tablet to healthy volunteers
Indications
Cmax Tmax AUC Ethionamide is indicated in combination with other
mg/ml (hrs) mg/hr/ml antituberculosis agents for the treatment of all forms of
2.16 1.02 7.67
tuberculosis caused by M. tuberculosis. It is only indicated
(0.61) (0.55) (1.69) as a second-line antimycobacterial drug when resistance
to or toxicity from first-line drugs has developed.
Cmax for film-coated tablets was significantly higher
(2.16 ìg/ml) than sugar coated tablet. Optimum dose for children
Optimum doses for children have not been established.
It can be used when the organisms are definitely resistant
Wang et al9 have emphasized that both ethionamide to primary therapy and there is systemic dissemination
(ETH) and prothionamide (PTH) are clinically effective in of the disease or other life threatening complications of
the treatment of M. tuberculosis, M. leprae and M. avium tuberculosis. A total daily pediatric dose is 10-20 mg/
complex infections. Generally considered Second-line kg. It can be either taken at a single occasion or split up
drugs for tuberculosis, their use has significantly increased in two doses over the day to improve tolerability.
due to increase in MDR and extensively drug resistant
tuberculosis. Using a cell-based activation method, it has Hepatic and renal impairment
been shown that both thioamides form covalent adducts Ethionamide is almost completely metabolized in the
with nicotinamide and adeninedinucleotide (NAD) and liver. Its use should be avoided in patients with severe
are tight binding inhibitor of M. tuberculosis. hepatic impairment. No data is available for mild to
moderate hepatic impairment. Very little eithionamide
Distribution
is excreted by kidneys. Dose adjustment is not necessary
Ethionamide is rapidly and widely distributed into body
tissues and fluids following administration of a sugar-coated in patients with renal impairment.
tablet with concentrations in plasma and various organs Duration of therapy
being approximately equal. Significant concentrations are The duration of antituberculous therapy depends upon
also achieved in cerebrospinal (CSF) fluid. the regimen chosen, the patient’s clinical and
Auclair et al10 demonstrated that pharmacokinetic radiographical responses, smear and culture results and
behavior of ethionamide (ETA) is not significantly susceptibility studies of M. tuberculosis isolates from the
modified by the different conditions such as when the patients or the suspected source case. If therapy is
drug is given with orange juice, food, or antacids. Mean interrupted, the treatment schedule should be extended
AUC ranged from 0.91 to 0.96 for the orange juice, food,
to a later completion date depending, e.g. on the length
antacid treatments, indicating a minimal effect on relative
of the interruption, the time during therapy (early or late)
bioavailability. ETA can be administered with food if
or the patient’s status.
tolerance is an issue.
Seifartabc 11 determined the cerebrospinal fluid Contraindications
ethionamide concentrations in 18 children with raised • Hypersensitivity to ethionamide or to any of the
intracranial pressure with the dosage schedule of 15 mg/kg excipients
used on 26 occasions. Spinal fluid ethionamide concentration • Severe hepatic impairment.
of 2.5 μg/ml (minimum inhibitory concentration) was
exceeded in 27% times with the dose of 20 mg/kg. MIC of Special warnings and precautions for use
2.5 μg/ml was not achieved in 15% of cases. Hence, the use • Resistance: There is rapid development of resistance
of 20 mg/kg of ethionamide is recommended when the if ethionamide is used alone in the treatment of
presence of isoniazid resistant M. tuberculosis cannot be tuberculosis. It is essential, therefore, to give a suitable
excluded. other antituberculosis drug or drugs, the choice best
made on the susceptibility testing. However, therapy
Elimination may be started depending upon the existing
The mean half-life was 1.92 (0.27) hours after administra- susceptibility pattern
tion of a 250 mg film coated tablet. Less than 1% of the
• Liver Toxicity: Toxic hepatitis, obstructive jaundice,
oral dose is excreted as ethionamide in urine.
acute hepatic necrosis, as well as modest elevations
Pharmaceutical form of hepatic transaminase levels, bilirubin and alkaline
It is a yellow circular deep biconvex film coated tablet phosphatase with or without jaundice have been
with plain surface on both sides. The tablet should not described during ethionamide therapy
430
• Neurological Effects: Psychotic disturbances, encepha- • Very common = ≥ 1/10

lopathy and optic neuritis, as well as pellagra-like • Common = ≥ 1/100, <1/10
syndrome have been reported with ethionamide. • Uncommon = ≥ 1/1000, <1/100
Administration of nicotinamide and pyridoxine • Rare = ≥ 1/10 000, < 1/1000
substitution have been able to improve the symptoms. • Very Rare = ≤ 1/10 000
Therefore, current recommendation of administering Nervous system disorders
pyridoxine is made to prevent neurotoxic effects of Common: Headache, dizziness, drowsiness, asthenia,
ethionamide. paresthesia.
• Blood Glucose: Hypoglycemia is associated with
ethionamide treatment, glucose should be admin- Gastrointestinal disorders
istered prior to and periodically throughout therapy. Very common: Epigastric discomfort, abdominal pain,
In diabetes, in adults one has to be very cautious to anorexia, nausea, vomiting, diarrhea.
avoid fall in blood glucose level. Hepatobilliary Disorders
• Hypothyroidism: Periodic monitoring of thyroid Very common: Elevated serum transminases.
functions is recommended as hypothyroidism with or
without goiter, has been reported with ethionamide. Overdose
• Allergic Reactions: Ethionamide may cause severe
allergic hypersensitivity reactions with rash and fever. Ethionamide is not dialyzable.
If this occurs, ethionamide must be discontinued.
Visual disturbance are also caused sometimes and FLUOROQUINOLONES
hence ophthal moscopy is recommended before and Fluoroquinolones (FQS) are important drugs used for
period ically during therapy. treatment of drug resistant tuberculosis. These are also
being considered as first line drugs to shorten the duration
Interactions of treatment of tuberculosis. Fluoroquinolones are
synthetic compounds structurally related to nalidixic acid
• Hepatitis and jaundice are more common if
but with certain advantages of having wider spectrum of
ethionamide is administered with rifampicin.
activity, better absorption, longer half-life, better tissue
Coadministration must be avoided unless the benefits
penetration and activity against a wide variety of
outweigh the risks. If it is a must, patient must be
microorganisms. They inhibit the enzyme DNA gyrase
periodically assessed by liver function tests and
which is involved in DNA replication. The competing
examined frequently for hepatic dysfunction clinically
actions of gyrase and topoisomerase. (the major relaxing
• Coadministration with isoniazid increases the serum
factor in bacteria) maintain the level of super-coiling within
concentration of the latter in both slow and rapid
a fixed range. The eukaryotic homologue of gyrase which
acetylators. If co-administration is a must, monitoring
is topoisomerase II, in order of magnitude, is less sensitive
of adverse effects such a peripheral neuritis,
than gyrase to quinolones.12 Fluoroquinolones such as
hepatotoxicity and encephalopathy must be looked
ciprofloxacin, ofloxacin (O), norfloxacin, pefloxacin,
for. Pyridoxine supplementation becomes mandatory. enoxacin, lomefloxacin, WQ 3034, gatifloxacin, sparflo-
• A reversible pellagra-like encephalopathy has been xacin and moxifloxacin have, gained worldwide usage as
reported with ethionamide and cycloserine broad spectrum antimicrobials over the last decade.13 They
coadministration. Again this is due to disturbance of are active against mycobacteria and no cross-resistance
the pyridoxine metabolism. has been reported between fluoroquinolones and other
Pregnancy and Lactation antitube rculosis drugs.14 Other tried fluoroquinolones
Teratogenic effect has been demonstrated in rabbits and include lomefloxacin, defloxacin, 6-fluoro-8-methoxy
rats. Some data indicate an excess of congenital quinolone, AM 1155, levofloxacin and trovafl oxacin.
malformations when ethionamide is given to pregnant These have also been evaluated for their antituberculosis
women. Therefore, the drug should not be given to action. 15-17Gatifloxacin, ofloxacin and ciprofloxacin
pregnant women or those who are likely to become have comparable activities against M. tuberculosis.16
pregnant. (Table 31.3).
In case of breast feeding, during ethionamide It is important to remember that if resistance develops
treatment the baby should be monitored for side effects to any of the fluoroquinolones, cross-resistance to all
of ethionamide. members of fluoroquinolone family is the rule. Therefore,
the most active of the flouroquinolones (moxifloxacin,
Undesirable effects gatifloxacin) should be used in combination with other
Frequencies of undesirable effects is defined as follows: antituberculosis drugs.16a
431
Table 31.3: Classification of quinolones quinolones are eliminated by both renal and nonrenal
route. Hence, dosages often need to be adjusted in patients
Quinolone Generation Drug with impaired renal and hepatic function. The majority of
• First generation Nalidixic acid quinolones are excreted renally, however sparfloxacin,
• Second generation Lomefloxacin moxifloxacin and trovafloxacin are excreted hepatically.
– Class I Norfloxacin
– Class II Ofloxacin, Ciprofloxacin Classification of Quinolones
• Third generation Levofloxacin
Sparfloxacin Antimycobacterial Activity
Gatifloxacin
Singh M et al18 studied the efficacy of five fluoro-
Moxifloxacin
• Fourth generation Trovafloxacin quinolones namely, ofloxacin (OFX), ciprofloxacin (CIP),
sparfloxacin (SPX), gatifloxacin (GAT) and levofloxacin
(LEVX) for treatment of tuberculosis. The isolates of M.
Pharmacokinetics tuberculosis were obtained from both treated and
untreated patients from Agra and Kanpur regions of
The quinolones exhibit concentration-dependent bacterial
North India.
killing. Bactericidal activity becomes more pronounced as
A total of 162 M. tuberculosis (MTB) isolates including
the serum drug concentration increases to approximately
110 MTB isolates from untreated patients (Cat I) and 52
30 times the minimum inhibitory concentration (MIC).
isolates from treated patients (Cat II) were tested for
Higher drug concentrations paradoxically inhibit RNA
sensitivity to FQS using standard minimum inhibitory
and protein synthesis, thereby reducing bactericidal
concentration (MIC) method on Löwenstein Jensen
activity. Quinolones have a post antibiotic effect of about
medium. Ninetyseven percent of the isolates in Cat I were
one to two hours. Quinolones are not synergistic when
sensitive to GAT, 89% to LEVX at 1 μg/ml where as 92.7%
used along with betalactams and aminolgycosides.
isolates were inhibited by OFL at 2 μg/ml which
increased to 89% at 4 μg/ml (higher than achievable peek
Absorption level). On the other hand, among the 52 isolates from
Quinolones are well absorped following oral administra- Cat II, 71.2 % were sensitive to GAT, 63.5% to LEVX at
tion, with moderate to excellent bioavailability. Serum 1 μg/ml concentration, 53.8 % to SPX at 0.5 μg/ml
drug levels achieved after oral administration are whereas 63.5% and 46.2% isolates were sensitive to OFL
comparable to those with intravenous dosing. This allows and CIP at 2 μg/ml respectively.
an early transition from intravenous to oral therapy and Singh et al18 showed that FQS were more effective in
potential reduction of treatment costs. Cat I cases whereas these drugs were comparatively less
Food does not impair the absorption of most effective in Cat II cases. The reasons being the prior use
quinolones. They chelate with cations such as aluminum, of these drugs alone in the failing regimens of Cat II cases.
magnesium, calcium, iron and zinc. This interaction This results in higher resistance rates. This emphasizes
results in significant reduction in absorption and that drug susptibility testing (DST) must be done before
bioavailability, resulting in lower serum drug adding this drug to a failing regimen.
concentrations. This causes less target-tissue penetration. The detailed analysis was very useful in studying the
extent of resistance to various fluoroquinolones. Among
Distribution the 8 MDR isolates (from Cat I) GAT showed highest
activity inhibiting 78.5% at 1 μg/ml concentration with
Quinolones are distributed widely throughout the body. LEVX, 87.5% of the isolates were inhibited at higher
Tissue penetration is higher than the concentration concentration (2 μg/ml) of the drug which is still much
achieved in plasma, stool, bile, prostate and lung tissue. below the peak serum value.
Intracellular concentration is exceptional in neutrophils Similarly 75% of isolates were sensitive to
and macrophages. These drugs also penetrate well in CIP at 4 and 87.5% to SPX at 4 and 2 μg/ml concentration
urine and kidneys, when renal clearance is the route of of the drugs respectively. These concentrations were
drug elimination. Penetration in saliva, bone and slightly higher than the peak concentrations i.e. 3.5 μg/
cerebrospinal fluid does not exceed serum drug levels. ml for CIP and 1.4 μg/ml for SPX. In isolates from treated
Because of the latter, these agents are inadequate for first- patients, GAT along with moxifloxacin was found to be
line treatment of meningitis. most effective fallowed by SPX, OFL, CIP and
lomifloxacin. In conclusion, fluoroquinolones hold
Elimination promising activity (97.2%), in inhibition for M. tuberculosis
Half-lives for quinolones vary from 1.5 to 16 hours. Hence, isolates from untreated patients) in concentration lower
these drugs are administered 12 to 24 hourly. The than the peak serum levels. FQS show better activity in
432
Cat I cases in comparison to Cat II. These drugs may be develop rapidly in a large proportion of patients 30
useful in the treatment of tuberculosis including MDR- required for replication and gene transcription. In a study
TB, moxifloxacin shows promising results in vitro and conducted by the TRC, the early bactericidal activity
animal studies, need further researching. (EBA) of ofloxacin and sulbactam/ampicillin, alone and
in combination with R and H on log-phase and stationary
Ciprofloxacin and Ofloxacin
phase cultures of a drug sensitive isolate of M. tuberculosis
They are the most extensively studied fluoroqui-
was studied in vitro.31 Ofloxacin had considerable early
nolones.18 When the activity of ciprofloxacin, ofloxacin,
bactericidal activity (EBA) activity against the log phase
pefloxacin, enoxacin and norfloxacin against fifty M.
culture and, at 5 µg/ml, was as bactericidal as 1µg/ml
tuberculosis strains sensitive to antituberculosis drugs was
of H or 1 µg/ml of R. However, it had little bactericidal
compared, ciprofloxacin and ofloxacin were observed to
activity against the stationary phase culture and was less
have the highest in vitro activity. In a study from active than H or R alone. These results suggest that
Tuberculosis Research Center (TRC) Chennai, it was ofloxacin may be most useful in the early stages of
observed that there was no difference in the activity of treatment and in preventing the emergence of resistance
ciprofloxacin and ofloxacin in fifty two SHR sensitive and to other drugs but may not be effective as a sterilizing
fifty two SHR/HR resistant M. tuberculosis strains.19 None drug to kill persisting bacilli in lesions. Kohno et al32 have
of the strains showed MIC > 4 µg/ml when the drugs compared ofloxacin and ethambutol (E) in the primary
were incorporated into LJ medium. While the peak serum treatment of 124 patients with pulmonary tuberculosis
level of ofloxacin attainable in normal dosage (Cmax 11 using 9 months regimens containing either O or E with
µg/ml; half-life (7 hr) is far above its mean MIC, the R and H. Culture conversion rates 3 months after starting
absorption of ciprofloxacin after oral administration is treatment were 98 and 94% for the O containing and the
poor (mean Cmax 2.4 µg/ml) with a relatively lower E containing regimens respectively. By 6 months, all
mean half-life (4.1 hr).20-22 Ciprofloxacin levels in patients in both groups were culture negative. This study
bronchial biopsy specimens exceed those in the serum, indicated that ofloxacin may be as effective as ethambutol
indicating an accumulation of the compound in the lung in the treatment of pulmonary tuberculosis when either
parenchyma23 and may inhibit all clinically important drug is combined with H and R. Thus, the reports
species of mycobacteria including those showing primary available to date indicate that against drug-resistant
resistance to one or more primary antimycoba-cterial M. tuberculosis, ofloxacin may be a better drug to use in
drugs. In one study, ciprofloxacin was active against all combination with any of the companion drugs still
strains of M. tuberculosis sensitive to S, H, R and E, and available in comparison with other second-line drugs.
against almost all strains showing intermediate Adult dose of ofloxacin is 400 mg BD and that of
sensitivity or resistance to one or more of these drugs at ciprofloxacin is 750 mg BD.19 In children, one can use 10
a concentration of 3.2 µg/ml.24,25 A study from TRC on to 20 mg/kg/day in two divided doses along with
53 SHR/HR resistant strains of M. tuberculosis, reported companion first-line antituberculosis drugs. The
geometric mean MICs of 3.7 µg/ml and 3.8 µg/ml experience with the use of quinolones in pediatric
respectively, for ciprofloxacin which are only slightly tuberculosis is no longer limited.15 Tsukamura et al27
lower than the peak serum concentration of 4 µg/ml treated 22 patients with multidrug resistant tuberculosis
obtained following oral doses of 500 to 750 mg of for 9 to 12 months with regimens containing 300 mg or
ciprofloxacin.26 800 mg of ofloxacin and other drugs with favorable
Resistance to fluoroquinolones arises rapidly and outcome in thirteen patients. Ciprofloxacin in
cross-resistance among quinolones is the rule,23 but no combination with other antituberculosis drugs has also
resistance has been reported between fluoroquinolones been used successfully for the treatment of several cases
and other antituberculosis drugs.14 of multidrug-resistant tuberculosis in HIV negative
In the case of ofloxacin, spontaneous resistance patients.
appears to occur in about 1 in 106 organisms which is
similar to that for other drugs. Ofloxacin appears to have Lomefloxacin
an additive effect in combination with other The main advantage of lomefloxacin is its relatively long
antituberculosis drugs. Resistance to ofloxacin appears serum elimination half-life (7-8 hr). The peak
to occur in a two step pattern with two phenotypes of concentration of lomefloxacin is 4.9 µg/ml following a
resistance levels 5 µg/ml and 10 µg/ml respectively, and single oral dose of 400 mg as compared to 10.7 µg/ml
no resistance levels beyond 100 µg/ml.27 The most following 600 mg dose of ofloxacin and 2.9 µg/ml
common mode of resistance results from mutation in following 1000 mg dose of ciprofloxacin. 33 These
the gyrA gene encoding the DNA gyrase,28 and enzyme.29 pharmacokinetic properties of lomefloxacin make it a
Quinolones should be used in combination with at least potential supplementary drug for intermittent treatment
two other antituberculosis drugs as resistance might regimens of tuberculosis. However, few studies have
433
been done so far to assess the in vitro activity of of third-generation fluoroquinolones like moxifloxacin
lomefloxacin against M. tubercuslosis. In one of the few and gatifloxacin have not been established as they have
reports available to date, when 90 M. tuberculosis strains for ofloxacin and levofloxacin 49,50 and given the
isolated from patients including those with AIDS were unanticipated toxicity of such agents as temafloxacin,
tested for susceptibility to ciprofloxacin, ofloxacin and trovafloxacin, sparfloxacin and grepafloxacin, this should
lomefloxacin, the MIC ranges were 0.125 to 4 µg/ml, 0.25 not be regarded lightly. Nonetheless, these drugs merit
to 4 µg/ml and 0.5 to 4 µg/ml respectively.34 In a recent careful study both as agents to augment conventional
study by the TRC, a total of 46 SHR/HR resistant M. therapy and as major drugs for MDR-TB.
tuberculosis strains and 51 SHR susceptible M. tuberculosis
strains were tested for their susceptibility to lomefloxacin. Moxifloxacin
The results showed that, though lomefloxacin had poor
TB wonder drug that shortens treatment span to be
in vitro activity compared to ciprofloxacin and ofloxacin
tested. India to be part of study to be conducted in 2400
with the MIC being generally higher (2 to 16 µg/ml), it
patients.
is probably within the levels achieved in tissues and
India is likely to soon become a part of an international
macrophages. The findings of this study need to be
trial to look at whether the drug moxifloxacin actually
substantiated with more in vitro and in vivo studies to
increases cure rate and helps shorten the duration of
clarify the role of lomefloxacin in antitubercular
treatment for patients suffering from tuberculosis.
treatment. In addition, lomefloxacin, because of its
Moxifloxacin works by stopping the life cycle of a
pharmacokinetic property, of long serum elimination
harmful bacteria. It has been identified as a drug which
half-life, seems an appropriate drug for the intermittent
has the potential of shortening the duration of treatment
treatment regimens of tuberculosis.
from to 4 months when used along with other first line
Sparfloxacin drugs.
The in vitro and in vivo activities of sparfloxacin have been The study will include 2400 fresh TB adult patients in
reported to be equal or better than those of ciprofloxacin over 20 sites across the globe, India being one. Christian
and ofloxacin. The MICs of ciprofloxacin, ofloxacin and Medical College (Vellore), Tuberculosis Research Center
sparfloxacin in 6H12 broth for 10 M. tuberculosis strains (Chennai) and National Tuberculosis Institute (Bengaluru)
ranged from 0.25 to 0.5, 0.5 to 1 and 0.1 to 0.2 µg/ml are being considered to be part of this consortium. This
respectively while in solid medium, they ranged from study costing US $ 20 million would be financed by the
0.51 µg/ml for ciprofloxacin and ofloxacin, and 0.2 to 0.5 TB Alliance and Bill and Melinda and Gates foundation.
µg/ml for sparfloxacin.35 However, more detailed in vivo Reduction of treatment time to four months would mean
studies are required to assess its antimycobacterial less exposure to drugs for the patient and less interaction
activity in adults and children. with health services reducing their workload.
The duration of the treatment makes adherence a
Status of Fluoroquinolones in Treatment of Tuberculosis significant problem. Incomplete adherence can lead to
failure of cure or relapse. In view of the escalating number
The question arises, whether fluoroquinolones can
of cases of TB globally, there is urgent need of regimens
replace drugs lost to resistance and can they improve
of shorter duration. The study is going to be a double-blind
the performance of conventional regimens versus drug-
randomized controlled trial (neither the patient nor the
susceptible disease. The fluoroquinolones are by far the
staff caring for them will know which combination they
most promising agents from both the angles mentioned
are taking).
above. Wild strains of M. tuberculosis are predictably
susceptible in vitro to fluoroquinolones36 and various
Summary of Adverse Effects and Drug Interactions
fluoroquinolones have been demonstrated to be active in
marine models.37,38 Incidence of adverse effects by ciprofloxacin is 14.8 %.
The most potent of the currently available drugs in Major side effects are related to GIT, CNS and skin
descending in vitro activity are moxifloxacin, gatifloxacin, including nausea, vomiting, diarrhea, headache,
levofloxacin, ofloxacin and ciprofloxacin.39-46 Considerable restlessness, tremors, dizziness, insomnia, hallucinations
experience in human disease documents the utility of and seizures, skin rash and pruritus have been reported
ciprofloxacin, ofloxacin and levofloxacin against TB in 9 % of cases.51 In children, the drug use is to be avoided,
including MDR strains.47 The data from Indonesia, Hong because of recognition of drug-induced arthropathy
Kong and Turkey48 have indicated that the outcome of in juvenile laboratory animals. Initially fluoroquinolones
treatment of MDR-TB was substantially better with in vitro were only recommended in those who were over 17 years
susceptibility to the fluoroquinolones. of age due to fear of quinolones-induced arthropathy and
While recent studies suggest that moxifloxacin is cartilage damage in this group. Recent safety studies have
particularly active, the long-term tolerability and safety employed MRI in the evaluation of children between 8
434
months to 13 years of age who had received ciprofloxacin mycobacteria, rifabutin is more active against
at a daily dose of 15 to 25 mg/day for 9 to 16 days, have environmental species that are naturally resistant to
found no such bone or cartilage damage and follow-up rifampicin, 57,58 including M. avium complex. 58-62
measurements done 2 years later detected no abnormality Although there is cross-resistance with rifampicin, it is also
in height.52 Transient increase in serum levels of hepatic active against a relative small subset of M. tuberculosis.60
enzymes, blood urea and serum creatinine have been This proportion is too small to make it generally a useful
noticed. Antacids delay absorption and probenecid is drug in rifampicin-resistant disease.63 Treatment results
reported to inhibit its renal excretion.15 It shows an among patients with drug-susceptible M. tuberculosis are
additive antimicrobial effect with other chemo- similar to those obtained with rifampicin.64-66 However,
therapeutic agents and delays the emergence of rifabutin is less active on extra cellular bacilli than
resistance.53 rifampicin.67
NEWER RIFAMYCIN DERIVATIVES Pharmacokinetics

Rifampicin (R) has been one of the most efficacious first- Protein binding of rifabutin is only 25% of that of
line drugs in use in the treatment of tuberculosis for the rifapentin. Further, rifabutin is more lipid soluble, thus
past two decades. However, it has a half-life of only about tissue penetration is superior 68 resulting in tissue
1.5 to 5 hours. This is progressively shortened by about rifabutin concentration several times higher than in the
40 % during the first 14 days of treatment by the action serum (0.49 µg/ml after 300 mg oral dose). This serum
of hepatic microsomal enzymes which accelerate the level is approximately 10 times lower than that with the
deacetylation of the drug. Moreover, when R is given same dose of rifampicin.68 Rifabutin has a serum half-
once weekly as part of an intermittent regimen, the life of 16 hours.69,70 This longer half-life may possibly
dosage required may lead to a high incidence of serious delay the emergence of resistance in patients who are
adverse reactions. The development of rifamycins with a resistant to companion drugs and this may make it
longer half-life giving sustained blood levels between particularly suitable for intermittent administration.
doses would overcome this problem and many novel Rifabutin is extensively metabolized.68
rifamycin molecules with long elimination half-life have
been designed with this aim. They include rifabutin and Drug Interactions
rifapentine. Some of the properties of new rifamycins
relevant to their use in antituberculosis therapy are given Rifabutin induces hepatic metabolism, but not as
in Table 31.4. extensively as rifampicin. 68 It does not affect the
pharmacokinetics of antiretroviral drugs that are excreted
in urine.71 It is a less potent inducer of the cytochrome
Rifabutin (Ansamycin)
P-450 family, and thus causes fewer or less pronounced
Rifabutin is a semisynthetic spiropiperidyl derivative of clinically significant interactions than rifampicin. 71
rifamycins. 54 It is active against a wide range of Interactions of rifabutin with protease inhibitors are
microorganisms, including gram-negative and gram- generally less than with rifampicin,72,73 and it is the
positive bacteria, and mycobacteria. 55,56 Among rifamycin of choice for patients receiving highly active
Table 31.4: Comparison of some characteristics of rifamycins

Rifampicin Rifampitin* Rifapitin* CGP CGP CGP FC
29861** 7040** 27557** 22250**
MIC against 0.3 0.08 0.04 0.04 0.08 0.04 ND
M. tuberculosis
(µg/ml)
Rifampicin 3 6 31 9 11 3 ND
resistant
M. tuberculosis
(% sensitivity)
Plasma t half-life 3 12 10 40 30 8 20
man (h)
Enzyme induction ++ ++ – – – – –
Sensitivity against 35 69 69 85 92 50 ND
M. avium complex (%)
ND = Not done, *Initial clinical trials have been done, **Under investigation
435
antiretroviral therapy. previously untreated patients with smear-positive

pulmonary tuberculosis.75 Peak plasma concentrations of
Resistance rifabutin after initial doses were proportional to dose sizes
and were approximately 7 times lower than those after
As compared to rifampicin, resistance in subinhibitory
the same doses of rifampicin. The EBA of rifabutin was
concentration of rifabutin is less rapidly acquired.
significantly different which may be due to the low plasma
Further, like rifampicin, acquisition of resistance is
concentrations of rifabutin that may not fully compensate
frequently accompanied by mutation in the rpoB gene are
for its slightly greater antituberculosis activity in vitro. This
susceptible to rifabutin.74 This difference is probably not
may be the reason why rifabutin appears to provide
due to additional mechanism of resistance but is likely
clinically disappointing results even though it has very
that some of the mutations selected by rifampicin do not
good in vitro bactericidal activity against M. tuberculosis.
sufficiently modify the rpoB structure so as to render this
protein resistant to rifabutin also.
Rifapentine
Antimycobacterical Activity Rifapentine is an RNA synthesis inhibitor like rifampicin
and shown to have antimycobacterial activities. It has 2
Rifabutin has good in vitro activity against both rifampicin
to 4 times the activity against a variety of clinical
sensitive and resistant strains. The activity is more than
mycobacterial isolates as compared to rifampicin. In
rifampicin for sensitive strains (MIC 0.006 µg/ml). In
experimental tuberculosis and in vitro studies, it has been
animal models, rifabutin has been found to be effective
found to be 10 times more potent than rifampicin against
against M. tuberculosis with relatively high tissue levels
M. tuberculosis, while against clinical isolates of M. avium
and long half-life. It has been found to be about 6 times complex tested in vitro, it was found to be twice as potent
more active than rifampicin in experimental infection of as rifampicin. Rifapentine is also bactericidal against
mice with M. tuberculosis or M. avium. The considerable actively growing bacilli with a rate of killing similar to
activity in murine disease may be indicative of high that observed for rifampicin.76,77 It also has better tissue
intracellular concentrations in mouse macrophages. On penetration unlike rifampicin. The serum half-life is 14
the other hand, caseating lesions in cavity walls containing to 18 hours 78-80 and is similar in adults and adolescents.
numerous acid fast bacilli, characteristic of human cavity Intrapulmonary concentrations of rifapentine are below
type of pulmonary tuberculosis, may contain lower those in serum.81 In contrast to rifampicin, higher peak
concentrations of the drug compared to the plasma. Thus, levels are achieved following food intake than after
in such human sites, rifabutin concentrations may not be fasting.79 Pharmacokinetics are not influenced in patients
sufficiently high for effective antimycrobial activity. This of HIV.79 The main concern is that rifapentine has high
is also borne out by the results of a few clinical studies. In protein binding, which might require higher dosage than
one study, 22 patients with chronic pulmonary used so far. In a study conducted by TRC, Chennai a
tuberculosis harboring tubercle bacilli resistant to H, S and total of 103 M. tuberculosis strains were tested against
R were treated with rifabutin.63 No evidence of sustained rifabutin and rifapentine. 82 All the 52 rifampicin-
benefit was observed in any patient. The results suggested susceptible strains were susceptible to rifapentine as well
that rifabutin may not have a useful role in retreatment of as rifabutin with a geometric mean MIC of 6 µg/ml for
patients with multidrug resistant pulmonary tuberculosis rifapentine and 1.3 µg/ml for rifabutin as compared to
especially in cases of R resistance while it may possibly be 13.3 µg/ml for rifampicin. All the 51 strains resistant to
beneficial in patients who harbor R-susceptible strains. In rifampicin were also resistant to rifapentine while 11
the same study, when 17 patients including 10 who had (22%) were susceptible to rifabutin. The clinical efficacy
earlier been treated with rifabutin, were retreated with of rifapentine in the treatment of pulmonary tuberculosis
ofloxacin along with other companion drugs there was was assessed in a study of 267 patients.82 The results
good response in 10 including quiescence in 3. These suggest that twice weekly administration of rifapentine
results suggest that ofloxacin may be a better drug to use is similar in effect to rifampicin given daily. Therefore, it
in treating patients with such drugresistant tuberculosis. is a suitable drug for intermittent regimens. The usual
In another study, the efficacy of 4 different doses of dose is currently 60 mg twice-weekly.76 However, higher
rifabutin (600, 300, 150 and 75 mg daily for 2 days), assessed doses are now under investigation. Adverse events
in terms of the early bactericidal activity (EBA) measured are similar to rifampicin.76 Interaction expected most
as the fall in viable counts of M. tuberculosis in sputum likely to resemble those of rifampicin and so also the
collections during 2 days, was compared to that of 3 mechanism of resistance. It has no activity against
different doses of R (600, 300 and 150 mg daily for 2 days) rifampicin resistant strains.12
and a single dose of H (300 mg daily for 2 days) in
436
BETA-LACTAMS WITH BETALACTAMASE INHIBITORS beta-lactam antibiotics penetrate poorly into mammalian
cells and this might limit their effectiveness in the
Mycobacteria produce beta-lactamase and are resistant treatment of tuberculosis.12 More recently newer beta-
to beta-lactam antibiotics. A group of beta-lactams have lactam antibiotics including imipenem and meropenem
been recently developed which, though devoid of have also been shown to have in vitro antimycobacterial
antibacterial activity, are potent inhibitors of beta- activity.85 The most important drug event seen with beta-
lactamase enzyme present in M. tuberculosis. Beta-lactam lactam antibiotics are hypersensitivity reactions, which
drugs penetrate poorly into mammalian cells. Recent might be immediate (urticaria, laryngeal edema,
efforts on improving the intracellular concentration of beta- bronchospasm, hypotension, or local swelling), late
lactamase antibiotics include investigation on liposomal (morbilliform rashes, serum sickness, or urticaria), or other
encapsulation of these antibiotics. Liposome encapsu- than late reactions (toxic epidermal necrolysis, interstitial
lation of streptomycin and amikacin showed greater nephritis, pulmonary infiltration, vasculitis, hemolytic
bactericidal activity on intracellular bacteria in anemia, neutropenia, or thrombocytopenia).
macrophage culture in experimental models.83 This new
drug delivery system may be useful for beta-lactam TUBERACTINOMYCIN
antibiotics. M. avium has much lower level of beta-
lactamase activity than does M. tuberculosis. Amoxycillin Tuberactinomycin is a water soluble drug structurally
alone showed promising activity against these organisms resembling viomycin. Tuberactino-mycin containing
in vitro; certain cephalosporins which are beta-lactamase regimens have been compared with viomycin-containing
stable, have shown moderate activity against M. regimens in Japan.88 The rate of sputum conversion by
tuberculosis in vitro.84 culture after 6 months ranged from 73 to 80% for
Clavulanic acid, a beta-lactamase inhibitor, is more tuberactino-mycincontaining regi-mens compared to 63%
active than the other inhibitors sulbactum and for viomycin containing regimens. In advanced cases, it
tazobactum.85 Clavulanic acid combined with amoxycillin was 67 to 76% for tuberactinomycin containing regimens
as an oral preparation (Augmentin) and with ticarcillin as compared to 59% for viomy-cincontaining regimens.
a parenteral preparation (Timentin) increase the Tuberactinom-ycin has been reported to be less toxic than
antimycobacterial activity of these two agents. In vitro kanamycin and capreomycin.89 In a study conducted by
studies have shown that Augmentin inhibits and kills most the TRC Chennai, crossresistance was not observed
strains of M. tuberculosis at a concentration of 4 to 8 µg/ml between tuberactinomycin and S, H, E, R and
of amoxycillin and 2 to 4 µg/ml of clavulanic acid. ethionamide. 82 However, 15 (54%) of 28 kanamycin
Timentin inhibited all strains of M. tuberculosis at resistant strains were not susceptible to tuberactinomycin
<32 µg/ml which is a clinically achievable concentration.86 at 25 µg/ml. The results indicate that tuberactinomycin
Sulbactam is being used increasingly in combination with may have limited use in the treatment of drug-resistant
ampicillin. Recently, at the TRC Chennai, the bactericidal tuberculosis. The use of tuberactinomycin has been largely
action of sulbactam/ampicillin (SA) alone and in limited to East Asia, where it was found to be a useful
combination with R and H on log-phase and stationary alternative to capreomycin in the treatment of multidrug-
phase cultures of a drug sensitive isolate of M. tuberculosis resistant, aminoglycosideresistant tuberculosis.
was studied in vitro.31 While SA was bactericidial against
log phase cultures, it had little bactericidal activity against MACROLIDES
stationary phase cultures. In 2 or 3 drug combinations, These are a group of antimicrobial agents origi-nally
SA did not have any antagonistic effect on H, R or HR. isolated from streptomyces species. Although
These results suggest that SA is more likely to be useful in erythromycin has got limited activity against
the early stages of treatment and in preventing the mycobacteria, newer semisynthetic macrolides appear
emergence of resistance to other drugs but is unlikely to to have promising activity.12,85 Roxithromycin has been
be effective in killing persisting lesional bacilli. Another shown to lead to significant inhibition of intracellular
recent study done in USA showed that ampicillin/ growth. This effect is potentiated by the addition of
sulbactam combination was effective against intracellular amikacin or TNF or both. Clarithromycin and
mycobacteria and could provide an effective alternative azithromycin have been shown to reduce the bacillary
therapy against infections caused by mycobacteria load in patients with disseminated Mycobacterium avium
resistant to other drugs.87 In an experimental study in mice, infection and advanced AIDS.
its combination with clofazimine was found to be superior
to other combinations in eliminating infections due to M. Clarithromycin
avium strains. Another good combination was ticarcillin
and clavulanic acid, which inhibited all strains of M. Clarithromycin is a new semisynthetic macrolide
tuberculosis at <32 µg/ml a clinically achievable serum antibiotic. Clarithromycin has wide antibacterial
concentration.86 It should be remembered, however, that spectrum that includes mycobacteria. 91 More often
437
clarithromycin has been used as prophylactic agent or disease and reduced mortality.96 In the treatment of M.
against disease caused by M. avium complex.92 While in avium complex disease, a twice daily dose of 1000 mg
vitro, it shows activity against M. tuberculosis complex in has been given.97
human macrophages,93 such high concentrations are not
achieved in the serum or lung tissue of humans,94 and Azithromycin
hence not widely used in the treatment of tuberculosis.
Azithromycin is semisynthetic derivative of erythromy-
When administered orally, it undergoes first pass cin. It is rapidly absorbed after oral administration and
metabolism so that the bioavailability is 55%. It can also the bioavailability is 40%. It is widely distributed into
be given intravenously. Clarithromycin is rapidly tissues and the tissue concentrations reach upto 100-fold
absorbed and Cmax is achieved in two to three hours95 higher than plasma concentrations. The plasma concen-
with serum elimination half-life of 2.5 to 5 hours. It is trations fall slowly. It has got long elimination half-life
metabolized to the active 14-hydroxyclarithromycin and and hence can be given once daily or even as once weekly
both reach high concentration in tissues, in part because dosing. It penetrates CSF poorly except when meninges
of intracellular uptake. Plasma protein binding is 80%. are inflamed. The metabolism of azithromycin is via
Clarithromycin is extensively metabolized in the liver, hepatic pathways other than CYP450 enzymes. It is
when it is both a substrate for and inhibitor of CYP3A. excreted mainly as unchanged drug in bile. It is a less
Metabolites are excreted mainly in urine with a small potent inhibitor of CYP3A than clarithromycin.
amount in feces via bile.
Interaction with Antiretrovirals
Interaction with Antiretroviral Drugs
Coadministration of azithromycin and efavirenz does not
Simultaneous coadministration of clarithromycin and significantly effect the concentration of either drug.
zidovudine reduces plasma concentrations of Nelfinavir significantly increases the Cmax and AUC of
zidovudine, but there is no reduction if the two drugs azithromycin by over 100% possibly via inhibition of
are given two hours apart. If there is malabsorption, then p-glycoprotein (P-gp). Azithromycin caused a small
the two drugs must be given two hours apart. decrease in nelfinavir concentrations, but no clinical
Clarithromycin and ritonavir are both inhibitors of significance. Ritonavir is a potent inhibitor of Pgp and
CYP3A enzymes. Clarithromycin has little impact on may also increase azithromycin levels significantly.
plasma concentrations of ritonavir. Coadministration of Azithromycin has no significant impact on the Cmax
clarithromycin with ritonavir result in complete and AUC of zidovudine. Didanosine pharmacokinetics
inhibition of the formation of the 14-hydroxymetabolite are not affected by azithromycin and hence it can be safely
of clarithromycin and an increase in clarithromycin AUC administered with these two antiretrovirals.
of 77%. This is not important if the patient has normal
renal function but patients with compromised renal PHENAZINES
function taking ritonavir, clarithromycin should be
Clofazimine is a substituted iminophenazine bright
reduced by 50% with creatinine clearance of 30 to 60 ml/
red dye that exerts a slow bactericidal effect on M. leprae.
min and by 75% if creatinine clearance is less than 30 to
It inhibits mycobacterial growth and binds preferen-
60 ml/min and the daily dose should not exceed 1 gm.
tially to mycobacterial DNA causing inhibition of
Simultaneous administration of clarithromycin and transcription. Clofazimine is active in vitro against
didanosine resulted in statistically significant change in M. leprae, M. tuberculosis, M. bovis, M. avium complex,
didanosine pharmacokinetics. Efavirenz induces CYP3A4, M. kansasii, M. scrofulaceum, M. simiae, M. marinum,
reduces clarithromycin concentration and increases M. chelonei and M. fortuitum.98 Side effects include
frequency of skin rashes. Nevirapine also reduces discoloration of eyes and skin, GI upset, severe
clarithromycin concentration of the 14-hydroxy abdominal pain and organ damage caused by crystal
metabolite, associated with an increased frequency of deposition. It is likely that this drug will emerge as a
skin rashes. Nevirapine also reduces clarithromycin useful agent in the treatment of resistant and atypical
concentration. Azithromycin should, therefore, be mycobacterial infections.
considered instead of clarithromycin in patients taking Lately a novel tetramethylpiperidine (TMP)
efavirenz or nevirapine. substituted phenazine (ATCC27294) has shown in vitro
Although it undergoes extensive hepatic metabolism, activity against M. tuberculosis that is superior to both
because of its predominant renal excretion, dose clofazimine and rifampicin.98 These agents together with
adjustment may be required in patients with severe renal clofazimine are significantly more active than clofazimine
impairment.65 Twice daily 500 mg clarithromycin in AIDS alone against M. tuberculosis including multidrug-
patients was well tolerated, prevented M. avium complex resistant organisms. Using tuberculosis-infected
438
monocyte-derived macrophages, all of the TMP when administered with orange juice, food or antacid
substituted phenazines were found to possess treatment respectively. However, PAS is usually taken
intracellular activity which was superior to both with food because of the problem of gastritis it produces.
clofazimine and rifampicin. In this experimental model It is 50 to 60% protein bound.
of intracellular bioactivity, the investigational compounds
inhibited bacterial growth at concentrations which were CYCLOSERINE
approximately 10-fold lower than the corresponding
minimum inhibitory concentration values obtained using Cycloserine is a broad-spectrum antibiotic and can be
in vitro sensitivity testing procedure. These results isolated from Streptomyces orchidaceus, S. garyphalus, or S.
demonstrate that the novel TMP phenazines are active lavendulae. It was first isolated from a fermentation brew
against multidrug-resistant M. tuberculosis strains and in 1955 and later synthesized. Cycloserine is active against
particularly effective against intracellular mycobacteria. M. tuberculosis and several species of grampositive
The therapeutic efficacy of liposome encapsulated bacteria.100 Cycloserine is indicated in combination with
clofazimine has been studied in mice and has been found other antituberculosis drugs in the treatment of
useful in the treatment of tuberculosis.99 It does not tuberculosis after failure of the primary medications, i.e.
penetrate CSF. It is likely to increase the plasma isoniazid, rifampicin, pyrazinamide, ethambutol and
concentration of drugs metabolized by CYP3A4 streptomycin. It is also used in the treatment of atypical
including protease inhibitors and etravirine. mycobacterial infections, such as Mycobacterium avium
complex. Not all species or strains of a particular organism
may be susceptible to cycloserine.
Para-aminosalicylic Acid (PAS)
It is an antitubercular agent often administered with Antibacterial Activity and Mechanism of Action
isoniazid. The sodium salt of the drug is better tolerated
than the free acid. Cycloserine may be bactericidal or bacteriostatic
depending upon the concentration at the site of infection
and the susceptibility of the organism. The MIC of
Mechanism of Action
cycloserine for M. tuberculosis ranges from 5 to 20µg/ml
There are two mechanisms responsible for aminosalicylic in vivo. There is no cross-resistance between cycloserine
acid’s bacteriostatic action again M. tuberculosis. and other tuberculostatic agents.
1. Aminosalicylic acid inhibits folic acid synthesis Cycloserine is an analog of the amino acid
(without potentiation with antifolic compounds). The D-alanine. It interferes with an early step in bacterial cell
binding of para-aminobenzoic acid, effectively wall synthesis101,102 by action of D-alanine racemase and
inhibits the synthesis of folic acid. As bacteria are D-alanine synthase.
unable to use external sources of folic acid, cell growth
and multiplication slows. Pharmacokinetics
2. Aminosalicylic acid may inhibit the synthesis of cell
well component of mycobacteria, thus reducing iron Cycloserine is rapidly and almost completely (70 to 90%)
uptake by M. tuberculosis. absorbed from the gastrointestinal tract following oral
administration.Plasma concentration of 20 to 35 µg/ml
Pharmacology is achieved after 20 mg/kg dose. It is widely distributed
to most body fluids including CSF, breast milk, lungs,
PAS is used for treatment of all forms of active pleural and synovial fluids and crosses the placenta. CSF
tuberculosis due to organisms sensitive to other concentration of cycloserine approach those found in the
antituberculosis agents. It produces a prompt production serum. Upto 35% of cycloserine is metabolized. It is
of a toxic inactive metabolite under acid conditions and excreted mainly in urine by glomerular filtration, 50%
the short serum half-life of one hour for the free drug. It excreted unchanged within 12 hours and 65 to 70%
is bacteriostatic against M. tuberculosis. It also inhibits the excreted unchanged within 24 to 72 hours. It accumulates
onset of bacterial resistance to streptomycin and in patients with impaired renal function and therefore,
isoniazid. the dose of cycloserine should be reduced to half in renal
failure.
Pharmacokinetic Parameters under Four Dosing
Conditions Adverse Effects
Food significantly enhanced the Cmaxx of PAS 1.5-fold Most common side effects of cycloserine are neurologic
and AUC (0-infinity) 1.7-fold, and doubled the time to and psychiatric,103,104 although it has been used in the
maximum concentration (Tmax), and the leastsquares treatment of psychiatric tuberculosis patients without
mean ratios (treatment) for Cmax were 0.90, 1.16 and 0.82 observation of major mental toxicity. Most frequently
439
observed adverse effects are vertigo and disorientation. aminoglycosides, and is frequently active against
Psychotic states with a suicidal tendencies, delirium, streptomycin-resistant strains of M. tuberculosis.109 Cross-
confusion, headache, convulsions, tremors, paranoid resistance with other aminoglycosides may occur,
reactions, catatonia and twitching has been reported.89 particularly frequent with kanamycin, and incomplete
Cardiac depression, pareses, paresthesias, drug fever, with capreomycin.110 Amikacin appears to have little
liver enzyme elevation and gastrointestinal disturban- early bactericidal activity, depending upon dose interval,
ces were less frequently reported events. These effects administered intramuscularly or intravenously. 111
are dose related and usually disappear when the drug is Amikacin may lead to neuromuscular blockade, an effect
withdrawn. Stevens-Johnson syndrome has been that may be reduced by lithium.112 Neurotoxicity might
reported in HIV-infected patient. 105 be increased by muscle relaxants such as tubocurarine,
succinylcholine or decamethonium. Indomethacin may
Drug Interaction interact with amikacin in newborns by increasing serum
levels to toxic concentration.113
Cycloserine interferes with elimination of phenytion
specially when taken with INH so that the dosage of
phenytoin must be reduced.106 Kanamycin
Kanamycin is also an aminoglycoside antibiotic. It is active
Therapeutic Status against a range of gram-negative bacteria and
Cycloserine should be used only where microorganisms mycobacteria including M. tuberculosis.114 Kanamycin, like
are resistant to other drugs and must be given with other other aminoglycosides is not absorbed orally. After
effective antituberculosis drugs. Cycloserine is available intramuscular administration peak serum concentration
for oral administration. Dose ranges from 10 to 15 mg/ is achieved within an hour and the serum half-life is about
kg/day. Cycloserine is contraindicated in individuals four to six hours.114 It is mainly excreted through kidneys,
with a history of epilepsy.89 It may be valuable in and dose adjustment is required in patients with renal
preventing appearance of resistance to ethionamide.1 failure. 114 Toxic effects include eighth cranial nerve
damage. Auditory toxicity is more pronounced than
AMINOGLYCOSIDES vestibular toxicity, affecting up to 20% of patients after
three months, and upto 60% if kanamycin is administered
The aminoglycoside group includes streptomycin, for six months. The other toxic effects include
kanamycin, amikacin, paromomycin, which are effective neuromuscular blockade and renal toxicity. Resistance to
antimycobactericidal antibiotics, in addition to kana-mycin is through a single extrachromosomal plasmic
gentamicin, tobramycin, netilmycin and neomycin. factor with multistep selection.115 Capreomycin resistant
Aminoglycosides have concentration dependent strains are not usually resistant to kanamycin. The usual
bactericidal activity. They bind to the 30S ribosome, dose of kanamycin is 15 mg/kg/day intramuscularly.
thereby inhibiting bacterial protein synthesis. Amino-
glycosides are poorly absorbed orally but are well Paramomycin
absorbed from peritoneum, pleural cavity, joints, denuded
skin. Aminoglycoside are usually given IV. These are well This is an aminoglycoside antibiotic with in vitro activity
distributed into the extracellular fluid except for vitreous against M. tuberculosis.12,85 The potential of paromomycin
humor, CSF, respiratory secretions and bile. For the in the treatment of tuberculosis lies with the advantage
treatment of meningitis, therapeutic levels can only be that there is little cross resistance with either streptomycin
achieved if the drug is administered intraventricularly or with amikacin/kanamycin. Its early bactericidal
for the treatment of meningitis. Aminoglycosides are activity indicates that it is at least as effective as
excreted by glomerular filtration and have a serum half- amikacin.107 Its toxicity, like that of neomycin, may
life of 2 to 3 hr the half-life increase exponentially as the preclude its prolonged parenteral use. The drug should
GRF falls. Streptomycin has been discussed with the first- prove to be useful in the treatment of both drug-resistant
line agents and amikacin, kanamycin and paromomycin and sensitive mycobacterial infection.
are discussed here.
CAPREOMYCIN
Amikacin Capreomycin is a polypeptide antibiotic. It is active
Amikacin is an aminoglycoside. Amikacin has activity against various species of mycobacteria, including M.
particularly against gram-negative bacteria107 and is tuberculosis.116 It is used for resistant or treatment failure
active against M. tuberculosis.108 Amikacin has been found cases in combination with INH and ethambutol.117 No
to be more active against M. tuberculosis than other cross resistance has been reported between capreomycin
440
and streptomycin.2 Cross resistance between kanamycin MISCELLANEOUS AGENTS

and capreomycin is incomplete.118 Capreomycin is given
intramuscularly at dose range of 15 to 30 mg/kg, two to Thalidomide
three times a week for two to four months. Capreomycin This drug has been shown to inhibit the in vitro release
causes auditory, vestibular and renal toxicity.119 Rarely of tumor necrosis factor (TNF) from stimulated
hypokalemia has also been reported.119 peripheral blood lymphocytes. TNF is a major cytokine
The pharmacokinetic parameters and important released in patients with tuberculosis and is believed to
adverse effects and contraindications of individual drugs be responsible for its toxic manifestations. In a patient
and doses in continuous and intermittent regimens are with tuber-culosis, thalidomide induces significant gain
given in Tables 31.5 to 31.8. in weight and inhibits TNF message in vivo.
Table 31.5: Pharmacokinetic parameters of individual drugs
Drugs Dose Peak serum Urine Vd Normal Anuria Protein Excreted

(mg/kg) conc# conc# (L/kg) half-life half-life bound unchanged
(µg/ml) (µg/ml) t ½ (h) t ½ (h) (%) (%)
Ethionamide 15-20(1000)* 20 Low ? 2 ? ? ?
Cycloserine 15-20(500)* 25-35 High 7 8-12 ? ? 50-70
Kanamycin 5-7.5 25 >500 0.25 2.1 >48 <10 95+
Capreomycin (1000)* 20-40 1000-2000 0.15 2-3 50-100 ? 60-80
Amikacin 7.5 20-25 High 0.3 2.3 >48 4 90-95
Viomycin 10-15 20-40 3000-5000 0.2 2-3 >48 Low 65-100
# Conc. = concentration, + and ++ t half-life in rapid and slow acetylators respectively, ? = Not known,
Vd = volume of distribution
* Figures in parentheses is the maximum dose (mg)
Table 31.6: Drug dosage recommended for children and adults
Daily regimens Intermittent regiments

Drug Daily doses Maximum Twice weekly Maximum
(mg/kg) daily dose (mg/kg) daily
Children Adults dose (mg) Children Adults dose(mg)
Ethionamide 15-20 (Po) 15-20 1000 _ _ _
Cycloserine 10-15 (Po) 15-20 1000 _ _ _
Kanamycin 10-15 (Im) 10-15 1000 _ _ _
Capreomycin 15 (Im) 15-30 1000 _ _ _
Amikacin _ 7.5 (Im) 1000 _ _ _
Viomycin _ 10-15 (Im) 1000 _ _ _
Po= Per oral route IM = Intramuscular
Table 31.7: Adverse effects of antituberculosis drugs
Drug Gastro- Hepatic Renal Neurological Others

intestinal
Ethionamide Yes Rare No Peripheral Gynecomastia, rash, alopecia,
neuropathy generalized CNS effects like: headache,
depression, diplopia, blurred vision, tremors
Cycloserine No No No Yes (dose Hypersensitivity rarely.
related) Monitoring of mental status of the
seizures, patients required
psychosis,
peripheral
neuritis
Amikacin Hypersensitivity, neuromuscular blockade,
Capreomycin regular monitoring of vestibular functions
Viomycin No No Yes 8th nerve and audiometry required
Kanamycin
441
Table 31.8: Antiretroviral drugs licensed response to mycobacterial infection.100 Agents showing
for use in HIV promise include interleukin-2 (IL-2), (interferon-gamma
(INF-γ), tumor necrosis factor (TNF), granulocyte mono-
1. Nucleoside reverse transcriptase inhibitors (NsRTIs):
cyte colony stimutating factor (GM-CSF) and antigen
Abacavir, didanosine, emtricitabine, lamivudine,
zidovudine
specific transfer factor.
2. Nucleotide reverse transcriptase inhibitor: Tenofovir IL-2 promotes the proliferation and differentiation of
3. Non-nucleoside reverse transcriptase inhibitors helper T-cells, cytotoxic T cells, B cells and augments the
(NNRTIs): Efavirenz, etravirine, nevirapine. cytotoxic activity of NK cells and monocytes. Depressed
4. Protease inhibitors (PIs): Atazanavir, darunavir, IL-2 generation and a decreased frequency of IL-2
fosamprenavir, indinavir, lopinavir, nelfinavir, responsive cells in the peripheral blood has been shown
ritonavir, saquinavir, tipranavir in patients with tuberculosis.101 It appears that low dose
5. Entry inhibitors:
subcutaneous IL-2 may be useful in active tuberculosis
i. Fusion inhibitor: Enfurvirtide
ii. CCRs antagonist: Maraviroc by enhancing the immune effect or response. INF-γ
6. Integrase inhibitors: Raltegravir enhances phagocytosis and immune function of
macrophages and also enhances intracellular killing.
More studies are required with regards to TNF.
Interferon alpha 2b is already under phase 2 trials in
Folate Antagonists
adults with advanced intractable multi-drug resistant
These group of drugs show promise in the treatment of tuberculosis.102
infection caused by mycobacteria other than tubercular
(MOTT) including M. fortuitum, M. marinum, M. chelonei Vitamin D
and possibly M. kansasii.12,85
Active metabolites of Vitamin D which is 1,25 (OH)2 Vit
D has been shown to activate peripheral blood monocytes
Gangamicin to kill mycobacteria.12,85
This is a vitamin K coenzyme analog found to be active
against M. tuberculosis and M. avium complex. It has been PHENOTHIAZINES
shown to be effective in animal studies.12,85 Gangamicin has
Chlorpromazine
been found to be active against both M. tuberculosis and
M. avium complex in vitro. This phenothiazine is an inhibitor of bacterial phos-
pholipases. The reason for considering phenothiazines for
Dihydromycoplanecin A the treatment of tuberculosis arises from the fact that
pulmonary macrophages concentrate chlorpromazine
This is a cyclic peptide antibiotic prepared by chemical
100-fold above of that achieved in plasma, concentration
reduction of mycoplanecin A with in vitro activity against
that are active against mycobacteria in vitro103 and in
M. tuberculosis, M. kansasii and M. bovis. However,
vivo.104 Chlorpromazine has a titrable ability to slow the
detailed studies are still needed.12,85
growth of intracellular tubercle bacilli in vitro105 It has been
shown in adults to be associated with clinical and
Fusidic Acid
radiological improvement when administered to schizo-
This is a tetracycline triterpenoid antibiotic with in vivo phrenics with tuberculosis.12,85
activity against M. tuberculosis and certain isolates of the
M. avium complex (MAC) but is still in investigational Trifluoperazine
stage.12,85
This phenothiazine is a calmodulin antagonist and would
inhibit the growth of mycobacteria.106 It is known that
Streptolydigin
there is a calmodulin-like protein (CAMLP) in
This is an antibiotic from Streptomyces lydicus that inhibits mycobacteria which is needed for their proper growth
the initiation of RNA synthesis and also the slow and its inhibition would suppress their normal
elongation of the RNA chain and has also been tried for growth.12,85
the treatment of tuberculosis.5,81
NITROIMIDAZOPYRANS
Immunomodulation
Nitroimidazopyrans, a group of compounds have been
This involves the use of agents that directly or indirectly shown to possess antituberculosis activity. While the
influence a specific immune function and enhance earlier agents were shown to be mutagenic, newer
various macrophage function and other aspects of host derivatives showed substantial activity against
442
M. tuberculosis. After activation by a mechanism antiretroviral drugs. Once absorbed, antiretroviral drugs
dependent on M. tuberculosis F-420 cofactor, nitro- bind variably to plasma proteins (principally to albumin,
imidazopyran inhibited the synthesis of protein and cell alph-1 acid glycoprotein).
wall lipid107 inhibiting fatty acid and mycolic acid Hepatic CYP450 enzymes are responsible for the
synthesis. 108 The multidrug-resistant strains of metabolism of a wide variety of drugs, NNRTIs and PI
M. tuberculosis exhibited susceptibility to the new are extensively metabolized by CYP450 and clinically
nitroimidazopyran (PA-824). It indicates that there is no significant drug interactions are common. Efavirenz and
cross resistance with current antituberculosis drugs,107 nevirapin are substrates for CYP450 and induce the
it might prove to be a useful agent in future. enzymes CYP2B6 and 3A4. Ritonavir is a potent inhibitor
of CYP3A4 used routinely to increase plasma
OXAZOLIDINONES concentrations of other PIs. Ritonavir-boosted PIs may
Oxazolidinones are a class of protein synthesis inhibitors therefore, lead to higher concentrations of other drugs
and include linezolid and eperezolid. metabolized by CYP3A4 or other isoforms inhibited by
Linezolid is active against gram positive and gram ritonavir (i.e. CYP2D6). In contrast, NsRTIs are not
negative organisms. Because of its unique mechanism of metabolized by CYP450.
action, linezolid is active against strains that are resistant Ritonavir is an inducer of glucuronidation and has
to multiple other agents. M. tuberculosis is moderately been clearly shown to be responsible for significant
susceptible with MIC of 2 µg/ml.109 decreases in concentration of drugs.
Linezolid inhibits protein synthesis by preventing Distribution of drugs is also mediated by plasma
formation of 70 S ribosome complex that initiates protein membrane influx and effux transporters including P-gp
synthesis by binding to 23 S subunit of the 50 S subunit. and multidrugs resistance protein (MRP). Three
There is no cross resistance with other drug-classes.110,111 transporters are present on many cell types including
Linezolid is well absorbed after oral adminis-tration intestinal epithelium, hepatocytes and kidney. They
and bioavailability is about 100% and dose for oral and control absorption, intracellular distribution, metabolism
intravenous preparation is same. At present linezolid is and elimination of drug through biliary canals and active
indicated in infections caused by multidrug-resistant tubular secretion. Table 31.9 gives the important
strains. No data is yet available in the treatment of MDR interactions of second-line agents and antiretrovirals.
tuberculosis.
THE NEW INVESTIGATIONAL DRUGS
Treatment of TB and HIV Together
Diarylquinoline TMC207
In patients with HIV-related TB, the priority is to treat
There appears to be a significant breakthrough in
TB, especially smear-positive PTB (on account of need
discovering a new class of antimycobacterial drug. The
to stop TB transmission). However, patients with HIV-
TMC207 is a diarylquinoline compound. TMC207 offers
related TB can have ART and anti-TB treatment at the
a new mechanism of antituberculosis action by
same time, if managed carefully, details discussed
specifically inhibiting mycobacterial ATP synthase. In
elsewhere.
murine model and a few human TB-patient-studies with
Table 31.9 enumerates the drugs licensed for use in
multidrug-resistance have given very promising results.
HIV and can have interaction with antituberculosis
In vitro TMC207 potently inhibits drug-sensitive and
drugs. Five classes of drugs are currently licensed for
drug-resistant M. tuberculosis isolates, and is bactericidal
the treatment of HIV.
against dormant (non-replicating) tubercle bacilli.120,121
Mechanism of Interaction with antiretroviral drugs In murine model, it is shown to be as active as the
combination of isoniazid, rifampicin and pyrazinamide,
As most of the 2nd line drugs and newer agents will be whereas the addition of TMC207 to this triple drug
used in cases with resistant TB which is often associated combination results in accelerated clearance of bacilli and
with HIV/AIDS, hence it is important to understand the synergistic interaction with pyrazinamide. Similarly,
mechanism of interaction of these drugs with antiretroviral TMC207 enhances the antibacterial activity of second-
drugs. line drug combination. It has acceptable adverse event
Pharmacokinetic interactions with antiretroviral drugs rates. In proof-of efficacy stage study, as compared with
may occur during absorption, distribution, metabolism and placebo, addition of TBM207 to the standard drug
elimination. Gastric pH, activity of transmembrane regimen of multidrug resistant tuberculosis resulted in
transporters such as enterocyte P-glycoprotein (P-gp) and quicker a conversion to a negative sputum culture. After
drug metabolism by enterocyte cytochrome P450 treatment with 400 mg once daily produced a steady
(CYP450) enzymes may all influence the bioavailability of plasma concentration of 3270 ng/ml.122,123
Table 31.9: Second-line antituberculosis agents and antiretrovirals evidence for drug interactions and recommendations for use
Second-line agent Antiretroviral
Protease inhibitors NNRITs NRTIs
• Broad spectrum Sparfloxacin and moxifloxacin are – –

– Fluoroquinolones metabolized by glucuronidation and
concentrations may be reduced by ritonavir,
atazanavir, might increase concentration
of sparfloxacin or moxifloxacin but
not clinically significant.
– Fluoroquinolones Use standard doses of ofloxacin, Use standard doses. Monitor Use standard doses separate
(Recommendations) levofloxacin or gatifloxacin, preferred ECG if using efavirenz with in time from duffered
monitoring of ECG, when sparfloxacin ofloxacin, levofloxacin didanosine.
and moxifloxacin are used. or gatifloxacin.
– Macorolides – Clarithromycin can be used at Azithromycin preferred to Clarithromycin and
Recommendations standard doses except in renal failure clarithromycin in combination zidovudin should be given
with ritonavir when dose is to be reduced. with efavirenz or nevirapine. separated by 1-2 hr.
– Cautious using azithromycin with – Clarithromycin can be
neltinavir or ritonavir. Use standard dose safely given with didanosine
but there is risk of toxicity of azithoromycin. – Azithromycin can be safely given
with ziduvudine and didanosive.
– Cycloserine Use standard dose but measure concen- Use standard doses but measure concen- Use standard doses but measure
tration of both PI and cycloserine. tration both NNRTIs and cycloserine concentration of cycloserine
– Risk of convulsions with alcohol. – Monitor for psychiatric
– Avoid ritanavir liquid if possible. morbidity with efavirenz
Narrow Spectrum Use standard dose but monitor Use standard does but minitor renal Risk of addition of additive toxicity
Amikacin renal functions functions. with tenofovir, use standard
– Aminoglycosides and dose but minitor renal function
polypeptides
– Aminoglycosides and – – –
polypeptides
recommendations
PAS evidence
– PAS—recommendations – Use standard dose of clofazamine. Clofazimine is a weak Use standard dose
– Clofazimine evidence. It is a weak inhibitor of CYP3A4, may inhibitor of CYP3A4. May
increase protease inhibitorconcentrations. increase etavirine concentration
* Modified from Coyne KM et al. Pharmacology of second-line antituberculosis drugs and potential for interactions with antiretroviral agents. AIDS 2009; 23:437-46.
443
444
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Pharmacokinetics
Vimlesh Seth, Alka Beotra, SD Seth, OP Semwal
INTRODUCTION GENERAL ASPECTS

In Europe the companies that wish to develop a drug The treatment of tuberculosis is protracted and burden-
for use in children, it is necessary to follow pediatric some and its control is further complicated by the synergy
investigation plan (PIP) as required by the European between tuberculosis and HIV/AIDS and by the
Regulation on better medicines for children. Defining emergence of multidrug-resistant (MDR) strains of M.
the optimum dose of a drug is one of the most difficult tuberculosis. Even when many countries are engaged in
parts of the developmental process. In phase I clinical trials dealing with increasing occurence of MDR-TB (resistance
to have standard pharmacokinetics/pharmacokinetic to isoniazid and rifampicin), a new trend in drug-
pharmacodynamic, (PK/PD) approaches involve in resistance has been emerging in some parts of the globe.
administration of either single or multiple doses of a This is the appearance of “extensively drug-resistant TB
drug in healthy adults. Blood samples are taken at (XDR-TB)” which is the form that is resistant to anyone
specified time intervals from the participants. Drug is of the fluoroquinolones and any of the second-line
subsequently assayed for its concentration and relevant antituberculosis injectable drugs (amikacin, kanamycin
metabolites, age based on absorption and distribution or capreomycin) in addition to the resistance to isoniazid
half-lives. These are the pharmacokinetic data and by and rifampicin (i.e. MDR-TB). Besides MDR-TB and XDR-
the pharmacodynamics, the effect of the drug at TB, other features also contribute to failure of TB-control
different concentrations can be assessed. in many developing countries which are — HIV
These approaches if used for all new drugs in children epidemic, collapse of public health infrastructure, war,
of each relevant age groups, present practical and ethical famine, population migration, increasing inequality and
challenges. For estimating the optimal dose or dose range poverty, and expensive drugs with dwindling
in pediatric population alternative methods can also be government support. In certain situations like poor drug
used. These are allometric scaling, a population compliance (due to any reasons) and use of lowquality
pharmacokinetic (PK) approach and in silico modelling. or spurious antituberculosis drugs, suboptimal serum
Scaling is a common tool which can be used to concentrations are achieved which are associated with
extrapolate within species at different age periods worse treatment outcomes. It is important to maintain
between animals and human beings. However, the factor high standards for drug-quality assurance as low quality
used for scaling differs. Though there is a nonlinear drugs often penetrate emerging markets, resulting in low
relationship between dose and body weight, the latter is cure rates for patients and increased drug-resistance.
the easiest to use. It is known for almost 60 years that Considering all these aspects it is important to know in
smaller species are more tolerant of drug treatment than details the kinetics of each of the antituberculosis drugs
larger species. Body surface area (BSA) was subsequently in transit in the human body from the time of its
found to be more satisfactory index of drug requirement administration (oral or parenteral) to the elimination from
as compared to body weight or age particularly during the body. Further, drug to drug interactions, drug to
infancy and childhood. In neonates BSA also overpredicts pathogen, drug to food and drug to immune response
clearance as it is the largest in them. In almost all species also play significant roles that may influence the
including human, the log of basal metabolic rate plotted pharmacokinetics and pharmacodynamics of the drug
against the log of body weight produce a straight line in question.
with a slop of ¾. Various theories exist for this
phenomenon. For scaling some PK parameters, this liner
Serum Concentrations of the Antimycobacterial Drugs
slop is superior to body weight and BSA. These PK
parameters are plasma clearance, volume of distribution Therapeutic drug monitoring (TDM) is the process of
and elimination half-life. This log relationship is used in adjusting drug dosages based on serum concentration
the allometric ¾ power model. However, none of these data or applied pharma-cokinetics, allows clinicians
parameter are ideal. to:
450
i. Quantify the relationships among drug doses. When low serum concentrations are demonstrated with
ii. Serum concentrations. normal dosing, higher doses are required even if they
iii. Therapeutic responses. exceed the so called “maximum” dose. Serious dose-
iv. Concentration-related adverse events. related toxicities are relatively uncommon with the
The use of TDM in the dosing of antimycobacterial antituberculosis drugs except cycloserine, ethambutol,
drugs is relatively new. Optimal use of TDM requires a streptomycin and other aminoglycosides under condi-
complete model of the serum concentration response tions such as renal failure. TDM has been proved to be
curve for a drug. These curves are only partially described beneficial in adults with HIV/AIDS and is a powerful
for the antimycobacterial drugs. It is known that if a tool for optimizing drug therapy in patients with difficult
patient fails to take a drug (serum concentrations of zero), to treat mycobacteria.
his treatment will fail. If they absorb isoniazid and
rifampicin normally, they are very likely to respond to Pharmacodynamics
treatment. Somewhere between the ‘normal’ serum
The aim of antituberculosis treatment, as with any other
concentrations and zero, activities of isoniazid and antibiotics, is to achieve adequate drug concentrations
rifampicin wane. This dropoff in activity occurs even at the site of infection for an appropriate length of time,
more rapidly for ethambutol and the second-line in order to ensure the eradication of the organisms and
antituberculosis drugs. Further complicating, the optimize clinical success. This desired outcome1 depends
relationships between serum drug concentrations and not only on the pharmacokinetics of the agent, but also
response is the fact that antituberculosis drug therapy on the characteristic of the pathogen, e.g. microbicidal
appears to have two distinct phases. First there is rapid susceptibility, and host related factors.
elimination of actively multiplying mycobacteria, known A new approach to this problem seeks to combine the
as early bactericidal activity; and second there is the slow microbiologic activity with antibacterial pharmacokinetics
elimination of semidormant organisms, and those in less data into a discipline called pharmacodynamics. The best
accessible areas, known as the sterilizing activity. It is pharmaco-dynamic parameter is the minimum effective
possible that the characteristics of a drug that are antimicrobial action in an area under the inhibitory titer
important for one phase may be less important during (AUC), which is calculated as the 24 hours serum AUC
the subsequent phase. Thus, while high maximum serum divided by minimum inhibitory concentration (MIC) of
concentrates relative to the minimum inhibitory the pathogen. These two basic principles of pharma-
concentrations (Cmax/MIC ratios) appear desirable early cokinetics and pharmacodynamics, in addition to,
on, they may be less critical later on. During the sterilizing microbicidal susceptibility of the organism are the rational
phase, it may be the ability of the drug to remain at the for combination chemotherapy applicable to myco-
site of infection for long periods of time, and its ability to bacterial infections.
quickly inhibit or kill mycobacteria. Unfortunately, these
phenomena differ from patient to patient.
Early Bactericidal Activity
Altered pharmacokinetic profiles for antimicrobial The rate at which an antituberculosis drug kills, rapidly
drugs in selected patient groups have been demonstrated, metabolizing and multiplying bacilli during the first two
e.g. AIDS patients display low serum concentration of days of therapy is termed the early bactericidal activity
antimycobacterial drugs. This also occurs in patiens (EBA). EBA can be used to determine the lowest effective
with cystic fibrosis and diabetes mellitus due to dose of these drugs. This has been estimated for
malabsroption. This drug malabsorption is responsible practically all drugs, i.e. isoniazid, rifampicin, pyra-
for failure to drug therapy in 2 out of 5% of compliant zinamide streptomycin, and even ethambutol. EBA
tuberculosis patients. TDM appears to be a useful tool reflects the ability of an agent to kill the metabolically
for identifying these patients early on and for adjusting active bacilli in the walls of cavities. It might also reflect
their doses before drug-resistance and or/clinical failure the capacity of an agent to protect companion drugs
occurs. TDM can be very cost-effective because it may against resistance. Hence, in addition to the pharmaco-
prevent the need for lengthy and expensive retreatment kinetics and pharmacodynamics of drugs, determination
of EBA is another important parameter to determine the
and prevent additional cases of tuberculosis that occur
efficacy of an antituberculosis agent.
before treatment failures or relapses are identified. TDM
has certain limitations and is not a replacement of direct
Pharmacokinetics
supervision which is the key factor in DOTS therapy.
However, it can be particularly effective in guiding Pharmacokinetics is the study and characterization of the
therapy in second-line drugs. In the latter, effective timecourse of drug absorption, distribution, metabolism
dosing against dose-related toxicities are very important. and excretion, and the relationship of these processes to
451
Chapter 32 Antituberculosis Drugs: Pharmacokinetics
intensity and timecourse of therapeutic and toxicologic dosage levels, but when the dose exceeds a certain critical
effects of drugs. 2 Although, principles of phar- level the elimination mechanisms get saturated and then
macokinetics are described in terms of mathematical a fixed quantity of the drug is eliminated per unit time.
equations which are used to quantitatively predict the This is called dose-dependent elimination or saturation
nature of these processes, understanding of basic kinetics or zero order kinetics.10
pharmacokinetic principles and the use of plasma level
determinations can greatly help the physician in taking Absorption
deci-sions regarding drug, dosages. From the time, a drug Absorption describes the rate at which a drug leaves its
enters the body until it is eliminated, a number of kinetic site of administration and the extent to which it occurs.
factors, which differ in infants and young children The absorption from gastrointestinal tract becomes the
from adults, may be responsible for the altered drug initial factor determining drug plasma concentration and
response.3-6 therapeutic effect. Absorption is influenced by
physiologic factors (e.g. rate of gastric emptying, GI
First Order Kinetics motility, food intake, etc.) which may vary greatly in the
neonate.11,12 Physicochemical properties of the drug (pKa,
After drug administration, a drug crosses several
molecular weight, lipid solubility) and manufacturing
membranes by passive diffusion to reach its site of action.
techniques (particle size) also affect absorption.
In general, drugs in which the rate of transfer is
proportional to the amount of drug remaining to be
Bioavailability
transferred is described by first order kinetics. It means
that a constant fraction of the drug in the body disappears The bioavailability of a drug is defined as its rate and
in each equal interval of time.4-6 Following a single intra- extent of absorption. It is used to indicate the extent to
venous dose, the plasma concentration of the drug is which a drug reaches its site of action. Bioavailability is
found to fall exponentially. 7-10 Half-life is the time determined from blood level or urinary excretion data
required for 50% completion of this process.9 In first order after oral administration, with reference to similar data
kinetics, the half-life is independent of the route of after intravenous administration. The total area under
administration, dose given and plasma concentration of the drug level in blood or plasma versus time curve, i.e.
the drug and is directly related to the duration of its area under the curve (AUC), after a single dose, reflects
pharmacological effect. A 93.7% of the drug is eliminated the amount of drug reaching the blood stream. For most
in 4 half-lives. In the case of an exponentially eliminated drugs, if we double the amount injected intravenously,
drug, a plot of the log of concentration against time gives we double the AUC. It follows that if one compares the
a straight line.6 Drug transfer can be considered to AUC after oral administration with that obtained after
proceed by first order kinetics when a semilogarithmic intravenous administration, one can determine the
plot of drug concentration versus time results in a straight fraction (F) of the oral dose available to the systemic
line (Fig. 32.1). circulation. In other words,
Most drugs are eliminated exponentially (first F = (AUC)oral/(AUC)iv
order kinetics). For some drugs, e.g. phenytoin and If only 60% of an oral dose reaches the bloodstream,
propranolol, the elimination is exponential at lower then F = 0.60; if the entire dose is available, then F = 1.00.
The determination of bioavailability is a time consuming
and expensive procedure and needs to be carried out only
in the cases of drugs with a narrow therapeutic index.10
First Pass Effect

After oral administration, a drug must pass sequentially
from the gastrointestinal lumen, through the gut wall,
then through the liver before reaching the systemic
circulation. Since, the gut wall and liver are sites of drug
metabolism, a fraction of the amount absorbed may be
eliminated (metabolized) before reaching the blood
stream. Therefore, a drug may be completely absorbed
but incompletely available because part of the dose is
metabolized to other products during the drug’s passage
from the gut lumen to the systemic circulation because
of first pass metabolism in the gut wall or liver. It results
Fig. 32.1: Semi-logarithmic plot of drug concentration versus time in decreased oral drug bioavailability.
452
Distribution compartments (i.e. bile, saliva and milk), and the

enzymatic or biochemical transformation (metabolism)
The transfer of drug from blood to extravascular fluids of drug in the tissues or plasma to metabolic products
(i.e. extracellular and intracellular water) and tissues is are usually irreversible processes. Drugs are eliminated
called distribution. Drug distribution is usually a rapid from the body either unchanged or as metabolites. The
and reversible process. After intravenous injection, drug kidney is the most important organ for elimination of
in the plasma exists in a distribution equilibrium with drug drugs and their metabolites. Excretion of drugs in the
in the erythrocytes, in other body fluids, and in tissues. breast milk is important not because of the amounts
As a result of this, changes in the concentration of drug in eliminated but because the excreted drugs are potential
the plasma are indicative of changes in drug level in other sources of unwanted pharmacological effects in the
tissues including sites of pharmacologic effect nursing infant.
(bioreceptors). Figure 32.2 shows schematic representation In vivo drug metabolic studies are most useful for
of drug absorption, distribution and elimination. estimating the clearance of a drug. It is a better index of
The moment a drug reaches the blood stream, it is efficiency of drug elimination than the more commonly
subject to both distribution and elimination. The rate used term half-life. Clearance is defined as the volume
constants associated with distribution, however, are of biological fluid that is irreversibly cleared per unit of
usually much larger than those related to drug elimination. time. In general, drug elimination is impaired in
Accordingly, drug distribution throughout the body is newborns, particularly, premature newborns. It improves
usually complete while most of the dose is still in the body. with age and tends to be more efficient in older infants
In fact, some drugs attain distribution equilibrium before and children.
virtually any of the dose is eliminated. In such cases, the
body appears to have the characteristics of a single
FACTORS RESPONSIBLE FOR ALTERED DRUG RESPONSE
compartment. But for most of the drugs, concentrations
in plasma measured shortly after intravenous injection
IN CHILDREN
reveal a distinct distributive phase. This means that a Dosing Guidelines
measurable fraction of the dose is eliminated before
attainment of distribution equilibrium. These drugs impart These are more complicated in children than those for
the characteristics of a multicompartment system upon adults. Evidence indicates that children require and
the body. These compartments can often be classified as: tolerate larger mg/kg doses of many drugs than adults.
(i) the central compartment consisting of the plasma and Estimates of the dose required for neonates, infants and
extracellular fluid and highly vascular tissue (usually the children should be given on the basis of the surface area
red blood cells, lungs, liver, kidney), and (ii) a of the young patient, but often this is not done in
compartment of poorly perfused tissue (fat, muscle, skin). developing countries except for anticancer drugs and
drugs used in renal disease. The drugs are usually
Elimination dispensed as mg/kg dose or mg/kg/day divided into 3
to 4 doses. Calculations based on body surface area
Elimination processes are responsible for the physical or indicate that in general, the average 3-month-old child
biochemical removal of drug from the body. The transfer weighing 6 kg should receive twice the mg/kg dose given
of drug from the blood to the urine or other excretory to an adult, whereas the average 5-year-old child
weighing 20 kg should receive 1.5 times the mg/kg dose
given to adults.11 Hence, there is overdosing of drugs,
antituberculosis being one such group. Streptomycin
used to be given in the dose of 50 mg/kg/day IM, but
now it has been amply demonstrated that a dose given
as 20 mg/kg/kg, that too, for two weeks is enough. This
is because the drug acts on the rapidly multiplying
extracellular organisms, which are very few in
tuberculosis of children, except in adolescence. This
occurs in this age period of childhood (adult type of
pulmonary tuberculosis sputum, +ve, or severe
pulmonary with sputum, –ve).
However, this concept does not hold true for
developing countries where a sizeable propor-tion of
Fig. 32.2: Schematic representation of drug absorption, children particularly preschoolers <5 years suffer from
distribution and elimination grades II and III of malnutri-tion. Hence, the same dose
453
which is therapeutic and least toxic for children belonging of drug tablets as well as absorption of drugs. Acidic
to western countries will not be right for developing and basic drugs are best absorbed in the stomach
countries. The glaring example is isoniazid which was and small intestine respectively. However, many
given in the dose of 10 to 20 mg/kg to children acidic drugs are absorbed more rapidly in the
particularly who had serious type of tuberculosis, i.e. duodenum than in the stomach, because of the larger
neurotuberculosis. Pharmacokinetic studies on isoniazid absorption area of duodenum. In the presence of a
which will be described in the later part of the chapter, it poor mucosal development in neonates, pH is of
was demonstrated by Seth that a dose of 5 mg/kg is good great importance.
enough for having sufficient MIC, with good therapeutics ii. The bacteria colonizing the intestinal tract are of
efficacy and least toxicity. Hence, in addition there are importance in the hydrolysis of drug conjugates
ethnic factors which change the pharmacodynamics of excreted in the bile.
drugs, antituberculosis drugs being one such group. iii. Irregular gut motility and slower gastric emptying
time may not affect the degree of absorption but do
The Requirement with Larger Doses in Children than in interfere with the achieve-ment of peak plasma
Adults concentration of a drug.
In general, age related changes in drug distribution
Clinical pharmacokinetics are different in neonates as
tend to decrease the volume of distribution in adults,
compared to adults.12 It is related in part to the fact that
compared with neonates for most water soluble drugs.
total body water (T-BW) and extracellular fluid (ECF)
Drugs that are lipid soluble may have a lower volume of
make up a larger percentage of the total body weight in
distribution in neonates because of age related differences
children than in adults. Total body water decreases with
in adipose tissue.
age, from 78% of the newborn’s body weight to 60% of
The most dramatic age related differences in drug
the adult’s weight.13 Differences in extracellular water
elimination often occur between the newborn and the
(ECW) are even greater. Extracellular water represents
adult. Most of the enzymatic microsomal systems required
about 45% of the body weight in the newborn but only
for drug metabolism are present at birth, but their titers are
20% of the adult’s body weight.14 Inspite of this, in
usually lower than adult levels. In general, drugs subject to
newborns a fairly large proportion, i.e. about one-third
biotransformation are eliminated more slowly in newborns than
are low birth weight, appropriate for gestation, drugs
in adults.16 Drug oxidation in the neonate is usually im-
given using surface area basis will be higher and likely
paired, whereas drug conjugation presents a mixed
to produce toxicity. Aggarwal et al14a have shown that
picture. Sulfate conjugation seems to be as efficient in
ciprofloxacin (not permitted in child and neonate) is used
newborns as in adults, but conjugation with glucuronic
increasingly in neonates for treating multidrug resistant
acid is considerably low, reaching adult levels only after
infection. The pharmacokinetics of this drug are
3 years of age.
necessary in the newborn. By multiple dose
pharmacokinetics it was demonstrated that 10 mg/kg
VARIOUS FACTORS WHICH CHANGE
I/V given 12 hourly is effective for neonatal sepsis but
higher doses are required for treating staphylococcal and PHARMACOKINETICS
pseudomonas infection. Hence, one should not blindly Drug Dose
follow the dosage schedule which is given in western
books. Children in India, right from the newborn age For a drug to be effective, its serum concentra-tion must
period to adolescence are lesser in weight except the ones exceed its minimum inhibitory concentration (MIC). Serum
who belong to top 25 percentiles. rifampicin and isoniazid concentrations are a good basis
for evaluation of efficacy of a rational antituber-culosis
The Morphology and Functions of the Gastrointestinal regimen. Unfortunately, in the pediatric population, the
recommended doses of the antituberculosis drugs are not
Tract
based upon well than designed pharmacokinetic studies
These vary almost continuously from birth till rather data generated in the western world, that too in
senescence.15 The effect of food on drug absorption is African countries on clinical observations. Animal studies
particularly important. Each drug must be considered and those in adults have shown that the serum and tissue
individually to see the effect on children. concentrations achieved by oral administration of rifampicin
Yaffe15 has summarized the following concepts: and isoniazid are much above their MIC.7 Olson et al17 and
i. The lower pH in children less than 3 years in Mount et al18 have demonstrated that the concentrations
comparison to adults may influence the gut motility, achieved in children are higher because doses given on
chemical stability of drug and the dissolution rate weight basis are almost double as compared to adults.
454
Pharmacokinetics Characteristics of INH Pharmacokinetics of Isoniazid in Isoniazid Resistant

Pharmacokinetic characteristics of INH have been Tuberculosis in Children
extensively studied in adults but data in respect of Isoniazid (INH) resistant and especially multidrug
children and especially younger children are limited. resistant (MDR) tuberculosis (resistance to both INH and
Where such data are available cognizance has not been rifampicin) poses an increasing problem for tuberculosis
taken of the genotype or of the trimodality of INH control programs. This does not spare the children.
elimination except a few studies by Seth et al19,20 have However, the value of using INH to which M. tuberculosis
demonstrated that considerable differences in exposure shows an in vitro resistance especially to INH, in
to INH that exist between homozygous acetylators of treatment has been debated.
INH and heterozygous and homozygous fast acetylaters The critical concentration for high level INH
in children described later in the chapter. Age resistance is defined as >1.0 µg/ml on Lowenstein Jensen
relationship analysis indicates that younger children medium. The most critical concentration in liquid
eliminate INH faster than older children. In a trimodel medium, such as the BACTEC460 drug susceptibility test,
model of INH elimination then is a significant age related are ≤ 0.1 µg/ml for low-level resistance and ≥ 0.4 µg/ml
decline in the first order elimination rate constnt (k, h-1) for high level resistance. However, concentration of INH
with age in all three genotypes. Further, the exposure of of more than 5 µg/ml are readily attainable with high
the children to INH, as reflected by the first order dosages of INH in children. (15-20 mg/kg/day) and 5
elimination rate constant, AUC for the period µg/ml serves as a practical measure of clinically relevant
2 to 5 hours after dosing, and INH concentrations at high level resistance.
different time intervals after dosing, is significantly less Children with drug resistant tuberculosis usually
than that of a group of adults drawn form the population have transmitted (new) resistance. Low-level INH
and receiving the same mg/kg body weight dose of INH. resistance is more common in adults with new (i.e. no
Schaaf et al21 concluded that on the basis of NAT2
previous treatment) INH resistant tuberculosis than in
genotype, younger children eliminate INH faster than
those previously treated for INH resistant tuberculosis.
older children and children as a group faster than adults.
As low level of INH resistance is more common implying
Faster elimination has been ascribed to the relatively
a potential therapeutic role of high dose INH (15-20 mg/
greater mass of the liver in proportion to total body
kg/day).
weight and hence recommended the calculation of the
Treatment is difficult and the armamentarium of
dose in relation to body surface area than body weight.
second-line drugs is limited. This data is important for
However, they had reservation of this recommendation
better defining the most appropriate use of INH and to
for use in the program conditions.
prolong the usefulness of this key agent in case
The normal range of INH concentration has been
management and tuberculosis control programs,
given as 3-5 mg/L, and has been suggested that a 3 hours
concentration of 1.5 mg/L is desirable. In their study 35% particularly in resource limited countries where the
of the homozygous fast acetylators had a 2 hours INH availability of second line drugs is not easy. The far
concentration of less than 3 mg/L and 45% did not reach reaching implication could be if appropriate, INH dosage
a 3-hour postdose concentration of 1.5 mg/L. From this regimens could eradicate the partially resistant M.
it seems that both homozygous and a significant tuberculosis organisms.
proportion of heterozygous fast acetylators will fail to There was no difference in the level of INH resistance
achieve the recommended concentrations. between new and previously treated cases. This
For this, Schaaf et al21 justified the use of higher mg/ emphasizes the importance of detailed history taking of
kg INH doses in children than adults. American contact with infectious tuberculosis cases and the
Academy of Pediatrics (AAPS) recommend an INH dose possibility of exposure to drug-resistant organisms.
of 10 to 15 mg/kg/day body weight. Many of the studies Schaaf et al21a have rightly emphasized in their study
including that is detailed below by Seth et al 19,20 is that drug susceptibility testing was not done at INH
demonstrated satisfactory clinical response with 5 mg/ concentrations of 0.4 µg/ml, 1.0 µg/ml and 2.0 µg/ml
kg of INH emanating from population in the North India. which would have given a better description of exact
The relative therapeutic disadvantage of heterozygote minimal inhibitory concentration for INH in their
fast acetylators will also be concealed by the synergistic isolates.
potential of a multidrug regimen. Under adverse In conclusion, whenever the minimal inhibitory
circumstances, such as failure of full compliance, concentration of INH can be determined, treatment can
compromised absorption of INH itself or its companion be individualized. When minimal inhibitory
drug rifampicin. To be on the safe side, Schaaf’s and AAPS concentration is below 1.0 µg/ml or is unavailable, high
recommendation suggested dose is at least 10 mg/kg. dose INH at 15 to 20 mg/kg/day could still possibly
455
value in the treatment of children with drug-resistant The evaluation after 4 months showed no difference
tuberculosis, although, it should not replace any other between the HIV-infected and HIV-uninfected
drug. children. The highest value was reached when RMP
was administered in the suspension form. Peak
Paradoxical effect of Isoniazid on the Activity of concentration of RMP varied from 3 to 5 µg/ml. On
Rifampicin – Pyrazinamide Combination in a Mouse the basis of these the recommended dosage of RMP in
Model of Tuberculosis children under 6 year was 15 mg/kg body weight.
RMP concentration under 4 µg/ml is considered low.
Almeida et al23 concluded that the simplest and perhaps Schaaf’s study demonstrated that the calculated 2
the most reasonable response of the paradoxical effect of hour-concentration was less than 4 µg/ml. By 4 months
isoniazid on the activity of rifampicin–pyrazinamide of treatment even with considerable improvement in
combination is that this antagonism is the price to pay nutrition, the levels achieved were not different
for having an excellent combined regimen that prevents implying that nutrition was not a significant factor for
the selection of drug resistant mutants. INH has a crucial achieving plasma RMP. It is concluded that low serum
role in the early bactericidal activity and prevents the RMP concentration in children with often recommended
emergence of resistance to companion drug. However, dose of 8 to 12 mg/kg body may be of no consequence in
one can now imagine replacing INH in the initial phase the management of less serious forms of childhood
with moxifloxacin which exhibits no antagonism with tuberculosis, the recommended doses of 10 to 20 mg/kg
RIF.–PZA combination. At the end of the initial phase body by American Academy of Pediatrics is more
(1-2 weeks) INH could again be prescribed with appropriate. Schaaf et al 11 further suggested AUC should
rifampicin. INH and RIF have a clear added effect. It is be calculated over 0 to 6, 0 to 12 or 0 to 8 hours.
emphasized that it is an experimental study and need a Thee et al25 reported that recommended RMP dosages
in childhood tuberculosis led to lower serum levels as
lot of future research.
compared to those recommend for adults attributed to
different pharmacokinetics and pharmacodynamic in
Review of Literature on Rifampicin Pharmacokinetics
children. They recommend that in children it appears to
Donald23a has summarized, in a tabular form, the be more valid to recommend RMP dosage on the basis
maximum serum concentration (Cmax) in relation to age of body surface area rather than body weight, leading to
in children after administration of a single oral dose. higher dosages especially in younger children.
There are no significantly quotable studies for the age Thee et al12 conducted the studies between 2 and 14
group below 8 months singly. The rest of the age groups years of age, a dosage of 10 mg/kg of RMP. The levels
studied are between 8 months and 14 years as below, were even lower when given with ethambutol. In adults,
(Table 32.1). after the standard dose of 600 mg RMP levels ranged
The dose of RMP calculated for children according from 8 to 24 µg/ml. Serum levels in the study by Thee et
to body weight and body surface area (Ansel and Stoklisa, al12 were even lower than the lower level reported in
2001) is given in (Table 32.2). adults.
As low drug concentrations reduce therapeutic
Introduction to Rifampicin Pharmacokinetics efficacy, higher doses than those recommended by WHO
(8-12 mg/kg body weight) might therefore, be necessary.
Rifampicin is a key drug in antituberculosis chemo-
therapy because it rapidly kills the majority of bacilli
in tuberculous lesions, prevents relapse and thus Table 32.2: The dose of RMP according to body weight
and body surface area in children
enables 6 months shortcourse chemotherapy. Little is
known about the pharmacokinetics of rifampicin in Weight 10 mg/kg Dose according BSA dose
children. Schaff et al 24 evaluated the pharmacokinetics dose to BSA as mg/kg
of ritampicin in children with severe forms of
2 20 54 27
tuberculosis, both human immunodeficiency virus type- 3 30 69 23
1-infected and human immunodeficiency virus- 4 40 84 21
uninfected. The authors documented very low serum 5 50 99 19.8
RMP concentration in children of which the great 10 100 162 16.2
majority received the often recommended standard 15 150 216 14.4
dosage of 8 to 12 mg/kg body weight. There was a 20 200 288 14.4
trend for lower concentrations in HIV-infected 25 250 330 13.2
children on the first evaluation 1 month after 30 300 372 12.4
commencing treatment but this was not significant. 35 350 414 11.8
456
Table 32.1: Maximum serum concentration (Cmax) of rifampicin in relation to age after administration of a single oral dose
Author Dose mg/kg Age n Cmax µg/ml

• Bergamnieted (1970) 20 8-12 months 14 10.2
10 8-11 months 14 3.7
• Acocelle et at (1970) 10 4-18 months 12 3.5
• Hussels et al (1973) 10 2-<6 years 7 4.5
10 2-<6 years 7 6.5
10 6-10 years 11 5.3
10 6-10 years 11 7.1
10 10-14 years 9 5.4
10 10-14 years 9 6.6
• Cracken et al (1980) 10 Suspension 6-58 months 21 9.2
10 Suspension in apple sauce 6-58 months 12 6.2
10 Powder in apple sauce 6-58 months 5 8.8
The use of RMP in the suspension form resulted in a much lead to a dosage of 15 mg/kg RMP to toddlers and young
higher serum levels with the same dose (10 mg/kg) used children decreasing to 10 mg/kg at adolescence with the
for prophylaxis in H. influenza infection. Peak serum combination therapy of HRZE. Minor hepatotoxic side
levels were attained after 2 hours of oral dose. The effects corresponding to RMP were found in 1.8% of the
absorption seems to be delayed in children as peak serum children.
concentration reaches at 4 hours. Elimination half-life is Peloquin et al 26 reported that changes in Cmax, Tmax,
on an average t½ of 2.9 hours in children given 10 mg/ and AUC0-oo can be avoided by giving rifamycin (RIF)
kg dose. on an empty stomach. Most Tmax values are reached near
Food seems to have been shown to significantly 2 hours. The Optimal sampling time for the two sample
reduce the absorption of RMP. The other factor strategy is recommended by Peloquin et al.26 These are
interfering with the absorption are gastric pH, emptying, 3.1 hours and as late as 14.9 hours after the dose. Samples
intestinal transit time, functional absorptive area, drawn between 1 to 6 hrs post dose approached Cmax, 2
metabolic capacity and carrier mechanisms or drug to 3 hours samples were closest.
transporters in the gastrointestinal tract, influence Antacids did not affect the absorption. High-fat meal
gastrointestinal absorption. The most important of these had significant affects on the RIF, reducing Cmax (-36%)
is intestinal absorptive area of the intestines in TB. In and increasing Tmax (+103%). Food affects to a lesser
addition to delayed absorption, in children only a extent.
bioavailability of 50% is reached after oral administration. With a carbohydrate rich diet, there was a 15%
It is well distributed through the body. As about 25% of reduction in Cmax, 19% increase in Tmax and 4% reduction
the drug is ionized at the physiological pH, while the in AUC. Studies on the rifampicin derivatives like
molecule as a whole is lipid soluble. Concentration of rifabutin showed that food had less of an affect on the
RMP in the various tissues of the body is variable. RMP Cmax (-17%) than shown for rifampicin. Cmax (-36%) Tmax
is mainly metabolized in the liver by B-esterases, (+80%) and AUC (-5%) of rifabution is similar to the
however, it is a strong inducer of the cytochrome P450 pharmacokinetics of RMP. Rifapentin, actually shows
system. Efficacy of RMP depends upon concentration improved absorption with food.
rather than time. RIF is cleared predominantly through nonrenal
There is considerable intra-inter individual variation mechanisms, with only 10% of the drug being excreted
in RMP serum levels. Uniform dosage of 10 mg/kg body unchanged through the kidney. RIF is converted to 25-
weight RMP does not appear to be appropriate and desacetylrifampin and other, less abundant metabolites,
especially not in children < 6 years of age. As these levels which are subsequently cleared by nonrenal mechanisms,
were measured at the beginning of the study, the levels 25-desacetylrifampin displays microbiological activity
would be lower during the course of therapy due to self- approaching that of RIF, with displacement of serum
induction of RMP metabolisation. In children the water concentrations approximately 10% of those for RIF. RIF
compartments at various ages are proportion to body is superior in its activity against M. tuberculosis as
surface area (BSA), dosing according to BSA might be compared to M. avium.
more appropriate. An RMP dosage of 300 mg/m2 BSA
given to children resulted in the serum levels of 9.1 µg/ Pharmacokinetics of Pyrazinamide in Literature
ml in the age group of 3 months to 2.9 years. This is closer Zhu et al29 reported concentration on time data analysed
to desired serum level of 10 µg/ml. These calculations using population methods in children. Pyrazinamide
457
concentrations increased linearly with increasing oral TB and new drugs. The development of shorter duration
doses. Median maximum serum concentration values of anti-TB regimens is the eradication of slowly
were 41.0 µg/ml with daily dosing and 66.1 µg/ml with replicating bacilli (SRB) and non-replicating persistent
larger, twice weekly dosing. Incomplete (18%) or delayed bacilli. If with the new drug, the bacilli are with in
(30%) absorption was more common in children than in macrophages, then a desirable property of the drug is
adults (1% for each). the capability of drug for intracellular penetration. If the
Thee et al30 estimated PZA serum levels alone or in bacilli are extracellualr, the crucial property of the drug
combination therapy with isoniazid and RMP. Serum has to be the capacity to achieve a high ELF concentration.
levels did not differ with age, in PZA monotherapy or in Relationship between PZA AUC/MIC as well as time
combination therapy with a dosage of 30 mg/kg PZA, and both sterilizing activity and resistance suppression
efficient serum levels were reached. Because PZA is is necessary to examine the likely success of different PZA
uniformly distributed in the body, serum levels are doses. The current recommended dose of 15 to 30 mg/
related to body weight and a dose of 30 mg/kg body kg in children is more successful in achieving the
weight is appropriate in children. exposure associated with optimal sterilization in large
Gumbo et al31 developed an invitro pharmacokinetic- proportion of patients.
pharmacodynamic model in which M. tuberculosis It is summarized that an invitro PK-PD model can be
replicating slowly at pH 5.8 was exposed to PZA by the used to examine the sterilizing effects of anti-TB drugs.
use of concentration — time profiles encountered in Microbial killing was linked to AUC/MIC, while
patients. Daily pyrazinamide dosing for 28 days resistance suppression was liked to Tmic.
accurately achieved: Graham et al32 evaluated the impact of age, nutritional
i. The PZA pharmacokinetics parameters. status, human immunodeficiency virus status to
ii. The lack of early bactericidal activity. characterize the pharmacokinetics of PZA. The children
iii. A sterilizing effect rate of 0.10 log 10 CF µ/ml per were on three weekly regimen of antituberculosis drugs.
day starting on day 6 of therapy. Serum drug levels were low for PZA in almost all the
iv. A time to the emergence of resistance of the from 2 cases. The maximum serum concentration (Cmax) failed
to 3 weeks of monotherapy encountered in patients to reach the MIC for M. tuberculosis. The Cmax of PZA
with tuberculosis. was significantly lower in younger children (< 5 year)
The next dose scheduling studies were done. The than in older children. The Cmax was also lower in those
sterilizing effect was linked to the PZA ratio of the area with human immunodeficiency virus infection and
under the concentration time curve from 0 to 24 hr (AUC0- children with severe malnutrition but the differences
24
) to the MIC (α2=0.75 – 0.94). The currently used dosage were not statistically different.
of PZA (15 – 30 mg/kg) achieved the AUC0-24 / MIC of Pharmacokinetic study has found poor absorption of
209.08 in the epithelial lining fluid (ELF) of only 15.1 to PZA in Malawian children. It was found that low levels
53.3% of patients. Doses of > 60 mg/day performed better were found in intermittent therapy. Young child is at an
but this dose is associated with hepatic toxicity. Gumbo important risk factor for low level.
et al’s 31 preclinical PK –PD model can be used to generate Sanchez and Maramba33 described therapeutic drugs
data on the relationship between level of drug exposure, monitoring (TDM) as a process of adjusting drug dosages
time and sterilizing effects. Second standard mathematical on the basis of serum drug concentration for the purpose
(PK-PD) models are used to describe the relationship of optimizing drug therapy. They used pyrazinamide
between the level of drug exposure, the level of microbial suspension for estimating pharmacokinetics.
killing, and suppression of resistance. PZA monotherapy Tmax of 2 hours, the mean serum concentration PZA
in patients has an early bactericidal effect of 0.05 ± 0.18 suspension is at 34.6 ± 11.86 µg/ml. The mean serum
log 10 CFU/ml per day, a time to start of slenderizing trough level is 4.55 ± 4.63 µg/ml. There was no significant
effect of ≥ 4 days, sterilizing effect rate of 0.11 log 10 CFU/ difference between the three brands tested. Most serum
ml per day, a time to the emergence of resistance of 2.5 concentration of PZA suspension falls within the
to 3 weeks. Thus their invitro model achieved: established therapeutic ranges for PZA.
i. The PK parameters of PZA. TDM requires the accurate timing of doses and blood
ii. The lack of early bactericidal activity. collection and avoidance of assay interferences.
iii. The daily rate of sterilization. Zhu et al34 reported that pharmacokinetic parameter
iv. The time to the emergence of resistance in patients of PZA were independent of human immunodeficiency
with TB. virus status and patient’s demographics except for body
This model has clinical relevance especially with PZA weight. Population elimination half-life values in
and could be used to study sterilizing effect of old anti- pediatric and adult patients were 3.5 and 6.0 hours,
458
respectively. Medium volume of distribution (L/kg) was – 127% CL) with orange juice, food, or antacid treatment
32% larger in children, and the median clearance (L/hr/ respectively. Corresponding ratios for AUC (0-infintiy)
kg) was 106% larger in children with a resultant median were 1.05 (71% – 158% CL), 1.52 (103% – 224% CL), and
half-life 43% shorter in children. Absorption of P2A in 0.84 (57% – 125% CL) respectively. It was concluded that
children was more incomplete or delayed. food significantly enhanced the absorption of PAS,
while orange juice and antacids had minor effects.
Pharmacokinetics of Ethambutol in Children Zhu et al40 conducted that ethionamide (ETA) PK
In a review on ethambutol (EMB) in children a parameters differed between TB patients and healthy
recommendation for dosing regimen by Donald.35 volunteers, possibly due to difference in the completeness
reported that serum concentrations of EMB were of absorption. Doses of atleast 500 mg appear to be
maximal “at about 2 hours” and were 10 µg/ml and 5 required to achieve serum concentrations above the
µg/ml following doses of 50 mg/kg body weight and typical ETA MIC.
25 mg/kg daily. Serum concentration were proportional Zhu et al41 researched on the pharmacokinetics of
to dose and less than 10% of the dose administered cycloserine and summarized that PK of cycloserine were
was present in the serum after 24 hours and there was minimally affected by orange juice, antacids, whereas the
no evidence in the serum of accumulation of the drug high-fat meal delayed absorption. Administering
over more than 3 months. Within 6 hours 28% of an cycloserine without a high fat meal avoids potential
oral dose was excreted in urine. The great majority of alterations in the pattern of absorption. Dose given to
the drug (approximately 80%) is excreted unchanged adults was 500 mg after a 12 hour fast with a high-fat
in the urine, that the T max tends to be somewhat
meal. The other companion drugs given was, (ETA),
delayed in comparison to other drugs (between 2-4
clofazimine and PAS.
hours). Following a meal, a lower Cmax is found than
Nixa et al42 as a part of (four) drug regimen of
when fasting (4.5 µg/ml VS 3.8 µg/ml after a dose of
25 mg/kg). Serum concentration in children are found clofazimine, cycloserine, (ETA), PAS recorded the PK of
to be lower than those found in adults with similar clofazimine for MDR-TB. It was inferred that administration
doses of EMB. Effective therapeutic concentrations are of clofazimine with a high fat meal provides the greatest
achieved in the majority of children with the dosage bioavailability, however, but it is associated with high
of 20 mg/kg, increased by 5 mg/kg in those aged < 3 inter and intra subject variability. Both orange juice and
year to decease it by 5 mg/kg in those aged > 11 year. alumimium–magnesium antacid produced a reduction
The review summarized after seeing the results of in mean bioavailability of clofazimine.
pharmacokinetic in children that a dose of 25 mg/kg Stambaugh et al 43 concluded that ofloxacin PK
is optimum. parameters increased linearly with increasing oral dose.
Zhu et al38 by their studies on pharmacokinetics of Delayed absorption was seen atleast once in 29% of
ethambutol (EMB) by concentration data analyzing patients. Ofloxacin elimination decreased with declining
using non-compartmental and population pharmaco- renal functions and increasing age. Higher daily doses
kinetics methods—inferred that very low levels of
were well tolerated and appeared to maximize the peak
ethambutol serum concentrations are achieved with the
concentration to Cmax, MIC.
usual recommended doses. Very low Cmax (1 µg/ml)
were common in children as was delayed absorption
(time to Cmax > 3 hrs) were common in children. Many PHARMACOKINETICS OF ANTITUBERCULAR DRUGS IN
Cmax were at or below typical TB minimal inhibitory RELATION TO VARIOUS FACTORS
concentration. Cmax values for HIV-positive patients Experience at AIIMS, New Delhi, India
were 20% lower than HIV-negative patients were 20%
lower than HIV-negative patient with daily dose but Pharmacokinetics with the use of more than One
were similar with larger twice weekly doses. Antituberculosis Drugs
Peloquin et al39 determined the pharma-cokinetics of PAS
under four dosing conditions in adults. Bioequivalence Seth et al44-46 conducted pharmacokinetic studies of and
testing was performed using the mean ratios of the isoniazid in the whole clinical spectrum of tuberculosis
maximum concentration (Cmax) and AUC (0-infinty) of in children—pulmonary primary complex (PPC),
PAS, with 90% confidence intervals. Compared with progressive primary disease (PPD) and tuberculous
fasting conditions, food increased Cmax 1.5-fold and AUC meningitis (TBM). The used were 6HR; 2HRZ, 4HR; and
(0-infinity) 1.7-folds, and doubled the time to least mean ½SHRZ, 1½ HRZE, 4HRE, 3HE; and 2SHRZ, 4HRE,
sequere rates (treatment/reference) for Cmax were 0.90 3HE. Rifampicin (RIF) and isoniazid (INH) were
(58% – 139% CL), 1.16 (75% to 179% CI), and 0.82 (52% administered in a dose of 12 and 10 mg/kg respectively.
459
Isoniazid and rifampicin were given together in the form isoniazid and rifampicin were higher in undernourished
of a syrup. Rest all the other drugs were given as and malnourished patients when compared to the
separate preparations. To have a general idea peak normally nourished ones. Polasa et al51 and Polasa and
levels of isoniazid and rifampicin were estimated and Krishnaswami52 have also reported higher Cmax, t½ and
compared with MIC. The peak levels and concentrations AUC values for rifampicin in adults with undernutrition.
In kwashiorkor and marasmic kwashiorkor patients on
achieved at 7 to 8 hours with these two drugs were much
antituberculosis therapy, the potential hepatotoxic drugs
above those required for therapeutic efficacy (MIC). The
like isoniazid and hepatic enzyme inducer rifampicin
levels were 50 to 250 times more for RIF and 35 to 60
should be given in their lower range, i.e. 5 to 10 and 10
times for INH. Keeping this in mind pharmacokinetics
mg/kg/day respectively as there is fatty infiltration of
of isoniazid were done using isoniazid in the dose of 5 liver. In tuberculous meningitis, hepatotoxicity is quite
mg/kg/day. Peak isoniazid levels were 40 times more high even with low dosage, due to associated
than MIC with the dose of 5 mg/kg/day. This is the malnutrition.53 Hence, drug dose and regimen should
dose, i.e. 5 mg/kg/day recommended by WHO and be judiciously chosen. A study was conducted by Seth53a
International Union Against Tuberculosis and Lung in tuberculous meningitis using two regimens R1–
Disease (IUATLD).47-49 Peak rifampicin level using 10 2SHRZ, 4HRE, 3HE [2 months daily streptomycin (S),
mg/kg/day of this drug was 5.4 µg/ml, which is 250 isoniazid (H), rifampicin (R) and pyrazinamide (Z)
times the MIC. Hence, it seems that after more followed by 4 months of HRE, followed by 3 months of
pharmacokinetic studies with lower doses, one may be HE] and R2–2SH2RZ, 4H2RE, 3H2E (2 months of daily
able to reduce the dose of rifampicin further. In both S, twice a week H and daily rifampicin and pyrazina-
these studies, the same brand of drugs were used and mide, SR followed by 4 months of twice a week H and
the study was blinded. The detailed pharmacokinetics daily R and E followed by 3 months of twice a week H
are described for individual drugs later in the chapter. and daily E) to see the efficacy and hepatotoxicity. It
clearly indicated (Table 32.3) that in regimen –1 the
Severity of Disease hepatotoxicity was fifty percent in children with severe
malnutrition. The dose of isoniazid used was 10 mg/
In relation to the severity of the disease, the peak levels of kg/day in regimen –1 and 20 mg twice a week in
rifampicin were maximum in TBM and minimum in PPC regimen –2. It has been suggested that malnourished
when the child was given intermittent therapy. The children with tuberculosis who develop hepatotoxicity,
sampling was done after two days of therapy, i.e. the drug rifampicin should be discontinued, or alternatively, it
was given on Sunday and Thursday and sampling was should be given in a dose of 12 mg/kg on alternate days
done on Wednesday. It indicates that as far as pharma- for initial 3 to 4 months followed by twice a week for 4
cokinetics is concerned effective levels are maintained even to 6 months.54
during intermittent therapy. This is more cost effective
but the only disadvantage is that the mother needs to be Fixed-Dose Formulation
strongly motivated to bring the child to the center for
giving medicine under directly observed therapy (DOT).50 Fixed-dose combination (FDC) of R, H and R, H, Z are
recent developments. Use of this simplifies combined
Nutrition therapy in the form of syrup or dispersible tablets for
the administration of drugs and is easy to maintain
Nutritional deficiencies may result in an altered drug dosage as mg/kg of the regimen. These are effective and
response requiring readjustment of drug dosages. There have shown to have no higher degree of toxicity than
are limited studies on drug disposition in children with single drug administration. They avoid the risk of
protein energy malnutrition (PEM). Physicians need to inherent lapse in monotherapy which may result in the
have practical guidelines regarding dosage and emergence of drug resistance and minimize the risk
frequency of administration of the commonly prescribed associated with prescription errors. A minor dis-
drugs in malnourished children in whom reversible advantage is of having accustomed patients to one form
structural and functional changes occur. As tuberculosis of medication in the initial phase, it is necessary to make
and malnutrition often coexist, the knowledge of kinetics an adjustment to a different formulation in the second
of rifampicin and isoniazid in the malnourished patients phase. Unfortunately, fixed dose combination of drugs
is important for successful therapy. Seth et al44-46 have have been marketed for which bioavailabity data are
shown that peak serum concentration (Cmax) of both inadequate. It is essential to use only those preparations
isoniazid and rifampicin in undernourished and for which pharmacokinetic and pharmacodynamic
malnourished children are higher than normal children. studies have been carried out and have shown that serum
The serum hal-flife of isoniazid and bioavailability of both drug concentrations are not altered by the combination.55
460
Table 32.3: Hepatotoxicity with respect to nutritional status in tuberculous meningitis
Nutritional status Regimen-1 Regimen-2 Total cases Percentage

No. Hepato- No. Hepato- No. Hepato-
toxicity toxicity toxicity
Normal 7 1 6 – 13 1 7.6
Undernourished 14 2 15 1 29 3 10.3
(Grade I + II)
Severe malnutrition 6 3 4 – 10 3 30
Regimen-1 = 2 SHRZ, 4HRE, 3HE; Regimen-2 = 2 SH2RZ, 4H2RE, 3H2E
In fact, this has led to a joint statement by the IUATLD Table 32.4: Some preparations of antituberculosis drugs
and the WHO pointing that antituberculosis fixed dose available either as syrup or dispersible tablets as single
combinations should be used only in National drug or in combination
Tuberculosis Programs if adequate bioavailability of
atleast the rifampicin component has been Drugs Syrup (mg/5ml)/DT(mg)
demonstrated.56 In fact, combining rifampicin in the same • Isoniazid
tablet with isoniazid with or without pyrazinamide has – Ipcazide 100
been shown to affect the bioavailability of rifampicin. It – Isokin 100
is known that many FDCs exist in the market which are • Preparation of isoniazid + rifampicin
of inferior quality but are unknowingly being used – Bicox KT H 100 +R 100
– Binex KT H 100 + R 150
extensively in tuberculosis control programs in low
– Faminex KT H 100 + R 150
income countries with high incidence and prevalence of
– Ipcacin KT H 100 + R 100
tuberculosis. Advantages of such FDCs are the – Montonex KT H 50 + R 100
simplification of procurement and prescribing practices – Rcinex KT H 100 + R 100
and the protection that they afford against the selection – Rcinex 150DT H 100 + R 150
of drugresistant mutants. In fact, some studies have – RF-Kid H 100 + R 100
shown that up to 62 percent of the antituberculosis drugs – Rifinex H 50 + R 100
sold in the market are FDCs. 56 There is convincing – R-Zid H 100 + R 100
evidence that the rifampicin absorption from FDCs – Ticnex H 50 + R 100
manufactured under suboptimal conditions may be – Xced 2 H 75 + R 100
significantly impaired and this appears to be especially Modified release form
• Preparation of INH + rifampicin + pyrazinamide
problematic with combined formulations of rifampicin,
– Binex Z DT H 50+R 100+Z 300
isoniazid and pyrazinamide.57 Seth used combination of
– Caviter/Forte H 80+R 120+Z 250
(i) isoniazid and rifampicin, (ii) isoniazid, rifampicin and – Rifacept –3 H 100+R 75+Z 250
pyrazinamide for pharmacokinetic studies, and the – RifaterH 80+R 120+Z 250
bioavailability was not affected. The children were chosen
H= Isoniazid, R= Rifampicin, Z= Pyrazinamide
keeping the factors of nutrition and age similar. Table
KT = Kid tablet, DT = Dispersible tablet
32.4 shows the preparation of antituberculosis drugs
available in various combination of isoniazid+rifampicin
or isoniazid+ rifampicin and pyrazinamide. • Physicians are more likely to prescribe an effective
Fixed-dose combination (FDC) tablets incorporate regimen
two or more drugs within the same tablet. The use of 2- • The opportunity for inadvertent medication errors is
drug combinations (e.g. rifampicin and isoniazid) is decreased
widespread and there is increasing use of rifampicin, • Many of the logistic problems which cause shortage
isoniazid and pyrazinamide combinations. of individual drugs are eliminated (shortage of
individual drugs may result in either patients
receiving monotherapy, or changing of regimen, both
Advantages of FDCs
of which may increase the risks of resistance)
• When programs use FDCs, providers and patients • The procurement, management and handling of
useless of single anti-TB drugs. This reduces the risk drugs is simplified. In many national and district
of emergence of drug resistant organisms. In a programs, there are major problems with inadequate
program using drugs supplied only in FDCs, in the event and uncoordi-nated drug supplies, and the ordering,
of interruption of treatment and relapse, organisms will shipping and storage of the individual drugs adds
remain sensitive to rifampicin and isoniazid enormously to the costs. If combination drugs are
461
used, there will only be one or two components to be on the weight band defined in each country and the
ordered, delivered and stored, with resulting savings particular FDC formulations provided by the NTP.
in costs and increased efficiency
• The regimen is simpler for the patient, involves Breastfeeding
consumption of fewer tablets, and promotes patient Most antituberculosis drugs appear to be safe for use
adherence to treatment during breastfeeding.58 These agents are secreted in
• The provision of rifampicin in FDCs may decrease breast milk in relatively small concen-trations. No
the unjustified use of rifampicin monotherapy for
adverse effects have been reported till date. The
infections other than TB.
percentage of the therapeutic dose of antituberculosis
agents that potentially may be delivered to the nursing
Disadvantages of FDCs infant ranges from 0.05 to 28 percent. Currently,
• The bioavailability of drugs, especially rifampicin, can isoniazid, rifampicin, ethambutol, streptomycin (first-line
decrease when combined in FDCs. The decrease in agents), kanamycin and cycloserine (second-line agents)
bioavailability is a particular problem with FDCs of are the only agents considered by the American Academy
rifampicin and two other drugs. Many FDCs of Pediatrics (AAP) to be compatible with breast
currently available may result in subtherapeutic blood feeding.58 Unfortunately, there are still no clear data on
levels of rifampicin. Bioavailability may vary among the safety of pyrazinamide, ethionamide and capreomycin
batches of drugs, and following minor changes in the during breastfeeding.
manufacturing process. Therefore, programs must
monitor regularly the bioavailability of drugs, Acetylator Status
especially isoniazid and rifampicin, in FDCs. WHO and The inactivation of isoniazid by acetylation shows a
the IUATLD recommend the use of only those FDCs genetic polymorphism. This was thought to be bimodal
for which human studies have demonstrated but now it is considered as trimodal distribution of the
satisfactory bioavailability of rifampicin population into slow rapid and intermediate acetylators.
• Currently, chemotherapy using FDCs is more costly. It has been suggested that rapid acetylators are more
From a program point of view, however, there will susceptible to hepatotoxicity by isoniazid.59 Studies in
be longterm savings as fewer patients develop drug adults60 and children61 have demonstrated that acetylator
resistant disease and receive the more expensive phenotype doesnot influence the incidence of isoniazid
retreatment regimen. Prices may fall as the use of
induced hepatotoxicity. However, Parthasarthy et al62
FDCs becomes more widespread
have reported that the incidence of hepatitis is more in
• Occasionally, it is necessary to adjust the dosages for
slow acetylators of isoniazid than the rapid ones. Seth et
an individual patient, or to adjust the regimen when
al63,64 have profiled the acetylation phenotype of North
serious side effects are experienced. Programs using
Indian children and showed 73% to be slow acetylators.
FDCs still require limited amounts of single drugs
Later, Seth et al65 designed a study to determine the
for flexible prescribing by senior medical officers.
relationship of the acetylator phenotype with the
incidence of hepatotoxicity in North Indian children
Selection of FDCs
suffering from pulmonary tuberculosis treated with
• The optimal formulation of FDCs chosen for a isoniazid and rifampicin. They reported that with the
program will depend upon the average weight of dosage of isoniazid and rifampicin at 10 and 12 mg/kg/
patients, and regimens used (whether daily or day respectively there was no evidence of hepatotoxicity.
intermittent)
• It is usually advisable to choose only one FDC for a ISONIAZID
program, to avoid stock management problems and Isoniazid is well absorbed in the gastrointestinal tract and
confusion between different formulations readily distributed to all body cells and fluids. Although,
• If a program uses FDCs of different formulations, then the drug readily crosses the placenta and is excreted in milk
the color and shape of the tablets for each formulation yet no fetal or neonatal risks are involved.66 Peak serum
should be different to avoid confusion. levels range from 6 to 20 µg/ml in children17,18 as com-pared
to adults, where the values are usually lower and range
Daily and Intermittent use of FDCs
from 3 to 5 µg/ml.7 Hence, the peak drug level is almost 20
Most adult TB patients fall within a certain weight band, to 80 times of the minimum inhibitory concentration and is
e.g. 45 to 55 kg. However, in children various weight achieved in 1 to 2 hours after oral dose of 5 mg/kg in
bands are required and hence require more attention. adults.17,67 Since, the peak level is more important than the
The recommended number of tablets of FDCs for sustained inhibitory concentration, the entire daily dose is
patients falling within a certain weight band depends given once daily.68 The absorption of drug from the GI tract
462
is so complete that oral and parenteral doses produce therapeutically effective dose. Hence, isoniazid was given
comparable plasma and tissue levels. The CSF concentration in a dose of 5 and 10 mg/kg/day to the children suffering
of the drug in normal human volunteers is 20% of plasma from pulmonary primary complex and those with TBM
levels but in tuberculous meningitis higher concentrations respectively. Pharmacokinetic studies were done in both
of up to 50% are achieved.69 The higher serum concentration groups. It was observed that adequate serum levels of
of isoniazid in children appears to be due to greater dosage isoniazid around 40 times the MIC could be achieved with
of isoniazid per unit of body weight. Hence, it seems that the dose of 5 mg/kg/day. It was also observed that 5 mg/
there is probably no need to give such a high dosage of kg dose was clinically as effective as 10 mg/kg dose.
isoniazid per unit of body weight. This misconception could Isoniazid along with rifampicin can be given as
only be removed after having the pharmacokinetic data. intermittent therapy without compromising on treatment
Seth et al44-46 and Beotra and Seth et al70 had undertaken efficacy. This cuts down the cost of the therapy which is
pharmacokinetic studies in different types of tuberculosis the main concern for poor drug compliance. The WHO
in Indian children giving different drug regimens (Table recommends that in twice weekly intermittent regimen,
32.5 and Fig. 32.3). Serum isoniazid levels ranged from 4.38 the dosage of isoniazid should be kept in the range of 12
to 8.17 µg/ml at 1 hour (peak level) and from 0.33 to 0.84 to 15 mg/kg body weight instead of 20 mg/kg, both in
µg/ml at 0 hour (or 24 hr) in different disease and regimen adults and children.25 These dosage recommendations
groups. These values are atleast 90 to 160 times of its MIC are based on clinical impressions rather than inferences
at the peak concentration time (1 hour) and 7 to 17 times at drawn from well designed pharmacokinetic studies. No
0 or 24 hours. The results of the present study and those of published data regarding pharmacokinetics of isoniazid
Hobby71 and Naito et al 72 suggest that isoniazid in intermittent regimen in children with tuberculosis is
pharmacokinetic studies should be undertaken in children available in medical literature.
with tuberculosis using isoniazid in much lower but Seth et al 73 designed to investigate serum and
excretion kinetics of isoniazid and acetyl isoniazid in
pulmonary primary complex in the biweekly phase of
the intermittent regimen. The study provides an insight
into the pharmaco-kinetic aspect of INH as a constituent
drug of intermittent regimen in Indian children (Table
32.6 and Fig. 32.4). The peak serum isoniazid
concentration of 2.6 µg/ml at 1 hour and that for acetyl
isoniazid of 5.5 µg/ml at 5 hours in the biweekly phase
of the intermittent regimen was observed in the study.
The concentration of isoniazid was on an average 52 times
and a maximum of 88 times of its MIC when adminis-
tered orally in the dose of 20 mg/kg/dose. The study
further shows that the concentration at 7 hours was 0.96
µg/ml which is 19 times its MIC. Even at 72 hours (3
days), i.e. just before the administration of next due dose
of isoniazid, the concentration was sustained at 0.47 µg/
ml which is 9 times higher than its MIC. It is thus clear
that an oral dose of 20 mg/kg of isoniazid in biweekly
Fig. 32.3: Serum isoniazid concentrations (mean + SE) in different
phase of therapy is able to sustain a concentration which
types of tuberculosis is much above its MIC value.
Table 32.5: Pharmacokinetic parameters of isoniazid
Type of TB and regimen Cmax (µg/ml) (mean) Tmax (h) (mean) T½ (h) (mean) AUC0-7hr (µg/ml/h)
PPC-6HR 4.38 1.0 4.98 34.1
PPD-2HRZ, 4HR 8.17 1.0 4.20 57.5
TBM 5.38 1.0 4.55 43.8
2SHRZ, 4HRE, 3HE
Cmax = Maximum serum concentration, Tmax = Time to attain Cmax, T½ = Serum half-life, AUC = Area under the serum
concentration-time-curve. PPC = Pulmonary primary complex, PPD = Progressive primary disease, TBM = Tuberculous meningitis
463
The concept of acetylation status is defined as: A rapid RIFAMPICIN

inactivator is one whose 6 hour serum level of active
It is highly lipid soluble and it penetrates well into most
isoniazid following a single test dose of 5 mg/kg is 0.2 of the tissues and is present in effective concentrations in
µg/ml or less while a slow inactivator is one whose 6 all the organs and body fluids including CSF. It also
hour level is 0.8 µg/ml or more after an equivalent dose.7 reaches in caseous foci, phagocytes and crosses the
Schaaf et al 74 defined the pharmacokinetics of placenta. Breast milk, fat tissue and the lungs contain
isoniazid in children with tuberculosis in relation to N- higher concentration of drug than serum.75 The mean t½
acetyltransferase 2(NAT2) geno-type. The first order in children after initial dose is 2.9 hours but shortens to
elimination rate constant (k) and area under the 2.5 hours on repeated dosing because of its hepatic
concentration curve (AUC) were calculated in 64 children
enzyme inducing action.76 Seth et al44,45 carried out
<13 years of age (median 3.8years) with respiratory
detailed pharmaco-kinetic studies of rifampicin in
tuberculosis. Isoniazid concentrations were determined 2
different types of tuberculosis with different drug
to 5 hours after a 10 mg/kg/isoniazid dose. The NAT2
regimens (Table 32.8 and Fig. 32.6). Serum half-life of
genotype was determined, 25 were classified as
rifampicin ranged from 3.03 to 3.81 hours, whereas Cmax
homozygous slow (SS), 24 as heterozygous fast (FS) and
ranged from 3.38 to 3.88 µg/ml. The results of these
15 as homozygous fast (FF) acetylators. Younger children
studies show a sustained serum concentration much above
elimate isoniazid faster than older children and, as a
the MIC of rifampicin even 24 hours after administration
group, faster than adults, and require a higher mg/kg/
of single 12 mg/kg dose of the drug. Further, rifampicin
body weights isoniazid dose to achieve serum
concentrations comparable to adults. was given in a dose of 10 mg/kg/day to children
Excretion of isoniazid in urine is fairly good and suffering from pulmonary primary complex and
comparatively early as its maximum concen-tration is pharmacokinetic studies of rifampicin were carried out.
seen between 3 and 6 hours and that of acetyl isoniazid Adequate serum levels of drug could be achieved that
between 6 and 12 hours of the drug intake (Table 32.7
and Fig. 32.5). It suggests that in patients with normal
renal functions, isoniazid does not have the tendency to
accumulate in serum and, therefore, can be given safely
in prescribed doses irrespective of the status of acetylator
phenotype (rapid or slow) of the patients in general.
Table 32.6: Isoniazid kinetics in serum in intermittent

regimen (2HR, 4 H2 R2 ) in pulmonary primary complex
Cmax* Tmax T½* AUC0-7h*

(µg/ml) (h) (h) (µg/ml/h)
2.6 1.0 4.5 20.78
* = Mean values
Fig. 32.5: Urine total isoniazid and acetylisoniazid levels (mean ±SD)
in intermittent regimen (2HR, 4H2 R-2) in pulmonary primary complex
Table 32.7: Urine total isoniazid (INH) and acetyl isoniazid

(AcINH) levels by HPLC in intermittent regimen (2HR,
4H2R2) in pulmonary primary complex
Time interval (h) No. of samples Total urine level

(mg) mean ± SD
INH AcINH
0-3 9 1.82 ± 1.29 6.7 ± 6.5
3-6 9 5.71 ± 4.82 15.7 ± 9.7
Fig. 32.4: Serum isoniazid and acetylisoniazid concentrations (mean 6-12 9 5.21 ± 6.41 21.5 ± 12.1
± SD) in intermittent regimen (2HR, 4H2 R2 )
12-24 9 2.19 ± 1.92 10.2 ± 6.6
in pulmonary primary complex
464
lower dose of 30 mg/kg/day with a much lower incidence

of hepatotoxicity, pyrazinamide regained a prominent
place in the antituberculosis pharmacotherapeutics.
At a time when no data from a well-designed
pharmacokinetic study on pyrazinamide in children with
tuberculosis was available at the international level, a
pathbreaking effort was undertaken in detailed profiling
of pharmaco-kinetic aspects of pyrazinamide (serum and
urine kinetics) in Indian children having tuberculosis in
1985 in the departments of Pediatrics and Pharmacology
of AIIMS, New Delhi by Seth,78 Seth79 and Arya,80,81 and
this was to become a reference work subsequently for
others. Prior to the studies by Seth at al78 and Arya et
al80,81 except for serum concentrations versus time (Cmax,
Tmax), values for no other important pharmacokinetic
parameters were available in children and particularly
so in children with tuberculosis. In past values for various
pharmacokinetic parameters for children used to be
extrapolated either from studies in the adult healthy
Fig. 32.6: Serum rifampicin concentrations (mean + SE) volunteers, or adult tuberculosis patients. Considering
in different types of tuberculosis in children theses facts, this work assumes even more importance
in contributing newer data in pediatric population
Table 32.8: Pharmacokinetic parameters of rifampicin suffering from tuberculosis. Comparative pharma-
cokinetic parameters of pyrazinamide following once a
Type of Cmax Tmax T½ AUC0-7h day oral dose of 30 mg/kg/day in 40 progressive primary
TB and (µg/ml) (h) (h) (µg/ml/h) disease (PPD) and 18 tuberculous meningitis (TBM)
regimen (mean) (mean) (mean)
children employing high performance liquid
PPC 3.88 2.0 3.03 28.3 chromatography (HPLC) is shown in Table 32.9.
6HR Significantly higher mean serum concen-tration
PPD 3.38 2.0 3.81 26.2 (Cmax) were achieved in PPD (43.43 ± 6.74µg/ml) as
2HRZ, 4HR
compared to TBM children (34.44 ± 1.75µg/ml) at Tmax
TBM 3.86 2.0 3.24 24.7
of 2.25 and 2.22 hours which are more than 2 times and
2SHRZ,
4HRE, 3HE 1.7 times the MIC of pyrazinamide (20µg/ml) for M.
tuberculosis respectively. The mean serum concentration
even at 8 hours post-dose was 1.5 times the MIC in PPD
were 50 times of MIC and drug was found to be clinically children (30.61 ± 1.18µg/ml) whereas it was nearly at
effective. Food interferes with the absorption of MIC in TBM children (19.44 ± 0.80µg/ml), thereby
rifampicin and results in a low plasma level and hence it showing adequate MIC coverage for a significantly
is advisable to give it atleast half an hour before longer time for its antituberculosis action. However, at
breakfast.58 Besides tuberculosis, rifamcipin is also used 24 hours the concentrations were sub-MIC (5.58 ± 29µg/
for prophylaxis against H. influenzae type B infection in ml in PPD and 8.18 ± 0.18 µg/ml in TBM). The fact that
infants and children.50 pyrazinamide concentration in cerebrospinal fluid equals
Jayram et al77 have demonstrated pharmaco-kinetics- that in the serum, makes it a very potent and useful
pharmacodynamics of rifampicin in an aerosol infection antituberculosis drug in TBM. The mean T ½ of 11.42
model of tuberculosis. They showed that, by the use of a hours in TBM children was significantly prolonged than
murine aerosol infection model with dose ranging and in PPD children (7.78 hours). This prolonged elimination
in TBM children can be attributed to frequently
dose fractionation over 6 days, the PD parameter that best
accompanying severe malnutrition in them affecting the
correlated with a reduction in bacterial counts.
renal-elimination of the drug and also may be the severity
of the disease. Similarly, volume of distribution (Vd) of
PYRAZINAMIDE 10.33 litres was marginally less in TBM than 12.94 litres
The major limitation to the wider use of pyrazinamide as in PPD children. The other pharmacokinetic parameters
an antituberculosis agent in humans in past was the high i.e. clearance (CI), AUC0-24h and elimination-rate
incidence of hepatotoxity, especially with a dose of 40 to constant calculated were comparable. Urine kinetics
50 mg/kg/day. When it was shown to be effective at a showed a highly significant difference in the total amount
465
development of resistance. In addition, owing to its action

Table 32.9: Comparative pharmacokinetic parameters of
pyrazinamide (30 mg/kg/day oral dose) in Indian children
entirely on rapidly growing extracellular bacilli, it is
with PPD80 and TBM81: AIIMS experience unsuitable for sterilization of the lesion. In children the
most prominent presentation is either pulmonary
Pharmacokinetic Mean (±SD) values primary complex (PPC) or the severest form such as
parameters tuberculous meningitis (TBM) and miliary tuberculosis.
PPD (n=40) TBM (n=18) In both these situations, the role of streptomycin is
Cmax (µg/ml) 43.43 (6.74) 35.44 (1.75) limited. In TBM it is used only for 15 days, that also in
Tmax (h) 2.25 (0.77) 2.22 (0.55) the dose of 20 mg/kg/day IM to kill rapidly multiplying
T ½ (h) 7.78 (1.3) 11.42 (3.64) extracellular bacilli, which are very few in the usual
Vd (L) 12.94 (5.57) 10.33 (4.15)
manifestations of tuberculosis in children except which
C1 (L/h) 1.16 (0.49) 0.77 (0.43)
AUC0-24h (µg/ml/h) 496.11 (138.15) 409.19 (63.72)
occurs at adolescence. The latter is cavitary type like adult
Kel (h1) 0.09 (0.002) tuberculosis.
Vd= volume of distribution, C1= clearance,
Kel= elimination rate constant
Ethambutol
The drug is used as a companion drug with INH and
rifampicin in various short course and long-term
of pyrazinamide excreted in 24 hours in PPD (37.12 mg)
regimens. However, it is a second-line drug because of
and TBM (65.12 mg) children. Even at 24 hours post–
dose significant amount of the drugs was detectable in its low efficacy and bacterio-static action. It is a good
urine in PPD (11.51 mg) and TBM (16.62 mg) children. A substitute for PAS and thiacetazone owing to its low
study by Carlone et al 82 on mouse macrophages toxicity at thera-peutic doses and better acceptance by
harbouring tubercle bacilli exposed to 30 µg/ml the patients. In very young children also it can be given
concentration of pyrazinamide has shown the highest as ocular toxicity can be monitored by visual evoked
rates of killing of 93 % for pyrazinamide and 92 % for responses (VER) under general anesthesia. Seth et al84
pyrazioic acid as compared to 59 % in the controls. It is periodically recorded VER in 49 children with
quite evident that serum pyrazinamide concentrations pulmonary tuberculosis above three years of age who
so achieved are in tandem with the microbiological were given ethambutol as part of therapy to detect any
parameter i.e. effective sterilizing actions. The kinetics evidence of ethambutol-induced ocular toxicity. In all
of pyrazinamide exhibited rapid absorption, a speedy patients both the latency and amplitude of the evoked
distribution and a longer elimination phase.79-81 potentials were comparable with age and sex matched
controls. No change in color perception and visual
Population Pharmacokinetics Modeling of pyrazinamide acuity was observed. Hence, it is suggested that etham-
in Children and Adults with Tuberculosis butol maybe given safely to children particu-larly those
with TBM, in a dose of 20 mg/kg /day. It has been
Zhu et al83 demonstrated that pyrazinamide concentration shown that ethambutol penetrates erythrocytes which
increased linearly with increasing oral dose. Median
probably serves as a depot from where the drug is
maximum serum concentra-tion value were 41.0 µg/ml
released into circulation. 10 Ethambutol serum
with daily dosing and 66.1 µg/ml with large, twice weekly
concentrations have been determined by several
dosing. Incomplete (18%) or delayed (30%) absorption was
authors. It has been demonstrated that great majority
more common in children than in adults. Human
of the drug is excreted unchanged in urine
immunodeficiency virus status and patient demography,
(approximately 80%). It has been observed that serum
except for body weight, did not interfere with pharmacokinetic
parameters. Population elimination half-life values in concentrations in children tend to be lower than in
pediatric and adult patients were 3.5 and 6.0 hours, adults following similar doses of ethambutol. Hence, it
respectively. Median volume of distribution (L/kg) was 32 is suggested to use ethambutol in children at a dosage
% larger and median clearance (L/hr/kg) was 106% larger of 20 mg/kg and to increase this by 5 mg/kg in those
in children. Compared with adults, absorption of aged <3 years and those aged >11 years. By this dosage
pyrazinamide in children is more likely to be incomplete schedule in 2634 children there was no ocular toxicity
or delayed. and effective therapeutic levels were achieved. As
recently as in 2004 Zhu et al83 found dose of 15 to 20
Streptomycin mg/kg/day quite sufficient for achieving a good
pharmacokinetic profile. Hence, this drug can be used
The use of streptomycin has become limited because of safely as a companion drug in the management of tuber-
its toxicity, need for parenteral administration and culosis in children.
466
Pharmacokinetics of Ethambutol in Children and Adults males. Despite these abnormal results, the dose of
with Tuberculosis rifampicin and isoniazid was altered in only 17 % of
patients. The service was considered valuable by 83 % of
Zhu et al in83 described ethambutol pharma-cokinetics the responders to questionnaire. Due importance must
in children and adults with active tuberculosis. A be given to TDM for these two drugs.
prospective, open labeled study was conducted in 56 Jayant et al85 studied the utility of rifampicin blood
adults and 14 children with active tuberculosis who levels in the treatment and follow-up of active pulmonary
received ethambutol as a companion drug with other TB in patients who were slow to respond to routine directly
antituberculosis drugs. Concentration data were observed therapy. The patient was labelled as a slow
analyzed using noncompartmental and population responder if even after three months, the patient improved
pharmaco-kinetic methods. Drug exposure increased neither clinically, nor bacteriologically or radiographically.
with dose, but less than proportionally at doses >3000 The serum levels of rifampicin were found to be
mg. Lower than expected maximum serum subtherapeutic. With the increased dose of rifampicin to
concentrations Cmax (<2 µg/ml) were common in adults 900 mg/day, blood levels were still subtherapeutic.
and very low Cmax (<1 µg/ml) in children, as was delayed However, these patients responded clinically,
absorption (time to Cmax >3 hr). Many Cmax values were radiographically and mycobacteriologically. Hence, slow
at or below typical TB minimal inhibitory concentration. responders before being considered as failure to treatment,
Cmax values for HIV-positive patients were 20 % lower should be given a trial with higher dose of rifampicin
than HIV-negative patients with daily doses, but were without any change of dose of the other drugs.
similar with larger twice weekly doses. Adult TB patients
often have lower than expected serum concentrations Ethionamide Population Pharmacokinetics in Patients
whereas most pediatric TB patients have very low with Tuberculosis
ethambutol serum concentrations. Hence, higher doses
maybe indicated in children with proper therapeutic Zhu et al 86 in 2002 determined the population
monitoring. pharmacokinetic (PK) parameters of ethiona-mide (ETA)
following multiple oral doses. ETA areas under the
Managing Antituberculosis Drug Therapy by concentration versus time curve (AUC) increased linearly
Therapeutic Drug Monitoring of Rifampicin and with increasing oral doses from 250 to 1000 mg.
Isoniazid Compared to the population pattern, delayed absorption
Therapeutic drug monitoring (TDM) is the process of was seen at least once in 15 % of patients. ETA PK
optimizing drug-dosages on the basis of serum drug parameter estimates were independent of age, weight,
concentration monitoring to achieve a desired therapeutic height, gender and creatinine clearance. TB patients
response or effect. TDM is useful when serum appeared to have larger volumes of distribution (3.22 L/
concentrations show a better correlation with the kg) and clearance values (1.88L/kg) compared to
therapeutic effects or the incidence of adverse effects than previously studied healthy volunteers. This resulted in
does the size of the dose alone. TDM requires the accurate lower AUC values (3.95 µg/ml/hrs) in TB patients. ETA
timing of doses and blood collection and the avoidance displayed a short elimination half-life (1.94 hr). ETA PK
of assay interference. parameters differ between TB patients and healthy
Gardiner and Marriott84b opine optimizing drug dose volunteers, possibly due to differences in the
using therapeutic drug monitoring (TDM) may be a better completeness of absorption. Doses of at least 500 mg
approach than administering therapy as a standard dose. appear to be required to achieve serum concentrations
Ninety patient episodes were accepted for study. The above the typical ETA MIC.
rifampicin plasma concentration showed significant
scatter, with 46 % of rifampicin concentration below Ofloxacin
normal range and 2 % above the normal range. Similarly
48 % isoniazid concentrations were below the lower Pharmacokinetics
target of the normal range and 29 % were above the upper Stambaugh et al 87 determined the population
limit. Hence, there is significant variably in pharmacokinetic (PK) parameters of ofloxacin as part of
pharmacokinetic parameters with rifampicin and their treatment. Delayed absorption was seen in 29 %.
isoniazid. Further, a substantial number of plasma Ofloxacin elimination decreased with increased oral dose,
concentrations fell outside the suggested normal range increasing age and declining renal function. Higher daily
for both drugs. Isoniazid plasma concentrations were dose may offer pharmacodynamic advantages for the
significantly higher in female patients as compared to treatment of TB.
467
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33 Pharmacogenetics of Tuberculosis
Manju Ghosh, Madhulika Kabra
WHAT IS PHARMACOGENETICS? pathogenic and/or response to therapeutic or other

interventions. 1
Pharmacogenetics Following the sequencing of the human genome, 1.4
It is the study of the genetic basis for differences in response million SNPs were identified, of which 60,000 were in
to drugs, or more specifically the study of variations in the coding sequence of the genes. Some of these have
DNA sequence as related to drug response. 1 been associated with changes in the metabolism or effects
The concept of altered response based on genetic of medications and some are now being used to predict
background was recognized by Pythagoras as early as clinical response. 4-6,10 The identification of common
510 BC, who observed that certain individuals developed polymorphisms across the human genome has expanded
hemolytic anemia on consumption of fava beans.2 In 1914, our understanding of the mechanisms of variability in
Sir Archibald Garrod, the pioneer of Inborn Errors of drug action as a consequence of DNA polymorphisms,
Metabolism, expanded this observation, stating that or sets of polymorphisms, among individuals. This
enzymes detoxified foreign agents so that they were approach defines the field of ‘pharmacogenomics’. This
excreted harmlessly. However, some people lack these knowledge would allow practitioners to integrate a
enzymes and experience adverse effects.3 Hemolytic molecular understanding of disease with an individual’s
anemia due to fava bean consumption was later genomic make-up to prescribe personalized, highly
determined to occur in glucose-6-phosphate dehydro- effective and safe therapies.11
genase deficient individuals. Thus Garrod laid the Originally, pharmacogenetic studies focused on
groundwork for the study of pharmacogenetics well monogenic traits, involving genetic variation in
ahead of his time. drug metabolism. However, contemporary studies
Unusual drug responses, segregating in families have increasingly involve entire “pathways” encoding
been recognized for decades and were first documented proteins that influence both pharmacokinetics—factors
in 1950s,4-7 giving rise to the field of pharmacogenetics. that influence the concentration of a drug reaching its
Inherited impairment in drug metabolism is a common target(s)—and pharmacodynamics, the drug target itself,
cause for adverse drug reactions. It is estimated that as well as genome-wide approaches. Pharma-
genetics can account for 20 to 95 percent of variability in cogenomics is also increasingly moving across the
drug disposition and effects.8 These interindividual “translational interface” into the clinic and is being
differences in drug response are due to sequence variants incorporated into the drug development process. 12
in genes (polymor-phisms) encoding drug-metabolizing
enzymes, drug transporters, or drug receptors, and most Pharmacogenetics/Genomics of Tuberculosis
of these polymorphisms consist of single nucleotide
polymorphisms (SNPs).9 Recently developed genotyping Single nucleotide polymorphisms of the genes encoding
techniques permit an accurate and rapid detection of drug-metabolizing enzymes are responsible for large
common SNPs that are relevant to clinical response to interindividual variability in drug metabolism. These
several drugs. polymorphisms are a major cause of drug toxicity, drug-
drug interactions, and lack of therapeutic effect. In the
past many years several polymorphisms of drug-
Pharmacogenomics
metabolizing enzymes have been described and typing
This is a broader aspect of pharmacogenetics involving tests have been developed for the in vivo evaluation of
a genome-wide approach to elucidate the inherited basis enzyme activities (phenotyping) or for the detection of
of differences between persons in the response to drugs. mutations that cause impaired metabolism (genotyping).
It involves the study of genomic biomarkers that are These tests are currently being used to prevent adverse
defined as a measurable DNA and/or RNA characteristic drug reactions in patients who have inherited
that is an indicator of normal biologic processes, impairment in drug metabolism.13
472
Although the causative agent of tuberculosis, methodologies for NAT2 polymorphism analyze
Mycobacterium tuberculosis, has been known for some 120 genomic DNA by allele- specific mutation amplification
years, the disease continues to plague humanity. Applied by PCR and restriction fragment length polymorphism
knowledge of pharmacogenetics and genomics of analysis 20 and newly developed genotyping kits based
Mycobacterium tuberculosis has greatly helped in on real time PCR and use of fluorescent hybridization
understanding the response to the important first-line probes.21 The seven major SNPs located in the coding
drugs like isoniazid, rifampicin, pyrazinamide and region of the NAT2 gene constitute diverse allelic
ethambutol and the cause of emergence of multidrug variants, having variable effect on enzyme activity
resistance at the molecular level. This knowledge has depending whether co-segregating in a dominant or
helped in providing optimal therapy for mycobacterial recessive manner. Mutations located at nucleotide
illness. positions 191, 282, 341, 590 and 857 are related to slow
acetylation. Therefore, any alleleic variant that contains
Isoniazid one or more of these mutations will affect the acetylation
status.22
Pharmacokinetics/Pharmacogenetics Extensive studies of the allele frequencies in various
Isoniazid (INH), considered the primary drug in the racial backgrounds, indicate that analysis of a few
appropriate SNPs can give high predictive capacity. For
treatment of TB, is still the most important drug
instance, SNPs at nucleotide position 341, 481 and 803
worldwide for treatment of all types of tuberculosis.
are at extreme linkage disequilibrium, hence analysis of
However, the response to treatment/drug toxicity to
just one of them would predict 60 percent of defective
INH therapy is all dependent on the rate at which the
alleles in the Caucasians. Adding analysis of SNP 282,
drug is metabolized in the body. The main excretory located on a different allele, would increase predictive
product of INH is the result of enzymatic acetylation capacity to 97 percent.23 In the Asian population, study
(acetylisoniazid) by liver N-acetyltransferases encoded of 2 SNPs, 282 and 341 would enable a phenotype
by an extremely polymorphic arylamine N-acetyl- prediction of approximately 100 percent.22 Molecular
transferase 2 (NAT2) gene on chromosome 8p21.3-23.1. genotyping studies of the NAT2 gene in 166 unrelated
Hereditary differences in N-acetylation activity among individuals belonging to eight Dravidian communities
individuals and in populations of diverse racio- in South India revealed very high prevalence of
geographic origin, have led to the phenotype nucleotide substitutions at 282T and 803G, which per se
classification of humans as rapid and slow acetylators.14 alone or in combination did not alter acetylator status of
Slow and rapid acetylators greatly differ in the occurrence the enzyme, but when present in combination with 341C,
of side effects after the use of drugs that are acetylated. 590A or 857A polymorphisms, resulted in slow acetylator
The average concentration of active INH in the circulation genotypes. The slow acetylator phenotype was found to
of fast acetylators is about 30 to 50 percent of that present be 74 percent in this Indian study.20
in persons who acetylate the drug slowly. In the general
population, the half-life of INH varies from 1 to 4 hours. Geographical Variation of Slow and Rapid Acetylator
The mean half-life in fast acetylators is approximately 70 Phenotypes
minutes, whereas 2 to 5 hours is characteristic of slow Significant racial variation of the acetylation status has
acetylators.15 Acetylation polymorphism arises from the been observed worldwide. Fast acetylation was found in
allelic variations in human NAT2 gene, which results in Eskimos, Japanese and Chinese,24 while American and
the production of NAT2 proteins with variable enzyme west European Caucasians showed slow acetylation status
activity or stability. Certain NAT2 traits may contribute ranging between 53 to 62 percent.25 Studies in the Asian
to the occurrence of adverse drug effects.16 population showed variable status of acetylators from slow
acetylators at 73 percent in Hongkong to 58 percent in
NAT2 Gene Polymorphism Singapore, in contrast to the fast acetylators in the Japanese
and Chinese races ranging between 92 percent and 80
Presently 26 different NAT2 allelic variants that consist percent respectively.26,27 Studies from India indicated an
of combinations of seven point mutations (SNPs) related average of high percentage of slow acetylators in our
to impaired drug metabolism are known to occur in population. Given the complex ethnic diversity of the
humans. 17,18 The wild type allele is represented as Indian population, considerable variation in the
NAT2;17,18 each of the remaining 25 mutated alleles proportion of slow acetylators was observed in different
possess a characteristic combination of 1 to 4 nucleotide studies from North and South India.28,20 It has been
substitutions that occur at defined positions within the reported by Seth et al,29 that almost two-third of North
870 bp of the coding sequence. 19 Most genotyping Indian children are slow acetylators while one-third are
473
Chapter 33 Pharmacogenetics of Tuberculosis
rapid acetylators. Hepatic functions in relation to mycobacterial genes, namely, katG, ahpC, kasA, ndH
acetylator phenotype in children with antitubercular drugs and inhA. Most of the INH resistant strains have amino
were investigated by Seth et al.30 Estimation of the levels acid changes in catalase peroxidase gene (katG) or inhA,
of SGOT and SGPT determined before therapy and at which codes for an enzyme important for mycolic acid
monthly intervals for the first three months, and then three biosynthesis. Because mycolic acids are unique to
monthly for one year, did not indicate any biochemical mycobacteria, this explains the high degree of selectivity
toxicity as an evidence of hepatic derangement in relation of the antimicrobial activity of isoniazid.35
to the type of acetylator. They further elucidated that mild Recent studies36 have demonstrated the presence of
degree of malnutrition does not predispose the child to arylamine N-transferase, homologous to the human
more hepatotoxicity. NAT2 enzyme, in Mycobacterium tuberculosis. This
intriguing finding has important implications in
Acetylator Status and Side Effects of INH modulating response to INH therapy. It may be,
Peripheral neuropathy is the most frequently observed therefore, important to investigate NAT in M. tuberculosis
side effect in slow acetylator adults receiving the for polymorphisms. Preliminary investigations suggest
intermittent high dose regimen of INH.31 Conversely, that NAT in different clinical M. tuberculosis isolates is
rapid acetylators are more likely to have treatment failure also polymorphic.36
with biweekly doses of INH. Hepatotoxicity has been
reported more commonly in Indian patients on INH, Rifampicin
where majority are slow acetylators28-31 in adults. Seth Rifampicin, a semi-synthetic derivative of Streptomyces
et al30 did not find so in children in their longitudinal mediterranei, is considered the most important and potent
study. In addition to the above side effects, slow antituberculous agent. It is active against a wide spectrum
acetylators on INH may develop drug-induced lupus.28 of other organisms.
Idiosyncratic reactions to other drugs like sulona-
mides, carbamazepine, diphenylhydantoin, warfarin and Mechanism of Action
alcohol should be anticipated in slow acetylators taking
INH.32,33 Rifampicin has both intracellular and extracellular
bactericidal activity by blocking RNA synthesis by
Hepatotoxicity specifically binding and inhibiting DNA-dependent RNA
polymerase. Details discussed elsewhere.
Anti-TB drug (ATD)-related hepatotoxicity is a
worldwide serious medical problem among TB patients. Bacterial Resistance
Apart from acting on the bacteria, isoniazid, the principal
Mycobacteria may develop resistance to rifampicin
ATD, is also metabolized by human enzymes to generate
toxic chemicals that might cause hepatotoxicity. It has rapidly in vitro, and one in 107-108 tubercle bacilli may
been proposed that the production and elimination of show resistance to rifampicin. At the molecular level this
the toxic metabolites depends on the activities of several is due to spontaneous point mutations that alter the beta
enzymes, such as N-acetyltransferase 2 (NAT2), subunit of the RNA polymerase (rpoB) gene. Studies
cytochrome P450 oxidase (CYP2E1) and glutathione S- have shown that 96 percent of rifampicin resistant strains
transferase (GSTM1). There is now evidence that DNA have a missence mutation within a 91bp central core of
sequence variations or polymorphisms at these loci the gene.37
(NAT2, CYP2E1 and GSTM1) could modulate the
activities of these enzymes and, hence, the risk of Pyrazinamide (PZA)
hepatotoxicity. Since the prevalence of polymorphisms A derivative of nicotinic acid, is an important bactericidal
is different in worldwide populations, the risk of ATD drug used in the short-course therapy of TB.
hepatotoxicity varies in the populations. Thus, the
knowledge of polymorphisms at these loci, prior to
medication, may be useful in evaluating risk and Mechanism of Action
controlling ATD hepatotoxicity.34 PZA is similar to INH in its narrow spectrum of
antibacterial activity essentially restricted to M.
INH Resistance tuberculosis only. The drug is bactericidal to only slowly
In addition to genetic polymorphism of the human NAT2 metabolizing bacilli in acidic environment of phagocytes
gene, response to INH therapy may be further and caseous granulomas. It is active only at pH < 6. It is
compromised by genetic resistance to the drug by the considered a pro drug as it is converted into the active
Mycobacterium tuberculosis. INH resistant mutants drug by the tubercle bacillus into its active form,
arise spontaneously at a rate of 105-106 organisms. This pyrazinoic acid. The target for this compound is a fatty
is attributed to mutations in atleast five different acid synthase gene.38
474
Resistance determined with great accuracy and speed, identifying

majority of cases resistant to rifampicin, isoniazid and
Susceptibility testing for PZA is difficult to demonstrate ethambutol.42,43
because of the requirement of acid pH for the activity of
the drug to be converted to its active form pyrazinoic
HIGHLIGHTS
acid by the bacterial enzyme pyrazinamidase. Resistance
to this drug is due to mutations in the Mycobacterial • Genomics will introduce a new dimension in drug
pncA gene, coding for pyrazinamidase, resulting in its research.
loss of activity. It has been established that more than 90 • Gene expression analysis and genetic polymorphisms
are important for determining incidence of adverse
percent of the isolates with MICs of > 100 µg/ml have
drug reactions and drug resistance.
mutations in the pncA gene.39
• A detailed knowledge of the genetic basis of
individual response is of major clinical and economic
Ethambutol importance and can provide the basis for a rational
Ethambutol is a water soluble compound that is active approach to drug prescription.
only against mycobacteria. Among the 1st line drugs,
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More recently, researchers have developed a 11. Evans WE, Mcleod HL. Pharmacogenomics—drug
Pyrosequencing assay for rapid detection of SNPs in the disposition, drug targets, and side effects. N Engl J Med
mycobacterium genes associated with resistance to 2003;348:538-49.
particular drugs. Pyrosequencing is a real time sequencing 12. Weinshilboum RM, Wang L. Pharmacogenetics and
Pharmacogenomics: Development, Science and
method able to rapidly detect mutations in a large number
Translation. Ann Rev Genomics and Human Genetics
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2006;7:223-45.
rapid screening of rifampicin, isoniazid and ethambutol 13. O’Kane DJ, Weinshilboum RM, Mayer TP.
resistant strains of M. tuberculosis based on characterization Pharmacogenomics and reducing the frequency of
of resistance-associated hot mutations. Thus mutations at adverse drug events. Pharmacogenomics 2003;4:1-4.
codon 526 and 531 of the rpoB gene, codon 315 of the katG 14. Blum M, Grant DM, Mcbride W, et al. Human arylamine
gene, and codon 306 and 406 of the embB gene can be N-acetyltransferase genes: isolation, chromosomal
475
Chapter 33 Pharmacogenetics of Tuberculosis
localization, and functional expression. DNA Cell Biol 29. Seth Vimlesh, Beotra A, Ray D. Acetylation phenotype
1990;9:193-203. profile in north Indian children with pulmonary
15. Petri WA, Jr. Chemotherapy of Tuberculosis, tuberculosis. Indian Pediatr 1987;24: 1007-11.
Mycobacterium avium complex disease and leprosy. In: 30. Seth Vimlesh, Beotra A. Hepatic function in relation to
Goodman and Gillman, (Eds) The Pharmacological acetylator phenotype in children treated with
Basis of Therapeutics. 11th Edn McGraw-Hill 2006; antitubercular drugs. Indian J Med Res 1989; 89:306-9.
1203-23. 31. Parthasarathy R, Sarma GR, Janardhanam B, et al.
16. Clark DW. Genetically determined variability in Hepatotoxicity in South Indian patients during treatment
acetylation and oxidation. Therapeutic implications. of tuberculosis with Short-course regimens containing
Drugs 1985;29:342-75. isoniazid, rifampicin and pyrazinamide. Tubercle
17. NAT2gene homepage-http:/www.Louisville. edu/ 1986;67:99-108.
medschool pharmacology/NAT2.html. 32. Snider DE Jr. Pyridoxine supplementation during
18. Vatsis KP, Weber WW, Bell DA, et al. Nomenclatures isoniazid therapy. Tubercle 1980;61:191-6.
for N-acetyltransferases. Pharmacogenetics 1995;5:1-17. 33. Spielberg SP. N-acetyltransferases; pharmacogenetics and
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376-83. cogenomics 2008; 9:311-21.
20. Anitha A, Bannerjee M. Arylamine N-acetyltransferase 35. Bannerjee A, Dubnau E, Quemard A, et al. inhA, a gene
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34 Management of Tuberculosis
The management of tuberculosis has evolved over DRUG REGIMENS

centuries. In pre-chemotherapy era it was mainly based
The drug regimens used for treatment of various forms
on rest, good food and fresh air. In chemotherapy era
of tuberculosis can be divided into two phases. In the
one of the first drugs discovered to be effective in
initial intensive phase 3 to 5 drugs are given to the child.
tuberculosis was streptomycin around 1940s. It had a
dramatic effect on the symptoms of tuberculosis. In the second maintenance phase 2 to 3 drugs are
However, since it was used alone, 80 percent of the prescribed for a period of 4 to 10 months, usually four
organisms became streptomycin resistant in 3 months. months for milder form such as pulmonary primary
Discovery of para-aminosalicylic acid (PAS) in 1949 and complex and for a longer duration for severe form of TB.
isoniazid in 1952 led to the use of all 3 drugs together Selection of antituberculosis regimen depend on the
and prevention of resistance. The drugs were given for type of tubercular disease. WHO has described
18 to 24 months for adequate therapy. With discovery of standardized treatment categories for adults with
rifampicin in 1960, the combination of isoniazid, tubercular disease in Directly Observed Therapy Short-
rifampicin and streptomycin was able to reduce the course (DOTS). The major problem in inclusion of
duration of therapy to 9 months. Pyrazinamide was then children in DOTS is difficulty in demonstration of AFB
discovered to have effect on special subgroup of on sputum-smear and classification of different clinical
mycobacterium which exists in the acidic pH manifestations according to categories described for
intracellularly. It is high sterilizing activity resulted in adults. There have been efforts to develop classification
being able to shorten chemotherapy to 6 months. of different types of childhood TB into 4 categories similar
to those for adults. A classification was developed and
evaluated in the tuberculosis clinic of All India Institute
COMMONLY USED DRUGS
of Medical Sciences, New Delhi, India1 a tertiary care
The drugs used for treatment of tuberculosis in children hospital.1 It is to be noted that the regimens used were
along with their doses are given in Table 34.1. all continuous unlike intermittent in DOTS. The reason
Table 34.1: Doses and important side effects of antituberculosis drugs

Drugs Doses (mg/kg/day) Side effects
Isoniazid 5 Hepatotoxicity, hypersensitivity rash, fever, optic neuritis, psychosis, seizures
Rifampicin 10 Nausea, vomiting, hepatotoxicity, flu like syndrome, blood dyscrasia, arthralgia,
wheezing
Streptomycin 10-30 Ototoxicity: Vestibular or hearing loss, rash, fever, arthralgia, neuromuscular blockade,
peripheral neuritis, anaphylaxis
Ethambutol 15-25 Hypersensitivity reaction—rash, fever, joint pain, optic neuritis, GI upset, confusion,
dizziness
Pyrazinamide 25-35 GI upset, hepatotoxicity, hyperuricemia, photosensitivity, dysuria, malaise, arthralgia,
fever, thrombocytopenia
Δ Thiacetazone 3-5 *GI upset, hepatotoxicity, exfoliative dermatitis, vertigo, tinnitus, ataxia
**Ethionamide 15-20 GI upset, hepatotoxicity, peripheral neuropathy, gynecomastia, rash, alopecia,
headache, depression, diplopia, blurred vision, tremors
Cycloserine 15-20 Seizures, psychosis, peripheral neuritis
*GI = Gastrointestinal
** The other drugs for resistant tuberculosis are discussed elsewhere.
Δ Practically not used now due to dermal hypersensitivity reaction.
477
Chapter 34 Management of Tuberculosis
is that the infrastructure required for DOTS is neither in the family was present in 42%. Table 34.3 gives in
available to practicing pediatricians nor to the details in the clinical profile and treatment outcome.
pediatricians in medical colleges. It is not possible to Cure rates ranged from 80 to 100%. In cavitary and
accommodate all children under the DOTS, as they come disseminated types only 66% of the patients got cured.
from different areas which may not be under the In tubercular lymphadenitis, in almost 15% treatment had
delineated zones. Though fairly large number of to be extended and in about 5% of the cases regimen had
adolescent children may be covered under DOTS, the to be changed.
others will have to resort to continuous therapy. Recently
a consensus statement jointly prepared by Indian
Academy of Pediatrics and Revised National Tuber- Factors Associated with Failure of Therapy
culosis Control Program (RNTCP) has also proposed a 1. AFB positivity at diagnosis
classification of different types of tuberculosis in children 2. Nonreceipt of BCG vaccination at birth or later.
of three categories2 now under two categories (discussed 3. Extrapulmonary tuberculosis
elsewhere). Table 34.2 gives standardized categories
given by WHO along with suggested clinical condition1 AFB Positivity Diagnosis
and antituberculosis drugs regimens in children. These
are modified continuous, more popular with pediatricians AFB positivity at the time of diagnosis indicates either
in medical colleges and those in practice. the disease was extensive or drug resistant. At AIIMS, (a
Patients not improving or deteriorating despite tertiary care center) AFB positivity was found more
administration of 5 drugs (as per Category II) for at least commonly in lymph node tuberculosis. Seven percent of
3 months are labeled as multidrug-resistant tuberculosis. children required change of regimen. MDR-TB was more
The drugs used for this category of patients are described common in lymph node tuberculosis, for which regimen
in detail elsewhere. had to be changed.
The continuous regimens used at AIIMS in the pediatric
TB clinic are: BCG
Category I – 2 HRZE, 4 HR or
2 SHRZ 4 HR BCG has not been studied systematically in relation to
Category II – 2 SHRZE, 1 HRZE outcome of tuberculosis in children. It has been
Category III – 2 HRZ, 4 HR (Table 34.2) demonstrated experimentally that in mice prior
These regimens were given to a total of 541 children immunization enhances macrophage phagocytosis and
(boys 58% and girls 42%) with TB disease over a period CD4 T-helper cell activity to contain mycobacterial
of five years (2000-2005). The data was statistically dissemination. A meta-analysis found overall protective
analyzed by bivariate analysis followed by multivariate effect of BCG as 50% against TB infections. BCG as is
analysis using STATA 70 software. Age range was 2 commonly interpreted limits the hematogenous spread
months to 15 years. History of contact with TB patients and thus facilitates cure.
Table 34.2: Standard WHO clinical categories and suggested clinical conditions
of tuberculosis in children at AIIMS TB clinic
Categories As suggested by Suggested conditions Suggested
• Category I New sputum positive PPD, TBL 2 HRZE
Pulmonary TB Pleural effusion 4 HR
Abdominal TB or
Osteoarticular TB 2 SHRZ
Genitourinary TB 4 HR
CNS TB
• Category II Relapse Relapse 2 SHRZE
Treatment failure Treatment failure 1 HRZE
Return after adult default Interrupted treatment 7 HRE
• Category III Sputum negative pulmonary with Single lymph node 2 HRZ
limited parenchymal involvement Small effusion 4 HR
Extrapulmonary TB (less severe forms) Skin TB, PPC
PPC—Pulmonary Primary Complex, PPD—Progressive Primary Disease,
TBL—Tubercular Lymphadenitis, CNS TB—Central Nervous System Tuberculosis
478
Table 34.3: Clinical profile and outcome of treatment of childhood tuberculosis

Type of TB Total Cured Extension of Change of regimen
No. % treatment
Primary pulmonary 98 98 100 9 1
Progressive primary disease 155 138 89 15 2
Cavitary tuberculosis* 3 2 66 1 0
Miliary tuberculosis 11 9 81 2 0
Pleural effusion 30 26 86 4 0
Tubercular lymphadenitis 153 124 81 22 7
Abdominal tuberculosis 19 17 89 2 0
Osteoarticular tuberculosis 22 18 81 3 1
Tuberculoma brain 10 8 80 0 2
Tubercular meningitis 4 4 100 0 0
Disseminated tuberculosis* 30 20 66 10 0
Pericardial tuberculosis 3 3 100 0 0
Genitourinary tuberculosis 3 2 66 1 0
Total 541 469 69 13
* Cure rate only 66%
Extrapulmonary Tuberculosis producing handicaps later in life. The drug regimen for
One of the chances of higher failure in extrapulmonary this category is 2H3 R3 Z3 E3, 4 H3 R3 under DOTS.
tuberculosis may be false perception of non-response/
failure as in lymph node tuberculosis. Earlier studies in Category II
nineties have reported that affected lymph nodes may Children who received full antituberculosis treatment in
enlarge when patients are receiving appropriate therapy past and were declared cured and presented again with
or after the end of treatment, without any evidence of tuberculosis disease (relapse cases) are included in
bacteriological relapse. Children with non-resolution of category II. Patients who are diagnosed to have
lymph node or reappearance of new nodes on treatment tuberculosis in the past and received irregular treatment
should only be labeled as failure if they have systemic for the same without improvement or deteriorated
manifestations (weight loss, fever) along with evidence (suspected resistance) are also placed in category II. A
of tuberculosis (granuloma/AFB) on FNAC. Resistant child who failed to respond or deteriorated (clinical/
TB can only be diagnosed if there is demonstration of radiographic evidence + bacteriology) after 12 weeks of
AFB in aspiration or biopsy material of lymph nodes and intensive phase with good compliance is defined as
provided the patients have taken the primary regimen treatment failure and is placed in category II. Patients
with appropriate compliance. At AIIMS, in the TB clinic, who have interrupted treatment for two months or more,
medicines are given to the patient as per regimen for a and return with active TB as judged on clinical and
period of 2 weeks in the intensive phase and every month radiological assessment (treatment after interruption) are
in the continuation phase. On each visit it is only enquired also classified in category II. The regimen for this category
from the parents or caretaker whether the medicine have is 2S3 H3 R3 Z3 E3/1 H3 R3 Z3 E3/5H3 R3 E3.
been given as prescribed. Empty blister packs are taken
Category III
and counted to ensure whether patient has been
compliant. Patients with primary pulmonary complex (PPC), single
lymph node tuberculosis, minimal pleural effusion and
CATEGORIES AND DRUGS isolated skin tuberculosis are included in category III.
REGIMEN UNDER DOTS The suggested regimen for this category is 2H3 R3 Z3, 4H3
R3 .
The basis for assigning a category to a particular type of
tuberculosis under DOTS is as follows: CORTICOSTEROIDS IN TUBERCULOSIS
Category I Corticosteroids have been used as an adjunct to
antituberculosis therapy. It may be useful to mention that
All freshly diagnosed serious cases of tuberculosis are although corticosteroids are helpful in decreasing
included in category I. In addition, patients with joint morbidity due to TB but it is advised that these should
tuberculosis are also included in category I, because it not be used indiscriminately. There is unequivocal
may have long-term sequelae, if treated inadequately evidence of benefit of systemic steroids in CNS tuberculosis.3
479
Corticosteroids should be routinely used in HIV-negative Response to antituberculosis treatment can be

people with tuberculous meningitis to reduce death and monitored by (i) Clinical improvement; (ii) Radiological
disabling residual neurological deficit amongst survivors. clearance; (iii) Clearance of mycobacterium and; (iv)
However, there is not enough evidence to support or Nonspecific laboratory tests.8
refute a similar conclusion for those who are HIV positive.
Children with bronchial obstruction due to tuberculosis Clinical Improvement
may benefit with systemic steroids but the evidence is Majority of the patients show clinical improvement in
restricted to a single randomized controlled trial.4 symptoms and signs within a few weeks. Patients on
Therefore steroids cannot be recommended routinely and antituberculosis drugs should be followed every week
should be used after weighing benefits and harm to the in the 1st month of intensive phase and then twice
patients in such situations. There are no strong evidence monthly in the intensive phase. On each clinical visit
for use of steroids in pleural effusion,5 may be used if improvement in fever, cough, appetite and subjective
there is massive pleural effusion. Other conditions may well-being is assessed by asking the parents or the child
be miliary TB, pericardial tuberculosis.6 Systemic steroids (if he is old enough). The child should be examined for
did not prevent appearance of new nodes during weight gain, reduction in lymph node size, improvement
antituberculosis treatment.7 Prednisolone is the preferred in chest findings and presence of side effect of
steroid preparation. The dose is 1 to 2 mg/kg/day for 2 medications.
to 4 weeks and then gradual tapering over next 4 to 6 Majority of the patients show clinical improvement
weeks. in symptoms and signs within a few weeks. In the
presence of poor response or worsening of symptoms and
MONITORING OF TREATMENT signs, the initial basis of diagnosis of tuberculosis is
Adherence to treatment and completion of assigned checked again. The patient should be assessed for
regimen is the key to success of treatment of tuberculosis. compliance to drugs, other associated problems and/or
Compliance of drugs is assessed by asking the patient resistant tuberculosis and managed accordingly.
directly, about the color of urine which would indicate The clinical criteria used for monitoring are weight
whether the child is taking rifampicin. Each visit must gain, resolution in symptoms and signs which is the most
be utilized to provide health education and reinforce the common outcome in treated patients. In a study on lymph
need for treatment for full period. [Patients are given node tuberculosis, nearly 10-12 percent patients showed
drugs which are provided by a Non-Government appearance of fresh nodes or increase in size of existing
Organization (NGO) for pediatric TB clinic at AIIMS]. nodes. Few patients had residual nodes at the end of
treatment (9 RHE). Some of these nodes increased in size
Interrupted Treatment or fistula was formed later on. However, these changes
were not associated with a bacteriological relapse. Hence,
Whenever the treatment is interrupted for more than 2 the study noted no advantage in further prolongation of
weeks, the child should be reassessed clinically and treatment.9
radiologically. Wherever possible, bacteriological Follow-up should be continued every 2 to 4 weeks
examination should be performed. A suggested guideline for the duration of treatment in the continuation phase.
for treatment after interruption of therapy is given in After the treatment is over, follow-up every 3 to 6 months
Table 34.4. for next 2 years is desirable.10a

S. Duration of Duration of Decision Category of treatment
No. therapy interruption (continuous)*
1. Up to 4 weeks <2 weeks Resume original regimen
>2 weeks Reassess and start appropriate regimen
2. 4-7 weeks <2 weeks Resume original regimen
>2-8 weeks Extend intensive phase by 1 month Category II therapy
>8 weeks Reassess and start appropriate regimen
3. > 8 weeks <2 weeks Resume therapy
>2 weeks: Resume therapy
Not active disease
>2 weeks: Resume therapy Category I
Active disease
*Continuous regimens as suggested in Table 34.3.
480
Radiological Improvement in sputum/gastric lavage/aspiration from lymph nodes

and in biopsy specimens in over 50 percent of patients
Clinical improvement precedes radiological clearance of
even in best centers. However, observing the dis-
lesion on X-ray film of chest (CXR). Frequency of doing
appearance of bacilli on treatment is as important as
CXR in children with pulmonary tuberculosis is not clear.
attempt to isolate the bacilli for diagnosis even among
In view of limited resources, the reasonable approach
children. This is particularly true for cases with
would be to obtain CXR after 8 weeks of treatment, and
pulmonary progressive primary disease or lymph nodes
if it shows significant improvement, further follow-up
with necrosis and fistula formation as these are more
should be based on clinical criteria. In patients who show
likely to yield acid fast bacilli. WHO recommends that
increase or little change in radiological features coupled
monitoring by AFB isolation is important and all cases
with delayed clinical response, it is suggested to extend
must undergo AFB tests at the end of intensive phase of
the intensive phase by one more month. Further X-ray
treatment to detect conversion to negative status among
films should be done after 4 weeks. If patient is better, he
those who were initially positive and detect early failures
should be put on continuation phase, else he should be,
in those who were AFB negative. Further bacteriological
investigated for failure of treatment and drug resistance.
tests are done at least once more before stopping
On the degree of the radiological clearance of the
treatment to establish ‘true’ cure.15
lesion, the response to therapy is graded as:11
Sputum examination, gastric aspirate or induced
• Complete clearance
sputum examination may be used for AFB demonstration.
• Moderate to significant clearance (1/2 to 2/3
clearance)
Nonspecific Test for Monitoring
• Mild clearance (1/3 decrease in size)
• Static lesion Although an elevated erythrocyte sedimentation rate
• No clearance or appearance of new lesions. (ESR) maybe expected in children with tuberculosis, a
If a patient has achieved complete or moderate to recent study found that one-third of children with TB
significant clearance there is no need to continue had a normal ESR at the time of diagnosis, suggesting
antituberculosis drugs beyond the duration of regimen little value in using ESR as a diagnostic and monitoring
selected for the patient.12 One should not attempt to treat test for childhood tuberculosis.16
till complete radiological clearance as the improvement
in X-ray may continue to occur even after stoppage of MONITORING FOR SIDE EFFECTS
treatment.13,14
The child should be examined for side effects on each
visit. The common side effects of antituberculosis drugs
Persistent Abnormal Shadows on
are given in Table 34.1. The important side effects that
CXR in Follow-up have clinical implication include hepatotoxicity, ocular
Abnormal shadows maybe due to evolving calcification toxicity, and skin hypersensitivity reactions. It has been
in lymph nodes, segmental/sub-segmental collapse or observed that children tolerate anti-TB drugs at currently
residual bronchiectasis. In these patients it is difficult to recommended doses very well, incidence of serious
assess the activity of disease by CXR alone. If the patient toxicity is very low. Occasional fatal hepatotoxic events
is clinically asymptomatic, the assigned antituberculosis are described in children.17 Monitoring for adverse effects
drugs regimen is completed and stopped. The patients will need to be improved if increased doses are to be
should be followed up regularly and CXR repeated after used in children especially in regions where co-
6 months. Persistence of static shadows on CXR without morbidities are common.18
clinical deterioration indicates inactivity of disease. In
some patients occurrence of posttuberculous Hepatotoxicity
bronchiectasis or bronchial hyperactivity, etc. may lead
Hepatotoxicity is the major fear when the combination
to situation where clinical signs and symptoms of cough,
of isoniazid (INH), rifampicin (RIF) and pyrazinamide
expectoration, etc. persist along with radiological
(PZA) is administered during intensive phase of
shadows even though TB may have responded to
treatment. The factors held responsible for hepatotoxicity
treatment.14
include acetylator phenotype, doses of antituberculosis
drugs, nutritional status of the patient and severity of
Bacteriological Criteria
the disease.2,10
Childhood tuberculosis is often a paucibacillary disease. It has been observed that acetylator phenotype does
It is difficult to demonstrate Mycobacterium tuberculosis not cause hepatotoxicity due to INH.14,17 The chances of
481
hepatotoxicity increase if higher doses or combination However, it is rare in doses of 15 mg/kg/day.27,28 It has
of INH, RIF, PZA are used.18,19 Children with severe been shown that children above the age of 3 years are
disease like tubercular meningitis, miliary tuberculosis, not at a great risk for developing ethambutol induced
etc. are at a greater risk of developing antituberculosis optic damage.29 In young children if ethambutol toxicity
drugs-induced hepatotoxicity.20,21 Similarly, children is suspected they need careful monitoring by
with pre-existing liver dysfunction, viral hepatitis and electroretinogram (ERG) in consultation with an eye
malnutrition particularly grade III are predisposed to specialist. However, in the older patients, regular
antituberculosis drugs-induced hepatotoxicity. monitoring of color vision maybe sufficient. If ocular
Monitoring of transaminases may pickup anti- toxicity is suspected, the drug should be discontinued.
tuberculosis drug-induced hepatotoxicity early. Ethambutol toxicity is dose related and in recommended
However, most experts prefer to substitute laboratory doses (15-25 mg/kg) it is safe and can be used in younger
monitoring with routine questions about appetite, children. 30-34 Seth at al 31 have demonstrated by
nausea, vomiting, appearance of jaundice, pain abdomen measuring visual evoked responses in children that these
and subjective well-being. The patient may be examined functions can be measured in children above 3 years of
for jaundice, hepatomegaly and weight gain. In case age. They further reported no ocular toxicity in this dosage.
nausea, vomiting, abdominal pain or jaundice occur,22
the patient can be counseled to stop INH and contact the Peripheral Neuritis
clinician immediately.
Clinically manifest peripheral neuritis in children on INH
Laboratory investigations including transaminases,
therapy due to pyridoxine deficiency is very rare.33 The
serum bilirubin, and alkaline phosphatase may be done
patients who are predisposed for development of
if antituberculosis drugs-induced hepatotoxicity is
peripheral neuritis include children who do not eat dairy
suspected on clinical ground. In certain high-risk cases
and animal products, malnourished and HIV
like pre-existing liver disease, routine monitoring is
infected.35,36 If at all it occurs, it manifests as pins and
recommended.23 Investigations for viral hepatitis, should
needles sensation in hands and feet. These children
be carried out as the hepatitis maybe because of viral
should be treated with pyridoxine 25 to 50 mg/day.9
infection rather than due to antituberculosis drugs.24,25
Adverse reactions due to antituberculosis drugs such
If a child on antituberculosis drugs develops clinically
as Stevens-Johnson syndrome, psychosis and other
evident jaundice or rise in blood transaminases more than
hypersensitivity reactions are very rare in children in
five times the normal, the INH, RIF and PZA should be
usual doses. If they occur, the most probable offending
stopped. Rifampicin alone causes true hepatotoxic
drug is withdrawn. Most of the other side effects are
reaction, though uncommonly, can perhaps potentiate
minor and self limiting and treated symptomatically.
hepatotoxicity due to other drugs like INH. However, if
Thiacetazone is not recommended for use in tuberculosis
the picture is that of cholestatic jaundice, i.e. increased
of children because Stevens-Johnson syndrome is more
bilirubin with minimal increase in transaminase levels,
likely to occur when there is associated HIV/AIDS
rifampicin is most likely the culprit.26 Isoniazid, rifampicin
infection.
and pyrazinamide should be stopped. The patient should
be started on streptomycin and ethambutol if the disease
is life-threatening. The transaminases are repeated every HIGHLIGHTS
week. When the transaminase levels decrease to less than • It is feasible to classify children with tuberculosis in
two times the normal, the child can be started on different categories for different antituberculosis
rifampicin, isoniazid and pyrazinamide in sequence. regimens.
Initially half the dose, then the full dose. It is preferable to • Children should be followed up at least every 4 weeks
add or modify the dose one at a time with monitoring of to judge the response to treatment, early detection of
transaminases weekly. However, in severe disease, 2 to 3 treatment failure and side effects of medication.
changes (i.e. increasing the dose/adding new drug) can • Clinical parameters are main indicators of
be made at a time with frequent monitoring of liver improvement.
enzymes.10 • For pulmonary tuberculosis, X-ray film may be
repeated after 8 weeks of starting the treatment, and
Ocular Toxicity thereafter, only if warranted clinically earlier, and
Ocular toxicity due to ethambutol may occur in up to 5 the 2nd film at the end of therapy.
percent of patients if the doses are between 25 to 50 mg/ • Important toxic effects of ATT include hepatotoxicity.
kg/day. The toxicity results in reversible optic neuritis, Ocular toxicity and hypersensitivity reactions are
blurred vision, scotoma and alteration in color vision. rare.
482
• Hepatotoxicity is managed by stopping INH, RIF 14. Seth Vimlesh, Jain RC. Drug resistant tuberculosis. In:
and PZA with weekly monitoring of transaminases, Sachdev HPS, Choudhary P (Eds): Frontiers in Pediatrics
(1st edn). New Delhi: Jaypee Brothers Medical Publishers
the drugs can be restarted gradually starting with
1996;139-56.
rifampicin.
15. Treatment of Tuberculosis: Guidelines for National
• Rare indications for withholding antituberculosis Programs. Geneva: World Health Organization 1993.
drugs include hypersensitivity reactions, such as 16. Marri MR, Kirkpatrick MB. Erythrocyte sedimentation
Stevens-Johnson syndrome and psychosis. rate in childhood tuberculosis: Is it still worthwhile? Int
J Tuberc Lung Dis 2000;4:237-9.
17. Centers for Disease Control and Prevention (CDC).
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41:927-37. 2010;59:24-5.
2. Chauhan LS, Arora VK. Management of pediatric 18. Frydenberg AR, Graham SM. Toxicity of first-line drugs
tuberculosis under the Revised National Tuberculosis for treatment of tuberculosis in children: review. Trop
Control Program (RNTCP). Indian Pediatr 2004;41:901- Med Int Health 2009; 14:1329-37.
6. 19. Rugmini PS, Mehta S. Hepatotoxicity of isoniazid and
3. Prasad K, Singh MB. Corticosteroids for managing rifampicin in children. Indian Pediatr 1984;21:119-26.
tuberculous meningitis. Cochrane Database Syst Rev 20. Tsagaropoulou-Stinga H, Mataki-Emmanouilidou T,
2008;(1):CD002244. Korida-Kavalioti S, et al. Hepatotoxicity reactions in
4. Toppet M, Malfroot A, Derde MP, et al. Corticosteroids children with severe tuberculosis treated with isoniazid-
in primary tuberculosis with bronchial obstruction. Arch rifampicin. Pediatr Infect Dis J 1985;4:270-3.
Dis Childhood 1990;65:1222-6. 21. Seth Vimlesh, Beotra A. Hepatic function in relation to
5. Galarza I, Cafiete C, Granados A, et al. Randomised trial acetylator phenotype in children treated with
of corticosteroids in the treatment of tuberculous antitubercular drugs. Indian J Med Res 1989;89:306-9.
pleurisy. Thorax 1995;50:1305-7. 22. Rahajoe NN, Rahajoe N, Boedman L, et al. The treatment
6. Strang JIG, Nunn AJ, Johnson DA, et al. Management of of TBM in children with a combination of isoniazid,
tuberculous constrictive pericarditis and tuberculous rifampicin and streptomycin: A preliminary report.
pericardial effusion in Transkei: results 10 years follow- Tubercle 1979;60:245-50.
up. Q J Med 2004;97:525-35. 23. Seth Vimlesh, Arya DS, Seth SD, et al. Pharmacokinetic
7. Hawkey CR, Yap T, Pereira J, et al. Characterization and of pyrazinamide in pulmonary tuberculosis in children.
management of paradoxical upgrading reactions in HIV- In: Choudhary P, Puri RK, Sachdeva HPS (Eds): Scientific
uninfected patients with lymph node tuberculosis. Clinic abstract of the 8th Asian Congress of Pediatrics and XXXI
Infec Diseases 2005;40:1368-71. National Congress of Indian Academy of Pediatrics. New
8. Kabra SK, Ratageri VH. Tuberculosis in children: Delhi: Jaypee Brothers Medical Publishers 1994;111.
Monitoring of treatment and management of side effects. 24. Byrd RB, Hom BR, Solomn DA, et al. Toxic effects of
Paediatr Today 1999;2:81-4. isoniazid in tuberculosis chemotherapy role of
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pediatric infectious diseases (5th edn). Philadelphia: WB 25. Starke JR. Tuberculosis in children. Diagnosis and
Saunders 2004; 1337-70. treatment. Annals Nestle 1997;55:10-23.
10. Seth Vimlesh. Clinico-immunoradiological spectrum: 26. Turktas H, Unsal M, Tulek M, et al. Hepatotoxicity of
Management. In: Seth Vimlesh (Ed): Essentials of antituberculosis therapy (rifampicin, isoniazid and
tuberculosis in children (1st edn). New Delhi: Jaypee pyrazinamide) or viral hepatitis. Tubercle Lung Dis
Brothers, Medical Publishers 1997;312-33. 1994;75:58-60.
10a. Seth Vimlesh, Kabra SK, Seth Rachna. Clinicoim- 27. Kumar R, Mishra PK, Mehrotra R, et al. Hepato-toxicity
munological profile: Indian scenario. In Seth Vimlesh, of rifampicin and isoniazid: Is all drug induced hepatitis?
Kabra SK (Ed): Essentials of tuberculosis In children (3rd Am Rev Respr Dis 1991;143: 1350-2.
edn). New Delhi: Jaypee Brothers Medical Publishers 28. O’Brien RJ. Hepatotoxic reaction to antituberculous
2006;95-105. drugs: adjustments to therapeutic regimens. JAMA 1991;
11. Mukhopadhyaya S, Gupta AK. Imaging in Childhood 265:23-33.
Tuberculosis. In: Seth Vimlesh, Puri RK, Sachdev HPS 29. Reed MD, Blumer JL. Clinical pharmacology
(Eds): Tuberculosis in Children. Indian Academy of of antituberculosis drugs. Pediatr Clin North Am
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12. Ramachandran P, Kripasankar AS, Duraipandian M. 30. Grahm SM, Daley HM, Banerjee A, et al. Ethambutol in
Short-course chemotherapy in pulmonary tuberculosis tuberculosis: Time to reconsider. Arch Dis Child
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13. Starke JR. Current concepts of epidemiology, diagnosis 31. Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual evoked
and treatment of childhood tuberculosis in the United responses in tuberculosis in children on ethambutol
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32. Thee S, Detjen A, Quarcoo D, et al. Ethambutol in review of the literature. Int J Tuberc Lung Dis 1997;
paediatric tuberculosis: aspects of ethambutol serum 1: 12-7.
concentration, efficacy and toxicity in children. Int J 35. Pellock JM, Howell J, Kendig EL Jr, et al. Pyridoxine
Tuberc Lung Dis 2007;11: 965-71. deficiency in children treated with isoniazid. Chest
33. Donald PR, Maher D, Maritz JS, et al. Ethambutol dosage 1985;87:658-61.
for the treatment of children: literature review and 36. Cilliers K, Labadarios D, Schaaf HS, et al. Pyridoxal-5-
recommendations. Int J Tuberc Lung Dis 2006; 10:1318-30. phosphate plasma concentrations in children receiving
34. Trébucq A. Should ethambutol be recommended tuberculosis chemotherapy including isoniazid. Acta
for routine treatment of tuberculosis in children? A Paediatr 2010;Feb 8.
Consensus Statement on Childhood
35 Tuberculosis—2010 IAP Working
Group on Tuberculosis
YK Amdekar
Justification: Revised National Tuberculosis Control Lymphnode enlargement >2 cm with or without
Program (RNTCP) has focused on adults with smear typical findings suggestive of TB and failure of antibiotic
positivity—a tool not so well used in children with response demands FNAC for histopathology and
tuberculosis. bacteriology. Clinical suspicion of tubercular meningitis
There is a need to redefine standardization of (TBM) should be confirmed by CSF examination and CT
diagnosis and management protocols for childhood scan though none of these investigations are confirmatory
tuberculosis. and hence should not be considered in isolation. CSF tests
Process: Indian Academy of Pediatrics (IAP) for TB antibody and PCR are not recommended for
constituted a working group to develop consensus routine use. Diagnosis of abdominal TB is made on
statement on childhood tuberculosis (TB). Members of circumstantial evidence and there are no standard
the group were given individual responsibilities to review guidelines.
the existing literature on different aspects of the childhood For treatment, disease is divided into three categories.
TB. The group deliberated and developed a consensus The Category I and III are recommended for different
which was circulated to all the members for review. types of new cases, i.e. those who have received treatment
Efforts were made to ensure that the recommendations for not more than 4 weeks. Category III includes primary
are standardized. pulmonary complex, one site peripheral lymphadenitis
Objectives: To produce recommendations and and pleural effusion, while all other forms of TB are
standard protocols for reasonably accurate diagnosis and included in Category I that corresponds to smear positive
rational treatment of tuberculosis in children. TB in adults. This is because AFB is often found in many
Recommendations: Fever and/or cough >2 weeks with Category I disease in children. Category II includes
loss of weight and recent contact with an infectious case defaulters, relapses and failure cases irrespective of the
should arouse suspicion of TB. Chest X-ray and trial with site of disease.
broad-spectrum antibiotic for 7 to 10 days is justified. In Standard protocol is followed for each of these
case of clinical and radiological nonresponse, Mantoux categories. Intermittent thrice weekly therapy with higher
test and sputum or gastric aspirate for AFB dose has been found to be equally effective as daily
is recommended. If AFB is positive, diagnosis is therapy and so is recommended in DOTS—Directly
confirmed. If AFB is negative but chest X-ray Observed Therapy Short-term. Compliance of treatment
is suggestive and Mantoux test is positive, it is a probable must be ensured. Repeat chest X-ray is ideal at the end of
case. If these tests are negative, alternate diagnosis must therapy. Liver function tests are not routinely
be sought and referral made to an expert. Ideally, it is recommended. Recommendations are also made for
recommended to use 1TU of PPD for Mantoux test but 2 special situations such as MDR-TB, TB and HIV and
or 5 TU may be acceptable (but less preferred). Cut-off neonate born to a mother suffering from TB.
point of 10 mm for natural infection may be used for test Tuberculosis is a single major infectious disease
done with 1, 2 or 5 TU. There is no linear relation of causing significant morbidity and mortality amongst all
reaction to tuberculin strength and so no more than 5 TU humans including children. Three sets of guidelines
should be used. BCG test is not recommended. Diagnosis related to the management of childhood tuberculosis have
must not be made without an attempt to look for AFB in been produced by the various consensus groups of the
gastric aspirate or sputum, as it is possible to get AFB IAP since 1997,1-3 with the last one coming out in 2004.3
even in primary complex. ELISA and PCR tests for TB Cases were classified into three categories, as per WHO
are not recommended. There is no place for trial of and Revised National Tuberculosis Control Program
antitubercular therapy. (RNTCP) guidelines. These guidelines also addressed the
Reproduced with permission from Indian Pediatrics 2010;27:41-55.

485
Chapter 35 Consensus Statement on Childhood Tuberculosis
issue of intermittent therapy and direct observation of

therapy.
OBJECTIVES
In consonance with the decision of Indian Academy of
Pediatrics to standardize and update the protocols for
diagnosis and treatment of childhood tuberculosis, a
meeting of IAP Working Group was held in Mumbai on
26th and 27th April 2008. Members of the Group were
given individual responsibilities to review the existing
literature on different aspects of the childhood TB and
present the review to the Group. The Group deliberated
in the light of presentations made by the members, based
on literature reviewed, and developed a consensus for
the topics covered.
The deliberations were than written as a draft
document and circulated to all the members for review.
The Group also informally interacted with the different
national and international bodies that were also working
on developing guidelines for TB management to
incorporate the latest changes that were in the offing.
Efforts were made to ensure that the recommendations
are standardized for reasonably accurate diagnosis and
rational treatment of childhood TB.
RECOMMENDATIONS
Pulmonary Tuberculosis — When to Suspect?
Figure 35.1 depicts the diagnostic algorithm for
pulmonary tuberculosis in a child.
Fever and/or cough of recent onset lasting for >2
weeks should arouse suspicion of tuberculosis. It is
important to document fever and not depend merely on
impression. Fever can be of any type and the often-
described evening rise of temperature is neither specific Fig. 35.1: Algorithm for diagnosis of tuberculosis in children
to this etiology nor commonly present. Cough can be dry
or moist and may be severe. Cough persisting beyond 2
immunocompromised state including steroid therapy.
weeks, particularly as an only symptom in an otherwise
Persistent lower respiratory infection not responding to
healthy child can be due to viral infection and is often
antibiotic therapy may point to a probable diagnosis of
not due to TB. Such children, therefore, do not always
tuberculosis. Significant superficial lymphadenopathy
warrant investigations. Recurrent symptoms with normal
must be specially looked for, as it may often coexist.
intervening period are less likely to be due to
For a clinically suspected case, further investigations
tuberculosis. Recent loss of appetite may be relevant but
are necessary. Diagnosis of tuberculosis should never be
unexplained recent loss of weight can be an important
made only on clinical features. The above mentioned
pointer to the suspicion of tuberculosis. A static weight/
features in isolation or in combination should only make
not growing well are not significant pointers to this
you suspect TB. Therapeutic trial with anti-TB drugs is
disease. History of contact with an infectious TB patient
therefore, not recommended and instead every attempt
(smear positive) should always prompt detailed
must be made to prove the diagnosis.
examination for likelihood of the disease. However, in a
symptomatic child, contact with a person with any form
of active tuberculosis within last two years may be Tuberculin Test
significant. The standard tuberculin test recommended for use is the
Diagnosis is also more likely in presence of risk factors Mantoux’s test. Commercially available tuberculin in the
such as recent history of measles or whooping cough and country are 1, 2 and 5 Tuberculin Unit (TU) PPD (RT23
486
equivalent). It is important to raise a wheal of about 6 necessarily due to TB. Asymptomatic patients may have
mm after the intra-dermal injection and the test is read persistent shadows due to parenchymal scarring, pleural
48 to 72 hours after an injection. Ballpoint or palpatory thickening, and healed fibroatelectatic changes. On the
methods are used to read the induration. other hand, a child with bronchiectasis or an interstitial
The width of reaction (induration) in the horizontal lung disease may have presence of nonresolving
plane is noted for interpretation. (see annexure for details) shadows with persistent symptoms.
Mantoux’s test or PPD skin test is considered positive if Ultrasonography of chest is helpful to assess pleural
the induration is 10 mm or more. This cut-off was fluid collection; although decubitus chest X-ray film may
recommended using a 1 TU PPD RT23. also reveal similar information. CT scan is rarely
Currently the laboratories more often use 5 TU PPD necessary and is not cost and radiation effective. Chest
(RT23 equivalent) or sometimes even some other higher CT scan, however, may offer an opportunity for CT
strengths or types of PPD are used. The standard cut-off guided biopsy for tissue diagnosis.
of 10 mm can actually not be justified for any higher
strength of PPD used. The reaction evoked is not Bacteriology
dependent on the amount of antigen given but also does
not have a linear relationship with the increasing Demonstration of AFB from any body fluid or tissue is
strengths. Therefore, the current practice may actually the gold standard of diagnosis of tuberculosis. Such a
lead to an increase in false positive reactions using the proof is often lacking in childhood tuberculosis because
10-mm cut-off with the higher strength of PPD. The of difficulty in collection of sputum and due to
Group recommends that the 10-mm cut-off may be paucibacillary primary disease in children. However,
continued to use for strengths of PPD only up to 5TU. studies do report that the yield of a positive test in
Efforts should be made to use only 1 TU PPD to decrease advanced cases may be as high as in adults.
the false positives4 and in no case strength higher than 5 Few studies have reported as high as 33%
TU should be used. Degree of reaction, including necrosis bacteriological positivity even in primary disease such
and ulceration, may not necessarily differentiate infected as hilar adenopathy.8,9 Therefore, every attempt must be
from diseased. Prior BCG vaccine has minimal influence made to bacteriologically prove the diagnosis in every
on PPD reaction.5,6 case of suspected tuberculosis.
If the patient returns for reading beyond 72 hours but Early morning gastric aspirate is a preferred specimen
by 7th day, a positive test can still be read. A repeat test for most young children with suspected TB for detecting
may be needed, if there is no induration and the suspect AFB or isolating M. tuberculosis. The child is kept fasting
presents beyond the stipulated time for reading. Repeat for about 6 hours (at night) and an appropriate size intra-
tuberculin test when required should preferably be done gastric tube is passed in the morning. Initially the aspirate
on the other arm. The reading of the same should be is drawn from the stomach and then a further washing
interpreted as in any other individual. with 15 to 30 ml saline is taken. The contents so recovered
are then immediately transferred to the laboratory. This
specimen can also be collected as an ambulatory
BCG Test
procedure after 4 to 6 hours fasting.10 Sputum collection
BCG test is not recommended in diagnosis of is possible in older children with extensive and cavitatory
tuberculosis.7 disease, particularly if the patient has a wet cough.
Induction of sputum by 3% nebulized hypertonic saline
Chest Radiograph can be tried in older children (after the age of 4 months).
The patient is pretreated with nebulized bronchodilators
Chest radiograph merely localizes the site of pathology prior to induction. Following saline nebulization, chest
and not etiology. There are no pathognomonic physiotherapy is done to loosen up the secretion and the
radiological signs of tuberculosis. In relevant clinical samples are collected from the throat or nasopharynx.11
setting, certain radiological lesions may strongly suggest Whichever method one chooses to use, one needs to
tuberculosis and they include miliary, hilar or collect at least two, preferably three, samples.
paratracheal lymphadenopathy with or without Where the facilities are limited, these tests may be
parenchymal involvement and fibrocaceous cavitatory
prioritized and at least be done in all children with wet
lesions. Rarely chest X-ray may be normal, such cases
cough or children who have definite parenchymal lesion
should be referred to an appropriate center for further
on chest skiagram. Experience with bronchoscopy and
detailed investigations, if the clinical suspicion is high.
In clinical practice, nonresolving chest shadows BAL as a diagnostic tool is limited but it is often needed
despite adequate antibiotic therapy in a symptomatic when evaluating a persistent pneumonia. TB remains an
child raises the possibility of tuberculosis. It is worth important cause of persistent pneumonia in our
mentioning that all persistent radiological lesions are not country.12
487
Ziehl-Neelsen stain can reveal AFB only if sample Extrapulmonary Tuberculosis

contains >10,000 bacilli per ml. Different culture methods
TB Lymphadenitis
are used, such as LJ medium, Radiometric (BACTEC) and
Nonradiometric (MGIT) can be used for confirming Clinical correlate of diagnosis includes progressive
diagnosis in paucibacillary state. The newer methods are enlargement of lymph node for more than 2 weeks, firm,
capable of giving faster results and may be used if minimally tender or not tender, fluctuating, further may
available. Mycobacterial culture assumes special get matted and develop chronic sinus formation.
significance in case of suspected drug resistance. Mantoux test is mostly positive in a significant
proportion. Fine needle aspiration cytology (FNAC) is
Serodiagnostic Tests usually adequate for accurate diagnosis and it correlates
well with biopsy in >90% of cases.18,19 Histopathology,
As mycobacterial antigens overlap in different stages of
typically, shows necrosis and epitheloid granuloma. It
infection and disease, there are no specific antigens that
is important to look for AFB in FNAC specimen and it
can confirm natural infection or active disease. Besides,
may be positive in 20 to 70% of patients. When FNAC is
antigen tests vary widely and are often negative in
inconclusive, biopsy is necessary for confirmation of
paucibacillary disease. Antibody tests share similar
diagnosis. In children lymphadenopathy is common due
problems for interpretation and in addition cannot
to recurrent tonsillitis and URIs as well. Reactive
differentiate natural infection from BCG vaccine induced lymphadenitis may closely clinically mimic tuberculosis
infection and active disease from old healed disease. but do not warrant anti-TB drugs. Hence anti-TB drugs
Thus, both antigen and antibody TB ELISA tests are should not be given unless the diagnosis of TB is
poorly sensitive and specific and are not recommended confirmed by FNAC or histopathology (Fig. 35.2).
for diagnosis of tuberculosis.13
Pleural Effusion
Interferon Gamma Release Assays (IGRAs)
If chest X-ray is suggestive of pleural effusion, pleural
A newer generation of tests which measure the aspiration should be performed for biochemical,
production of interferon gamma by the peripheral cytological and smear examination by ZN stain to
mononuclear cells have been developed to identify the confirm the diagnosis. Typically, a tubercular effusion
patients with TB disease or latent infection. These use fluid is straw colored (pus, if aspirated, is very rarely
two antigens, early secretion antigen target (ESAT 6) and
culture filtrate protein 10 (CFP 10), which are specifically
present only in Mycobacterium tuberculosis and not in other
mycobateria or the BCG vaccine strain. These tests
though have a principle similar to skin test but do away
with the need for a repeat visit by the patient for reading
purposes.14 QuantiFERON Gold and T spot are two of
the commercially available IGRAs. These are being used
in place of the skin test in low prevalence countries to
detect latent TB infection. However, these expensive tests
do not differentiate the TB infection from disease. Its exact
utility in high burden situation is still not clear.15,16
PCR Test
Nucleic acid amplification tests using polymerase chain
reaction (PCR) cannot differentiate living from dead
bacilli and so continues to be positive even after
successful treatment. PCR is positive in 95 to 100% of
culture positive cases but only in 50 to 60% of culture
negative cases. It may be false positive in 1 to 30% of
cases. Thus no decisions can be made only on the basis
of PCR tests and hence these tests are not recommended
in clinical practice.17 Fig. 35.2: Diagnostic algorithm for tubercular lymphadenitis
488
due to TB etiology) has large numbers of cells (in routinely available nor reproducible. They are, therefore,
hundreds; predominantly mononuclear), with high not recommended. CSF antibody tests have poor
proteins (>3 g/dl). Adenosinedeaminase (ADA) levels sensitivity and specificity and hence are not useful.
over 60 IU/l may be suggestive of tuberculous pleural
effusion but is not diagnostic of TB.20,21 Pleural biopsy Tuberculoma
may be performed, where facilities are available, Often seen in older children, it may present as a focal
particularly when the fluid aspirate findings are seizure in supratentorial cortical lesion or with symptoms
inconclusive. and signs of raised intracranial tension with multiple
localizing signs and hydrocephalus in posterior fossa
Tubercular Meningitis (TBM) lesion. It may sometimes also be seen as a part of TB
Children with TBM present with a rather longer (>1 meningitis.
week) duration of fever, with vague CNS symptoms such Differentiation from other ring lesions, especially
as behavior changes, irritability, drowsiness, headache, neurocysticercosis (NCC) is difficult in cortical lesion. A
vomiting and seizures. Physical examination reveals ring enhancing lesion is not pathognomonic of
typically global encephalopathy with focal deficits, tuberculoma. A larger lesion >20 mm, disc lesion or ring
hydro-cephalus and movement disorder. Risk factors for lesion with thicker rim with central nodule favors
TBM include age <5 years, contact with an adult suffering tuberculoma while multiple, smaller, thin rim with
from tuberculosis, PEM grade III and IV, and HIV epicentric nodule favor NCC. MR spectroscopy may help
infection. in diagnosis of tuberculoma as it shows lipid peak.
Typically CSF is clear, usually does not show very
high cell count (under 500 cells/cumm) with Abdominal Tuberculosis
lymphocytosis. Biochemical investigations reveal
It may present as localized disease such as mesenteric
increased proteins and mild reduction in glucose. The
lymphadenopathy, intestinal disease, peritoneal
typical CSF picture may, however, not always be seen.
involvement or systemic disseminated disease presenting
Furthermore, the typical CSF picture described above can
as hepatosplenomegaly. Large matted lymph node mass
also be mimicked by partially treated pyogenic
may be clinically evident and ultrasound guided biopsy
meningitis. In such a situation, CSF can be repeated after
may help in confirming the diagnosis.
48 to 72 hours of treatment with a fresh set of broad
There are no standard guidelines for sonography
spectrum potent antibiotics to evaluate change in clinical
diagnosis of abdominal tuberculosis. However,
status as well as in CSF. During this time, efforts are made
corroborative evidence includes: echogenic thickened
to establish the diagnosis by collecting more evidence
mesentery with lymph nodes >15 mm in size; dilated
using PPD, chest skiagrams, and bacteriological
and matted bowel loops; thickened omentum, and
diagnosis from appropriate samples including CSF.
ascites.23 Barium follow-through examination may be
Many a time concomitant TB lesions elsewhere in the
suggestive of intestinal disease but is not confirmatory.
body (say, pulmonary) coexist and can clinch the
Exudative peritoneal disease presents as ascites that is
diagnosis. Mycobacterial culture from CSF should also
often clinically evident. The ascetic tap should always
be attempted but CSF culture has poor sensitivity (16%)
be done in such situations and the fluid tapped is an
though specificity is high (90%).
exudate, typically showing lymphocytic predominant
Neuroimaging is an important diagnostic modality.
cellular response with high proteins (>3g/dl).
It may reveal one or more of the following findings: basal
meningeal enhancement; hydrocephalus with or without
periventricular ooze; tuberculoma(s); or infarcts may be
Treatment of Tuberculosis
seen in different areas, especially in basal ganglia. Basis of Pharmacotherapy
Normal CT scan does not rule out TBM and in case of
strong clinical suspicion of diagnosis, a repeat follow-up Choice of anti-TB drugs is based on several determinants
CT scan after few days may show newly developing such as bacillary and metabolic subpopulation, bacillary
lesions. CSF abnormalities in TBM may take variable time load, drug resistant strains, lag period of bacterial
up to few months to return to normal. Besides routine population, pharmacokinetic profile and pathological
CSF examination. CSF adenosinedeaminase (ADA) is factors. There are different types of bacillary population
high in TBM. Various studies have a cut-off point in every case of tuberculosis and hence drugs are
between 7 and 11.3 IU/L for diagnosis. This may offer selected in a combination to attack entire (extracellular
supportive evidence in favor of TBM but should not be and intracellular, slow and rapidly growing) bacillary
taken in isolation.22 CSF antigen and PCR tests are neither population for successful chemotherapy. Isoniazid
489
(INH) and rifampicin (RMP) kill the fast growing bacilli, In case of delayed response to assigned therapy,
pyrazinamide (PZA) take care of intracellular organisms intensive phase may be prolonged by one more month
in acidic medium while extracellular slow growing in Category I and II. Similarly, continuation phase may
bacilli are best killed by RMP. Thus every case of have to be prolonged by 3 months for TB meningitis,
tuberculosis must be treated at least with these three miliary and spinal TB. There are studies to suggest that
drugs. The chances of naturally occurring mutants are 6 months therapy may be adequate in these situations
higher if the bacillary load is more and therefore, such as well. Yet, the group felt that the prolongation of the
cases need more drugs in intensive therapy, say as in continuation phase is justified in these situations as (a)
smear positive cases. the lesions may take longer to sterilize in such
As dividing time of TB bacilli is about 21 hours, all pathology, and (b) due to the risk of serious morbidity
the drugs are administered in such a way that they
associated with relapse.
achieve peak concentration all at one time so as to hit
Category II therapy utilizes all the first line drugs as
bacilli hard. The drug concentration is poor in caseum
it is used to treat relapsers, treatment defaulters and
and sequestrated tissue, so these should be removed
treatment failures who are more likely to have drug
surgically wherever feasible.
resistance. It is generally considered to add two drugs to
Mycobacterium tuberculosis when exposed to certain
concentration of most currently used anti-TB drugs in the failed regime till culture and drug sensitivity reports
vitro shows an inhibition of growth for 1 to several days. are available. However, this categorization can also mean
This suggests that the drugs can be effective even when addition of a single drug — Streptomycin — to a failed
used on an intermittent basis as a continuous high serum regime (say a Category I failure). Evidence suggests that
level of these drugs is not needed. This forms the basis most common drug resistance is limited to first line drugs
of intermittent therapy. While RCTs in children using singly or in combination and the multidrug resistance
thrice weekly regime are awaited, RCTs from adults as with bacilli resistant to at least INH and rifampicin is
well as observational studies including programatic data relatively uncommon (<5%). Therefore, except for
in all age groups have shown that intermittent thrice a multidrug resistance, this regime would work well for
week therapy with higher dose is as effective as daily most. Complete adherence to therapy being the key to
therapy with conventional dose and is an effective achieving cure and decreasing the chances of
alternative.24 However, intermittent therapy is not safe development of resistance, this is imperative that the
when self-administered, as there is no margin for any treating pediatrician makes all efforts to ensure
error in taking medications. The directly observed compliance. DOTS provide a great opportunity for the
therapy under DOTS takes care of the adherence issues same. Patients who are nonresponsive to a well-
and therefore uses thrice a week intermittent therapy. supervised Category II are likely to have MDR-TB and
should therefore be referred to an appropriate facility.
Antitubercular Therapy The above definition, categorization and duration of
therapy should be used for every child with TB whether
The appropriate management of tuberculosis requires
the patient is under individual care or under the program.
assessment of the patient correctly with respect to the
This protocol should form the current standard of care
site of disease, bacteriological status, treatment type of
patient and the severity of disease. These definitions are and should override all earlier recommendations.
detailed in Table 35.1. After appropriately defining the
disease, the patient is then categorized to receive Steroids in Tuberculosis
appropriate anti-TB therapy (Table 35.2). The drug Definite indications for concomitant steroid therapy
dosages are given in Table 35.3. include TBM and pericarditis. Steroids are routinely not
The Group agreed to include all children with indicated in lymphadenitis and pleural effusion. They
extensive pulmonary lesions (anything beyond the may be used in endobronchial tuberculosis or mediastinal
primary pulmonary complex) under Category I because compression syndrome due to tuberculosis, pleurisy with
of the evidence and experience that a significant severe distress and miliary disease with alveolocapillary
proportion of these turn out to be smear positive when block. Predinsone 2 to 4 mg/kg/day or its equivalent is
diligent efforts are made. It is only milder forms of the used for 2 to 4 weeks and then tapered over next 2 weeks.
disease, also more likely to be paucibacillary, such as
primary complex (mediastinal or hilar lymphadenitis Fixed Drug Combination (FDC)
with or without a parenchymal lesion, single site
peripheral lymphadenitis and unilateral pleural effusion These combinations contain 2 or more drugs in a single
that are treated as Category III.25 formulation and therefore simplify the prescription of
490
Table 35.1: Definitions for categorizing for treatment of pediatric TB
A. Case definitions for site

Pulmonary: Refers to disease involving lung parenchyma.
Extrapulmonary: Refers to disease involving sites other than lung parenchyma
Both pulmonary and extrapulmonary constitutes
Pulmonary extrapulmonary involving several sites is defined by most severe site.
B. Case definitions for severity
• Pulmonary TB Less severe Pulmonary TB

Severe Pulmonary TB • Primary Pulmonary Complex (PPC)
All other except PPC, e.g.
• Progressive primary disease
• Fibrocavitatory disease
• Miliary
Extrapulmonary TB
Severe extra Pulmonary TB Meningitis, Spinal or Bone or Less severe extra pulmonary TB
Peripheral joints • Single Lymph node site
Bilateral or extensive pleural effusion • Unilateral pleural effusion
Intestinal
Genitourinary
Peritonitis
Pericarditis
Adrenal glands
C. Case definition for bacteriology
Smear positive: Sputum / Gastric aspirate /BAL/any other tissue or fluid

Any sample positive for acid-fast bacilli on staining
Smear Negative: None positive
D. Type of patient as per history of previous ATT
New case : A patient who has had no previous ATT or for less than 4 weeks.
Relapse : Patient declared cured/completed therapy in past and has evidence of recurrence.
Treatment failure : Patient who fails to respond/deteriorates after 12 weeks of compliant intensive phase.
Treatment after default : A patient who has taken treatment for at least 4 weeks and comes after interruption of treatment
for 2 months and has active disease.
drugs. More importantly, they limit the risk of drug- CURRENT TRENDS IN CHEMOTHERAPY OF TB UNDER
resistant tuberculosis arising as a result of inappropriate REVISED NATIONAL TB
drug selection due to prescription errors or due to
omission of some drugs by the patient. FDC is patient Control Program (RNTCP)27,28
friendly but there are some relevant issues about them.
Bioavailability of liquid formulations is not dependable. TB is considered a global emergency and in countries
One of the problem with FDC is that it is “fixed” and like India, despite effective chemotherapy, control has
makes titration of individual drug dosage difficult. While not been achieved due to poor therapeutic practices.
the combination of rifampicin and INH as a single The emerging threat of poorly treatable rifampicin
formulation are still well accepted, the bioavailability of resistant TB warrants that the first line drugs be
individual components, particularly rifampicin, may be used appropriately to give them longevity in the
affected in other 3 or 4 drugs FDC formulations. It is armamentarium. RNTCP has evolved to take care of
reported that in most situations, blood levels of the drugs these problems by using DOTS strategy. This includes
are inadequate because of poor drug quality rather than quality diagnosis by sputum microscopy, supervised
poor absorption. 26 Currently, there are several drug therapy (thrice weekly visits in intensive phase
formulations available with varying combinations with followed by weekly visit to the clinic during
confusing and similar sounding brand names. This could continuation phase when one dose is administered
make the prescription not simplified but error prone. under supervision and two doses are given to the patient
FDCs from standard manufacturers with proven to be taken at home subsequently), regular drug supply,
bioavailability should only be used. patient tracking (progress to be monitored till end of
491
Table 35.2: Treatment categories and regimens for childhood tuberculosis
Category of treatment Type of patients TB treatment regimens

Intensive phase Continuation phase
Category I • New smear-positive pulmonary HRZE (2 mo) HR (4 mo)
Tuberculosis (PTB)
• New smear-negative severe
forms of PTB
• New severe forms* of
extrapulmonary TB
Category II • Smear-positive relapse, treatment SHRZE (2 mo)+ HRE (5 mo)
failure or treatment after default HRZE (1 mo)
• Cases who are smear negative but
considered to have relapse,
treatment failure or defaulted
Category III • Less severe forms of HRZ (2 mo) HR (4 mo)
pulmonary TB*
• Less severe forms of
extrapulmonary TB*
H = INH, R = Rifampicin, Z = Pyrazinamide, E = Ethambutol, S = Streptomycin
*Refer Table 35.1 for details of severity
• In patients with TB meningitis on Category I treatment, the four drugs used during the intensive phase can either be HRZE or
HRZS. The present evidence suggests that ethambutol can be used in children.
• Continuation phase of treatment in TB meningitis, miliary and spinal TB with neurological complications should be given for 6-7
months, extending the total duration of treatment to 8-9 months.
• Under Revised National Tuberculosis Program (RNTCP) all patients shall be covered under directly observed intermittent (thrice
weekly) therapy. While the supervised therapy is considered the most optimal treatment, this very same combination of drugs can
also be used on a daily basis, for a similar duration, in case the treatment is being given unsupervised. It is important to ensure
completion of treatment in every case put on treatment to prevent emergence of resistance, particularly to rifampicin.
Table 35.3: Antituberculous drugs, dosages and adverse effects
Drug (symbol) Daily dosages per Maximum per Intermittent Maximum per Major side
Kg body weight day dose (daily thrice weekly day dose effects
regime) dosage as under (intermittent
RNTCP per Kg regime)
body weight
Streptomycin (S) 15-20 mg 1000 mg 20 mg 1000 mg tinnitus
Rifampicin (R) 10 mg 600 mg 15 mg 600 mg hepatotoxicity
gastritis, flu
like illness
Isoniazid (H) 5-10 mg 300 mg 15 mg 600 mg peripheral
neuropathy,
hepatoxicity,
Pyrazinamide (Z) 30-35 mg 2000 mg 35 mg 2000 mg arthralgia,
hepatotoxicity,
Ethambutol (E) 20 mg 1000 mg 30 mg 1200 mg oculotoxicity
therapy) and administrative and political commitment. Chemoprophylaxis

Each patient on diagnosis has an entire box of drugs It is estimated that in developing countries the annual
allocated with his name on it, though not handed over, risk of tuberculosis infection in children is 2 to 5%.29 The
to ensure supervised uninterrupted therapy. The Indian estimated lifetime risk of developing tuberculosis disease
program is the first program in the world to provide for a young child infected with Mycobacterium tuberculosis
pediatric patient’s weight wise boxes for childhood TB as indicated by positive tuberculin test is about 10%.30
cases and the pediatricians should help their patients About 5% of those infected are likely to develop
in using these facilities. disease in the first year after infection and another 5% in
492
rest of their lifetime. These rates increase in HIV infected Paradoxical upgrading reaction (PUR)—worsening
individuals. Nearly 8 to 20% of the deaths caused by of lesion on treatment or appearance of new lesion is often
tuberculosis occurring in children.31 The age of the child seen in TB irrespective of their HIV coinfection. Immune
at acquisition of tuberculosis infection has a great effect reconstitution syndrome occurs in HIV infected
on the occurrence of tuberculosis disease. individuals on treatment with HAART.
Approximately 40% of infected children less than 1 Routine monitoring of liver transaminases in patients
year of age if left untreated develop radiologically on ATT is not recommended though hepatitis is the
commonest serious drug toxicity seen. As the anti-TB
significant lymphadenopathy or segmental lesions
drugs are hepatic enzyme inducers, asymptomatic
compared with 24% of children from 1 to 10 years and
biochemical derange-ment without increase in billirubin
16% of children from 11 to 15 years of age.32
level may be tolerated till the enzymes remain up to 5
Six months of chemopropylaxis is recommended for times the normal range. However, if patient develops
all under 6 years age contacts of an infectious case, jaundice or other signs of liver dysfunction during
irrespective of their BCG or nutritional status. PPD therapy, it’s prudent to stop ATT immediately
positive children over 6 years of age and who do not irrespective of enzyme levels. The drugs are withheld
have any evidence of active disease but are planned for till the serum bilirubin becomes normal and the enzymes
immunosuppressive therapy (e.g. children with also start touching the normal range. Although many
nephrotic syndrome, acute leukemias, etc) may also be patients with drug-induced hepatotoxicity can be
given the benefit of chemoprophylaxis. While there is successfully rechallenged, this is best done in a place
evidence that HR combination can make the prophylaxis where liver function can be carefully monitored. The
shorter (3 months) but the group does not recommend drugs should be reintroduced in sequential order starting
this due to the risk of misuse of rifampicin. with rifampicin, followed by isoniazid and then
pyrazinamide. We add the first drug and reassess for its
Follow-up During and After Completion of Treatment impact on liver enzymes. If the enzymes remain within
the acceptable range, then only the subsequent drugs are
With correct evaluation of type of patient, site and added in the given sequence every 5 to 7 days. Some
severity of disease and compliant treatment, one can
experts prefer building up the doses of each of the
anticipate clinical and radiological improvement over a
drug; starting with half the dose and then increasing
standard time frame. Symptoms of active disease such
to full dose after 3 to 4 days, and then adding the next
as fever, cough and loss of appetite usually disappear
drug in half the dose and continuing the same way till
within 2 to 4 weeks. Weight gain is evident only if active
all the drugs are reintroduced. Drugs causing severe
disease had resulted in loss of weight. Children often do
intolerance on reintroduction are best avoided and
not loose significant weight and so would not show
substituted with other drugs. If the period without drugs
weight gain even after successful treatment.
is likely to be prolonged, and the patient is sick and
The present evidence does not suggest any cost
requires treatment, at least two other drugs (e.g.
benefits of repeating X-ray chest at the end of intensive
streptomycin, ethambutol, floroquinolones) should be
phase, if the clinical improvement is on expected lines.
given until it is determined whether the offending drug
Few patients who have persistence of symptoms on
can be resumed. All patients who require alteration from
therapy will need investigations for bacteriological and
the standard regimen should be referred to experienced
radiological response. They should be given the benefit
pediatricians.
of extension of intensive phase by 4 weeks provided the
alternative diagnosis and comorbidities are ruled out. Efforts should be made to ensure drug adherence in
At the end of stipulated therapy, patient must be every patient. If the patient is under non-DOTS treatment,
shown to have achieved cure by demonstrating negative then the treating pediatrician should monitor adherence
bacteriology. A chest radiograph at the end of treatment to therapy and follow-up. At each visit a pill count or
is desirable to document the radiological status. This may prescription review should be done with the patient or
be helpful to diagnose any subsequent disease in this the caregiver. It is very important to realize that the
high-risk group. emergence of multidrug resistant TB (MDR-TB) is always
Repeat chest X-ray may sometimes be considered a man made problem and failure of the patient to
early in case of unanticipated clinical progress. In the complete the prescribed course completely and
presence of clinical improvement but radiological adequately is one of the major reasons. When you have
persistence of lesion, it is best to wait for radiological a patient who has returned after a break in therapy,
clearance over time, as it may not signify active disease. further management becomes difficult. Table 35.4 details
The patient should be followed up every 3 months for at the guidelines for treatment after a period of interruption
least one more year for a possible relapse. in therapy. Whenever treatment is interrupted for more
493
Table 35.4: Managing patients with interruptions in treatment
Duration of therapy Duration of interruption Decision

Up to 4 weeks <2 weeks Resume original regime
>2 weeks Reassess and start treatment again
4-8 weeks <2 weeks Resume original regime
2-8 weeks Extend intensive phase by 1 month more
>8 weeks Category II if diagnosis is still TB
>8 weeks <2 weeks Resume original regime
>2 weeks. Review • Continue same treatment if; no active disease.
activity • Category II therapy for active diseases.
than 2 weeks, the child should be reassessed clinically When to Consider HIV Testing
and radiologically, with bacteriological examination,
wherever possible. In all such cases the resumption of Clinical markers of HIV infection such as oral thrush,
treatment must be preceded by evaluation for activity chronic diarrhea, clubbing of nails, herpes infection,
and investigating the causes for nonadherence. The failure to thrive obviously demand HIV testing. Beside
pediatrician should not merely restart the treatment but these, history of HIV infection in parents and past history
also enable the completion of treatment by addressing of blood transfusion justifies HIV testing. In case,
issues related to nonadherence in the first instance. tuberculosis in a child does not respond as anticipated
Addressing issues like side effects of the therapy (real or to compliant treatment, HIV infection may be one of the
perceived), cost involved as well as educating about the causes. HIV testing may be considered especially if there
need for a complete treatment even after the symptoms is no other cause for poor response to treatment.
abate may help adherence. Both the child as well as the
caregivers must be involved in decision making for re- MANAGEMENT OF A NEONATE BORN TO A MOTHER
initiating treatment. WITH TUBERCULOSIS
Prophylactic INH is recommended for newborns born
Special Situations to mother with tuberculosis after ruling out congenital
When to Suspect MDR-TB tuberculosis. Modern chemotherapy is so efficacious that
separation of the mother and infant is no longer
It may be suspected prior to starting therapy in case of considered mandatory, once the mother’s therapy is
contact with proven MDR-TB. It is also likely in a child started. Separation should occur only if the mother is ill
who has had one or more courses of ATT in the past or enough to require hospitalization, if she has been or is
had been noncompliant with prescribed therapy. expected to become nonadherent to her treatment, or if
Persistence of positive sputum or symptoms she is infected with a drug resistant strain of M.
after extended intensive phase (3 months) in spite tuberculosis. INH therapy should be continued in the
of compliant therapy should alarm you to the possibility infant at least until the mother has been shown to be
of drug resistant TB and all necessary cultures should noninfectious (culture negative) for 3 months. The infant
be sent while the patient is put on Category II should receive INH for a total of 6 to 9 months.
therapy. The patients who are nonresponsive to a well- Vaccination with BCG appears to decrease the risk of
supervised Category II regime are likely to have MDR- tuberculosis in exposed infants, but the effect is variable.
TB and should therefore be referred to an appropriate The mother can continue to breastfeed the baby. The ATT
facility. excreted in the milk has no therapeutic or adverse effect
Multibacillary lesions are more likely to be drug on the baby. Appropriate cough hygiene should be
resistant than paucibacillary. HIV infection by itself does observed by the mother.
not predispose to MDR-TB but the MDR-TB prevalence
is higher in such cases due to several factors.
GAPS IN KNOWLEDGE
Malabsorption of anti-TB drugs in such patients may lead
to suboptimal concentration of drugs in spite of The group strongly identified the following key research
compliance. Due to frequent hospital visits, they may also areas which can provide answers to some of the
come in contact with MDR-TB. unresolved issues.
The treatment of MDR-TB should only be done by 1. Feasibility and utility of induced sputum in children.
experts. The details of the management of MDR-TB in 2. Tuberculin test and redefining cutoff values for
children are beyond the scope of this consensus diagnosis of infection with the different strengths and
guidelines. formulations available.
494
3. Role of GA in ambulatory setting. 9. Singh M, Moosa NV, Kumar L, et al. Role of gastric lavage
4. Role of Interferon gamma release assays in diagnosis and bronchoalveolar lavage in the bacteriological
and assessment of activity in children. diagnosis of childhood pulmonary tuberculosis. Indian
Pediatr 2000;37:947-51.
5. Possibility of shorter duration of ATT for CNS/ renal
10. Lobato MN, Loeffler AM, Furst K, et al. Detection of
and bone and joint TB by RCTs. Mycobacterium tuberculosis in gastric aspirates collected
Finally, in conclusion we submit that the current from children: Hospitalization is not necessary. Pediatrics
guidelines have been developed keeping in mind the 1998;102:e40.
earlier guidelines of IAP, the national program guidelines 11. Zar HJ, Hanslo D, Apolles P, et al. Induced sputum versus
and the International standard for TB care. We hope that gastric lavage for microbiological confirmation of
guidelines henceforth will form the basis of childhood pulmonary tuberculosis in infants and young children:
A prospective study. Lancet 2005;365:130-4.
TB management in the country in both public and private
12. Singh M, Moosa NV, Kumar L, et al. Role of gastric lavage
sectors.
and bronchoalveolar lavage in the bacteriological
diagnosis of childhood pulmonary tuberculosis. Indian
ACKNOWLEDGMENTS Pediatr 2000;37:947-51.
13. Ichhpujani RL, Agarwal SP, Chauhan LS. Diagnostic
YK Amdekar, Varinder Singh, Sushil K Kabra and GR
needs and status of new diagnostic tools for tuberculosis.
Sethi Following members attended the meeting(s): YK In: Agarwal SP, Chauhan LS (Eds). Tuberculosis control
Amdekar: Convenor; Varinder Singh, GR Sethi, Sushil in India. Directorate General of Health Services, Ministry
Kabra, Mahesh Babu, D Vijayasekaran, Joseph Mathews, of Health and Family Welfare, Government of India. New
RK Agarwal; President IAP 2008, Panna Choudhury: Delhi 2005;165-78.
President elect IAP 2008; and Rohit Agarwal: Secretary 14. Dheda K, Udwadia ZF, Hugget JF. Utility of antigen
General IAP 2008. specific interferon gamma assay for the management of
Funding: The meeting of the group was facilitated by tuberculosis Curr Opin Pulm Med 2005;11:195-202.
an academic grant from M/s Lupin Pharma. 15. Bianchi L, Galli L, Moriondo M, et al. Interferon-gamma
Conflict of interest: None of the members of the group release assay improves the diagnosis of tuberculosis in
have reported any conflict of interest in the current work children. Pediatr Infect Dis J 2009;28:510-4.
due to their existing or past association with the industry 16. Kampmann B, Whittaker E, Williams A, et al. Interferon
and other stakeholders (if any). gamma release assays do not identify more children with
active TB than TST. Eur Respir J 2009;33:1374-82.
17. Kabra SK, Lodha R, Seth V. Some current concepts on
REFERENCES childhood tuberculosis. Indian J Med Res 2004;120:387-
1. IAP Working Group. Treatment of childhood 97.
tuberculosis: Consensus statement of IAP working group. 18. Verma K, Kapila K. Aspiration cytology for diagnosis of
Indian Pediatr 1997;34:1093-7. tuberculosis—perspectives in India. Indian J Pediatr
2. IAP Working Group. Consensus statement of IAP 2002;69 Suppl 1:S39-43.
Working Group: Status report on diagnosis of childhood 19. Sharma M, Agarwal S, Wadhwa N, et al. Spectrum of
tuberculosis. Indian Pediatr 2004; 41:146-55. cytomorphology of tuberculous lymphadenitis and
3. Management of Pediatric Tuberculosis under the Revised changes during anti-tubercular treatment. Cytopathology
National Tuberculosis Control Program (RNTCP). A joint 2007;18:180-3.
statement of the Central TB Division, Directorate General 20. El Jahiri Y, Chellak S, Garcia C, et al. The usefulness of
of Health Services, Ministry of Health and Family adenosine deaminase determination in biological fluids
Welfare, and experts from Indian Academy of Pediatrics. for tuberculosis diagnosis Ann Biol Clin 2006:64;117-24.
Indian Pediatr 2004;41:901-5. 21. Kaur A, Basha A, Ranjan M, et al. Poor diagnostic value
4. Chadha VK. Tuberculin test. Indian J Pediatr 2001;68:53-8. of adenosine deaminase in pleural, peritoneal and
5. Araujo Z, de Waard JH, de Larrea CF, et al. The effect of cerebrospinal fluids in tuberculosis. Indian J Med Res
Bacille Calmette-Guérin vaccine on tuberculin reactivity 1992;95:270-7.
in indigenous children from communities with high
22. Gambhir IS, Mehta M, Singh DS, et al. Evaluation of CSF-
prevalence of tuberculosis. Vaccine 2008;16:26:5575-81.
adenosine deaminase activity in tubercular meningitis. J
6. Wang L, Turner MO, Elwood RK, et al. A meta-analysis
Assoc Physicians India 1999;47:192-4.
of the effect of bacille Calmette Guérin vaccination on
23. Jain R, Sawhney S, Bhargava DK, et al. Diagnosis of
tuberculin skin test measurements. Thorax 2002;57:804-9.
7. Singla M, Sahai V, Sodhi S, et al. BCG skin reaction in abdominal tuberculosis: Sonographic findings in patients
mantoux negative healthy children. BMC Infect Dis 2005; with early disease AJR 1995;165:1391-5.
5: 19-20. 24. Mwandumba HC, Squire SB. Fully intermittent dosing
8. Somu N, Swaminathan S, Paramasivan CN, et al. Value with drugs for treating tuberculosis in adults. Cochrane
of bronchoalveolar lavage and gastric lavage in the Database Syst Rev 2001;(4):CD000970
diagnosis of pulmonary tuberculosis in children. Tuber 25. Kabra SK, Lodha R. Seth V. Category based treatment of
Lung Dis 1995;76:295-9. tuberculosis in children Indian Pediatr 2004;41:927-37.
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26. Blomberg B, Spinaci S, Fourie B, et al. The rationale for 29. Chugh S. Paediatric tuberculosis and DOTS strategy
recommending fixed-dose combination tablets for under RNTCP. J Indian Med Assoc 2008;106:799-802.
treatment of tuberculosis. Bull WHO 2001;79:61-8. 30. Enarson DA. The International Union Against
27. Kumar P. Journey of tuberculosis control movement in Tuberculosis and Lung Disease Model National
India: National tuberculosis control program to revised Tuberculosis Programmes. Tuber Lung Dis 1995;76:95-9.
national tuberculosis control program Indian J Tuberc 31. Comstock GW, Livesay VT, Woolpert SF. The prognosis
2005;S2:63-71. of a positive tuberculin reaction in childhood and
adolescence. Am J Epidemiol 1974;99:131-8.
28. Kelkar-Khambate A, Klelmann K, Pawar S, et al. India’s
32. Munoz FM, Starke JR. Tuberculosis in children. In:
Revised National Tuberculosis Control Program:
Reichman LB, Hershfield ES, editors. Tuberculosis: A
Looking beyond detection and cure. Int J Tuberc Lung Comprehensive International Approach: NewYork.
Dis 2008;12:87-92. Marcell Dekker Inc 2000;553-95.
ANNEXURE
Tuberculin Test After a successful injection the needle is removed

without massaging or pressing the area. Sometimes there
Purified protein derivative (PPD) solution must be kept may be minor bleeding which can be dabbed with a 2x2
refrigerated at 2 to 8°C and to avoid fluctuations in gauze pad or cotton ball till oozing of blood stops. There
temperature, never store in the refrigerator door. The vial is no need to cover the site with an adhesive bandage.
should be discarded if it has been open for more than 30 The patient can get mild itching, swelling, or irritation
days or the expiration date has passed. Select a well-lit which is normal and usually goes away within 1 week.
area for administering the test. The patient is advised to avoid scratching the site,
keeping the site clean and dry and is also advised to
Administration of Skin Test return within 48 to 72 hours for reading of the test result.
The patient’s forearm is exposed with the palm-side-up
and slightly flexed at the elbow. The injection is to be Reading the Mantoux Tuberculin Skin Test
given about 2 to 4 inches below the elbow avoiding areas The site of injection on the forearm of the patient is
of skin with veins, sores, rashes, scars, or excess hair. located. The fingernails of the reader should be short and
Using standard precautions for injection safety. should not extend beyond the fingertip. The induration
The injection site is cleaned with alcohol swab, using may not always be visible, Therefore palpation of the
circular motion beginning in the center and working the area with fingertips to determine induration at the
way outward. injection site is needed. The area is touched lightly with
The 1 ml tuberculin syringe is loaded with PPD just the pads of fingertips and the fingertips are lightly swept
prior to administration ensuring that all air and excess in 2-inch diameters from the injection site in all four
solution is expelled from the syringe, leaving exactly 0.1 directions to locate the edges of the induration.
ml of tuberculin solution in the syringe. Alternatively, one can use a zig-zag feather-like touch to
The skin is stretched taut over the injection site to palpate the area for margins of induration. Some times a
provide a surface that is easy for the needle to penetrate. margin of induration may be confused with a margin of
The syringe is held between thumb and index finger with
muscle on the forearm. In such a case a repeat palpation
the needle bevel facing up and the syringe parallel to the
with the patient’s arm raised to a 45° angle is done.
forearm. With the needle against the patient’s skin, the
Once the outer edge of the induration is reached rest
needle is inserted slowly at a 5 to 15° angle, just below
one fingertip firmly against the induration margin on one
the surface of the skin (one should be able to see the bevel
side before marking the margin. The fingertip should
of the needle just below the skin surface). Once the bevel
remain in contact with the skin at all times. A ball point
of the needle has fully entered just beneath the superficial
pen is used to mark the margin lightly with a fine dot at
most part of the skin, the stretched skin is released
the widest edge of the induration. The procedure is
holding the syringe in place. The tuberculin solution is
reported on the opposite margin on the other side of the
then injected slowly forming a 6 to 10 mm wheal (pale,
induration. It is ensured that the induration was marked
raised area with distinct edges; has orange peel
correctly by a repeat palpation. If needed, the dots are
appearance and does not disappear immediately). If no
wheal forms or if it is less than 6 mm in diameter, the test altered on repeat measurement.
should be repeated about 2 inches from the original site Alternatively, the induration may be detected by the
or on the opposite arm. Ball point method. In this technique, a medium-point
496
ballpoint pen is used to draw a line starting 1 to 2 cm should not be measured. Reactions to the tuberculin skin
away from the skin reaction and moving toward its test at the injection site vary and if there is blistering, the
center. When the pen reaches the margin of the induration should be palpated gently as it may be painful.
induration, an increased resistance to further movement Sometimes the margins are not equally clear all the way
is felt and the pen is lifted. The procedure is repeated on around the induration but it is still necessary to mark
the opposite side of the skin reaction. The distance the margins on each side of the induration. For irregular
margins of induration, mark and measure the longest
between the ends of the opposing lines at the margins of
diameter across the forearm. The exact measurement in
the induration is measured.
millimeters of induration should be recorded and not the
Usually, a millimeter ruler is used to measure the interpretation of the results as positive or negative along
widest diameter of the induration perpendicular to the with the date and time the test was read. If there is no
long axis of the forearm. Only the margins of the induration, this measurement should be recorded as 0
induration are relevant for measurement and the redness mm of induration.
36 Drug-resistant Tuberculosis
in Children
36.1 DRUG-RESISTANT TUBERCULOSIS

HS Schaaf, PR Donald
THE DEVELOPMENT OF DRUG-RESISTANCE AND SM treatment. SM-resistance develops within 2 to 3

DISCOVERY OF BASIC PRINCIPLES OF DRUG-RESISTANT months of SM treatment in patients with cavitary
TUBERCULOSIS pulmonary TB and further treatment with SM is unlikely
to be effective. Hence SM-resistant strains could be a
Streptomycin (SM) and para-aminosalicylic acid (PAS) public health risk.7 They also found that patients with
were the first antituberculosis drugs to be discovered in cavitary pulmonory TB were far more likely than
the early 1940s. Although PAS was the first used in noncavitary pulmonary TB patients to develop resistance,
treating a patient, SM was the drug with the most which was due to higher bacillary load and therefore
promise, showing the best clinical response. Resistance more naturally resistant mutant strains in cavitary
of Mycobacterium tuberculosis (M. tuberculosis) emerged disease.8,9
soon after in vivo and in vitro exposure to SM.1 The first documented cases of transmission of SM-
The finding that a small number of tubercle bacilli resistant M. tuberculosis occurred in 3 health care workers.
were resistant to SM in the sputa of patients who had In 1949, a nurse working with SM treated patients
tuberculosis but had not received any previous contracted TB and the M. tuberculosis strain recovered
chemotherapy. They also had probably not been in from her sputum was resistant to 1000 μg/ml on original
contact with other patients who previously had isolation.10 Two further cases of primary (i.e. no previous
chemotherapy with SM. This led to the conclusion that treatment with antituberculosis drugs) SM-resistant
“any large number of tubercle bacilli may be expected to pulmonary TB in health care workers were described
contain organisms which are relatively resistant to SM during the same year.11,12 These cases highlighted the
without having been exposed to the drug”.2 This was public health risk of drug-resistant TB.
confirmed by the presence of naturally resistant The first child known to present with drug-resistant
organisms in stock cultures of the control M. tuberculosis TB was an 11-week-old infant diagnosed with SM-
strain H37RV.3,4 SM-resistance gradually increased (both resistant miliary TB in 1948. 13 The mother was
number of resistant organisms and degree of resistance) diagnosed with TB when the infant was aged 2 weeks
in patients within 4 weeks of starting monotherapy but and they were immediately separated. Neither of them
only became predominantly resistant at 6 to 13 weeks.2 had received previous SM-treatment. Primary SM-
SM did not cause resistance, but caused selective growth resistance could not be confirmed because no isolate
of the resistant organisms. Once the organism was was obtained from the mother. This case confirmed the
resistant to SM, resistance remained.5,6 In these early days desirability of doing drug-susceptibility tests on all
it was already concluded that SM-resistance was an diagnostic cultures obtained from new TB patients.
inherited genetic change, a conclusion which later proved
to be correct.2 Early Solutions to Prevent Development of
British Medical Research Council (MRC) studies with Drug-resistance
SM monotherapy for TB showed that therapeutic results
were related to the degree of drug-resistance that Drug-resistance was perceived as an important problem
developed. In 35 of 41 patients in whom data was and possible solutions were sought, one of which was to
available, resistance was >10 to 2000 times that of the use more than one drug in the treatment of TB. Patients
original strain of the patients or control (H37RV) strain. receiving PAS also showed considerable improvement
The researchers concluded that emergence of SM- compared to a placebo control group.14 Further studies
resistance may be prevented by adding another drug to showed that PAS and SM had a synergistic effect when
498
given together, if the strain was not resistant to SM,15,16 in treatment studies and in every case drug-resistance
and this regimen showed a substantial reduction in the developed, often within one month of starting single drug
development of drug-resistance in the treatment of therapy.
pulmonary TB.17,18 However, a high dose of PAS was Important lessons on the development of drug-
needed, causing severe gastrointestinal adverse effects, resistance became clear from well performed studies by the
which eventually led to abandonment of PAS in most British Medical Research Council (MRC). Antituberculosis
regimens. An interesting observation was that resistance drugs should not be used alone in the treatment of
to PAS took much longer to develop than with SM pulmonary tuberculosis; Treatment regimens should
(22-26 weeks).16,19 include 2 drugs to which the organism is susceptible,
implying that drug susceptibility tests should be done at
New Drugs and Further Problems diagnosis before starting treatment. If this was not done,
inadvertent monotherapy can result, which will lead to
Thomas et al20 documented the first case of primary resistance developing to that drug as well, and; Taking a
polydrug-resistant TB with resistance to both SM and history of previous antituberculosis treatment before compiling a
PAS (Box 36.1.1). In 1952, isoniazid (INH) was introduced treatment regimen could be of great value as culture and drug
for the treatment of TB. In the series of Thomas et al20 susceptibility test (DST) results are not always available. A
two patients developed resistance to INH while on a two- history of previous treatment with any (single) drug or
drug regimen (including INH), but the strain was already contact with a previously treated source case with known
resistant to one drug before treatment started. Adding DST results may be a guide in making the correct choice of
one drug to a failing regimen was then already confirmed treatment.22,23
to be bad practice.
Several other antituberculosis agents were developed Bacillary Populations and Drug-resistance
during the period mid-1940s to mid-1960s, including
Resistance is a phenomenon linked to large bacillary load.
rifampicin (RMP), the last official current first-line
antituberculosis drug discovered in 1965.21 Despite the fact The largest number of bacilli are found in pulmonary TB
that it was clearly shown early on that a combination of cavities (approximately 107 to 109 bacilli), while those
drugs was needed to prevent the development of drug- found in caseous foci, such as in some forms of
resistance to a drug, every drug was used as monotherapy extrapulmonary TB or primary TB in children, usually
do not exceed 102 to 104 bacilli.24 Wild type strains of M.
tuberculosis do contain a few resistant mutants for almost
Box 36.1.1: Definitions in drug-resistant tuberculosis all drugs among 106 bacilli.24 Spontaneous mutations
• Monodrug-resistance: M. tuberculosis isolate resistant to one vary in number for different drugs with rifampicin the
first-line antituberculosis drug highest at about 1 in 108, INH at 1 in 106 and ethambutol
• Polydrug-resistance: M. tuberculosis isolate resistant to two or at 1 in 104 bacilli. Second-line drugs usually have a higher
more first-line antituberculosis drugs, but not both isoniazid spontaneous mutation rate than first-line drugs, which
and rifampicin (previously called multiple drug-resistance) makes it even more important to use an adequate
• Multidrug-resistance: M. tuberculosis isolate resistant to at combination of drugs to prevent the development of
least isoniazid and rifampicin further drug-resistance.
• Extensive drug-resistance: M. tuberculosis isolate resistant to Both the bacillary load and the possible presence of
at least isoniazid, rifampicin, the fluoroquinolones and resistant mutants have important treatment implications.
a second-line injectable drug (amikacin, kanamycin or
In latent TB infection, with low numbers of bacilli, there is
capreomycin)
• Pre-extensive drug-resistance: M. tuberculosis isolate resistant an almost negligible chance of eliciting resistance by using
to at least isoniazid and rifampicin plus resistance either to INH as single drug preventive treatment.24 An important
the fluoroquinolones or a second-line injectable drug (amikacin, question at the time was whether an intensive phase of
kanamycin or capreomycin). Not an official definition, but treatment with multiple antituberculosis drugs and a
mentioned in articles continuation phase with fewer drugs for a longer period
• Primary drug-resistance: Resistance found in patients not would be sufficient treatment and still prevent emergence
previously treated for tuberculosis of resistance.24 The rationale behind this was that the
• New drug-resistance: No previous antituberculosis treatment majority of the bacilli are killed with the initial multidrug
or previous treatment for < 1 month. Often used instead of
treatment, and the low number of remaining bacilli would
primary drug-resistance
• Acquired drug-resistance: Resistance that developed in patients have a low-risk for the development of resistance during
previously treated for tuberculosis the continuation phase. This principle was confirmed in
• Previously treated drug-resistance: Previously treated for TB the first International Union against TB trial and is now
for > 1 month—often used istead of acquired drug-resistance. current treatment practice.25
499
Chapter 36 Drug-resistant Tuberculosis in Children
Early Epidemiology and Drug-resistance Surveillance Steiner et al 36 investigated transmission by comparing

DST results found in adult-child contact pairs. They
In several large, mostly hospital-based, surveys in the
confirmed a high rate of concordance with 14 of 15
United States in the early 1950s the incidence of primary
INH-resistant strains (93%) from adult-child pairs and
drug-resistance was low (1.6-2.6% for SM and INH).26,27
20 of 29 (69%) adult-child pairs with any drug-resistance
However, in previously treated patients, today a well
showing identical DST results.36 This was followed many
recognized risk factor for drug-resistant TB, SM-
years later by a study from South Africa showing that 18
resistance was 20.4%.26 Several experts thought that
of 22 MDR strains (82%) obtained from adult-child pairs
primary drug-resistance was not a public health risk
had identical DSTs.37 Transmission was confirmed in a
except maybe in institutions, because multidrug
prospective study by identical restriction fragment length
treatment regimens would reduce the number of drug-
polymorphism (RFLP) analyses in 5 of 6 adult-child pair
resistant cases developing.28,29 However, in the United
M. tuberculosis isolates in a prospective study.38
Kingdom (UK) the prevalence of primary drug-resistance
to one or more of the commonly used drugs was 5.1%
(95% confidence interval: 4.1-6.5%) with SM-resistance Cause of Drug-resistance
at 2.3%, PAS at 2.2%, and INH at 0.7%, which experts Although M. tuberculosis organisms have spontaneous
interpreted as a possible public health problem of natural mutations causing resistance to individual drugs,
importance.30 This led to the introduction of three-drug drug-resistant TB is mainly a man-made disease. Poor
regimens for tuberculosis treatment 1956–1959 in the management of drug-susceptible or drug-resistant TB
UK.30 Drug-resistance was already a worldwide problem cases will lead to development of resistance or further
in 1957, with primary drug-resistance at 6.5% and resistance, for example, prescribing poor regimens (e.g.
acquired (previously treated tuberculosis) at 42% in a adding a single drug to a failing regimen or prescribing
hospital-based study covering several countries.31 With a weak combination of drugs), interruption of treatment
the development of multidrug treatment regimens and because of drug supplies not being available, using drugs
especially short-course chemotherapy after the discovery with poor bioavailability of components such as
that RMP and pyrazinamide (PZA) were good sterilizing rifampicin and poor adherence to antituberculosis
drugs, scientific interest in drug-resistant TB waned treatment by patients and health systems.
despite warnings from eminent TB researchers such as Once patients (mainly adults) have developed drug-
Canetti.24 resistant TB, poor management of cases may lead to
transmission of drug-resistant M. tuberculosis strains
Infectiousness of Drug-resistant (primary or new drug-resistance). In many high-burden
M. Tuberculosis Strains TB countries new TB cases are diagnosed by sputum
smear microscopy only:
The infectiousness and the risk of developing disease
i. Measures should be in place to identify drug-
after infection with INH-resistant and therefore probably
resistant cases early by doing culture and DST on
also multidrug-resistant (MDR) strains of M. tuberculosis
sputum of patients who have a known drug-
has long been a point of discussion. MDR-TB is defined
resistant source case.
as resistant to the two most potent anti-TB drugs viz.
ii. Patients not responding to treatment (smear or
isoniazid (H) and rifampicin (R). Some investigators
culture-positive at 2 to 3 months or at end of
found these strains to be less infectious than drug-
treatment, latter called treatment failure).
susceptible strains, but in practice new (no previous
iii. Any patient with relapse or retreatment TB and, as
antituberculosis treatment or treatment for <1 month)
recently recommended by the WHO.
INH-resistant TB in children soon followed the develop-
iv. Patients with HIV infection.39
ment of INH-resistant TB in adults in the early 1950s.
Poor infection control measures especially in health
The prevalence of INH-resistant TB in children and adults
care settings but also in other institutions such as prisons
identified from the same area was approximately the
are a further preventable cause of transmission of drug-
same and the rapid rise of drug-resistant TB among
resistant TB.
adults in New York City during 1985-95 was soon
followed by a similar trend in children.32,33 In a landmark
Epidemiology of Drug-resistant Tuberculosis
study Snider et al found that the infection rate amongst
children was similar or higher in children in contact with Despite effective antituberculosis treatment regimens, a
isoniazid-resistant source cases compared to drug- dramatic worldwide increase in the incidence of TB
susceptible source cases.34 A study from South Africa occurred during the late 1980s. This was mainly due
confirmed this finding with similar infection rates in to the growing epidemic of HIV infection, now known
childhood contacts of adults with drug-susceptible (48% as the most potent facilitator of TB disease after infection.
infection) and MDR pulmonary TB (64% infection).35 Outbreaks of MDR-TB with high mortality, originally
500
described in HIV-infected persons, were responsible for Molecular epidemiology has added a new dimension
refocusing the attention of developed countries on TB.40 to tuberculosis. RFLP analysis is used to confirm
Drug-resistant TB has always been a global problem and transmission 38 and spoligotyping has been used to
developing countries had higher rates of primary identify strains of M. tuberculosis to see whether any
and acquired resistance than developed countries.41 particular strain is more often associated with drug-
MDR-TB was, however, mainly a problem in countries resistant tuberculosis. The W-Beijing strain and in some
making use of the more expensive RMP-containing short- instances the Haarlem strain have been implicated in
course chemotherapy regimens. This was reflected in drug-resistant TB although this has not been a constant
data from several global reviews of drug-resistance finding.47
surveillance.42-44
The increase in MDR-TB led to drastic measures Human Immunodeficiency Virus and
including second-line drug regimens for MDR-TB, Drug-resistant TB
upgrading of TB health services including directly
observed therapy, and improved infection control Although HIV infection was associated with an increase
measures in developed countries, effectively reducing the in drug-resistance in some studies, mainly from
numbers of MDR-TB in these countries. However, developing countries, this was not the case in several
worldwide MDR-TB numbers have increased. In the 2006 other studies, specifically from Africa, where the
worldwide WHO survey (data from 116 countries) of incidence of HIV is extremely high. A large childhood
drug-resistant TB, it was estimated that any resistance survey also found no significant difference between HIV-
occurred in approximately 20.0%, INH resistance in infected and HIV-uninfected children with drug-resistant
13.3% and MDR-TB in 5.3% of all TB cases annually. TB.46 Monoresistance to RMP is generally rare,42,48 but
The total number of MDR cases were estimated at recently it was noted that mono-resistance to RMP was
approximately 490,000 per year. Fifty percent of these on the increase and RFLP analysis found the strains to
MDR-TB cases are from China and India with the Russian be of independent origin.48 Most of these strains were
Federation contributing a further 7%.39 obtained from HIV-infected patients, and one of the
In 2006, the term extensive drug-resistant (XDR)- possible explanations was selective malabsorption of
TB was coined and the definition finalized, i.e. M. RMP in some HIV-infected patients, or poor protection
tuberculosis isolate resistant to at least isoniazid, of RMP by low levels of INH in patients who are fast
rifampicin, the fluoroquinolones and a second-line acetylators of INH receiving once or twice a week
injectable drug (amikacin, kanamycin or capreomycin). therapy.
Although extensively resistant cases were known to
occur long before 2006, focus was placed on this
Diagnosis of Drug-resistant Tuberculosis in Children
condition following a 98% mortality in 53 mainly HIV- The diagnosis of drug-resistant tuberculosis is primarily
infected patients in KwaZulu-Natal, South Africa.45 a microbiological diagnosis, confirmed only if the M.
This led to a worldwide search for XDR-TB patients tuberculosis organism can be retrieved from the patient
and according to WHO, XDR-TB cases have already and DST or genetic mutation analysis done on the
been diagnosed in all regions of the world with isolate. Child contacts of infectious pulmonary TB cases
between 2 and 19% of MDR-TB strains in 49 countries with microbiologically confirmed drug-resistant TB
having XDR-TB.39 most likely will be infected with the same strain and
The incidence or prevalence of drug-resistant TB in therefore, if they develop TB, will have probable drug-
children is not well documented, as a microbiological resistant TB. 37,38,49 Drug-resistant TB should also be
diagnosis of TB in children is more difficult. However, suspected in children if, disease becomes worse on
Steiner et al published several 4-year surveys of drug- adherent first-line antituberculosis treatment. This is
resistance in children from a New York hospital from particularly so amongst those having contact with adult
1960 to 1992, showing an increase in the prevalence of TB cases, with unknown DST results, who failed TB
resistance and the development of MDR-TB after the treatment. Further there is history of previous TB
introduction of RMP.32,33 A number of mainly hospital- treatment or an adult has died while on TB treatment.
based surveys of drug-resistant TB in children from Such children need cultures and DST done. According
several countries have been published in the past two to the WHO 2008 guidance for drug-resistant TB update,
decades. In South Africa, follow-up surveys in one region all HIV-infected TB patients should also have culture
showed a rising trend in MDR-TB in children.46 More and DST done.39
studies are needed in children, because drug-resistance Drug-resistant TB is not a clinical or radiological
in isolates obtained from children are a good indicator diagnosis, as several studies50,51 showed no difference
of currently circulating strains in the community. between clinical findings or radiological features in drug-
501
susceptible and drug-resistant cases. Other than mycobacteria from culture. The underlying principle
obtaining specimens for culture of M. tuberculosis from involves multiplex amplification of extracted myco-
every possible source in a child with suspected drug- bacterial DNA by PCR, with subsequent hybridization
resistant TB, the most important part of the evaluation is of the biotin labelled amplicons to oligonucleotide probes
the history of contact with infectious TB cases and previous bound to a membrane strip (also called line-probe tests).
TB treatment in both the child and the source case, as this is This test can at the same time identify the majority of
important information in building a treatment regimen for RMP and INH resistance—identification is done by
the child. Schaaf et al50 have emphasized that previous evaluation of the resultant banding pattern. The kits
antituberculosis treatment in the child is a risk factor for have been shown to have excellent correlation with
drug-resistant TB, not because the child developed drug- conventional methods, usually over 95%.54
resistance because of poor management but because
drug-resistant TB was initially missed due to an Management of Drug-resistant Tuberculosis
incomplete history of contact or culture and DST was The basic principles of the management of adult and
not initially done.46,52 childhood drug-resistant TB are the same. However,
because children often have paucibacillary disease, some
Confirmatory Tests for Drug-resistant TB aspects of management may differ. Fewer drugs and
shorter duration of treatment may be sufficient in
The conventional way of diagnosing drug-resistance is
children with early primary disease. Children will more
by culture and DST. Conventional methods such as
often receive drug-resistant treatment without it being
indirect proportion method on solid media (agar plate
microbiologically confirmed because of known contact
or Löwenstein-Jensen media) are less expensive but slow
with an adult drug-resistant TB case. Some of the
and can take up to 6 weeks. Culture is first done and
important principles are as follows:55
culture growth is then subcultured on drug-containing
• Never add one drug to a failing regimen
and drug-free media. Growth of >1% on the drug-
• Give directly observed treatment with daily treatment only
containing medium confirms drug-resistance to that drug
(not intermittent treatment)
at the specific concentration of the drug used in the
• Be guided by the adult source case’s isolate DST result
culture medium. Lately, more rapid DST methods using
if no M. tuberculosis isolate is obtained from the child
semi-automated radiometric (e.g. BACTEC 460 TB
• If resistance to INH and/or RMP is found, do second-
system) or automated fluorescence [e.g. BACTEC MGIT
line DST
(Mycobacterial Growth Indicator Tube) 960 system]
• Give 3 or preferably more drugs to which the isolate
liquid broth are more often used. These systems are much
from patient or adult source case is susceptible or
more expensive, but can give results within 10 to 14 days
when there is no history of previous antituberculosis
after a positive culture has been obtained. Because of the
drug therapy
risk of infectiousness and the risk of acquiring further
• Use drugs from the different drug groups (as defined
drug-resistance with incorrect treatment regimens, there
by WHO—see Table 36.1.1) and be aware of possible
is a strong drive for development of more rapid
cross-resistance between drugs
diagnostic methods for drug-resistance. Currently under
• Support the caregivers by counseling about adverse
investigation is the Microscopic Observed Drug
effects, treatment duration and importance of
Susceptibility (MODS) assay, where culture and DST is
adherence at every follow-up visit
performed at the same time. Daily examination of wells
• Clinical, radiological and culture response to
for mycobacterial growth by inverted microscopic
treatment should be carefully monitored
observation, may give both confirmatory culture result
• Although the optimal duration of treatment for MDR
and DST results within 7 to 10 days.53 This method is
and XDR-TB is not known, a minimum of 18 months
being field tested and holds much promise.
after the first negative culture is usually recom-
Genotypic evaluation tests used either for detection
mended. In children with early primary disease this
of M. tuberculosis directly from clinical samples or for
could probably be less.
identification of mycobacteria from culture, currently
hold the biggest promise in the diagnosis of drug-
resistant TB. The major advantages of the nucleic-acid Treatment of INH-Monoresistant TB
based assays are speed and ease of interpretation. The
tests are still expensive and laboratory infrastructure is If INH resistance is diagnosed before the onset of
needed. The GenoType MDR-TB Plus (Hain Lifesciences, treatment and the child has primary disease, a 2-month
Nehren, Germany) is probably the best known of intensive phase of rifampicin (RMP), ethambutol (EMB)
these tests. The kit can be used to detect M. tuberculosis and pyrazinamide (PZA) and a 7-month continuation
directly from clinical samples, or for identification of phase of RMP and EMB should be sufficient. However,
502
Table 36.1.1: Drug groups for MDR and XDR-TB treatment regimens
Drug Group Drug name Daily dosage Maximum dose
(mg/kg) (mg)
a
Group 1: Oral first-line drugs Ethambutol 20-25 2000
to which the organism shows Pyrazinamide 25-35 2000
in vitro susceptibility by DST
b
Group 2: Second-line injectable Amikacin 15-22.5 1000
agents (streptomycin is first-line Kanamycin 15-30 1000
drug–not for use in MDR/XDR-TB Capreomycin 15-30 1000
b
Group 3: Fluoroquinolones Ofloxacin 15-20 800
Levofloxacin 7.5-10 750
Moxifloxacin 7.5-10 400
c
Group 4: Second-line oral Ethionamide 15-20 1000
bacteriostatic agents (or prothionamide) 15-20 1000
Cycloserine 10-20 1000
(or terizidone) 10-20 1000
Para-aminosalicylic 150 12g
acid (PAS)
d
Group 5: Drugs of unclear High-dose INH 15-20 400
use in drug-rsistant TB treatment Linezolid 10-12 twice daily 600 twice daily
Amoxicillin/clavulanate 30-40 amoxicillin
Clarithromycin 7.5-15 twice daily 500 twice daily
Thiacetazone 3-4 (only IV) 150
Imipenem/cilastatin
a
Cannot rely on DST—use as additional drug if DST result susceptible or not done.
b
Choose one drug in each of these groups; amikacin preferred to kanamycin in children.
c
Choose one or more of these drugs to make up total of 4 new drugs.
d
Consider use of these drugs if insufficient drugs to build an acceptable regimen with previous groups. Linezolid dosage for
TB is still uncertain. Thiacetazone should NOT be used in HIV-infected patients.
once this treatment regimen fails or the INH resistance in case with minimal disease. Four active drugs
is diagnosed long after the start of therapy, 2 or more (additional drugs from group 4) need to be given in
drugs, preferably including a fluoroquinolone should advanced disease. The duration of treatment is 12 to 18
be added as further resistance could have developed. months depending on extent of disease whether RMP or
The continuation phase should also be prolonged. PZA susceptibility remains. Either of these latter drugs
is given throughout the treatment course.
Treatment of RMP-Monoresistant TB
Treatment of MDR and XDR-TB
First and foremost is to determine whether there is no
contact history of MDR-TB and to ensure that DST results If either the child or the source case had previous
are correct. Many experts will still treat these patients as treatment with pyrazinamide and/or ethambutol for >1
MDR-TB, with the addition of INH, ethambutol, a month, the remaining first-line drugs (group 1, Table
fluoroquinolone, pyrazinamide with/without an 36.1.1) could be used if DST shows susceptibility.
aminoglycoside. Some second-line drugs may have to However, because of unreliability of the DST for these
be added taking into account the extent or type of disease drugs, they would count only as additional drugs. In
for 12 to 18 months. children with early primary (not extensive or disse-
minated) TB, 3 bactericidal drugs should be sufficient,
more extensive disease, four or more active drugs should
Treatment of Polydrug-resistant TB39
be included in the regimen—one drug each from groups
All available oral first-line drugs (group 1, Table 36.1.1) 2 and 3, and one or more drugs from group 4. If these
together with other preferably bactericidal drugs (groups groups are not sufficient to build an acceptable regimen
2 and 3) to make up a minimum of 3 active drugs required of 4 active drugs, drugs from group 5 could be added.39
503
INH at a high-dose, especially when given in hydrocephalus and some other, need surgery the same
combination with ethionamide, may be beneficial as for drug-susceptible cases.
depending on which mutation causes INH resistance, the Resectional (pulmonary) surgery has proven to be a
child may have low-level INH resistance, but could then useful component of the management of MDR-TB in
be resistant to ethionamide. Studies have shown low- adults infected with strains resistant to most drugs.58,59
level INH resistance in 80% children with INH-resistant Surgery remains an important adjunct to medical therapy
TB.56 Further, in an adult randomized controlled trial, especially in cases not responding to adherent adequate
the addition of high-dose INH to a MDR-TB treatment MDR-TB treatment regimens, with mainly localized
regimen, compared with normal dose (5 mg/kg daily) disease and the remaining lung tissue should be relatively
or no INH, found earlier sputum conversion and free of disease. These procedures are not without
improvement in chest radiographs in the high-dose INH complications, and stump breakdown with broncho-
study group.57 pleural fistulas, empyemas, bleeding and even death may
Treatment duration for MDR and XDR-TB in children
occur, therefore, patients should be carefully selected.
should also be 18 months after the first negative culture,
as in adults, with cultures being done at least monthly
Adverse Effects of Second-line Antituberculosis Drugs
until it becomes negative. Thereafter cultures could be
done 2-monthly until the end of treatment. Early primary Second-line antituberculosis drugs are generally more
[hilar adenopathy or contained primary pulmonary toxic than first-line drugs. Although children have less
(Ghon) focus] MDR-TB could probably be treated for 12 adverse effects than adults treated with the same drugs,
months only. they need to be monitored carefully, as it is more difficult
to assess adverse effects in children than in adults.
Role of Surgery in the Management of MDR Important adverse effects to monitor and how to monitor
and XDR-TB these are summarized in Table 36.1.2. Adverse effects
The role of surgery remains controversial. Some should be treated as soon as possible, because it could
conditions, such as lymph node obstruction of airways, lead to serious irreversible problems such as hearing loss
draining of pericardial effusion, insertion of ventri- and peripheral neuropathy, but it could also lead to poor
culoperitoneal shunt for non-communicating obstructive adherence to treatment if not adequately managed.
Table 36.1.2: Important adverse effects of second-line drugs and how to monitor them
Second-line drug Adverse effect Tests to monitor
Amikacin Ototoxicity Hearing test (audiology)
Kanamycin Nephrotoxicity Serum creatinine and
Capreomycin potassium levels
Fluoroquinolones Gastrointestinal disturbance Clinical observation

Insomnia Serum uric acid if used with
Arthralgia pyrazinamide
Ethionamide Gastrointestinal disturbance Clinical observation

(or prothionamide) Hepatotoxicity Jaundice—serum alanine
Hypothyroidism transferase and billirubin
Thyroid stimulating hormone
levels and free T4
Cycloserine (or terizidone) Psychosis, Convulsions, Clinical observation

Paresthesia, Depression
Para-aminosalicylic acid (PAS) Gastrointestinal disturbance Clinical observation

Hypothyroidism Thyroid stimulating hormone
levels and free T4
Linezolid Myelosuppression Full blood counts

Lactic acidosis Serum lactate level
Peripheral neuropathy Clinical observation
Pancreatitis Clinical observation
504
Outcome of MDR -TB in Children the preferred regimen. In case of MDR-TB, WHO
recommends INH chemoprophylaxis only, not to prevent
Treatment of MDR and XDR-TB patients is often initially MDR-TB but in case the child may have been infected by
administered in hospital firstly, because they may have a drug-susceptible source case.49 Several failures of INH
extensive disease secondly, because primary health care or INH/RMP combination chemoprophylaxis for MDR-
clinics often do not want to administer daily injections to TB contacts have been documented.62
children. Further, the source case’s poor adherence to In INH-resistant contacts, RMP as monotherapy for
treatment, who could be the mother or caregiver, causes 4 months has been shown to be effective and is currently
doubt whether the child will actually be taken for daily recommended by the American Academy of Pediatrics.63
directly observed therapy. It is also important to do follow- In case of MDR-TB contacts, the situation is more
up cultures to determine the final duration of treatment. complex and there is no universally accepted regimen.
Obtaining specimens for culture of M. tuberculosis from WHO does not recommend using second-line drugs for
children is quite difficult and health care workers are often chemoprophylaxis of MDR-TB contacts and recommends
reluctant to take gastric aspirates or induced sputum only regular follow-up of these children for a minimum
specimens at clinic level. We usually admit children for of two years.49 However, one study has shown that giving
the time that they receive second-line injectable drugs and, a combination of two drugs to which the source case’s
if social circumstances and the clinical condition of the isolate is susceptible or naïve prevents the development
child permit, the rest of the treatment is given at primary of disease in high-risk child contacts.64 This is also the
health care level as daily directly observed therapy. current recommendation of the American Aademy of
However, in a study from Peru, the majority of the children Pediatrics. 63 We prefer a combination of a fluoro-
managed for MDR-TB were not admitted to hospital but quinolone, ethambutol (if DST shows susceptibility) or
treated in the community by directly observed therapy ethionamide plus high-dose INH for 6 months in high-
with cure or probable cure in 36 of 38 cases.60 A South risk cases.
African study of 39 culture-confirmed childhood MDR- There is no effective chemoprophylaxis for XDR-TB
TB cases also had good outcome with only 4 (10%) deaths contacts. Regular follow-up as for MDR-TB contacts is
and a majority of children clinically cured.37 More data the only option, with early treatment once disease occurs.
are needed to compare cure rates of HIV-infected and HIV-
uninfected children, with MDR-TB and specific types of Infection Control Measures
TB. In general, MDR tuberculous meningitis has a very
high mortality. No discussion about drug-resistant TB can be complete
without mentioning the importance of good infection
Management of Child Contacts of Infectious control measures. Children with acid-fast bacilli sputum
smear-positive or cavitary pulmonary TB are most likely
Drug-resistant Cases
infectious and should be isolated until they are at least
In general, all children in close (usually household) smear-negative. In the developing world good ventila-
contact with an infectious TB case should be screened tion is the most important and most easily implemented
for TB and active TB disease excluded. Once TB disease measure for infection control other than diagnosing and
has been excluded, WHO guidelines recommend that all treating infectious cases early and effectively. In case of
children less than 5 years of age and all HIV-infected children presenting with possible TB, it should be
children irrespective of age should receive preventive remembered that the adult accompanying the child may
therapy (chemoprophylaxis).61 However, in case of drug- be the source case, therefore, it is important that a history
resistant contacts, no randomized controlled trials for of TB from the adult should be obtained or they should
chemoprophylaxis have been conducted. As long as there be screened if they are symptomatic to prevent possible
is no resistance to INH, INH for 6 to 9 months remains transmission of disease in the health care setting.
36.2 MULTIDRUG-RESISTANT TUBERCULOSIS

Multidrug-resistant (MDR) TB is defined when or rifampicin can be treated with other first-line
M. tuberculosis isolates are resistant to both isoniazid and antituberculosis drugs. However, multidrug-resistant TB
rifampicin with or without resistance to other drugs. (MDR-TB) demands treatment with second-line drugs
Isoniazid and rifampicin are the most important drugs that have limited sterilizing capacity, are less effective and
in the management of TB. Resistance to either isoniazid more toxic.
505
The management of MDR-TB in adults has been re-evaluated, culture and sensitivity studies should be
extensively documented, relatively little is known about undertaken using rapid methods for identification of AFB
its diagnosis and management in children. Soon after on smear and culture. In children emphasis has to be on
streptomycin was introduced for the treatment of repeated examination of gastric lavage and induced
tuberculosis, it became apparent that initial success was sputum specimen, fine needle aspiration (FNA) material
frequently followed by relapse and the emergence of a in nonresolving lymphadenitis. Additional drugs should
population of streptomycin resistant M. tuberculosis. As not be added piecemeal to the existing regimen as this
more antituberculous drugs became available, it was will lead to reduction of choice of drugs for use in an
discovered that this problem could be prevented by using effective alternative therapeutic regime.
drugs in combination.
The phenomenon of drug-resistance in Mycobacterium Definition of Drug-resistance
tuberculosis was observed as early as 60 years ago, Drug-resistance in mycobacteria is defined as a decrease
however, the current threat is due to the emergence of in sensitivity to a sufficient degree to be reasonably
strains resistance to the two most potent anti-TB drugs certain that the strain concerned is different from a
viz., isoniazid (H) and rifampicin (R). The response of sample of wild strains of human type that have never
patients with MDR-TB to treatment is poor and the
come in contact with the drugs.
mortality rate is usually high. Since these patients need
Multidrug-resistant TB (MDR-TB) is caused by
to be treated with expensive and toxic second-line drugs,
bacteria that are resistant to the most effective anti-TB
and may require hospitalization to manage their toxic
drugs (isoniazid and rifampicin). MDR-TB results from
reactions and other complications, they require a sizeable
either primary infection or may develop in the course of
proportion of health care resources. Further, an alarming
increase in infection due to the human immunodeficiency a patient’s treatment.
virus (HIV) has aggravated this situation and it is Extensively drug-resistant TB (XDR-TB) is a form
believed that, as of now, about 3 to 5 million people in of TB caused by bacteria that are resistant to isoniazid
India are infected with HIV. There is a grave concern in and rifampicin (i.e. MDR-TB) as well as any fluoro-
India regarding the increase in HIV-associated TB and quinolone and any of the second-line anti-TB injectable
the emergence of MDR-TB both in terms of magnitude drugs (amikacin, kanamycin or capreomycin).
and severity of TB epidemic.
It is now known that any population of M. tuberculosis Types of Drug-resistance
will contain a small number of resistant organisms, Drug-resistance in TB may be broadly classified as primary
irrespective of previous exposure to the drugs in or acquired. When drug-resistance is demonstrated in a
question. These are the result of constant but relatively patient who has not received anti-TB treatment previously,
low rate of mutation. As the number of organisms are it is termed primary resistance. Acquired resistance is that
low in the lesions of children, resistant mutants are less which occurs as a result of specific previous treatment.
likely to be found, unless the child has been infected by The level of primary resistance in the community is
a resistant strain. considered to reflect the efficacy of control measures in
There is some evidence that isoniazid resistant the past, while the level of acquired resistance is a measure
(catalase-negative) organisms are less pathogenic than of on-going TB control measures. However, the World
isoniazid-sensitive (catalase-positive) organisms in Health Organization (WHO) and the International Union
experimental animals, however, there is no doubt that Against Tuberculosis and Lung Disease (IUATLD), in the
resistant organisms can cause human disease. Such light of discussions in several international fora, have
infection can be transmitted to children and can cause replaced the term primary resistance by the term “drug-
disseminated forms of tuberculosis such as tuberculous resistance among new cases” and acquired resistance by
meningitis.
the term “drug-resistance among previously treated
cases”. For more details see Chapter 36.1.
When to Suspect Drug-resistance?
Drug-resistance should be suspected whenever:
Cause of Drug-resistance
• Therapeutic progress is not maintained.
• Whenever bacterial relapse occurs during course of The emergence of drug-resistance in M. tuberculoses has
treatment. been associated with a variety of management, health
• Recurrence occurs in patients previously treated for provider and patient-related factors, these include:
tuberculosis and their contacts including children. (i) deficient or deteriorating TB control programs
Once there is strong possibility of drug- resulting in inadequate administration of effective
resistance complicating therapy, all treatment should be treatment; (ii) poor case holding, administration of
506
substandard drugs, inadequate or irregular drug supply EPIDEMIOLOGY

and lack of supervision; (iii) ignorance of health care
The emergence of MDR-TB in the United States attracted
workers in epidemiology, treatment and control of
attention in the 1990s. Till then drug-resistance was
disease; (iv) improper prescription of regimens; (v)
considered to be only a potential problem. WHO and
interruption of chemotherapy due to side effects; (vi)
the International Union Against Tuberculosis and Lung
nonadherence of patients to the prescribed drug therapy;
Disease (IUATLD) conducted three rounds of survey
(vii) availability of anti-TB drugs across the counter,
between 1996-2002. The third round included new data
without prescription; (viii) massive bacillary load; (ix)
from 77 settings or countries that were collected between
illiteracy and low socioeconomic status of the patients;
1999 and 2002. In the third survey it was found that
(x) the epidemic of HIV infection; (xi) laboratory delays among new cases, the prevalence of MDR-TB (Median,
in identification and susceptibility testing of M. 1.1%) ranged from 0% in eight countries to 14.2% in
tuberculosis isolates; (xii) use of nonstandardized Kazakhistan (51 of 359 patients) and Israel (36 of 253
laboratory techniques, poor quality drug powders and patients). Among previously treated cases the median
lack of quality control measures; and (xiii) use of anti-TB prevalence of MDR-TB was 7.0%. The prevalence of
drugs for indications other than tuberculosis. MDR-TB was exceptionally high in all countries from the
Isoniazid, the most powerful antimycobacterial drug former Soviet Union surveyed, including Estonia,
available, ensures early sputum conversion and thus Kazakhistan, Lativ, Lithuania the Russian Federation,
helps in reducing the transmission of TB. Rifampicin, by and Uzbekistan. High prevalence of MDR-TB were also
its mycobactericidal and sterilizing activities is crucial found among new cases in China, Ecuador, and Israel.
for preventing relapses. Thus, for the management of Central Europe and Africa, in contrast reported the
tuberculosis, these two drugs are most important. If there lowest median levels of drug-resistance. A recent
is resistance to one of them, the disease still can be estimate of global prevalence in 184 countries suggest
managed with other first-line drugs. If there is resistance that an estimated 458,000 new cases of MDR-TB occurred
to both isoniazid and rifampicin, MDR-TB requires world wide in 2003, with 276,000 of those, i.e. (60%) from
treatment with second-line drugs. These drugs have high-burden countries. Poor or worsening TB control,
limited sterilizing capacity and are not suitable for short- immigration of patients from areas of higher resistance,
course treatment. Thus, the problem of transmission is outbreak of drug-resistant disease and variation in the methods
crucial to the occurrence of disease in children, is of grave of surveillance are some of the factors which could be responsible
concern when there is contact of a child with MDR for increases in the prevalence of resistance.
tuberculosis in the family resulting in primary resistant
infection. MDR-TB has important implication both for Global Situation
individual patient and tuberculosis control program.
A review by WHO of a series of 63 surveys of drug-
The modern era of tuberculosis recently has been
resistance carried out worldwide between 1985 and 1994
characterized by a rise in the number of cases of infection
led to the conclusion that the new epidemic maybe
with multidrug-resistant (MDR) M. tuberculosis. This has global.3,4 The highest rates of MDR-TB were from Nepal
also led to outbreaks and individual cases that are only (48%), Gujarat state (India) (34%), New York City (USA)
marginally treatable and often fatal. World Health (30%), Bolivia (15%) and South Korea (15%). Subse-
Organization (WHO) on World Tuberculosis Day in 1993 quently, between 1994 and 1997, WHO and the IUATLD
declared tuberculosis as a global emergency. This was conducted drug-resistance surveillance for the four first-
prompted firstly, by the resurgence of tuberculosis in the line antituberculosis drugs namely isoniazid, rifampicin,
west in the mid-1980s and, secondly, by the outbreak of streptomycin and ethambutol, through extensive
MDR-TB in many countries, including USA in the late network of reference laboratories in 35 countries
1980’s and early 1990s.1 MDR-TB has been described as including India. The prevalence of primary multidrug-
the third epidemic, complicating the epidemic of HIV. resistance was 1.4%. It was further reported that India
The conditions that have led to the resurgence of accounts for almost a third of the worldwide burden of
tuberculosis have also contributed to an increasing tuberculosis and the combined prevalence of multidrug-
incidence of resistant forms of tuberculosis in the resistance to the tune of 13.3%. Although tuberculosis
developed and developing world. The resurgence of remains endemic in many parts of Asia, primary drug-
tuberculosis in the USA has been more striking for resistance has dramatically declined in Korea, having
children than for the adults. Although the incidence of shown a fall from 31% in 1960 to 15% in 1990, reflecting
new cases increased by 20% from 1987 to 1992, the improved tuberculosis control measures.5
incidence of new cases in children less than fifteen years In the recently released WHO report, it is estimated
of age increased to 40% in 1993.2 that in 2008, 390,000 to 510,000 cases of MDR-TB emerged
507
globally (best estimate, 440,000 cases).6 Among all clinics were tested for drug susceptibility to streptomycin,
incident TB cases globally, 3.6% [95% confidence interval isoniazid, para-aminosalicylic acid (PAS) and thiacetazone.
(CI): 3.0–4.4] were estimated to have MDR-TB. Almost The first study was on patients who had denied any history
50% of MDR-TB cases worldwide were estimated to occur of previous treatment, while in the second study, patients
in China and India. While the TB case populations of with and without previous chemotherapy were included.
China and India may have proportions of MDR-TB lower The results showed that in the first study resistance to
than Eastern European and Central Asian countries, the isoniazid ranged from 11 to 20%, to streptomycin from 8
sheer sizes of the two countries’ TB case populations to 20% and to both drugs from 4 to 11%. The second study
result in the highest estimated numbers of MDR-TB cases showed resistance to isoniazid in the range of 15 to 69%,
emerging annually in these two countries: approximately to streptomycin from 12 to 63% and to both drugs from 5
100,000 cases each. In 2008, MDR-TB caused an estimated to 58%. Further, the level of drug-resistance was propor-
150,000 deaths globally. tional to the duration of previous treatment.9
The Russian Federation, which was able to provide A decade later, a study at the Chest Clinic of
high-quality continuous surveillance data from 12 of its Government Stanley Hospital (GCI-SH), Chennai
oblasts and republics, reported proportions of 23.8 to (formerly Madras) yielded results similar to those in
28.3% MDR-TB among new TB cases in three of its oblasts earlier ICMR surveys, indicating that the prevalence of
in the northwest part of the country.6 initial drug-resistance had not risen during the span of
A 4 years prospective study in the Western Cape ten years. However, both the above studies were
province of South Africa evaluated 149 child contacts of 80 undertaken in the pre-rifampicin period and are not of
adult MDR pulmonary TB cases. Culture for relevance in the present setting.
M. tuberculosis was obtained from both the adult source cases During the 1980s, though the levels of initial drug-
as well as the child contacts. Isolates were compared by
resistance to isoniazid and streptomycin in 11 reports
drug susceptibility pattern and restriction fragment length
were similar to those in the earlier studies, rifampicin
polymorphism (RFLP) analysis. Six adult-child pairs with
resistance was observed in all centers studied except
cultures positive for M. tuberculosis were identified. Drug
susceptibility pattern and RFLP analysis were identical for Gujarat. The level of MDR-TB in all centers (except
five adult-child pairs. One child, with no other known Wardha) was observed to be less than 5%. The reason
source case, had a strain different from that of the identified for the emergence to rifampicin-resistance during this
source case, but the MDR-M. tuberculosis strain with which period may be the introduction of short-course chemo-
he was infected was prevalent in the community he resided. therapy (SCC) regimens containing rifampicin. Further,
This study confirms that most of the childhood contacts of a higher level of initial drug-resistance to isoniazid
adults with MDR-TB are likely to be infected by these MDR (32.9%) was observed among the rural population in
source cases despite their exposure to other drug-susceptible Kolar compared to the urban patients, contradicting a
adults with TB in some instances. Child contacts of adults Korean study, where a much higher level of initial
with MDR-TB should be treated according to the drug resistance was seen among urban patients, attributed to
susceptibility patterns of M. tuberculosis strains of the likely easy access to the antituberculosis drugs. There was also
source cases unless their own strain’s susceptibility testing an increase in the proportion of initial drug-resistance to
indicates otherwise. Contact tracing remains of fundamental rifampicin (4.4%) encountered in this rural population
importance in identifying children at risk.7 In Western Cape in Karnataka.
province of South Africa, initial isoniazid (INH) resistance
In the early 1990s, a retrospective study done at New
and MDR among adults was 3.9 and 1.1%, respectively,
Delhi showed a high level of initial drug-resistance to
during 1992-1993.7 In a report of 306 of 338 children with
isoniazid (18.5%) and a low level of resistance to
cultures positive of M. tuberculosis the incidence of INH
resistance was 5.6% and MDR 1% in children aged < 5 years rifampicin.10
in South Africa.8 Data on the prevalence of drug-resistance from the
Army Hospital, Pune showed a very low level of initial
resistance to isoniazid and the authors have explained
Initial Drug-resistance in India
that this lower level of drug-resistance in this population
The Indian Council of Medical Research (ICMR) under- could be due to the minimal chance of indiscriminate
took drug-resistance studies during 1965-67 in nine urban exposure of anti-TB agents prior to reporting to the
areas of the country. However, this exercise was not a hospital. However, it should be emphasized that several
surveillance study and did not use strict sampling of these reports, except those from the Tuberculosis
techniques, the centers being selected more for logistic Research Center (Chennai) TRC, National Tuberculosis
considerations than for epidemiological reasons. Sputum Institute (Bengaluru) (NTI) and the Armed Forces
specimens collected from all patients attending chest Group, may have inherent limitations due to flaws in
508
methodology and hence need to be interpreted with in such children. Programmatic changes could facilitate
caution. earlier diagnosis and treatment of pediatric MDR-TB and
The ICMR and the TRC, Chennai, have conducted in other DOTS-Plus Programs.16
drug-resistance studies in different parts of the country.
These have been supplemented by various other drug- Mechanism and Transmission of Drug-resistance
resistance surveys.9-13 A study conducted at the New
Drug-resistance in M. tuberculosis occurs by random,
Delhi Tuberculosis Center showed initial resistance to
single step, spontaneous mutation at a low but
isoniazid and rifampicin at 18.5% and 0.6% respectively
predictable frequency, in large bacterial populations.
and acquired resistance as 50.7% and 33.0% respec-
The probability of incidence of drug-resistant mutants
tively.10 A referral hospital based study in Mumbai
is 10-8 for rifampicin, while for isoniazid and some of
recently reported primary drug-resistance to isoniazid
the other commonly used drugs it is 10-6. Therefore, the
as 45%, to rifampicin as 27%, to ethambutol as 9% and to
probability for resistance to both isoniazid and
streptomycin as 54%.11 Secondary resistance to isoniazid
rifampicin to develop is 10-14, which is much larger than
was reported as 68%, to rifampicin as 60%, to ethambutol
the number of organisms present in a medium sized
as 8% and to streptomycin as 36%. Thirty percent cases
cavity in a patient with open pulmonary TB.
showed multidrug-resistance to isoniazid and rifampicin.
Although for several years, drug-resistant strains of
The estimated overall prevalence of primary drug-
M. tuberculosis were considered to be less infectious
resistance in adults has been reported to be 20 to 30% for
than the drug susceptible ones, recent studies have
INH and 2 to 3% for rifampicin. Acquired drug-resistance
demonstrated that the drug-resistant mutants are equally
is much higher at 50 to 60% for INH, 20 to 30% for
infectious and can cause severe disease in an individual
rifampicin and 15 to 20% for streptomycin.12
exposed to the same.
In the recent WHO report6 it is estimated that the %
MDR among new TB cases (95% CI) is 2.3 (1.8–2.8), while
Microbiological Basis
that among previously treated cases is 17.2 (14.9–19.5).
In a recently published representative state-wise survey Several types of mycobacterial drug-resistance have been
in the state of Gujarat (2005 population: 56 million), of defined.
1571 isolates from new patients, 1236 (78.7%) were
susceptible to all first-line drugs, 173 (11%) had INH Natural Resistance
resistance and MDR-TB was found in 37 (2.4%, 95%CI
Natural resistance is defined as resistance to a drug when
1.6-3.1).13,14 Of 1047 isolates from previously treated
a strain has never been previously exposed to the drug,
patients, 564 (54%) were susceptible to all first-line drugs,
e.g. Mycobacterium bovis is naturally resistant to
387 (37%) had INH resistance and MDR-TB was found
pyrazinamide.
in 182 (17.4%, 95% CI 15.0-19.7%). Among 216 MDR-TB
isolates, 52 (24%) were ofloxacin (OFX) resistant; seven
Primary Drug-resistance
cases of extensively drug-resistant TB (XDR-TB) were
found, all of whom were previously treated cases. Primary drug-resistance is when the patient is infected
In a study from Uttar Pradesh, a total of 686 M. with drug-resistant population without having received
tuberculosis isolates were obtained from 1162 patients, of prior treatment. The infection is transmitted from a
which 318 were from untreated subjects and 368 were person with drug-resistant tuberculosis.
from patients who were treated for tuberculosis in the
past.15 Prevalence of MDR was 19.8 percent, initial and Acquired or Secondary Drug-resistance
acquired being 13.2 and 25.5 percent respectively. Acquired or secondary drug-resistance is when the
There is a paucity of reports of drug-resistance in patient harbors organisms which were initially drug
children due to comparatively few centers where facilities susceptible, and the resistance has developed during the
for culture and drug sensitivity exist. Therefore, much course of treatment. This could be due to poor compliance
of drug-resistance has been presumed clinically when or a faulty treatment plan.
patients do not improve or the symptoms return after
initial improvement. There are large number of patients Wild Type Resistance
carrying resistant strains of M. tuberculosis and since the Wild type resistance is when in a large population of
disease in children is just a reflection of the disease in drug susceptible mycobacterium, individual organisms
adults, similar conclusions can be drawn. are resistant to a single drug. This results from
The diagnosis of pediatric MDR-TB is often extremely spontaneous mutations in the mycobacterial chromo-
delayed due to reliance on the adult case definition and some. Table 36.2.1 gives the frequency of spontaneous
should be changed to prevent progressive, chronic illness mutation to various drugs.
509
Table 36.2.1: Frequency of spontaneous mutation Table 36.2.2: Antituberculosis drug and the genes
against different drugs involved in their resistance
Drug Incidence of spontaneous Drug Genes involved in drugs resistance
mutation
Group 1
INH, Streptomycin 1-5 × 10-6 Isoniazid Enoyl acyl carrier protein (acp),
Rifampicin 10-8 reductase (inhA)
Ethambutol 10-4 Catalase-peroxidase (katG)
Alkyl hydroperoxide reductase
(ahpC)
Since resistance to the various antituberculosis drugs Oxidative stress regulator (oxyR)
occurs independently, chances that the organism have B-Ketocyl acyl carrier protein
wild type resistance to two drugs is very rare, e.g. for synthase (kasA)
INH and RIF is 10-6 and 10-8 respectively and together Rifampicin RNA polymerase subunit B (rpoB)
10.-14 A tubercular cavity containing 107 to 109 bacilli will, Pyrazinamide Pyrazinamidase (pncA)
therefore, have no organism which is resistant to two Ethambutol Arbinosyl transferase (emb A, emb B,
drugs. Similarly, closed caseous lesion in children, having and emb C)
105 to 107 bacilli will have no resistant organism. Group 2
Resistant tuberculosis in children is usually of the Streptomycin Ribosomal protein submit 12 (rpsL)
primary type caused by exposure to a case of resistant 16s ribosomal RNA (rrs)
tuberculosis. Because they have a lower bacillary burden Aminoglycoside
they are less likely to develop acquired resistance, even phosphotransferase gene (strA)
if suboptimally treated.17 Capreomycin Haemolysin (tlyA)
However, Karande et al18 described a 12-year-old boy Group 3
in Mumbai with secondary multidrug-resistant TB. He Fluoro- DNA gyrase (gyr A and gyr B)
had received multiple courses of inadequate treatment quinolones
with various anti-TB treatment regimens for 9 years. The
TB gradually progressed in severity and was dissemina- The genes involved in drug-resistance is given in
ted with the bacterial load increasing sufficiently for Table 36.2.2.
multidrug-resistant TB to develop.
Potential Causes of Drug-resistance
Genetic Basis
Drug-resistance appears to be chromosomal in origin, Patient-related Factors
caused by specific mutations that occur in independent
Nonadherence to treatment is the single most important
genes. This type of drug-resistance is not transferable
factor for emergence of drug-resistance. 28,29 Non-
from one organism to another and is not linked between
antimicrobial drugs, however, the bacilli may show cross- adherence to a single drug is more dangerous than failure
resistance to drugs with similar structure. 19,20 The in taking all the drugs. The adherence to treatment may
molecular mechanism of rifampicin resistance in most be particularly difficult for children. Children with
M. tuberculosis is a missense mutation in the gene (rpoB) tuberculosis are generally not very ill, and convincing
encoding the beta unit of the RNA polymerase.21 Some them or their parents to take several medications for
strains of M. tuberculosis that are resistant to INH have many months maybe difficult. Moreover, tuberculosis in
reduced catalase-peroxidase activity. A specific gene children is often associated with socially disadvantaged
(katG) controls this activity. A complete absence of katG households which further compromises adherence to
from the chromosome has been detected in some strain treatment.30
of INH resistant M. tuberculosis.22,23 Another gene (inhA) The most effective means to prevent acquired drug-
is also thought to be involved in INH resistance. 24 resistance is the use of directly observed therapy (DOT),
Mutations in the 16S ribosomal RNA gene are associated whereby a health care worker or other second party is
with resistance to streptomycin.25,26 With the emergence directly involved in the administration of each dose of
of MDR strains of M. tuberculosis resistance has also been medication to the patient.
observed to quinolones with a missense mutation at the
area of gyrA.27 Physician-related Factors
Chromosomally borne mutations occur spontane-
ously in M. tuberculosis only at a predictable rate as Many cases of drug-resistant tuberculosis have resulted
described earlier. A characteristic feature of these muta- from inadequate management by the physician. The
tions is that they are unlinked. most common errors are addition of a single drug in a
510
failing regimen (thereby creating serious resistance for Diagnosis

several drugs), an inadequate initial regimen, failure to
Since the clinical presentation of both, drug-resistant and
recognize primary or acquired resistance, inability to
drug-susceptible tuberculosis is the same, the only certain
and deal with nonadherence with prescribed treatment,
way of diagnosing resistant tuberculosis is by isolating
and inappropriate single-drug therapy.31
the infective strain and assessing its susceptibility pattern.
Multiple inappropriate prescriptions for treatment of
But AFB isolation from children with tuberculosis except
tuberculosis by physicians may be promoting drug-
in miliary or cavitary disease is low (25-44%), even in
resistant tuberculosis. A study of 100 prescriptions in
the most advanced centers.35 Adult contacts of children
Mumbai reveled 80 different anti-TB regimens; most were
should be assessed for history of prior antituberculosis
both inappropriate and expensive.32
therapy with persistent sputum-positivity. Since this is
a pointer towards drug-resistance, children with such
Detection of Drug-resistance adult contacts should be watched for any lack of response
The conventional methods of culture, identification and or deterioration on treatment.
drug susceptibility testing of the isolated organism Diagnosis of drug-resistance is further confounded
require a minimum of 10 to 12 weeks. Although most by certain peculiarities of tuberculosis disease. The
widely used, the long waiting period in obtaining the resolution of radiographic abnormalities of chest can take
results by these methods may delay the initiation of months or years after successful treatment. Also, post-
proper treatment, resulting in the patient transmitting tuberculous bronchial hyper-reactivity, bronchiectasis
drug-resistant infection in the community. The use of and other residual lesions can cause symptoms with
direct sensitivity tests, especially to isoniazid and persistence of radiological shadows. About 15 to 20% of
rifampicin has resulted in a saving of at least 4 weeks in patients with susceptible organisms continue to have
obtaining the resistance status. However, this method is lymph nodes of considerable size even after complete
not very useful in smear negative and paucibacillary therapy. They may disappear gradually or persist or
specimens. fluctuate intermittently. In such cases, histopathology
Several newer methods including molecular may show persistence of sterile granuloma, however, no
diagnostics have resulted in cutting down the time AFB will be isolated except in cases of relapse or drug
interval between collection of the specimen and failure. Also, tuberculomas of brain may increase in
availability of results in 2 to 3 weeks or even less. number as well as size even on successful treatment and
However, these methods require considerable technical ultimately heal over a period of months to years. A
expertise and impose financial constraints in a routine patient can have recurrence of seizures during the healing
laboratory set up in the developing nations. phase, but such symptoms do not necessarily imply a
relapse or resistance to antituberculosis therapy.
Clinical Features of Resistant Tuberculosis The diagnosis of MDR-TB is often delayed due to
various reasons. In a recent report of 39 children with
The spectrum of disease caused by drug-resistant MDR-TB average delay in starting appropriate MDR
organisms is similar to that caused by drug susceptible treatment after TB diagnosis was a median of 2 days, if
bacilli.16 Children with drug-resistant primary tuber- MDR-TB source cases were taken into account, but 246
culosis tend to have typical radiological patterns days if the drug susceptibility pattern of the source case
including hilar adenopathy, segmental lesion and was not considered. There was a delay of 283 days in the
collapse consolidation and those with reactivation absence of a known tuberculosis source case. Correlation
disease tend to have apical cavities.16,33 The incidence of between the drug susceptibility results of the child’s and
extrapulmonary tuberculosis appears to be similar adult source case’s isolates was 68%.34 Observations of
among children infected with MDR bacilli and drug this study suggest that there is need to change the
susceptible strains.12 When tuberculosis exists with HIV, definition of MDR-TB in children. If a child has an adult
the disease pattern is no different from that seen in HIV patient with documented MDR-TB he can be considered
seronegative children. to be suffering from MDR-TB. He should be started on
In a recent study of 39 culture confirmed MDR-TB appropriate treatment after taking appropriate samples
from South Africa primary tuberculosis was observed in for culture and sensitivity for M. tuberculosis. Similarly,
26 (67%) and adult type of tuberculosis was documented a patient who fails to improve after appropriate
in 11 (28%) children. Remaining children had extra- antituberculosis drugs with good compliance, it is likely
pulmonary tuberculosis including CNS tuberculosis.34 that he maybe suffering from drug-resistant tuberculosis.
In CNS tuberculosis only 8% had meningitis and 13% The child should be referred to specialized center dealing
had granuloma. with drug-resistant tuberculosis cases. The primary care
511
physician should not start the child on regimen for drug- units. This method is rapid (average time taken is 9.3
resistant tuberculosis. days), uses liquid media in which drug concentrations
remain stable and even susceptibility to PZA can be
Predictors of Drug-resistance in Children estimated. But this method is expensive and cannot be
used for reserve drugs, e.g. cycloserine, ethionamide.
Patterns of drug-resistance among children with
tuberculosis tend to reflect those found among adults in Luciferase phage system: In this system the mycobacteria
the same population.33,34 Predictors of drug-resistance are infected with a phage carrying the enzyme luciferase,
in children are: which is responsible for the glow of the firefly. When the
• Residence in country or area with high rates of drug- infected M. tuberculosis carrying the enzyme is grown in
resistance culture containing the drug, to which the substrate
• Previous antituberculosis therapy luciferin is added, light is produced if the M. tuberculosis
• HIV infection in the child or the adult source case strain is resistant to the drug in the medium. If the strain
• Known contact with adult patient with MDR-TB. is sensitive to the drug, it is killed and there is no
luciferase in the system and no light is produced.39 The
Laboratory Diagnosis of Drug-resistant Tuberculosis test is both highly sensitive and specific.
Polymerase chain reaction (PCR): Single stranded
Various methods are used for drug susceptibility tests.36-
39 conformation polymorphism has made possible the rapid
They include the conventional and the newer tests
identification of rifampicin resistant M. tuberculosis.40,41
utilizing phenotype and genotypic resistance testing.
Results are available within 24 hours. The analogous
setting for isoniazid resistance is less favorable, since
Direct Methods
more than one gene maybe involved in isoniazid
The clinical material is inoculated directly onto drug-free resistance.22,23 Restriction fragment length polymorphism
and drug-containing media, thereby, allowing simulta- (RFLP) using insertion element IS986/IS6110 based DNA
neous isolation and susceptibility testing. They are probe has been used with success in epidemiological
generally performed for smear-positive material only. studies in MDR-TB outbreaks.42
The results of this method may be more accurate as they Slide culture sensitivity systems: This system which can
are representative of entire bacterial population present. provide results in 7 days is particularly useful for guiding
Results are available in 3 to 6 weeks time. The methods the treatment of smear-positive patients. In this method
used are 7H10 media, gradient plate method or L-J smear-positive sputum is spread on slides and incubated
media. without prior decontamination in a selective lyzed
human blood medium. Drug concentrations and
Indirect Method definitions of resistance are suggested for tests against
Colonies from a pure culture isolate are subcultured into first and second-line antituberculosis drugs. They need
a broth media and then plated on drug-free and drug- further evaluation in clinical settings in developing
containing solid media. The colony selected may not be countries.43
truly representative of the entire bacterial population. Using these methods the time spent in awaiting
Now modified proportion method is used, i.e. evaluation reports is cut down to 2 to 3 weeks. However, there are
is done as proportion of growth permitted on drug financial and technological constraints in applying these
containing media compared to drug free media. methods in developing countries. Since, in most
Resistance is present when 1% or more growth occurs developing countries, the diagnosis of drug-resistant
on drug containing media compared with drug free tuberculosis is often made without isolation of AFB from
media. This test can be performed on smear-negative but the child, all other possible confounding alternatives
culture-positive cases. But it takes a long time and cannot must be carefully excluded before starting treatment with
be used for pyrazinamide (PZA) susceptibility testing. reserve drugs. Also, attempts should be made to isolate
the bacteria by all possible modalities, i.e. induced
Rapid Method sputum (3% hypertonic saline), concentrated smears,
bronchoalveolar lavage or direct fine needle aspirates of
BACTEC system: This automated radiometric system can
the involved areas such as lymph nodes.
significantly shorten the time for mycobacterial detection
and susceptibility testing.36 This method consists of MANAGEMENT OF PATIENTS WHO HAVE
growing M. tuberculosis in liquid media containing
14 DRUG-RESISTANT DISEASE
C-fatty acid substrate with and without critical
concentration of drugs. As the bacilli grow, they release Microbial resistance to antimycobacterial drugs may be
14
CO2. The instrument quantitates this in growth index either initial or secondary. Initial resistance occurs in
512
patients who are not known to have had previous 1. Take a careful history of previous treatment, or in the
antimycobacterial treatment. Risk factors for initial case of child, the previous treatment of possible index
resistance include exposure to a patient who has drug- cases; susceptibility testing may have been carried out
resistant tuberculosis, being from a country with a high on the index cases.
prevalence of drug-resistance, and greater than 4% 2. If possible, obtain material for culture and sensitivity
primary resistance to isoniazid in the community. testing and if the clinical situation permits await the
Secondary resistance occurs in patients who have been results before altering or starting any regimen.
treated in the past. The frequency of both types of 3. Where resistance to isoniazid and rifampicin (MDR)
resistance is to a large extent determined by the adequacy is suspected or found, at least three and preferably
of tuberculosis treatment programs. Poor treatment five drugs to which the patient has not previously
programs enable resistant organisms to emerge, been exposed should be used. Ethionamide,
producing secondary resistance in inadequately treated ofloxacin, ethambutol, possibly pyrazinamide and
patients. These organisms are then transmitted and, when an aminoglycoside (amikacin or kanamycin) is a
disease occurs, the infected person has “primary” suggested combination. This regimen is continued
resistant disease. to smear “conversion” after which ethambutol and
In the past primary isoniazid resistance rates in most ofloxacin or another bacteriostatic agent should be
areas of the United States were < 4%; thus, two-and continued for a further 18 months.
three-drug regimens for tuberculosis were considered 4. The use of “second-line” drugs carries the risk of an
adequate. Community rates of primary isoniazid increased incidence of side-effects which may be both
resistance < 4% may be an indication that an initial unpleasant and potentially dangerous. Patients,
regimen of fewer than four drugs is acceptable. therefore, require careful observation and continual
However, continued surveillance of drug susceptibility encouragement to persevere with treatment. This may
patterns is necessary to ensure that low rates of primary be the patient’s last chance for survival.
drug-resistance continue.
Recently, pockets of tuberculosis caused by organisms Relationship of Development of Resistance to a
that are resistant to both isoniazid and rifampicin have
Particular Drug with the Clinical Response
been described. Resistance to both of these potent agents
considerably complicates patient management, making a 1. Resistance to rifampicin is of particularly ominous
successful outcome much less likely than if susceptibility significance as this drug is especially valuable for the
to one or the other of these two agents were maintained. sterilization of lesions and in preventing the
The basic principle of managing patients whose emergence of resistance during therapy.
organisms are resistant to one or more drugs is 2. The most common form of resistance is that against
administration of at least two agents to which there is isoniazid, with a small number of patients harboring
demonstrated susceptibility. organisms resistant to both isoniazid and rifampicin.
Unfortunately, good data are not available on the This is referred to multidrug-resistance (MDR).
relative effectiveness of various regimens and the 3. If a patient harbors organisms resistant to isoniazid
necessary duration of treatment for patients with and is being treated with a regimen containing
organisms resistant to both isoniazid and rifampicin. isoniazid, rifampicin and pyrazinamide, as is the case
Moreover, many such patients will have resistance to in primary complex will be effectively receiving
other first-line drugs (e.g. ethambutol and streptomycin) pyrazinamide and rifampicin only. Pyrazinamide
when drug-resistance is discovered. Because of the poor although effective in the sterilization of lesions, is less
outcome in such cases, it is preferable to give at least effective in preventing the development of resistance.
three new drugs to which the organism is susceptible. It is, therefore, particularly important that rifampicin
This regimen should be continued at least until should be used in properly designed regimens
bacteriologic sputum conversion is documented, under supervision, in fixed combination with other
followed by at least 12 months of two-drug therapy. antituberculosis drugs, so that there is no chance of
Often, a total of 24 months of therapy is given monotherapy.
empirically. Finally, surgery appears to offer consider-
able benefit and significantly improved cure rate for Management of Multidrug-resistant (MDR)
those patients in whom the bulk of disease can be Tuberculosis
resected.
To summarize in the management of drug-resistance The treatment of MDR tuberculosis is a challenge since
whenever possible, obtain expert opinion and advice it involves the use of second-line reserve drugs which
when it appears likely that a patient harbors drug- are not only more expensive and toxic, but also less
resistant organisms.44 effective than ‘standard’ first-line drugs. Second-line
513
Table 36.2.3: Drugs useful in the treatment of MDR-TB

Drugs Daily dosage Adverse drug reactions
• Aminoglycosides Pain at injection site
Streptomycin 15 mg/kg (750-1,000 mg) Ototoxicity (vertigo and deafness), nephrotoxicity
Kanamycin 15 mg/kg (750-1,000 mg) hemolytic anemia, aplastic anemia, agranulocytosis,
Amikacin 15 mg/kg (750-1,000 mg) Thrombocytopenia, and lupoid reactions
Capreomycin 15 mg/kg (750-1,000 mg) Hypokalemia, hypocalcemia and hypomagnesemia,
and occasionally hepatotoxicity; may potentiate the
effect of neuromuscular blocking agents administered
during anesthesia
• Thioamides § Epigastric discomfort, anorexia, nausea, metallic
Ethionamide 10-20 mg/kg (500-750 mg) taste and sulfurous belching, vomiting, excessive
Prothionamide 10-20 mg/kg (500-750 mg) salivation; psychotic reactions including hallucina-
tions and depression: hypoglycemia, hypothyroidism,
and goiter; hepatotoxicity, gynecomastia, menstrual
disturbance, impotence, acne, headache, and
peripheral neuropathy; tolerance varies with
ethnicity; usually well tolerated in Africa and Asia
• Pyrazinamide 20-30 mg/kg Hepatotoxicity, GI intolerance, hyperuricemia, and
(1, 200-1,600 mg) arthralgias
• Fluroquinolones Uncommon, GI intolerance (e.g. Dizziness, headache,
mood changes, and rarely convulsions)
Ofloxacin 7.5-15 mg/kg (600-800 mg)
Levofloxacin 500-1000 mg
• Ethambutol 15-20 mg/kg Dose-dependent optic neuritis,* and peripheral
(1,000-1,200 mg) neuritis;
• Cycloserine 15-20 mg/kg (500-750 mg) Dizzness, slurred speech, and convulsions;
|| Terizodone 15-20 mg/kg (600 mg) Headache, tremor, insomnia, confusion, depression;
and altered behavior; suicide risk generalized
hypersensitivity reaction or hepatitis.
• Para-aminosali- 150 mg/kg (10-12 g) GI disturbance (e.g. anorexia, nausea, vomiting,
cylic acid abdominal discomfort, and diarrhea); general skin or
other hypersensitivity, and hepatic dysfunction;
hypokalemia; hypothyroidism and goiter; best
avoided in renal failure as it may exacerbate acidosis;
sodium salt should not be given when a restricted
sodium intake is indicated
§ Chemical structure resembles thiacetazone, with which there is frequent and partial cross-resistance. However, strains that
are resistant to thiacetazone are often sensitive to thioamides, but the reverse is seldom the case. Therapy is more acceptable
if the drug is administered with orange juice or milk ingestion, or at bedtime to avoid nausea.
|| Terizidone is a combination of two molecules of cycloscrine.
* Optic neuritis is not a problem as researched by Seth Vimlesh.50
drugs include aminoglycosides, thioamides, fluoro- • Aminoglycoside or capreomycin should be one of the
quinolones, cycloserine and para-aminosalicylic acid medicines as studies have indicated that its use is a
(PAS). They are enumerated in Table 36.2.3. predictor of culture conversions and survival.45
• Use bactericidal drugs as far as possible.
Principles of Treatment of MDR-TB • Treatment should be given for at least 12 months after
M. tuberculosis cultures have converted to negative.
• MDR-TB should always be treated in consultation with • In children with HIV infection or cavitary lesions it is
a clinician who has experience in treating the disease. extended to 24 months.46
• Patients should be treated with at least 2 or preferably • Intermittent regimens are not recommended.47
3 to 4 medications, to which the strain of the patient • If patient’s M. tuberculosis culture remains positive
or source case is known or likely to be susceptible. after 4 to 5 months of treatment it should be tested
514
for susceptibility to first-and second-line drugs. If this ascertained again, appropriate specimen should be
is not available as in most centers in our country collected for demonstration of M tuberculosis and category
at least two new drugs should be added while 2 treatment be started (2 SHRZE 1 HRZE 5 HRE). The
continuing original medication. If available, and family should be counseled to achieve 100% compliance.
patient is clinically stable it is preferable to wait for Children who are already on category 2 regimen and do
susceptibility studies and add drugs accordingly. not show improvement even after 3 months of intensive
• If patient develops an adverse drug reaction, the phase may be considered for treatment regimen for MDR-
offending drug can be removed and the rest of the TB in a TB Hospital which is equipped for this under
regimen continued. Alternatively, a new medication WHO program of treating MDR tuberculosis.
can be substituted. In general the first-line drugs are
well tolerated by children but adverse effects with Treatment of Drug-resistant Infection
second-line drugs are higher. Children taking second-
line drugs need to be closely monitored and liver All children with infection caused by an MDR strain of
enzymes, renal functions and hearing tests done M. tuberculosis should be treated. A difficult issue is
periodically. treatment of children who have had recent (< 3 months)
close exposure to an adult with MDR-TB but whose
Treatment of Drug-resistant Tuberculosis Disease Mantoux test is negative. In a similar situation but when
the adult has drug susceptible disease the child is given
Even under ideal conditions, M. tuberculosis is isolated INH and the Mantoux is repeated 3 months after
from sputum or gastric aspirate of only 50% of children exposure has ended. Because of toxicity of drugs used
with pulmonary tuberculosis, while culture yields from for MDR-TB the risk benefit has to be evaluated.49 But,
other anatomic sites are lower. For this reason, the since children less than 2 years have risk of rapidly
clinician needs to be aware of the resistance pattern in developing life-threatening tuberculosis, they should be
the community. Also, since the vast majority of resistance treated. If the Mantoux test remains negative 3 months
in children is primary, susceptibility information can after exposure has ended, the treatment can be stopped.2
come from the M. tuberculosis isolate that is obtained from Also, any child having any immunocompromising
the adult who transmitted the infection. condition, i.e. AIDS should be treated. For other details
refer to Chapter 36.1.
Children with Tuberculosis Disease with Known Adult Another suggested approach to design a treatment
Patients with MDR Tuberculosis regimen for MDR-TB is given in Figure 36.2.1.
All children with MDR tuberculosis need an individual-
ized treatment regimen (ITR). For children with known
Monitoring of Treatment
adult contacts and the sensitivity of M. tuberculosis is It is recommended that children getting treatment of
known, following principle maybe followed for ITR. MDR-TB should receive supervised treatment to ensure
Children first should receive any oral first-line agents to 100% adherence. The person giving medications should
which the isolate (from adult contact) is sensitive. observe for side-effects daily and report to doctor
Second, all regimens should include an injectable agent
regularly. Sputum/gastric aspirate should be done every
for a minimum of six months after culture conversion,
month and treatment is continued for 18 to 24 months
and an oral quinolone for the duration of therapy.
till 12 consecutive cultures are negative.48
Children who do not yet have five drugs in their regi-
men should receive additional second-line drugs In the pediatric tuberculosis clinic at All India Institute
(ethionamide, cycloserine or PAS). If a strain is highly of Medical Sciences all children who fail to respond to
resistant and the child’s regimen still contains less than category 2 regimen (drugs are used daily and not
five drugs, additional agents with known antituberculo- intermittent) for 3 months are admitted in-hospital,
sis activity (e.g. amoxicillin/clavulanate, linezolid, diagnosis is ascertained again, sputum/gastric aspirates,
clarithromycin) can be added.48 bronchoscopic lavage, FNAC aspirate from lymph nodes
are sent for M. tuberculosis culture and child is started on
Children with Tuberculosis Disease individualized treatment regimen (ITR) (as described
without Known Contact above). Child is observed for at least two to three weeks
These are children who fail to respond to appropriate in hospital for drug toxicity and parents are counseled
antituberculosis treatment. The treatment failure maybe about adherence. After three week of observation child
due to several reasons including inappropriate regimen, is followed up every 2 to 4 weeks till therapy is
poor adherence or wrong diagnosis. In this group it is completed. After completing the therapy child is
recommended that the diagnosis of TB should be followed every 3 month for at least 2 years.
515
Fig. 36.2.1: Suggested approach to designing a treatment regimen for MDR-TB
Improvement in the result of bacteriologic tests resistant to most drugs and sensitive to only one or two
(sputum/gastric lavage, etc.) is the main marker of weak drugs.51 Surgery remains a crucial adjunct to
response but decreased fever, cough, sputum and gain medical therapy for the treatment of MDR-TB and
in weight are important indirect evidences of success of medically failure lesions. Proper selection of the patients
chemotherapy. Radiological improvement may lag and early decision for surgical intervention can achieve
behind other changes. a high success rate and can salvage the lung parenchyma
in this difficult group of patients. Resectional surgery
In general, the first-line drugs are well tolerated by
has a role in patients with predominantly unilateral or
children, and monitoring for adverse reactions by
localized disease with adequate respiratory reserve and
laboratory testing is unnecessary. While children usually
in whom chemotherapy alone has failed. Surgery is
tolerate the second-line drugs better than adults do, the usually considered when following criteria are met:
rates of adverse reactions among children are much higher i. An adequate chemotherapeutic regimen including both
than for the first-line drugs. Children taking ethionamide first and second-line antituberculosis medication have
frequently develop gastrointestinal disturbances and failed to cure.
rarely hepatitis. Aminoglycosides can cause renal toxicity ii. The extent of disease is limited enough to necessitate
and eighth cranial nerve dysfunction. Cycloserine, though, only a lobectomy or pneumonectomy.
generally well tolerated can rarely affect central nervous iii. The remaining lung tissue is relatively devoid of
system and cause personality disturbances. Ethambutol tuberculosis.
is reported to cause optic neuritis and children taking this
drug should have visual testing but it is not true as has Role of Immunotherapy
been demonstrated by Seth et al.50 Monitoring of liver and Immunotherapy with M. vaccae vaccine has been used
renal functions and hearing tests are needed periodically. in small trials in adult patients. Results of these trials
have shown some benefit.52 A series of small trials in
Role of Surgery Argentina, India, Nigeria, Romania, South Africa and
Resectional surgery is a useful component of treatment Vietnam have pioneered the way forward, disclosing
of MDR-TB in adults infected with bacilli which are geographic variability, with South Africa as the only
516
country where almost no effects were recorded. Table 36.2.5: Some of the older drugs and newer drugs
Together the studies have shown that a single dose may with potential of being an anti-TB agent at various stages
not be sufficient. These studies have confirmed the of development
mode of action of M. vaccae to be regulation of cell- Drugs
mediated immunity with enhancement of Th1 and
• Older drugs
down-regulation of Th 2. Benefits have been shown in
Rifamaycin derivatives
faster bacteriological conversion, reduction in ESR,
Rifapentine
recovery of body weight and resolution of radiological Rifabutin
opacities, leading to better recovery from the disease
• Fluoroquinolones
even when given to patients receiving directly observed
Ofloxacin
therapy, short-course (DOTS). There are currently no Sparfloxacin
reports of immunotherapy in pediatric drug-resistant Levofloxacin
cases. Moxifloxacin
Gatifloxacin
Cytokine Therapy • Newer drugs
Diarylquinoline
The other agents investigated include aerosolized
R 207910/TMC 207
INF-γ, granulocyte—macrophage colony— stimulating
Nitroimidazopyran
factor—aerosolized IFN-α, and low dose recombinant
PA-824
human interleukin-2 as an adjunctive treatment for
Nitro-dihydroimidazo-oxazole
patients with MDR-TB.
OPC 67683
A number of other nonspecific immunopotentiating
Pyrrole
agents are listed in Table 36.2.4.
LL3858, LL3522
Table 36.2.4: Other agents used in the treatment Macrolides
of MDR-TB Clarithromycin
Telithromycin
• Thalidomide
Oxazolidinones
• Pentoxifylline
Linezolid
• Levamisole PNU—100480
• Transfer factor Diamine
• Inhibitors of transforming growth factor β [TGF-β] SQ 109
• Interlukin-12 [1L-12] Ring-substituted imidazoles
• Interferon-α [IFN- α]
• Imiquimod (an oral agent that stimulates the production
of interferon-α) from the patient. DOTS regime uses isoniazid and
rifampicin as the basis of the short-course chemotherapy.
Patients with MDR-TB are infected with strains resistant
Newer Drugs to at least isoniazid and rifampicin, thus, the failure of
Even though the need for newer drugs to combat MDR- DOTS in MDR-TB. To combat this problem, in 1997 WHO
TB exists, there are no drugs showing promise. In the Global Tuberculosis Program, CDC, IUATLD got
recent past there have been few reports qouting the value together in an effort to expand DOTS in manner that
of agents like imipenem, amoxicillin-clavulanic acid, would take into account MDR-TB. In early 1999, the
interferon gamma via aerosol, newer rifamycins WHO formally announced the establishment of a
(rifabutin, rifamycin, rifatazil) and recombinant human working group to plan the implementation of pilot DOTS
interleukin 2.53 A recently investigated group of com- Plus interventions.55
pounds which appears encouraging is oxazolidinones.54 Two basic approaches to DOTS Plus have been
Table 36.2.5 gives the list of some of the older drugs proposed: individualized treatment regimens and
and newer drugs with potential of being anti-TB agent. standardized regimens incorporating second and third-
line drugs.
In individualized treatment regimens (ITRS), the
Concept of DOTS Plus
regimen is designed as per the resistance pattern of the
In spite of introduction of highly effective therapy for strain infecting each patient. ITRS is unlikely to fail since
tuberculosis in the form of DOTS (Directly observed inadvertent monotherapy would not occur, but they
therapy, short-course) treatment failure continues. Strict require intensive laboratory facilities. It has limited
implementation of DOTS removes the onus of adherence applicability in resource poor countries.
517
Standardized approach can be of two types. Firstly, limited number of highly specialized centers, at least one
uniform throughout the world and, secondly, adapted in each state, which have ready access to an RNTCP
to local epidemiology according to common resistance accredited culture and DST laboratory, with qualified
patterns identified in a given population. The advantage staff available to manage patients, using standardized
of such a regime is its lower cost, less laboratory work second-line drug regimens given under daily DOT and
and less technical expertise required to administer it. standardized follow-up protocols, and have systems in
As we know, the way towards tuberculosis place to deliver ambulatory DOT after an initial short
elimination is by effectively treating all cases. DOTS period of inpatients care to stabilize the patients on the
was envisioned as the most effective means of doing second-line drug regimen, and with a logistics system
it, but with the advent of MDR-TB it is failing. and standardized information system in place.
Furthermore, if rifampicin and isoniazid based regimes Following months of preparatory activity, DOTS-Plus
are used for patients resistant to these medications, it activities under RNCTP have been initiated in the states
not only is a waste of resources, but also serves as a of Gujarat and Maharashtra for the last few months. On
means of acquiring resistance to ethambutol, pyrazina- the 29th of August 2007, Gujarat became the first state in
mide and streptomycin. In such a scenario, where drug the country to initiate MDR-TB patients on treatment
susceptible and drug-resistance disease coexist, DOTS under RNTCP with its Category IV regimen. On this date,
plus needs to be evaluated. When treating children 14 confirmed MDR-TB patients were initiated on
with MDR-TB, the treating expert will have to be treatment under RNTCP in Gujarat.
guided by the drug susceptibility studies of their adult Similar provision will be extended to other states in
infectious source. the phased manner.
RNTCP Launches Category IV Treatment (DOTS-Plus Prevention

Treatment) for Multidrug-resistant Tuberculosis The prevention of drug-resistant tuberculosis depends on
Patients in Gujarat on the 29th of August 2007 effective use of the principles of tuberculosis control. The
The emergence of resistance to drugs used to treat timely identification and adequate treatment of patients
tuberculosis (TB), and particularly multidrug-resistance who have MDR-TB infection and disease is of foremost
TB (MDR-TB), has become a significant public health importance in preventing further spread. The integrity of
problem in a number of countries and an obstacle of public health system which has the responsibly, do tracing
effective TB control. To address this issue, the Revised of source case through contact investigation of children of
National Tuberculosis Control Program (RNTCP) has an adult with MDR tuberculosis. All patients with
initiated DOTS-Plus activities under the program for the tuberculosis should be treated by clinicians who have some
appropriate management of MDR-TB patients and to expertise in TB treatment. Drug regimens should be
prevent any further propagation and dissemination of adequate and simple errors avoided.
MDR-TB.
The RNTCP views the treatment of MDR-TB patients HIGHLIGHTS
as a “standard of care” issue. Recognizing that the
• We are living in a time in which a series of MDR-TB
diagnosis and treatment of MDR-TB cases is complex,
epidemics are progressing unchallenged.
RNTCP has developed national guidelines based on
• In a complex epidemic where drug-susceptible and
the WHO recommended international DOTS-Plus
drug-resistant disease coexist, DOTS which relies on
guidelines. These guidelines promote full integration of
fixed-dose, short-course chemotherapy may not be
DOTS and DOTS-Plus activities under the RNCCP, so
effective in preventing the progression of this
that patients with MDR-TB are both correctly identified
epidemic.
and properly managed under the guidelines set out in
this document. • Some drug regimens have been highlighted for the
The diagnosis of MDR-TB will be made at a network treatment of latent MDR-TB or the disease in a child
of at least 24 RNTCP state level Intermediate Reference with MDR-TB by literature search.
Laboratories (IRLs) accredited to perform culture and • There is an urgent need to seriously consider the
drug sensitivity testing (DST). RNCTP has initiated the application of DOTS-Plus to the National Tuberculosis
establishment of the IRL network in a phased manner at Programs already committed to DOTS. This has
National Tuberculosis Institute (NTI), Bengaluru already been started in India including children. This
(formerly Bangalore) LRS Institute, New Delhi; and has been possible with International cooperation for
JALMA, Agra. The treatment of MDR-TB patients is clinical and laboratory support and financing and
planned to being at DOTS-Plus sites established in a drug supply.
518
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37 Organization of Pediatric
Tuberculosis and HIV Clinic
Vimlesh Seth
INTRODUCTION extensive bacillary load. Even when the disease develops

endogenously, it is a severe pulmonary disease like adults.
Inspite of a National Tuberculosis Control Program in
Till recently in the National program, emphasis has
India since 1962 with modifications, off and on, the
been on directly observed treatment short-course (DOTS)
problem of tuberculosis still exists in epidemic proportion.
therapy based on the principle of sputum-positivity or
Since the beginning, emphasis has been on the
severe lung disease in sputum negative adults. Now
management in adults both in diagnostic parameters and
India is the first country to adopt DOTS for children.
use of various drug regimens for treatment. The basic
Though still there are some lacunae discussed elsewhere
assumption was that children acquire infection from adults
and hence the transmission should be reduced by treating by the program managers themselves.
adults. Further the disease is paucibacillary and dose not Over the years, there has been complete dichotomy
contribute to transmission which is a myth. The children in both the diagnostic criteria and treatment regimens
have been completely neglected. Now it is realized that used for children by Pediatricians and Program managers
the children who acquire latent tuberculosis from an of National Tuberculosis Control Program (NTP) and
infectious adult, if neither develop mild pulmonary nor now Revised National Tuberculosis Control Program
disease serious manifestations such as TBM or miliary TB (RNTCP). The current concept of blanket use of
in infancy, they keep on harboring the bacilli. This group intermittent therapy regimens for children advocated in
at a later age, i.e. near adolescence can develop endogenous RNTCP is not very palatable to Pediatricians. The
(cavitary) tuberculosis. Hence, they are a source of children have not been given the due attention they
transmission of TB. Now the importance of latent deserve both for diagnosis and treatment. It is only since
tuberculosis has been recognized, though action being 2004, for the management of tuberculosis in children,
taken to manage it is far from satisfactory in the National there is an attempt to involve Medical Colleges, again
Program atleast in India. An adult patient with under the departments of Internal Medicine. The
tuberculosis in household will transmit the infection to all involvement of Pediatric departments has not been
children in the house and young children are at risk of ensured. Lately with the insistence of the members of
developing disease within a year. Chemoprophylaxis Indian Academy of Pediatrics, a workshop was held in
given to these children may prevent development of illness 2009 in Mumbai. The outcome of which is the publication
in near as well as later in life. Because of nonspecific clinical of guidelines for management of tuberculosis in children
features and difficulty in documenting M. tuberculosis, in (detailed in another chapter) totality barring a few
diagnosis is delayed or children may present with severe specific conditions like MDR-TB, organ specific TB and
and life threatening illness like miliary, disseminated congenital TB. Hence there is hope that some benefit will
disease such as bronchopneumonia and serious forms of be ensured for children. The Government of India with
the help of WHO has opened a DOTS center in every
extrapulmonary tuberculosis like tubercular meningitis.
medical college. To make use of this facility, the Pediatric
BCG which is included in the Universal Program of
departments of all medical colleges should have a
Immunization for children only prevents dissemination
Pediatric TB clinic like all the other super specialties such
but not transmission. In the school age period and before
as neurology, neonatology, oncology and so on.
adolescence, the major manifestations are tuberculous Uptill now in all the conferences organized by
lymphadenitis, pulmonary tuberculosis and its local Tuberculosis managers and TB Hospitals, and TB
complications, skeletal and abdominal tuberculosis. Lobar Association, Pediatrics is represented just in the form of
pneumonia with complication of collapse consolidation one or two lectures by pediatricians who have worked
can lead to bronchiectasis, if not properly treated. Pleural in the field of tuberculosis in children, or a panel
effusion also can lead to collapse and subsequent discussion at the most. In isolation, the pediatricians have
bronchiectasis. In the adolescent age group of 12 years and been holding various regional workshops on the subject.
above, manifestations are like adults, cavitary lesions with The pediatricians are very conscious of the problem more
523
Chapter 37 Organization of Pediatric Tuberculosis and HIV Clinic
so with increasing incidence of HIV/AIDS and MDR-TB regimen. Even if a patient is being treated under DOTS
in adults, a constant threat for childern. There is a TB it is responsibility of treating Pediatrician to follow up
chapter in the Indian Academy of Pediatrics. Two the patient every 4 weeks and monitor for improvement
consensus statements, one on diagnosis and the other in symptoms and weight gain, contact tracing, etc.
on treatment have been published in Indian Pediatrics.1,2 It is important to have separate tuberculosis clinic for
The latter have been published in the 3rd edition of book children immaterial of who is treating. Pediatric
in the form of separate chapter. The latest has been Department of each medical college must have one in
published in Indian Pediatrics 2010 of has been like the other superspeciality, clinics. Seth Vimlesh has
reproduced in this book. Hence now is the time to set up given the following guidelines how to go about it:-
a proper Pediatric TB Clinic in each Pediatric Department.
All India Institute of Medical Sciences (Pediatric STARTING TUBERCULOSIS CLINIC FOR CHILDREN
department) has been running a separate Pediatric TB • Minimum infrastructure
clinic for almost five decades. In the beginning the A separate day, with involvement of atleast one
proforma used was difficult to analyze. Now there is a faculty member and junior and senior residents of,
well designed patient case record form (previously called his unit equipments for measuring weight and height
precoded proforma). The latter ensures better case of infants and children, facility for CXR, (a committed
records, which can be objectively analyzed. The junior radiologist for review of xrays) USG, mantoux test,
residents are compelled to fill up these proformas and basic microbiology services for smear and culture.
there is a check list for follow-up visits. Each case is These facilities are available in every medical college.
worked up by a junior resident but drug regimen is Involvement of the microbiologist like radiologist is
decided by the faculty member along with senior resident mandatory to ensure that all efforts have been made
depending upon the system involved and severity of to look for AFB on smear and culture.
disease. (See annexures I, II and III). • Personnel
It is recommended by the adult TB experts that all A pediatrician who is interested in tuberculosis, nurse
children with any type of tuberculosis should be treated (for doing gastric aspirates and induced sputum,
with DOTS. (Table 37.1) manoux test, dispensing medications, counseling for
To assist in calculating required dosages and good adherence), medical social worker (counseling),
administration of anti-TB drugs for children, medication DOT worker from the DOT center for dispensing
should be made available in the form of combipacks in medicines, psychologist (for special conunselling for
patient-wise boxes, linked to the child’s weight. These
HIV).
are now available from DOT center but need some
modifications. Try to involve a DOT provider from the
Methods
DOT center so that two purposes are taken care off i) the
children will get medicine and ii) the information as per For starting pediatric TB clinic following steps should
DOTS criteria will be collected. be followed.
For details of treatment of children under Revised
National Tuberculosis Control Program, specific Step 1
guidelines have been made by a group of renowned
Fix a day for clinic. Depending on the number of patient,
Pediatricians of Indian Academy of Pediatrics, TB experts
number of clinics can be fixed per week. It is important
and members of Central TB Division of Ministry of
that it should be at least once a week.
Health. However, it is neither feasible and practical nor
right to put all the children under DOTS because the kind
Step 2
of infrastructure required for this is neither available for
all types of TB nor for all children. For uniformity of Prepare a case record form for diagnosis, treatment and
treatment regimen, it is suggested that all children should follow up of childhood TB. (Annexure I, II, III, IV) To
be categorized as DOTS and if it is not feasible to send have uniformity as per WHO guidelines, similar table
the patients to DOTS center, they should receive same has been designed by Seth et al. for continous therapy
regimen except that it will be daily inplace of intermittent which is given Table 37.2.
1. Consensus statement recommendation of Indian Academy of Pediatrics, 1997: Inidan-Pediatr 1997;34:

1093-6.
2. Diagnosis of childhood tuberculosis. Consensus statement of Indian Academy of Pediatrics working Group-Indian Pediatr
2004;41:146-55.
524
Table 37.1: Treatment categories and regimens as per DOTS
Treatment category Type of patients TB treatment regimens

IP CP
Category I New sputum smear-positive PTB, 2H3R3Z3E3*** 4H3R3
Seriously ill* sputum smear-negative PTB,
Seriously ill EPTB
Category II Sputum smear-positive relapse, 2S3H3R3Z3E3/ 5H3R3E3
Sputum smear-positive treatment failure, 1H3R3Z3E3
Sputum smear-positive treatment after default
Category III Sp utum smear-negative and EPTB not seriously ill** 2H3R3Z3 4H3R3
TB–Tuberculosis, CAT–Category, H–Isoniazid, R–Rifampicin, Z–Pyrazinamide, E–Ethambutol, S–Streptomycin, PTB–Pulmonary TB, EPTB–
Extrapulmonary TB, IP–Intensive Phase, CP–Continuation Phase.
*Seriously ill sputum smear-negative PTB includes all forms PTB other than primary complex. Seriously ill EPTB includes TB meningitis
(TBM), disseminated/miliary TB, TB pericarditis, TB peritonitis and intestinal TB, bilateral or extensive pleurisy, spinal TB, with or without
neurological complications, genito-urinary tract TB, bone and joint TB.
**Not seriously ill EPTB includes lymph node TB and unilateral pleural effusion.
***Prefix indicates month and subscript indicates thrice weekly.
Step 3 Screening of Patients to be Registered for TB Clinic

Prepare a case record form for HIV clinic (Annexure V) This must be done by the senior resistant who has got
that include history, examination, and followup some knowledge about TB and faculty incharge knows
information. what is expected of him. The patients registered must
have the benefit of treatment in the Pediatric TB clinic.
Step 4 The senior resident sees that at least the basic
investigations of Mantoux and X-ray chest and family
Prepare treatment and follow up guidelines. Hand out
survey have been done. This would be able to find the
of chapter 29 and 34 on principles of treatment and
management of TB in children are given to the residents adult who is diseased in the family. If all this is available,
on the 1st day of their posting in the Pediatric TB clinic then only the case is registered. Senior resident must
so that they understand and revise their essential known how and what medicines will be dispensed to
knowledge about the disease in pediatrics. They are the patient. For this purpose one DOT worker should be
explained by the faculty incharge about how to fill the posted for the pediatric TB clinic out of the strength of
case record form explaining the importance of filling those with internal medicine. This will help both in the
them accurately and completely. Each case is discussed proper screening and dispensing of medicines at the
with the faculty incharge and the decision to which clinic. Besides DOTS, for pediatric TB clinic at AIIMS,
category of treatment will be administered is taken. Those the medicines are provided by a Non-Governmental
who can be put on DOTS should be done so and Organization (NGO) with limited budget. Hence only
medicines procured by DOT worker who is involved and select cases are registered, e.g. pulmonary and naïve case
made responsible to report to the faculty in the clinic of peripheral lymphadenitis so that full treatment is
about the case. ensured. Few cases of resistant TB detected at AIIMS are
also looked after in the clinic on ambulatory basis after
Step 5 initial stabilization in the isolation bed of the pediatric
ward. They are usually of peripheral lymphadenitis.
Ensure that on the day of TB clinic one responsible person
is available to take care of patients attending the clinic. It
INSTRUCTIONS FOR RESIDENT DOCTOR
is important that some of the staff including doctors is
present in clinic. It is important that the person sitting in A written protocol should be available for the doctors
the clinic is interested in TB. If a child or parents sees attending the clinic. It is desirable that all residents must
same doctor each time in clinic, they will come to clinic have the latest booklet on RNTCP published by Central
regularly. This helps both in capacity building for the TB Division of Ministry of Health and Family Welfare,
clinical and better follow up of the patient. To ensure New Delhi. These can be procured from Deputy Director
this at AIIMS, junior resident is made to work up the General of Central TB Division of Ministry of Health. This
case and present to the senior resident who in turn along booklet is revised from time to time and the latest should
with junior resident discusses it with the faculty. be collected for the residents. This will help the residents
525
to have the latest insight about RNTCP in India. The NEW CASES
regimens under non-DOTS program as used at AIIMS
pediatric TB clinic are given in (Table 37.2). Registration of Patients in Tuberculosis Clinic
Duration of interruption of treatment and suggested A doctor (senior resident doctor) shall screen all the
regimens are given in Table 37.3. referred patients for registration. He/she will
Dosages of antituberculosis drugs in daily and recommend registration of all the patients who have
intermittent regimen is given in (Table 37.4). probable or confirmed TB. If diagnosis of tuberculosis is
in doubt or the investigations are not complete, the
FLOW OF PATIENTS IN TB CLINIC resident doctor shall fill appropriate investigation forms
and give only symptomatic treatment and ask them to
Diagnosis and Referral to TB Clinic come on next visit for registration.
It is important that a written protocol for diagnosis of TB
is circulated to all the doctors in the hospital particularly Work-up
Pediatric surgery department who after initial treatment New cases once registered should be worked up by a
of TB lymphadenitis refer the children to Pediatric TB junior resident in a designated room and all the history
Clinic mainly for the procurement of antituberculosis and examination findings should be filled up on patient
drugs. This is discourged and such cases are only advised case record forms (Annexure I, II, III). The case is then
proper regimen and sent back to the parent department. presented to the senior resident and then faculty in charge
Based on clinical findings, laboratory results and protocol and diagnosis made and appropriate regimen advised.
cases are defined as suspect TB, probable TB and Case Record Form (Annexure IV) has been designed
confirmed TB. It should be made mandatory to send all for other medical college to send their data to the tertiary
the patients with probable and confirmed TB to TB clinic. care center like All India Institute of Medical Sciences
To have uniformity, it is desirable that unless it is an (AIIMS). The latter should make a concerted effort to have
emergency, all the patients are referred to TB clinic a research project funded from either Indian Council of
without starting ATT. Medical Research of Government of India (GOI) or
Table 37.2: Clinical categories of WHO and, the suggested conditions in children accordingly followed
drug regimens in pediatric TB clinic in children
Categories Suggested by Suggested conditions Suggested
• Category I New sputum positive Pulmonary PPD, TBL 2HRZE
TB (PTB) Massive pleural effusion 4HR*
New smear-negative PTB Abdominal TB
with extensive parenchymal Osteoarticular TB
involvement Genitourinary TB
New cases of severe forms of CNS TB
extrapulmonary TB. Pericardial TB
• Category II Relapse Relapse 2SHRZE
Treatment failure Treatment failure 1HRZE
Return after adult default Interrupted treatment 5HRE
• Category III Sputum negative pulmonary Single lymph node 2HRZ
with limited parenchymal Small effusion 4HR
involvement Extrapulmonary Skin TB
TB (less severe forms) PPC
PPC–Pulmonary Primary Complex, PPD–Progressive Primary Disease,
TBL–Tubercular Lymphadenitis, CNS TB–Central Nervous System Tuberculosis,
2HRZE 4HR-2 months of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampicin,
2 SHRZE 1 HRZE 5HRE – first two months daily isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin followed by one month
of isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 5 months of isoniazid, rifampicin and ethambutol,
2HRZ 4HR–2 months of isoniazid, rifampicin and pyrazinamide, followed by 4 months of isoniazid and rifampicin.
*10 HR in cases of osteoarticular and CNS tuberculosis.
526
S. No. Duration of therapy Duration of interruption Decision

1. Upto 4 weeks <2 weeks Resume original regimen
>2 weeks Reassess and restart appropriate regimen 4-7 2.
2. 4-7 weeks <2 weeks Resume original regimen
>2-8 weeks Extend intensive phase by 1 month
>8 weeks Category II therapy*
3. >8 weeks >2 weeks: Not active disease Resume therapy
>2 weeks: Active disease Category II
* DOTS and Non-DOTS category of treatment keeping in mind the original regimen on which the patient was started.
PS: Whenever the treatment is interrupted for more than 2 weeks, the child should be reassessed clinically and radiologically, wherever
possible bacteriological examination should be performed, by gastric lavage in younger children and induced sputum or spontancously
collected sputum. Technique of induction of sputum is described in chapter on pulmonary tuberculosis.
Department of Biotechnology (GOI) to employ personnel intensive phase he should be instructed to come on
for collating this as National Data Base. AIIMS should alternate days to collect medicines. The referral to the
hold a meeting involving representatives of 5 zones of resident doctor is required for the following:
India, Center, North, West, East and South. In each of i. All patients in first two months of treatment where
these centers one medical college should be designated full workup is still awaited, or where symptom relief
to collect data as suggested in the chapter research is not adequately documented.
agenda. This will provide national data base of pediatric ii. Doubtful or poor compliance.
TB with uniform criteria of diagnosis, management of iii. Self reported adverse effects or new symptoms.
TB in children. iv. No weight gain on 2 successive visits.
Initial Evaluation Sheet to be Filled by DOT Worker on v. Completion of treatment duration prior to stopping
All Old Patients whether on DOT on non DOT therapy and treatment.
to be checked by senior resident vi. Every two months for need to decide if
X-ray is indicated.
1. Improvement in symptoms
The referral to the drug collection center is done if
• Fever Yes/no
a. Patient is doing well,
• Days to Number of days
b. Compliance is documented to be normal.
defervescence c. No new adverse effect.
• Anorexia Improving/Improved/
unchanged CHECK LIST FOR THE SENIOR RESIDENT DOCTOR ON
• LN size Increased/same/ FOLLOW-UP VISIT
decreased
• Cough Increased/same/ First He/She should check the Case Record form of
decreased Annexure I, II, III
2. Weight kg
3. Height cm 1. Mantoux of siblings less than 5 years preferably 10
4. Compliance Color of urine years.
2. X-ray of siblings, parents, grand parents and servant,
INH test* (urine)
if any.
No. of sachets (empty)
3. Enter family survey X-ray reports.
5. Self reported adverse effects
a.
b. Table 37.4: Dosage of drug in daily intermittent
6. Cost incurred on drugs in the previous months. regimen (mg/kg/day)
7. Source of medicine DOT center, NGO, purchased Medicine Daily Intermittent
from market. Isoniazid 5 10
8. Any other family member fallen sick. Pyrazinamide 30 50
Social scientist will then decide either to send the Rifampicin 10 10
patient for further evaluation by the resident doctor or Ethambutol 20 30
Streptomycin I/M 25 —
send the patient to collect the medicines for next two
Ciproflox. when used 20 —
weeks if he is in the continuation phase and during
527
4. Check drugs compliance and scheduled attendance make these sachets in the clinic premises. The patient
in clinic. should be clearly explained the importance of procuring
5. Record symptoms. the drug which is not available.
6. Follow-up proforma to be filled every month for 1st
3 months then 3 monthly. Old Patients
7. Hemogram (Absolute Eosinophil count). All patients started on antituberculosis therapy should
8. Category based diagnosis first be examined by senior resident doctor who evaluates
i. Pulmonary specify the type PPC, PPD, cavitary, the child for improvement in symptoms, drug
pronchopnevmonia, collapse consolidation, compliance, weight, height gain and any adverse effects.
disseminated. The evaluation procedure for that is as follows:
ii. Lymph Nodes. Initial evaluation sheet to be filled by social worker
iii. Neurotuberculosis. with the involvement of DOT worker.
iv. Bone Tuberculosis. 1. Improvement in symptoms
v. Abdominal Tuberculosis. • Fever Yes/no
9. Category-based treatment. • Days to Number of days
10. Check compliance defervescence
• Status of symptoms • Anorexia Improving/Improved/
• Weight gain unchanged
• Compliance of the Regimen. • LN size Increased/same/
1. = 100% drug dosage intake decreased
2. = 80 to 100% drug dosage intake • Cough Increased/same/
3. = 70 to 80% drug dosage intake decreased
4. = 60 to 70% drug dosage intake 2. Weight kg
5. = 50 to 60% drug dosage intake 3. Height cm
6. = <50% drug dosage intake 4. Compliance Color of urine
The resident doctor should also explain the drugs to INH test (urine)
patients/attendants and check whether the social worker No. of sachets (empty)
5. Self reported adverse effects
has done it properly. Should give requisition forms for
a.
family survey and Mantoux test of children (sibs) below
b.
5 years in all the patients. The resident doctor should
She should also evaluate socioeconomic impact of
direct the patients for drugs to other room where the drug
disease by asking:
are given at least for fifteen days. Under DOTS the drugs 6. Cost incurred on drugs in the previous months?
should be given as per advise recommended in DOTS. 7. Any other family member fallen sick?
Responsibility of the Senior Resident Doctor
Resident should then Decide
1. Evaluation of patients, referred for registration.
1. To either send the patient for further evaluation by
2. Evaluate completeness of the case record forms.
the consultant doctor or assess the patient to collect
3. Evaluation of all patients in 1st 3 months of treatment.
medicines for next 2 weeks. The referral to the
4. Supervise treatment or research protocols.
consultant doctor is required for:
i. All patient in first three months of Rx, where full
Drug Collection Center
workup is still awaited, or where symptom relief
All patients maybe dispensed drugs for fifteen days in is not adequately documented.
the 1st three months and then every one month by the ii. Doubtful or poor compliance.
dispenser (DOT worker). The dispenser should explain iii. Self reported adverse effects or new symptoms.
by demonstrating the drug bottle/strip and the amount iv. Failure to gain weight on 2 successive visits.
to be consumed. He/she should ask the attendant of the v. Completion of treatment duration prior to
patient to make 15/30 sachets of the dispensed drugs stopping treatment.
(one for each day) and physically check these before the vi. The X-ray done after the intensive phase and then
patient is sent back. In case one or more of these drugs at the end of treatment.
have to be bought from the open market, the attendant If no problem send the patient to the drug
should be encouraged to procure that drug and then collection center as the:
528
a. Patients is doing well, 8. Any increase in size on Rx.

b. Compliance is documented to be normal 9. LN size at the end of 6 months in (cm).
c. No new adverse effects seen. 10. LN size increase during follow-up:
2. Consultant doctor should see the child at the end of 11. Chest X-ray finding (describe).
continuation phase of the regimen. All patients started Health Education by social worker to parents and
on antituberculosis drugs should be followed every child care taker. It should be done as per the following
2 to 4 weeks till the regimen is over. After that, every
proforma:- This should be computer typed in big font
6 months for two visits and then every year for 4 visits,
and a poster formed and hanged at the entry of TB clinic.
for a total of 3½ years.
1. Tuberculosis (TB) is a common disease in India and
3. On each visit a detailed clinical symptomatology, i.e.
may occur in all age groups including very young
fever, cough, appetite should be assessed. A detailed
children.
physical examination for weight gain, toxicity of
2. TB is caused by a bacterium named Mycobacterium
antituberculosis drugs should be done. All findings
tuberculosis.
should be entered at appropriate place in the file.
4. Repeat X-ray films – Repeat X-ray should be done at 3. Large number of these bacteria are added to
the end of intensive phase or earlier if there is no surrounding air by a person suffering from
improvement. X-ray film should be done at the end tuberculosis when he/she coughs. These bacteria
of therapy and then every year for 3 to 4 years. enter in the lung of healthy people through air.
All X-ray film shall be kept in the envelops along with Once the bacteria in the lungs of an individual they
the requisition slip and the files with X-ray maybe handed may produce disease irrespective of the caste,
over to staff helping in dispensing the medicines. X-ray religion, sex or age of person. The chance of disease
should be reviewed every week of new cases and old is more in children, elderly and malnourished.
cases with the radiologist who is particularly interested 4. TB can affect all the organs of body including lungs,
in Pediatric Imaging. intestine, brain, bones, etc. the spread of disease in
the body is more common in children because of less
Other Investigations resistance, thus it is a serious disease in children.
5. Unlike adults, TB in children may not manifest with
A base line LFTs of patients with severe malnutrition, specific symptoms (i.e. cough, blood in sputum). In
progressive primary disease, disseminated tuberculosis, children the symptoms may be fever, cough, not
suspected viral hepatitis, drug toxicity should be carried gaining weight, or weight loss and decreased
out. The same shall be repeated only if hepatotoxicity appetite.
occurs. 6. TB is curable. The treatment is longer. The number of
medications and duration of treatment depends on
Change in Regimen the type of disease. It is decided by the doctor.
The antituberculosis drug regimen decided at the time 7. If treatment of TB is taken irregularly (i.e. less doses,
of registration shall be continued. Any change if indicated less duration) the disease may recur and may not
shall be only after discussion with consultant doctor of respond to routine drugs. This is called resistant
tuberculosis clinic. tuberculosis.
Suggested workup plan for lymph node tuber- 8. Treatment of resistant tuberculosis is difficult and
culosis very expensive. Hence for prevention of resistance
1. Presence of systemic symptoms. regular treatment as advised by doctor should be
2. Mantoux test positive in mm. taken.
3. LN group involved – Cervical 9. TB is not a hereditary disease as it is caused by a
Axillary bacteria. However, it may occur in multiple members
Inguinal of a family because of infectious nature of disease.
4. FNAC 10. The spread of TB can be prevented by observing
Necrosis certain precautions such as early diagnosis of disease,
AFB the patient should like regular treatment, patient
Granuloma should cough with a cloth covering his mouth and
Solid Media proper disposal of sputum of the patient.
5. Culture Mycobact, method 11. BCG vaccination at birth provides protection against
Liquid Media severe form of tuberculosis.
Sensitivity 12. Children suffering from tuberculosis do not need
6. BCG Yes/No isolation. They should be treated with drugs and
7. Rx regimen. nutritious diet at home.
529
ANNEXURE I
CASE RECORD FORM
PEDIATRIC T.B. CLINIC
Date of Registration ______________

1. T.B. Clinic No.
No. Year
Name :_____________________________ 3. Age in months
Postal Address:______________________ 4. Sex 1. Male

2. Female
____________________________________
____________________________________ 1. Yes 2. No Duration in months

5-6 Fever
7-8 Cough
9-10 Weight Loss/
Not gaining weight
11-12 Loss of appetite
13-14 Lymph nodes enlarged
15-16 Contact with TB
patient at home
Family History
17. 1. Positive Present Past If yes Type of TB
2. Negative 1. Yes 1. Yes How many month 1. Pulmonary
2. No 2. No ago 2. Lymph node
3. Abdominal
4. Other (specify)
18-21 Mother
22-25 Father
26-29 Sibling
30-33 Sibling
530
34-37 Sibling
38-41 Grandmother
42-45 Grandfather
Others
Immunization
46-48 BCG 1. Given 1. Scar positive Age at BCG vaccination
2. Not Given 2. Scar negative in months (*)
* 00 month = at birth or within the first month
Physical Examination
49. Weight (kg)
50. Nutritional status (Grade) Percentile (NCHS)
Percentile (KN Aggarwal)

1. Normal
2. PEM grade 1
3. PEM grade 2
4. PEM grade 3
5. PEM grade 4
51-52 Height in cms Percentile (NCHS)
Percentile (KN Aggarwal)

Lymph Nodes
Present Site Gr. of Size Number Consistency Sinus
1. Yes 1. Right LN in cms 1. Sing. 1. Soft 1. Matt. Mob. 1. Yes
2. No 2. Left 1. <1 2. Mult. 2. Firm 2. Matt. Fix. 2. No
3. Bilat 3. Bilat 2. 1-2 3. Fluc. 3. Disc. Mob
3. 2-3 4. Hard 4. Disc. Fix
4. >3
53-59 Cervical
1. Ant cerv.
2. Post cerv.
3. Subocc.
531
4. Subman
5. Sub ment.
6. Jug dig.
7. Superf.
8. Deep
60-68. Axillary
1. Central
2. Apical
3. Lateral
* Sing – Single; Mult – Multiple; Fluc – Fluctuant; Matt – Matted; Mob – Mobile; Fix – Fixed; Ant – Anterior; Post – Posterior;
Cerv – Cervical; Subocc – Suboccipital; Subman – Submandibular; Submen – Submental; Jug dig – Jugulodigastric; Superf –
Superficial
532
69-77. Inguinal
78-86. Other
87-88. Liver Enlarged Cms below costal margin
1. Yes
2. No
89-90. Spleen
91. Chest 1. Clear 5. Decreased air entry

2. Loc. crepts 6. Rhonchi
3. Gen. crepts 7. Others (specify)
4. Bronchial breathing
Investigations
92. Mantoux test
(measurement in mm) (Horizontal) (Vertical)
93. Hemoglobin gms/dl
94. Total leukocyte count (x 103/cumm)
95,96,97,98. Differential leukocyte counts

Polymorphs Lymphocytes Monocytes Eosinophils
99. AST ALT Absolute eosinophilic Count (x 102)
100. Gastric Lavage Induced Sputum Sputum

Smear Smear Smear
Positive (1) Positive (1) Positive (1)
Negative (2) Negative (2) Negative (2)

Culture Culture Culture
Positive (1) Positive (1) Positive (1)
Negative (2) Negative (2) Negative (2)
Smear: Lab Technique Used for Gastric Lavage Loc. crepts – Local crepitations
Culture: Lab Technique Used for Sputum Gen. crepts – General crepitations
SGOT – Aspartate Transaminase
SGPT – Alanine Transaminase
533
1. X-ray film of chest

1. Normal 2. Parenchymal lesion 3. Lymph nodes
4. (2+3) 5. Lobar consolidation 6. Collapse-Consolidation
7. Pleural effusion 8. Bronchopneumonia 9. Miliary
Calcification/Fibrosis
2. Fine needle aspiration cytology (Histopathology report)/Biopsy
1. Necrosis 2. Granuloma 3. AFB
3. CNS Tuberculosis 1. Yes 2. No

(if yes, fill following, if no go to next)
Type of CNS TB
1. Tuberculoma 2. TBM 3. Other – specify

CSF Proteins Sugar Cells
mg/dl
Cells Lymph% Polys

(per cubic ml)
• Smear for AFB
• Culture for AFB
• CT Scan
1. Basal exudates 2. Hydrocephalous 3. Tubercles 4. Infarct 5. Other-specify

Other investigation – specify
• MRI – describe the findings
4. Abdominal Tuberculosis
1. Yes 2. No
If yes, fill following if no go to next type of abdominal tuberculosis
1. Ascitic 2. Intestinal 3. Lymph node 4. Other specify
• Ascitic fluid 1. Done 2. Not done

(if 1 fill following, if 2 go to next)
Protein Sugar Cells AFB smear

gms/dl (per cubic ml) (Present 1, Absent 2)
• Ultrasound abdomen 1. Abnormal 2. Normal

If abnormal describe the findings.
*For other organ involvement
534
5. Osteoarticular TB* 1. Yes 2. No

1. Osteomyelitis, 2. Arthritis
If Arthritis, Joints involved
1. Knee, 2. Hip, 3. Ankle, 4. Others
6. Renal Tuberculosis * 1. Yes 2. No

• Urine AFB smear 1. Yes 2. No
• Culture 1. Yes 2. No
• Ultrasound abdomen
• Intravenous pyelography
• CT abdomen.
* After recording preliminary findings as mentioned, refer the child to orthopedic department and Pediatric Nephrology
clinic respectively.
535
X-ray Review Report of Patient
S. No. Date Sr. No. of X-ray Findings

Parenchymal/Pleural/Nodal
536
FAMILY SURVEY
S. No........................................... X-ray No./Date...........................................
Findings ....................................
Father ................................................................................................................................
Mother ..............................................................................................................................
Siblings: Tuberculin (mx) Test

Age (Years)
Sex Male 1
Female 2 1.
2.
3.
4.
5.
Other relatives:
Grandmother
Grandfather
Treatment Sheet
Treatment Required Out Patient In Patient
Name of Medicine Duration Dosage (mg/kg) Category assigned: DOTS/nonDOTS

(months)
• Intensive phase
I. INH
II. Rifampicin
III. Pyrazinamide
IV. Ethambutol
V. Streptomycin
VI. Others
• Maintenance phase
I. INH
II. Rifampicin
III.Pyrazinamide
IV. Others
537
ANNEXURE II
Check List for the Resident Doctor on Follow-up Visit

1. Mantoux of siblings less than 5 years preferably 10 years.
2. X-ray of siblings, parents, grand parents and servant, if any
3. Enter family survey X-ray reports.
4. Check drugs compliance and scheduled attendance in clinic.
5. Record symptoms.
6. Follow-up, case record form CRF to be filled every month for 1st 3 months then 3 monthly.
7. Hemogram (Absolute eosinophilic count).
8. Category based diagnosis.
i. Lungs.
ii. Lymph Nodes.
iii. Neurotuberculosis.
iv. Bone tuberculosis.
v. Abdominal tuberculosis.
9. Category based treatment.
10. Check compliance.
– Status of symptoms
– Weight gain
– Compliance of the Regimen.
1. = 100% drug dosage intake
2. = 80 to 100% drug dosage intake
6. = <50% drug dosage intake
*CRF – Case record form

538
ANNEXURE III
FOLLOW-UP SCHEDULE FOR PEDIATRIC TB CLINIC
Name:.................................................................. Date:..................................................................
1-2. T.B. Clinic No.

year of enrollment No. Year
3. Follow-up No.
4. Scheduled or Nonscheduled visit 1. Sch. 2. Nonsch.
Physical Examination
5. Weight (Kg)
6. Nutritional status
1. Normal
2. PEM grade 1
3. PEM grade 2
4. PEM grade 3
5. PEM grade 4
7-8. Height in cms Percentile (NCHS)
Lymph nodes (TBL)

Present Site Gr. of Size Number Consistency Sinus
1. Yes 1. Right LN in cms 1. Sing. 1. Soft 1. Matt. Mob. 1. Yes
2. No 2. Left 1. <1 2. Mult. 2. Firm 2. Matt. Fix. 2. No
3. Bilat 2. 1-2 3. Fluc. 3. Disc. Mob
3. 2-3 4. Hard 4. Disc. Fix
4. >3
9-15 Cervical
1. Ant cerv.
2. Post cerv.
3. Subocc.
4. Subman
5. Sub ment.
6. Jug dig.
7. Superf.
8. Deep
539
16-23 Axillary
as a group
24-31 Inguinal
as a group
32-39 Other
(spec.)
40-41 Liver Enlarged Cms below costal margin

1. Yes
2. No.
42-43 Spleen
44. Chest
Physical Examination 1. Clear 5. Decreased air entry
2. Loc. Crepts 6. Rhonchi
3. Gen. Crepts 7. Others (specify)
4. Bronchial breathing
45. Write the site in the rectangle
Investigations
46. AST ALT
47. Gastric Lavage/Sputum/Induced sputum

Smear Smear
Positive (1) Positive (1)
Negative (2) Negative (2)
Culture ............................................... Culture

Positive (1) Positive (1)
Negative (2) Negative (2)
SGOT – Aspartate Transaminase

SGOT – Alanine Transaminase
Smear: Lab Technique Used for Gastric Lavage
Culture: Lab Technique Used for Sputum
48.X-ray film of chest
540
1. PPC
1. Normal 2. Parenchymal (infiltrative lesion (P))
3. Nodal (N) 4. P + N
2. PPD
1. Consolidation 2. Cavity 3. Collapse with nodes
4. Pleural effusion 5.Bronchopneumonia 6. Miliary
3. PPL (Post Primary Lesion)

1. Calcification 2. Fibrosis 3. (1 + 2)
48. Type of Clearance in X-ray Chest film

1. Complete clearance 2. Moderate to significant (½ to 2/3 clearance)
3. Mild clearance (1/3 clearance) 4. No change
5. Deterioration
49. Tubercular lymphadenitis

Reduction in size
1. 1/3
2. 1/2
3. 2/3
4. Complete
5. No change
Size of Gland
50. Fine needle aspiration cytology (FNAC)/Biopsy

Histopathology report
*Similar case record forms can be designed for other systems for follow-up.
For AFB
Smear Culture 1. Positive
2. Negative
51-52. Treatment
• DOTS equivalent category continuous therapy
1. Cat I
2. Cat II
3. Cat III
• DOTS as under RNTCP
1. Cat I
2. Cat II
3. Cat III
53-54. Regimen
Non-DOTS but equivalent category
a. PPC Cat III of DOTS
b. PPD Cat I of DOTS
c. Tubercular Lymphadenitis Cat I of DOTS
d. Symptomatic Mantoux +ve any age 3 HR
Asymptomatic Mantoux +ve <5 years 3 HR
Post Primary Lesion (calcification or No ATT
Fibrosis)
e. Multidrug Resistant Tuberculosis
Individualize the regimen
541
ANNEXURE IV
CHILDHOOD TUBERCULOSIS – NATIONAL DATABASE
National code Name the medical college with state
Center code
Name of Medical College....................................................................................

With complete address........................................................................................
Pulmonary Tuberculosis
Name........................................................... Age Sex

(Months) 1M, 2F
1. Presenting complaints and their duration:

1 Yes 2 No Duration (Months)
Fever
Cough
Loss of appetite
Weight loss
Not gaining weight
Other – Specify
2. Contact with TB patient 1 Yes 2 No

(if yes, fill following, if no go to next column)
TB at present Type of TB *TB in past Duration of Type

TB month 1. Renal
(1 Yes, 2 No) 1 Pulmonary, 2 Lymph node 2. Bone
3 CNS, 4 Abdominal 5 Others
Mother
Father
*TB at present include treatment for TB in last 2 years

542
Sibs
Grand Mother
Grand Father
Neighbors
Relatives
3. BCG vaccine 1 Yes 2 No

If yes fill following, otherwise go to next
Age at vaccination (months)
Scar (+) (1), (–) (2)
4. Weight Height
(kgs) (cms)
5. Mantoux test Vertical

(mm)
Horizontal
PPD used (type and strength)........................................................................................
6. Hb TLC
gm/dl
DLC% P L E M
7. CXR
(More than 1 response maybe present)
1 Normal 2. Adenopathy 3. Infiltration 4. Consolidation 5. Bronchopneumonia
6. Miliary 7. Cavity 8. Pleural effusion 9. Others-Specify
8. Serology: done (1) or not (2)

(If yes what antigen used) .............................................................................................
9. Diagnosis:
Pulmonary TB, Yes 1 No 2
(If yes, fill following, if no go to next)
543
Type of pulmonary TB
1. Normal 2. Adenopathy 3. Infiltration
4. Consolidations 5. Bronchopneumonia 6. Miliary
7. Cavity 8. Pleural effusion 9. Other Specify
10. Gastric lavage Positive Negative Not done
11. Sputum smear Positive Negative Not done

culture
Positive Negative Not done
12. Pleural fluid

Proteins (gm%) TLC
(Per cubic ml)
P L
2. Lymph Node Tuberculosis Yes 1 No 2
Group of lymph nodes involved

1. Cervical 2. Axillary 3. Inguinal 4. Other Specify
• Fine needle aspiration cytology of Lymphnode
1. Necrosis 2. Granuloma 3. AFB 4. Not done 5. Other specify
• Biopsy of Lymph node
1. Necrosis 2. Granuloma 3. AFB 4. Not done 5. Other specify
3. Abdominal Tuberculosis Yes 1 No 2

Type of abdominal tuberculosis
1. Ascitic 2. Intestinal 3. Lymph nodes 4. Other specify

• Ultrasound abdomen 1. Abnormal 2. Normal
• Ascitic fluid 1. Done 2. Not done
Protein (mg/dl) Sugar cells (cu mm)
Polys Lympho cells (cu ml)
AFB Smear Present (1)
Culture Absent (2)
4. CNS Tuberculosis Yes 1 No 2

544
Type of CNS TB
1. Tuberculoma 2. TBM 3. Other –specify Cells
CSF Proteins Sugar
(mg/dl) (mg/dl)
Cells Lymph% Polys%

cells (per cubic ml)
• CT Scan
1. Basal exudates 2. Hydrocephalus 3. Tubercles 4. Infarct 5. Other-specify
Other investigation – specify
• MRI – describe the findings
5. Osteoarticular TB 1 Yes 2 No
1. Osteomyelitis, 2. Arthritis
If Arthritis Joints involved
1. Knee, 2. Hip, 3. Ankle, others
6. Renal Tuberculosis 1 Yes 2 No

• Urine AFB smear 1 Yes 2 No
• Culture 1. Yes 2 No
• Ultrasound abdomen*
• Intravenous pyelography
• CT abdomen
7. Other TB
Treatment Required
Out Patient In Patient
Name of Medicine Duration Dosage (mg/kg) Category DOTS/Non-DOTS
• Intensive phase
*INH
Rifampicin
Pyrazinamide
Ethambutol
Streptomycin
* Describe findings of each investigation

545
Others
• Maintenance phase Duration Dosage (mg/kg)

INH
Rifampicin
Pyrazinamide
Others
* Give the dosage in mgs/kg used.
Non-DOTS
The case record form given above for National Data Base can be modified by the faculty member incharge of TB
clinic in the Pediatric Department of Medical College as per details used at Pediatric TB clinic at All India Institute of
Medical Sciences, New Delhi.
These forms are to be filled by the individual Medical college for each patient and then centrally collected and
Data can be analysed by National Institute of Medical Statistics, Indian Council of Medical Research. It can be
546
submitted as a project by Pediatric Department (faculty incharge of TB clinic) to Indian Council of Medical Research
and Department of Biotechnology as mentioned earlier for funding for data analysis.
ANNEXURE V
CASE RECORD FORM
PEDIATRIC HIV CLINIC
1. HIV Clinic No. No. Year
Name............................................................... Date of Registration.....................................
3. Sex: M/F 4. Age: in months
1 Male 2 Female
Address Postal ...........................................................................................................................................
...........................................................................................................................................
5-6 Age at first symptom: Months Years
7-8 Age at diagnosis: Months Years
9-11 Per capita income:
12 Family history 1. Positive

2. Negative
Age Occupation HIV status H/O promiscuitry Symptoms Medication

(yrs) 1. Known Blood transfusion 1. Present 1. Anti-TB
2. Unknown (When, Where) 2. Absent 2. Antiretroviral
3. Others
13-18 Father
547
19-23 Mother
24-29
Sibling
30-35
36. Knowledge of disease/awareness in parents: Present- Yes, Absent No.

Yes 1
No 2
37. 1. Nature
2. Transmission
3. Outcome
4. Prevention
38. Mode of diagnosis of /1index case –screening /2 referred / 3 clinical suspicion

4. Diagnostic test: ELISA
39. Mode of infection in index case

a. Perinatal – Parental promiscuity,
b. Blood transfusion
c. Unknown
40-50 Presenting symptoms

Duration (months) Age at onset (months)
40-41 1. Asymptomatic
42-43 2. Pyrexia of unknown origin
44-45 3. Failure to thrive / with loss
46-47 4. Oral thrush
48-49 5. Anemia
548
50-51.6. Development
Number of Episodes
57-62 7. Pneumonia
52-53 - Nature 1 2
1. Consolidaton
2. Bronchopneumonia
54-56 - Severity Mild Moderate Severe
57-59 - Duration
(Days) <5 6-10 >10
60 - Investigation
Describe
61 - Therapy
Describe
62- Response
Describe
63-64 8. Diarrhea
– Nature
– Duration
(days, months)
65-67 Past History

1. Contact with tuberculosis
2. Breast feeding
3. Blood transfusion/patenteral therapy
68-69 Immunization status

1. Routine
2. Hepatitis B/H. influenzae / Pneumococcus
70-75 Nutritional intake

1. Calories / Proteins
76. Others
77. Examination
78-82 Anthropometry
Parameter Percentile
Weight
Height
549
Wt. For Ht.

Head circumference
Nutritional status
83 Development = Describe as per age

84-92
General physical Yes / No Comments

1. Fever
2. Pallor
3. Cyanosis
4. Parotid enlargement
5. Clubbing
6. Lymphadenopathy
7. Oral thush
8. Skin rash
9. Fundus (chorioretinits/tubercles)
Respiratory system
93-96
1. Respiratory Rate
2. Recessions
3. Shape
4. Air Entry and adventitious sounds
97-100 CVS
1. Pulse rate
2. JVP
3. BP
4. Precordium
1-2 Abdomen
1. Liver
2. Spleen
3-4 CNS
Diagnosis & Staging
550
Summary of Problem
1. Investigation
5-19
Date 1st Visit 2nd Visit 3rd Visit 4th Visit
Hemoglobin (g/dl)
TLC (/mm3)
DLC
Absolute eosinophil
PBS
ESR (mm/1st hr)
Serum Na/K/C1
Urine Na /K/Cr
OT/PT/SAP
Ca/Po4
Creatinine/BUN
Blood Sugar®
USG abdomen
Others
20. Tuberculin Status
21-24Chest X-ray
Normal / abnormal
Infiltrates
Hilar / Perihilar / Alveolar / Intersitial
Bronchiectasis
25 Family survey a. Positive
b. Negative
26-27 Gastric aspirates for AFB
a. Positive
b. Negative
28 CECT chest ⎤
Describe
29 SaO2/ABG ⎥⎦
Culture a. Positive
b. Negative
30 Stool parasites
a = present
b= absent
551
31 ECHO
32 Others
33 Treatment (Check List)
34 1. Nutrition
35 2. Counseling
36 3. Immunization
37-40 4. Prophylaxis
– PCP
– Tuberculosis
– Bacterial infection
– Fungus
41 5 Antiretroviral therapy
42 6 Others
552
39. Follow-up 3 sheets
Date New Complaints Compliance /side effects Caloric Wt/Ht Physical Investigation
intake & ΔWt Examination
PS. This case record form can be modified according to the place of clinic by the faculty member incharge.
SECTION 7
PREVENTION AND CONTROL

OF TUBERCULOSIS
• Bacillus Calmette-Guerin (BCG)

– Bacillus Calmette-Guerin (BCG) Vaccination
– BCG Vaccination—Frequently Asked Questions
• Latent Tuberculosis
– Latent Tuberculosis Infection in Children and
Adolescents
– Symptoms-based Screening of Child
Tuberculosis Contacts—Improved Feasibility
in Resource Limited Settings
• Tuberculosis Control Program in Children:
Lacunae and Experiences
• Prospective of Prevention, Diagnosis and
Management of Tuberculosis in the
National Program
• Frequently Asked Questions about Tuberculosis
• Ethical Issues and Concerns about Tuberculosis
Research in Children
• Tuberculosis in Children —Research Priorities
38 Bacillus Calmette-Guerin (BCG)
38.1 BACILLUS CALMETTE-GUERIN (BCG) VACCINATION

INTRODUCTION There are hardly any studies in India where the

immune parameters of cell mediated immunity have
The epidemiological data available to date demonstrate
been estimated to assess the level of its efficacy. Seth et
that the spread of tuberculosis (TB) is a global health
al5-8 have done a number of studies for evaluation of cell
emergency. The continuous spread of the TB pandemic
mediated immunity by leukocyte migration inhibition
justifies a need for the accelerated development of safe,
index by LMIT in children who have had BCG at birth,
more effective and affordable vaccine with old and new
its relation to nutritional status, correlating the cell
therapeutic strategies. The currently available vaccine,1
mediated immunity by tuberculin test and LMIT. It has
the only one available against tuberculosis was developed
been further estimated by them, is that how long does
more than 100 years ago. Several variants of the vaccine
the protecting response remains. Further, it has been
based on different attenuated strains of M. bovis (BCG-
illustrated by their studies that in preterm, low birth
Pasteur, Tokyo, Glaxo Smith Kline Biologicals, Tice, etc.)
weight newborns, the BCG vaccination needs to be given
are being used as part of childhood immunization
at the age, when the baby would have born as full term.8
programs in many parts of the world, supported by WHO
It has been shown that the immunological response
and UNICEF. Over the past years, BCG has been shown
declines in a year or so, CD4 subset of T cells which
to be safe and inexpensive. However, it has been
regulate the immune responses to M. tuberculosis by being
established that BCG vaccine is not able to prevent
directly cytotoxic for monocytes pulsed with
infection with wild type M. tuberculosis in children,
mycobacterial antigens also decrease. These cells cross
although they are still effective in preventing meningitis
inflamed endothelial surfaces to reach the sites
and miliary tuberculosis in 80 percent of vaccinated
of mycobacterial infection. It has been shown
children.2 This protective efficacy varies significantly in
experimentally in mice that infection by M. tuberculosis
different geographical locations and different
substantially enhances the depletion of CD4 subset of T
populations. There are additional safety concerns related
cells.9 Orme10 has further demonstrated the IFN-γ an
to BCG vaccines in populations with high prevalence of
essential component of host defense against mycobacteria
HIV. In recent years, no vaccine other than BCG has been
which is responsible for the activation of macrophages
the subject of such extensive reviews and controversies
and stimulation of their antimycobacterial properties is
regarding its efficacy for protection against tuberculosis.3,4
increased after BCG vaccination.
Notwithstanding these controversies, BCG vaccine
NEED FOR BCG VACCINATION continues to occupy an important place in the Universal
The incidence of tuberculosis is on the rise in India in Program of Immunization in developing countries.
spite of the National Tuberculosis Control Program by Although it has been in use since 1921, the efficacy of the
the Government of India, even with the help of vaccine continues to be debated.9,10
International agencies. The occurrence of multidrug-
resistant tuberculosis in adults is a great threat for same History
type of tuberculosis in children. The increase in the
Ever since, Koch’s discovery of the tubercle bacillus in
incidence of tuberculosis in children cannot be decreased
1882, numerous workers tried to attenuate the bacillus
by chemotherapy alone in adults, immunoprophylaxis in the hope of producing a vaccine for the prevention of
with BCG need continuous researching for the availability tuberculosis. In Lille, Albert Calmette and Camille Guerin
of more efficacious vaccine. were also trying to attenuate a highly virulent strain of
556
Section 7 Prevention and Control of Tuberculosis
tubercle bacillus of bovine origin isolated by Nocard of subculturing. With the distribution of the vaccine strain
Alfort from tuberculous mastitis in a heifer. In 1908, these to multiple laboratories in the world, each using slightly
scientists observed that addition of beef bile divided the different technique for strain maintenance, it is not
aggregates of tubercle bacilli almost to single units. They surprising that the BCG family shows large diversity.13
soon prepared a suitable culture medium incorporating The first freeze-dried French strain (1949) from the
pieces of potato cooked at 70° C in beef bile containing 5 Pasteur Institute in Paris was strain 1173-P2, from which
percent glycerine. As the bacilli multiplied in this medium the Glaxo and Danish strains descended.14
they were repeatedly subcultured every three weeks. Over Recent work based on molecular characterization of
the next few months the culture lost its characteristic the various substrains points to various mutations that
appearance and the bacilli lost their virulence first for the have occurred at different points in time15-17 and indicates
calf followed by guinea pigs. In 1921, after a total of 231 that the various BCG substrains are morphologically and
transplants, the strain proved to be completely harmless genetically different from each other.
even in highly susceptible guinea pigs, yet its antigenicity The original strain of BCG was replaced by a variant
was unimpaired. This strain was named bacillus Calmette while it was being maintained by serial transfer on
and Guerin (BCG). In 1924, Calmette declared the bacillus artificial culture media at the Pasteur Institute. Since
incapable of reverting to virulent form. then it has been maintained by many different
laboratories, using many different methods. As a result,
Mechanism of Protection of TB Disease by BCG the BCG strains used today are not bacteriologically
identical. Three parent strains (Glaxo, Tokyo, and
Despite routine vaccination with Mycobacterium bovis
Copenhagen) account for more than 90 percent of
bacillus Calmette-Guérin (BCG) soon after birth,
the vaccine used in the world today. 18 In 1966, a
tuberculosis in babies and adults remains epidemic in
WHO Expert Committee on Biological standardization
South Africa. The immune responses of the naïve
adopted a series of recommendations for the production
newborn child and how are they affected by vaccination
of BCG vaccine. It states that the vaccine should be
with BCG are as yet not fully understood. Immunity
freeze-dried, and that the vaccine strain should be
during pregnancy and in healthy human newborns may
maintained by the seed-lot-system whereby no vaccine
be skewed toward type 2 cytokine production; however,
is produced from a seed more than 12 passages removed
it is type 1 cytokines that are required for protection
from a primary freeze-dried lot.19 This eliminated the
against M. tuberculosis infection. To better understand
possibility of more attenuated variants in later BCG
neonatal cytokine responses prior to and following
vaccine lots.
exposure to mycobacteria, Watkins et al11 collected cord
blood and peripheral blood samples and evaluated the
Safety Record of BCG Vaccination
cytokine response following ex vivo incubation with BCG.
Gamma interferon (IFN-γ), interleukin 10 (IL-10), IL-12, A large review has shown BCG to be one of the safest
and low levels of IL-13 and IL-5 but no IL-4 were secreted vaccines. The demarcation between a normal reaction and
into the culture supernatant of cord blood mononuclear an adverse reaction is not always clear.20,21 The normal
cells. Intracellular staining showed that IL-10 and IL-12 reaction is a red indurated area measuring 5 to 15 mm in
were produced by monocytes and that IFN-γ was transverse diameter. A crust is formed around this
produced by natural killer (NK) cells but not by CD4(+) induration, which is soft at the center for three to four
or CD8(+) T cells. In contrast, in the peripheral blood weeks. At six to ten weeks, the crust falls off, leaving a
samples collected from babies 13 weeks post-BCG flat scar measuring three to seven millimeters.22 Regional
vaccination, IFN-γ was detected within CD4(+) and lymphadenopathy in the absence of erythema or vesicle
CD8(+) T cells. Taken together, the data suggest a central formation should also be considered a normal reaction
role for Th1 cytokines in naïve as well as BCG-vaccinated to the vaccine.23 Complications include cutaneous lesions
neonates in the protective immune response to and regional suppurative lymphadenitis; more severe
tuberculosis. NK cell-derived IFN-gamma produced in localized or multiple lesions (such as musculoskeletal
naïve neonates likely plays a key protective role via lesions); 24-26 and non-fatal and fatal complications
monocyte activation and the priming of a subsequent resulting from hypersensitivity reactions or
adaptive Th1 response.11 mycobacterial dissemination. 20,21,27-34 The risk of
complications varies with the type of vaccine and with
The BCG Strain Family the age at vaccination. The risk of osteomyelitis ranged
from 0.01 to 50 per 1 million vaccinations, that of multiple
Until the introduction of freeze-drying in Japan in 1943,12
or generalized lesions from 0.01 to 2 and that of fatal cases
the only means of maintaining a viable strain was through
557
Chapter 38 Bacillus Calmette-Guerin (BCG)
from 0.01 to 1 per million vaccinated individuals.20,21 The of BCG vaccination must be asked it there are symptoms
lowest complication rates were reported with the Tokyo and signs on the left upper arm.
strain, and the highest with the Gothenburg strain BCG vaccine is considered safe, however, some
produced in Denmark.25,35 complications may occur such as abscess at the site of
In a prospective study in South Africa among 10000 inoculation, ulceration at the vaccination site, and
neonates receiving the Copenhagen strain intradermally regional lymphadenitis. Some vaccine strains have been
at birth, at six weeks post vaccination, the vaccination responsible for osteomyelitis in 1 case per million doses
scar had healed in more than 95 percent of children, 1.5 administered. A meta-analysis of published literature
percent had no vaccination scar, and in 3 percent, adverse between 1950 to 70 indicated the frequency of
events were noted.35a All adverse events were local osteomyelitis after BCG vaccination as 1 in 80 000 in some
(oozing, abscesses, rarely combined with lymphad- European countries. The lesions are localized in the
enopathy). metaphysis or epiphysis of long bones.
Tabatabaie et al36 reported osteomyelitis due to BCG Risk of osteomyelitis due to BCG vaccination in
vaccine in a six-month-old immunocompetent boy who immunodeficiency patients is much higher and is
had received BCG at birth but developed multiple associated with fatal disseminated infection.
abscesses in the left subaxillary region and swelling and Because BCG is a live vaccine, concerns were raised
wound infection on the left arm. Radiograph revealed early on about the safety of its use in persons infected
osteolytic lesions in the left humerus. A biopsy from the with HIV, 37-39 and several case reports about
site revealed chronic granulomatous lesion positive for disseminated mycobacteriosis40-46 and mycobacterial
M. bovis on tissues culture. Hence, the diagnosis of
meningitis due to BCG40,42,47 have been published. A
osteomyelitis due to BCG vaccination was confirmed. The
study among mother-child pairs with and without HIV
child was put on 4 drugs in the intensive phase 2SHRE
infection has shown that children of mothers with HIV
and three drugs 10HRE in the continuation phase which
infection who also had HIV infection themselves had a
lasted for ten months.
slightly increased risk of suppurative lymphadenitis, but
Hematogenous spread of BCG vaccination may result
the manifestations were mild and easily manageable.48
in osteomyelitis, but this is a rare complication.
Apparently, living BCG can persist for decades and cause
Symptoms resulting in pediatric orthopedic referral may
be vague and present as late as 30 months following localized 49 or disseminated 50 complications after
vaccination. These can be osteitis and septic fulminant acquisition of immunosuppression. Nevertheless, most
osteomyelitis. The lesion can be distant to the site of of these case reports appear to be isolated events,
injection but usually on the same side of vaccination. In although it has been argued that disseminated disease
a complication such as osteomyelitis, the child must be attributable to BCG vaccination in HIV-infected children
thoroughly investigated for humoral and cell-mediated might be exceedingly difficult to diagnose.51 However,
immunity. Timely diagnosis of BCG osteomyelitis is a study in Zambia among HIV-symptomatic children
important since therapy is effective if instituted early in with a median age of 15 months, showed that
the course of disease. The diagnosis can be delayed due mycobacteremia due to BCG must be exceedingly rare.52
to late development of symptoms because the early A recommendation by WHO states that no principal
course is often benign. Chest X-ray does not reveal any changes in BCG vaccine policy are warranted unless
specific diagnostic lesions. children present with symptomatic HIV infection,53 a
statement that has not been challenged.54,55
Treatment of BCG Osteomyelitis
It consists of:
Indications and Recommendations for the Use of BCG
1. Antituberculosis therapy Vaccination
2. Surgical intervention Approximately 100 million children now receive BCG
The advantages of surgical intervention are two-fold, every year.55 The number of doses produced in the year
(i) one can get a specimen for bacteriologic confirmation 2000, in descending order, were the Copenhagen 1331
both by smear and culture. (ii) Healing process is quicker. strain, D2PB302, Tokyo 172, Sofia SL 222, Pasteur 1173,
Osteomyelitis due to BCG vaccination has a benign Glaxo 1077.55
course. Hence, if osteomyelitis does not respond to While there have been wide variations in the
appropriate and adequate antibiotic therapy, its etiology protection afforded by BCG vaccination in different trials,
in a baby (neonate or infant) more often the former is the evidence is overwhelming that BCG provides
likely to be due to BCG vaccination complication. History protection against tuberculosis, especially against
558
tuberculous meningitis and death from disseminated attenuated Calmette Guerin strain of bovine M.
tuberculosis in children. Where it worked, its protective tuberculosis is present in a concentration of 0.1 to 0.4
effect waned over time, to disappear after 15 to 20 years. million viable bacilli per dose of vaccine. The WHO
The evidence for protection against bacteriologically recommends the “Danish 1331” strain for the production
confirmed tuberculosis in adults has been less consistent. of BCG vaccine, which has been used by the BCG
Several low-prevalence countries are reviewing their Laboratory, Guindy, Chennai since 1966. Quality control
policies, usually shifting from universal vaccination to is ensured by the International Reference Center at
vaccination of infants in high-risk groups only. In a Copenhagen.
recently published report from Netherlands, it is
demonstrated that in the absence of vaccination, the Storage
annual risk of developing severe TB for a children
If stored at subzero temperatures (–20° C) the vaccine
belonging to high risk group was 3/100 000, while BCG
remains potent for two years. The undiluted vaccine can
vaccination reduces this risk by 73 percent. This study
be stored in the middle compartment of the refrigerator
estimated that about 9000 children would need to be
(2° to 4°C) without loss of potency upto six months. At
vaccinated to prevent 1 case. Vaccinating children from
the peripheral level, at 2 to 8° C, it is good enough for
high-incidence countries would then cost about Euro
use up to one week. Strict attention should be paid to
4,500 per discounted disability-adjusted life year averted.
maintenance of the cold chain and it should be
The authors in this study conclude that current Dutch
transported in thermos flasks with ice to the outreach
BCG strategy, as well as the proposed inclusion of
immunization clinics. As the vaccine deteriorates on
immigrant children from Turkey, Surinam and former
exposure to light it is usually supplied in dark colored
Yugoslavia, is on average cost-effective.56
ampoules and wrapped in black paper/cloth.57
BCG Vaccine Production in India
Reconstitution
In India, the BCG vaccine laboratory was started in
Ampoules of freeze dried BCG vaccine are long and
Chennai in 1948 for the production of BCG vaccine for
sealed under vacuum. Thus they have to be opened
use in India and also for supply to some neighboring
carefully by gradually filing at the junction of the neck
countries. Since 1966, Danish strain 1331 is being used
and the body of the ampoule so that air does not rush in,
for preparation of both the liquid and freeze-dried
causing spillage. The vaccine is then reconstituted by
vaccine.
dissolving in normal saline as distilled water acts as an
For preparing the liquid and freeze-dried BCG vaccine,
irritant.58 The diluent should always be kept with the
the Guindy (BCG) Laboratory in Chennai used the method
vaccine in the main compartment of the refrigerator/cold
followed at the State Serum Institute, Copenhagen, i.e.
box/vaccine carrier to ensure that it is cold enough when
using Sauton potato medium for maintaining the BCG
one needs it. Reconstituted BCG vaccine should be used
strain. The prepared vaccine is tested for purity by Ziehl-
within three hours. It can be prevented from
Neelsen smear for acid fast bacilli, and by culture on
contamination by proper hand washing and sterilization
nutrient broth, thioglycollate medium and Sabouraud’s
of equipment, and using separate needles for each child.57
agar medium. Total bacterial count and the number of
culturable particles in the preparation are estimated.
Dosage
Biological tests are carried out in guinea pigs to estimate
the degree of virulence, allergenicity and safety. In The standard dose of BCG vaccine is 0.1 mg in 0.1 ml
addition to the above tests, in the case of freeze-dried volume. Some experts recommend a dose of 0.05 ml to
vaccine, tests are carried out to estimate residual moisture newborns aged less than 4 weeks as they fear a higher
and heat stability. Both types of vaccines are to be stored incidence of regional lymphadenitis with the
at 2 to 4°C temperature, protected from light. Under these administration of full dose.58 In controlled trials, the
conditions of storage, the liquid vaccine can be used for incidence of lymphadenitis was 1.3 percent as compared
four weeks from the date of manufacture while the freeze- to 1 percent with a lower dose. However, doubts on the
dried-vaccine can be used for three months. efficacy of the lower dose exist. Hence the same dose (0.1
mg) should be given at all ages.59
Constitution
Optimal Age of Vaccination
Previously BCG vaccine was available in both the liquid
form and the freeze-dried form, however, now only the The use of BCG started in early 1950’s under the mass
freeze-dried vaccine is used in all countries. The BCG campaign. It was later included in the Expanded
559
Program of Immunization (EPI) and is currently given healing may repeat 2 to 3 times over a period of 2 to 3
to infants under the Universal Program of Immunization months. Healing is usually complete by 10 to 12 weeks
(UPI). Most studies have shown good sensitization when and the site is marked by a small pigmented scar of 5 to
BCG has been given at birth.59-62 A randomized clinical 7 mm in size.66
trial has shown that delaying BCG vaccination from birth Vaccine assessment in groups of school children has
to 10 weeks of age enhances the quantitative and shown that for the usual vaccines the mean diameter of
qualitative BCG-specific T cell response, when measured the scar is 5 to 7 mm, with a standard deviation of not
at 1 year of age.63 However, since it is difficult to get more than 2 mm. If no scar is observed during the
children back for immunization and BCG immunization months following vaccination, it may be concluded that
at birth shows an adequate cell mediated immune BCG was not given properly and the dose be repeated.
response (CMIR),8 it is preferable to give BCG at birth. Variations in the number of culturable particles in the
Thus it is recommended that BCG be given either at birth vaccine only slightly influence the size of the local lesion.
or at the time of earliest contact with the child, preferably The latter, therefore, is related to the technique of the
before the child is one year of age. vaccination rather than of the quality of the vaccine.
Mussi-Pinhata et al 64 determined the effect of
intrauterine growth retardation (IUGR) on the response Contraindications to BCG Vaccination
of BCG vaccination. The infants were evaluated using
BCG should not be given to persons:
post-vaccination skin tests to PPD and tuberculin
i. Whose immunologic responses are impaired because
lymphocyte transformation tests. They found similar rate
of congenital immuno-deficiency, HIV disease,
of response to the BCG in the term babies who were small
leukemia, lymphoma or other malignancies.
for gestational age and term babies having weight
ii. Whose immunologic responses have been
appropriate for gestational age. Thus, the presence of
suppressed by steroids, immunosuppressant drugs,
IUGR should not be a reason for delaying BCG
alkylating agents, antimetabolites or radiation.
vaccination. Similarly, it has been found to be equally
effective in preterm infants >34 weeks of age.65 It is best to avoid BCG for a period of 4 to 6 weeks
following a viral infection (e.g. measles, chicken pox,
Administration hepatitis B) since all viral infection affect the immune
response of an individual. It is also advisable to postpone
Conventionally BCG is given by intradermal route in the BCG for at least three months in a child who has received
left upper arm region. The vaccine is reconstituted as immuno-globulins.18 BCG vaccine can be administered
described earlier. No special preparation of the skin is
safely with all other childhood vaccines. Even in HIV
necessary before its administration; cleaning with sterile
infected newborns BCG vaccine does not appear to
water is enough. BCG is usually administered in a single
adversely affect the immune response to the other
dose as part of the immunization schedule.
childhood vaccinations given simultaneously.19
Sequence of Events
Efficacy and Effectiveness of BCG Vaccination
When 0.1 ml of the vaccine is injected intradermally it
raises a wheal 8 mm in diameter over the injection site. Efficacy is the extent to which an intervention produces
Hair follicles are seen as small pits on the wheal a beneficial result under ideal conditions. The best setting
produced. Failure to observe this means that either the to address efficacy is thus prospectively, in a controlled
volume actually injected was inadequate. (e.g. because clinical trial. In contrast, effectiveness takes the various
of leakage from the syringe) or that the injection was constraints into account that are found in the field in the
given too deep. The latter should be avoided because it actual routine delivery of the intervention. Effectiveness
will produce a subcutaneous abscess that heals only is often ascertained retrospectively, such as in case-
slowly and often produces an ugly, retracted scar. The control studies. Efficacy (in clinical trials) and
wheal is absorbed in 20 to 30 minutes. No rubbing or hot effectiveness (in case-control studies) have been
fomentation at the injection site is recommended. ascertained in various settings. The principle underlying
Nothing is visible at the site of injection for some days. the design of prospective and retrospective studies
By the 3rd or 4th week induration is felt at the vaccination should be well understood. These trials were
site that becomes a lump of 6 to 10 mm by the 6th week. supplemented by community trials and contact studies.
This is not painful but is tender to touch. This lump would The variation in estimates of protection ranged widely,
soften with pus formation and discharge, leaving a tiny from harm (more cases among the vaccinated than among
ulcer that heals by itself. This cycle of ulceration and controls) to a high level of protection.
560
Because BCG vaccination is given early in life, the not synonymous with lack of efficacy. Revaccination at
protection afforded is limited in time, and its effect on school entry is likely to be inefficient (even if it were
bacteriologically confirmed tuberculosis in adults is efficacious), because it falls into the period in life when
inconsistent, it cannot be expected to have a great impact the risk of tuberculosis is lowest.
on the epidemiology of tuberculosis.67-69 Finally, concerning HIV infection, the WHO has
It seems inappropriate to conclude from metaanalyses concluded after careful review of available data, that BCG
that BCG provides some average protection.70,71 The vaccination schemes do not need to be altered unless
observed range in protection is real and remains largely HIV infection is symptomatic (AIDS).51 This, too, seems
unexplained. to be a reasonable recommendation given the lack of
In light of the evidence, WHO recommends its use in evidence of an increased frequency of serious adverse
newborn children or as early in life as possible.72,73 This events in BCG-vaccinated children who also have
is still a sound policy for those countries in the world acquired HIV infection from their mother. However, it
where tuberculosis is highly prevalent, and tuberculous appears that HIV infection lowers the protective effect
meningitis is frequent, disabling and has fatal occurrence against extrapul-monary tuberculosis.76 In industrialized
because it is diagnosed late. It fails to address the role of countries, where the need for BCG vaccination is
BCG where tuberculosis in children has become a rare generally lower, it is usually recommended not to give
occurrence. BCG vaccination to individuals known to have HIV
The IUATLD has developed recommendations on infection.77
criteria for the discontinuation of mass BCG vaccination.74 The freeze-dried vaccine should be kept refrigerated
Three key issues enter into the decision making process and protected from light, and diluted only immediately
on the discontinuation of BCG vaccination. before vaccination. In most countries, BCG vaccine is
The first is the extent of protection BCG actually given by the intradermal route, generally by injection
imparts in a given location. In the USA, the low efficacy with a 25 or 26 gauge needle, in the deltoid insertion
of BCG vaccination in Georgia, Georgia-Alabama, and region on the left side.78 Most manufacturers (including
Puerto Rico had an important impact on the decision not all those who provide vaccine for UNICEF, the largest
to routinely utilize BCG vaccination. As such prospective purchaser in the world) recommend a 0.05 ml dose for
studies are usually beyond the realm of resource infants, and the double dose for children.
availability, effectiveness might alternatively be studied Difficulties have arisen for decision makers about the
utilizing the case-control or contact study approach. value of vaccinating health care workers at increased risk
The second is the frequency of serious forms of of infection with M. tuberculosis, particularly in settings
tuberculosis in children (meningitis, disseminated forms) where multidrug-resistant tuberculosis is common. The
weighed against the frequency of adverse reactions from uncertainty stems from the scarcity of data on protection
the vaccine itself. This has been best studied in Sweden against tuberculosis among adults, and the generally low
where the frequency of serious adverse reactions from level of protection (or none at all) among adults in clinical
BCG vaccination (osteoarticular and disseminated trials. While decision analyses appear to favor the use of
mycobacteriosis due to BCG) out-weighed the incidence BCG vaccination in such settings.79 Such a conclusion has
of cases that the vaccine was intended to prevent.35 BCG been disputed, largely based on the argument that it
vaccination may become noncosteffective as the deprives those vaccinated from ever learning whether they
frequency of childhood tuberculosis decreases, so that have acquired tuberculous infection or not (loss of
an increasing number of children need to be vaccinated specificity of the tuberculin test).80 Nevertheless, in areas
to prevent one case. where BCG has been demonstrated to provide appreciable
The third consideration is the value attached to the protection against tuberculosis among adults, where there
preservation of the utility of the interpretation of is a high-risk for health care workers of becoming infected,
tuberculin skin test results. BCG vaccination induces and where multidrug-resistant tuberculosis is common, a
tuberculin sensitivity and complicates the interpretation BCG vaccination policy for health care workers might
of tuberculin skin testing results. In industrialized deserve consideration. Where these conditions are not met,
countries with an elimination strategy in mind, the nonvaccination of health care workers might be more
tuberculin skin test is an important means of identifying appropriate.
persons with tuberculous infection at a high-risk of In summary, barring a better alternative, BCG
progression to tuberculosis who would benefit from vaccination remains a useful adjunct for the individual
preventive chemotherapy. protection against disabling and lethal forms of childhood
WHO discourages revaccination because there is no tuberculosis in most parts of the world where tuberculosis
evidence of its usefulness.75 Lack of evidence is, however, remains highly prevalent. It cannot be expected, however,
561
to have great impact on the epidemiologic situation of comparable to cases in every respect except for the outcome.
tuberculosis.68,69 Selection bias resulting from a failure to ensure this
The efficacy of BCG vaccination is best ascertained in comparability may thus invalidate any findings.
a prospective clinical trial, while an estimate of its The results of some of these case-control studies are
effectiveness in routine application might be obtained summarized below. Vaccine effectiveness (in per cent)
through retrospective studies, such as case-control, contact, from a case-control study is estimated as (1 - odds ratio)
or case-population studies, although possible confounding x 100.82 For unmatched case-control studies, the 95
effects cannot be controlled so easily. percent confidence intervals were calculated (or
Briefly, clinical trials are a prospective ascertainment recalculated where appropriate) using Woolf’s method.84
of cases occurring among the exposed. Clinical trials thus For matched and adjusted analyses, the confidence
start with looking at the exposure (BCG vaccination given interval published by the authors of the study was
or not) and then ascertain the outcome (tuberculosis) in chosen. If not stated for matched studies, the confidence
a group of individuals, preferably randomly assigned to interval around the crude odds ratio was calculated as
exposure.81These are population-based studies and the above.
denominator is the number of person-years of
observation. The measures are incidence rates among the Efficacy of BCG Vaccination
exposed and unexposed and the summary measure is AS Pulickal 85a has quoted a number of studies
the relative risk (the risk among the exposed divided by demonstrating scar formation in > 90% after BCG
the risk among the unexposed). Vaccine efficacy (in per vaccination. The fact that needs to be pointed out is
cent) is calculated as (1 - relative risk) × 100.732. The 95 Pulickal85a has not highlighted that these studies were
percent confidence intervals were calculated (or done using Copenhagen 1331 BCG vaccine where as in
recalculated, where appropriate) using the formula India BCG vaccine is manufactured in Guindy
proposed by Orenstein in his review on assessment of Laboratory Chennai. This might be the underlying cause
vaccine efficacy,82 unless adjusted or stratified summary of less percentage of children retaining scar after BCG
estimates were provided by the authors. vaccination by school age. Further in the studies quoted
To defray the costs incurred in clinical trials and to by Pulickal1-4 the scar formation was evaluated in the
obtain results more quickly, it was proposed to ascertain neonatal period itself and not at school age. By school
the effectiveness of BCG vaccination by means of age, scar formed immediately in the neonatal period does
retrospective case-control studies.83 Briefly, case-control disappear but the cell-mediated immunity measured in
studies start with looking at the outcome (tuberculosis) vitro by T cell functions does remain.
and then ascertain exposure (BCG vaccination given or
not) in a group of patients with the outcome, compared Prospective and Retrospective Studies on BCG
to an appropriately selected control group of persons Vaccination
without the outcome. 84 A relative risk cannot be
In one of the first clinical trials with a methodo-logically
calculated as this measurement is confined to population-
fairly acceptable design (systematic alternate allocation),
based studies. The measurement of risk in a case-control
BCG was given to children exposed to a parent with
study is the odds ratio (or relative odds). For rare diseases,
tuberculosis and compared to a similar group who did not
the odds ratio approximates the relative risk in a clinical
receive the vaccine.86 The impact on fatality was dramatic,
trial.
with 82 percent reduction in the risk. Nevertheless,
The advantages and disadvantages in the use of the
suspicion about the efficacy of BCG vaccination persisted,
case-control approach are linked to its being
particularly in the United States,87 but also in the United
observational, having subjects selected on the basis of
Kingdom,88 largely because the design of many studies was
disease status, and using controls from the population
dubious at best.
from which the cases emanated.85 The advantages of case-
One of the most conspicuous differences observed in
control studies include avoidance of ethical problems
the protection afforded by BCG reveals that age at
arising in situations where there is already evidence that
vaccination is important. Of further crucial importance
the vaccine is better than placebo; allowing much faster
is the type of tuberculosis that is targeted for protection
conduct than randomized trials; and requiring a much
by vaccination.
smaller number of subjects. They are thus substantially
In the following summary of the best-known studies
cheaper to conduct than randomized clinical trials.85
in the English literature, the studies are identified as being
The most challenging difficulty in the design of case-
prospective or retrospective. For each of these two study
control studies is the selection of appropriate controls in
types five classes were examined:
that they have to be selected in such a way that they are
562
• Protection against disseminated and meningeal level of protection of less than 30 percent. In Chingleput,
tuberculosis, and against death from tuberculosis. south India, where BCG gave little or no protection, there
• Protection afforded to children by vaccination of was a tendency to provide some protection in children
newborns or infants. below the age of 15 years, but a similar tendency towards
• Protection afforded by vaccinating children beyond harm (more cases in the vaccinated than the
the age of one year. nonvaccinated) in older persons.116
• Protection afforded by vaccinating adolescents or Three retrospective studies among children also
adults. showed very variable levels of protection, from 16 to 74
• Protection afforded by vaccinating people of various percent.101,120,121
ages. These studies seem to show that vaccination of older
children does not offer protection against tuberculosis
Protection Conferred by BCG Vaccination Against that is as reliable as vaccination at an earlier age.
Disseminated and Meningeal Tuberculosis, and Against
Death from Tuberculosis Protection Conferred by BCG Vaccination Among
Adolescents and Adults
Eight major prospective studies have looked into the
protection afforded by BCG vaccination against death Six prospective studies have examined the protection of
from tuberculosis. 86,89-95 All of these studies were BCG vaccination against tuberculosis among adolescents
conducted before the advent of curative chemotherapy. or adults.114-117-119,122,123 The study in Ulleval, Norway, was
Four of the studies showed a point estimate of the the first ever conducted prospective study. It does,
protective efficacy of 80 % and above, and one afforded however, not live up to current requirements for a
no protection. The confidence interval was wide in all controlled trial, as student nurses with a negative
studies, because the number of events was small. tuberculin skin test at entry could choose whether to be
Several retrospective studies (including two using vaccinated or not. In this context, the study conducted in
two different control groups) examined the protection England (where M. microti, not BCG was used) remains
against disseminated and meningeal tuberculosis.96,97-105 the only study of high standard that has shown a very
The protective effectiveness was usually in excess of 80% high level of protection, of close to 80 percent, in this age
and in no case did the 95% confidence interval include zero. group.124-129 The other studies show little or no protection,
It may be concluded from these studies that BCG with a tendency to reveal a potentially harmful effect in
affords very good protection against death from India.114-117,130 In England, protection appeared to last for
tuberculosis, and against disseminated and meningeal about 10 years before dropping rapidly.129 In contrast, in
tuberculosis. Chingleput, where there was no overall protection,
vaccination appeared to confer harm (more cases than in
Protection Conferred by BCG Vaccination of Newborns the control group) in the first five years and minimal
and Infants protection subsequently.131
These studies seem to indicate that vaccination of
Three prospective studies looked into the protective adolescents or adults is rarely a useful intervention.
efficacy of BCG given to newborns or infants against all
forms of tuberculosis or morbidity.93,94,106 The point Protection Conferred by BCG Vaccination Across Various
estimate of the efficacy was between 50 and 80 percent.
Age Groups
Several retrospective studies examined the effectiveness
of newborn or infant vaccina-tion.98,99,104,107-113 The level of Of the seven clinical trials’ studying protective efficacy
protection in these studies varies widely, but frequently across a wide range of age groups, with a preponderance
above 50%. Noteworthy is the study from Zambia, which of persons other than infants, two showed a high level of
stratified effectiveness estimates by HIV status, 111 protection, of around 80 percent, while all of the others
showing that HIV-infected children had no protection showed little or no protection.89,114-119
as compared to 60% protection among HIV-negative These observations reconfirm that utilization of BCG
children. vaccination in age groups other than infants is rarely an
effective intervention.
Protection Conferred by BCG Vaccination of Children One retrospective study from the Gambia reported
Over One Year of Age that 35 patients among 200 without a BCG scar died
during chemotherapy, while none of 85 with a BCG scar
Only six protective studies of BCG vaccination of older did so. 92 While considerable attention was paid to
children are available.114-119 All six showed a very low adjustment for potential confounding factors (yet the
563
affect remained), the authors were still cautious in infectious cases, therefore, makes it possible to investigate
concluding that BCG vaccination reduces case fatality the protective effect of BCG vaccination in an efficient
from pulmonary tuberculosis. manner. By comparing the incidence of the disease in
the vaccinated and in the unvaccinated groups the
Controlled Trials efficacy of BCG vaccination can be estimated. The
The protective efficacy of BCG varies substantially. disadvantage of active case finding is that the type of
Several well planned large scale controlled trials have tuberculosis can not be studied precisely as treatment is
been conducted in various parts of the world including started at the earliest. The results of contact studies are
India.131-135 These show that the range of protection shown in Table 38.2.142-144
offered by BCG varies enormously from no protection In a meta-analysis conducted by Colditz and
to 85 percent protective efficacy. The report of the coworkers145 in 1995, based on the available literature, it
Chennai Tuberculosis Prevention Trial conducted in the was concluded that BCG vaccine reduces the risk of
Chingleput District of Western Chennai has been widely acquiring tuberculosis by 50 percent irrespective of the
misinterpreted as showing that BCG offers no protection study design or the form of tuberculosis. Although, the
against tuberculosis under any epidemiological protection from tuberculosis deaths, meningitis and
condition. However, since extrapulmonary forms of disseminated disease was found to be higher than for
tuberculosis and children under 10 years of age were not total tuberculosis cases but the authors attributed this to
included in the assessment, the results of this study lower diagnostic error in identifying severe forms of
cannot be extrapolated on to the pediatric population. tuberculosis.
A recent publication from Ireland reports that in 2007,
Case-control Studies an outbreak of tuberculosis occurred in a toddler
The protective effect of BCG vaccination is calculated population attending two child care centers in Cork,
from the vaccination converge among cases and Ireland. Of 268 children exposed, 18 were eventually
comparable controls. The Table 38.1 shows the results of diagnosed with active tuberculosis. 24 percent of the
various case control studies for which BCG product was exposed children had been previously vaccinated with
used. There is lot of variation in the results. The highest BCG, and no case of active disease was found in this
protection was observed in the studies in Brazil and India. group (p = 0.016), suggesting a profound protective effect
These studies have shown that highest levels of of BCG in this population.146
protection were against the types related to the
hematogenous spread of the bacillus, e.g. meningeal and How Do We Explain the Variable Results with BCG
miliary tuberculosis (Table 38.1). Vaccine?
Several hypotheses have been put forward to explain the
Contact Studies variability in results of the field trials with BCG vaccine.147
A young child in contact with an infectious adult in the None has emerged as the obvious solution and it seems
family runs a high-risk of developing tuberculosis within more reasonable to accept that several mechanisms may
only a few months from the time the infectious case is be involved. A few of these hypotheses are discussed
detected. Examination of child contacts of newly detected below:
Table 38.1: Case-control studies on the efficacy of BCG vaccination of the newborn
Country Age group No. of cases No. of controls Efficacy (%)
(vaccine used) (observed months)
Brazil136 0–12 45 90 82
(Rio de Janeiro strain)
Brazil137 0–5 73 604 82–84
(Rio de Janeiro strain)
Burma138 0–5 311 1536 38
(Japan BCG Lab)
Canada139 0–18 71 213 60
(Connaught Lab)
England140 0–1 111 555 49
(Glaxo Lab)
Chennai141 0–5 107 321 7
(Japan BCG Lab)
564
Table 38.2: Contact studies on the efficacy of BCG vaccination against tuberculosis in children
Country No. of contacts No. of cases among contacts Efficacy (%)
(Vaccine used) Vaccinated Unvaccinated Vaccinated Unvaccinated (95% C.I.)
157
Thailand 1253 253 218 66 53 (38–64)
(Merieux)
Togo158 875 546 62 113 62 (50–70)
(Glaxo lab)
Korea159 806 417 45 84 75 (62–82)
(Paris seed lot)
Hypotheses About the Variation in the Efficacy of BCG following vaccination, against death from tuberculosis,
Vaccination disseminated disease manifestations, and bacteriolo-
gically unconfirmed tuberculosis. In summarizing these
While the overall evidence is clearly in favor of a
effects, BCG is generally most effective against serious
protective effect of BCG vaccination, the observed
forms of tuberculosis occurring shortly after infection
variations are large in both prospective and retrospective
acquired at an early age. Thus, any evaluation of the
studies. A number of hypotheses have been formulated
protective efficacy of BCG vaccination should be
to address these discrepancies. Smith148 and Smith and
stratified according to these variables.
Fine149 have comprehensively reviewed the evidence,
and the following outline is guided by, and draws heavily Differences in Vaccine Strains
on, their assessment.
The principal hypotheses to explain the variations The available BCG vaccine strains differ widely in
observed in the protection offered by BCG include: phenotype and geno-type.150,151 It has been proposed152
• Differences in methodological stringency that differences in vaccine strains may account for
• Differences in vaccine strains observed variations in vaccine efficacy. In the rabbit
• Differences in vaccine dose model, not all BCG (and M. microti) strains provided the
• Differences in virulence of M. tuberculosis strains same level of protection. However, the most powerful
• Differences in risk attributable to exogenous argument against this hypothesis arises from the
reinfection tuberculosis Chingleput study, where two vaccine strains were used
• Differences in genetic make-up of vaccinees that had documented high efficacy in other settings but
• Differences in nutritional status of vaccinees were not shown to be efficacious in Chingleput.
• Differences in prevalence of infection with Furthermore, one of the studies (a case-control study
environmental mycobacteria from Indonesia) cited for evidence of differential
effectiveness of strains, examined successive vaccination
• Other factors.
policies, and was thus by necessity a nonconcurrent study
which additionally failed to adjust for time elapsed since
Differences in Methodology in Conducting Study
vaccination.153
The most relevant trial showing no protection against The recent delineation of genetic differences between
bacteriologically confirmed tuberculosis, conducted in BCG vaccine strains has renewed interest in the influence
Chingleput, India, was judged to be of high scientific of the vaccine strain on the protective efficacy against
quality by a WHO expert committee specifically charged tuberculosis. Although there is good evidence to support
to ascertain the trial’s validity.70 It must be kept in mind the notion that the induced immune response and
that the range of protection cannot be taken at face value, protection afforded against tuberculosis differs between
but must also be seen in the context of what the study in BCG vaccine strains, currently, there are insufficient data
question sought to address. BCG trials (be they to favour or recommend one particular strain. Identifying
prospective or retrospective) ascertained protection BCG strains with superior protection would have a
against various outcomes such as morbid state dramatic effect on tuberculosis control at a population
(tuberculosis or death from tuberculosis) and site of level: a small increment in protection provided by BCG
disease, e.g. pulmonary, extrapulmonary single site, and immunization will prevent large numbers of cases of
disseminated tuberculosis, taking into account such severe tuberculosis and deaths, particularly in children.154
things as bacteriologic certainty of the case, age of the
patients, and time elapsed since vaccination. What seems Differences in Vaccine Dose
apparent from the studies is the tendency of BCG to
BCG has been administered through various routes,
provide its greatest protection within the few years
initially orally, then parenterally. The latter administration
565
may have been given intradermally or transdermally via This is not borne out by observations. The annual risk
multipuncture devices. The dosage reaching the target of infection in the United Kingdom decreased
thus may well have varied. Nevertheless, the following considerably over time, yet the level of protection
observations seem to contradict the argument of an afforded by BCG remained high and virtually
influence of differential dosage effect. Three controlled unchanged.
clinical trials with low efficacy used multipuncture
administration, and one with high efficacy did not differ Differences in Genetic Make-up of Vaccinees
in their efficacy. Furthermore, the trial in Chingleput
Because differences in protection from BCG among males
specifically considered in its design the possibility of
and females were observed in at least one study, other
deterioration (vaccine potency in the field, and allocated
genetic factors may also play a role in the differential
vaccinees also to two arms receiving a ten-fold difference
protection conferred by BCG. Nevertheless, the finding
in dose, but with no difference in effect.
that BCG gave virtually no protection to children in
Chingleput, but high protection in children from the
Differences in Virulence of M. Tuberculosis Strains
Indian sub-continent living in the United Kingdom
That not all tubercle bacilli are equally virulent has been would tend to disfavor this hypothesis.
demonstrated repeatedly both for M. bovis BCG and M.
tuberculosis in general, and for isoniazid-resistant strains Differences in Nutritional Status of Vaccinees
in particular. As nutritional status affects the functioning of the cellular
The hypothesis that the relative frequency of more or
immune system, it might be expected that poor
less virulent tubercle bacilli affects the observed
nutritional status would adversely affect the protective
protective efficacy of BCG vaccination is based on the
efficacy of BCG vaccination. However, BCG provided
argument that tubercle bacilli of lower virulence might
very high protection against tuberculosis death among
also cause tuberculin skin test reactions of smaller size.
poorly nourished North American Indian children, even
Such persons then might be classified as “non-reactors”,
somewhat higher than among well-nourished British
i.e. persons not infected with tubercle bacilli, thus
adolescents, a finding that would tend to contradict this
becoming eligible for vaccination. Vaccination of actually
hypothesis. Studies conducted by Seth et al 5-8 also
infected persons may thus mask any protective effect of
demonstrated that mild to moderate degree of
BCG vaccination, as vaccination is not expected to
provide protection against those who are already malnutrition did not affect the induction of cell mediated
infected. immune response in children after BCG.
The argument fails to account for the fact that BCG
provided no protection at all in some trials. Depending
Difference in the Burden of Mycobaterial Infection in
on the proportion of individuals who had escaped Community
infection with environmental mycobacteria at the point A study from low burden countries (Norway and
of BCG vaccination, masking of protection by BCG Sweden) demonstrated the protective effect of newborn
vaccination would be expected to be incomplete. BCG vaccination in nativeborn 0 to 14-year-olds in
Finland, and of adolescent BCG vaccination in 15 to 29
Differences in Risk Attributable to Exogenous Re- year-olds in Norway. The Norwegian BCG vaccination
infection Tuberculosis program conferred 61 to 64% protection to 15 to 29-year-
olds; however, 21699 to 25125 vaccinations were needed
BCG vaccination is expected to provide protection against
tuberculosis resulting from infection acquired subsequent to prevent one case.155
to vaccination. It is not expected to provide greater
BCG Vaccine and Tuberculin Surveys
protection than a naturally acquired primary infection.
Protection conferred by a primary infection against Chadha et al155a conducted a study in selected villages
disease from re-infection is incomplete. Thus, the in three defined zones of India for comparison of
protective efficacy of BCG might be increasingly masked prevalence of tuberculous infection among children with
as the contributory fraction of cases attributable to re- and without bacille Calmette-Guerin (BCG) scar. The age
infection increases. Thus, following this argument, the group was 1 to 9 years and tuberculin testing was done
protection afforded by BCG is expected to be lower where using 1TU-PPD RT 23 with Tween 80. In the age group
the risk of infection with M. tuberculosis (and thus re- of 1 to 4 years, the estimated prevalence of infection
infection) is high. among those with BCG scar was considerably higher than
566
in those without BCG scar. The difference was small in It has been postulated that different mycobacterial
those aged 5 to 9 years. species induce different immunologic responses, some
Tuberculin surveys may be conducted irrespective of beneficially increasing protection against superinfection
BCG scar status among children aged 5 to 9 years, when with another mycobacterial infection, while others may
BCG vaccination is given using Danish 1331 strain during increase susceptibility to progression to clinically overt
infancy under the expanded program of immunization. disease. In experimental models, protection afforded by
Chadha et al155b qualitatively estimated the size of vaccination with M. bovis BCG, M.fortuitum, M. avium,
tuberculin reaction in children who were vaccinated with M. kansasii, and M. scrofulaceum (then called Gause strain)
Danish BCG at birth in the age group of 1 to 9 years. 45 against M. tuberculosis was examined in the guinea pig.
to 60% of the BCG vaccinated children evoked reaction All environmental mycobacteria used in this study
< 5 mm in size and 70 to 80% had reaction <10 mm. The provided some protection, but with a wide variation, yet
study also revealed that a proportion of children did have none provided as high a level of protection as BCG
reaction between 10 to 14 mm and 15 to 19 mm. 19 mm vaccination. It has, therefore, been postulated that the
was the upper limit of induration. Hence, it is low protection afforded by BCG in Georgia as compared
recommended that among scar positive BCG given to the high protection observed in Britain maybe
children a reaction > 20 mm in size must be considered attributable to a differential prevalence of infection with
due to infection with tubercle bacilli irrespective of BCG environmental mycobacteria. 156 Edwards and
vaccination. Chadha et al 155b in the same research colleagues 157 demonstrated similar protection by
protocol on protective efficacy of BCG in children did vaccinating with M. avium complex against M. tuberculosis
case control analysis. It was a little surprise to found to a isolated in Chingleput as with the Danish BCG strain.
little surprise that though the protective efficacy of BCG Orme and Collins158 demonstrated that airborne infection
against extrapulmonary TB was observed to be higher with M. avium in mice was as effective as intravenous
than pulmonary TB, it was not statistically significant. BCG in protection against a challenge with virulent
In AIIMS data on the extent of BCG positivity was almost tubercle bacilli. Brown and colleagues159 administered
30 percent in proven case of TBM (unpublished work). M. vaccae in drinking water to mice, subsequently
This does not make a case for stoppage of BCG challenged them with BCG and measured the
vaccination but does alert us about the need of a new
proliferative response of spleen cells. The results showed
vaccine. These two papers emphasize that the size of the
that, depending on the timing of the exposure of the mice
reaction should also be considered along with other
to M. vaccae before BCG vaccination, M. vaccae could
diagnostic tests and the cutoff for clinical use in India
enhance, mask or interfere with the expression of
may need to be modified, based on these recent
sensitization by BCG.
observations.
If environmental mycobacteria do indeed provide
protection against M. tuberculosis, and infection with them
Differences in Prevalence of Infection with occurs before the administration of BCG, then the effect
Environmental Mycobacteria of the latter will be at least partially masked.153 This may
BCG vaccination has been used not only for protection explain the larger protection conferred by BCG given
against tuberculosis, but also against leprosy, often with earlier in life than if given later as demonstrated in
more success than in the prevention of tuberculosis. It is Chingleput.135
thus apparent that different mycobacterial species (in this Furthermore, the risk of tuberculosis would be
case M. tuberculosis, M. bovis BCG, M. microti, and expected to be greater in initially tuberculin negative
M. leprae) produce a modification of the immunologic persons than in individuals with small tuberculin skin
response to infection with another mycobacterial species. test reaction sizes (more likely attributable to infection
It is thus postulated that infection with one species of with environmental than tubercle bacilli).
mycobacterium triggers a cellular immune response In Puerto Rico, protection from BCG was lower in
prepared to act more swiftly in the killing of mycobacteria rural areas, where nonspecific sensitivity was higher than
of another species acquired during a subsequent in urban areas, where protection from BCG was higher.
infection. This is most apparent from the (limited) However, in Chingleput, the rate of tuberculosis among
protection provided by infection with nontuberculous persons with a reaction size of more than nine millimeters
mycobacteria against super infection with tubercle bacilli, to a sensitive produced from M. avium complex (PPD-B)
and the apparently similar effect of M. bovis BCG under was identical to that among those with zero to nine
millimeters reaction sizes.116
certain circumstances. That BCG can also afford protection
In the United Kingdom, the risk of tuberculosis was
against leprosy would indicate that cross-protection is not
higher among initially tuberculin skin test negative
limited to closely related mycobacterial species.
567
adolescents than among those reacting to 100 tuberculin type’(Th-1). Koch response is a delayed hypersensitivity
units only, but the risk decreased over time. The response which increases the susceptibility to develop
protection afforded against tuberculosis by a tuberculin disease by rendering tissues more sensitive to destruction
skin test reaction that can be elicited only by this large by TNF following infection, with M. tuberculosis whereas,
dose of tuberculin is remarkably similar (but smaller) to Listeria type of response correlates with the appearance
that imparted by BCG vaccination. of macrophage activating lymphocytes and provides
In the Karonga, Malawi trial, the risk of tuberculosis immunity against tuberculosis. Different species of
during follow-up was lowest among those with an initial nontuberculous mycobacteria produce varying levels of
tuberculin skin test reaction size of 6 to 10 mm. After these responses, e.g. Mycobacterium vaccae produces
adjustment for age and sex, the risk was also lower Listeria type response while Mycobacterium scrofulaceum
among those with reactions of one to five millimeters produces Koch type response, thus explaining the
than among nonreactors. variable results seen in the trials conducted in different
That different species of mycobacteria seem to act on geographical locations.
the immune system has also been demonstrated by
observations from Sweden. After the cessation of mass Other Factors
BCG vaccination, there was a large increase in peripheral
It has been suggested that infestation with parasites, in
lymphadenitis due to environmental mycobacteria.
particular with helminths, may affect the human T cell
Similarly, in the Czech Republic, the incidence of
immune responses to mycobacterial antigens. Treatment
lymphadenitis among children due to M. avium following
of helminths resulted in significant improvement of T
cessation of BCG vaccination was 3.6, compared to 0.2
cell proliferation and interferon-gamma production. This
per 100,000 person-years among children vaccinated on
the insistence of their parents, suggesting a protection of could explain to some extent the reduced efficacy of BCG
95 percent (95% confidence interval 88 to 98%) from BCG in countries in the world where helminthic infestation is
common.
against lymphadenitis due to M. avium.
While not all findings are consistent with the
hypothesis that environmental mycobacteria may mask Differences Between BCG Vaccine Used
the protection that BCG can confer in their absence, it Differences in the potency and immunogenicity of the
may explain to a considerable extent certain variations vaccine strains also may contribute to the variability in
in observed efficacy. the efficacy of BCG; however, few data support this
hypothesis. In Chingleput trial the recipients were
Infection with Nontuberculous Mycobacteria randomized to receive either a low dose or a high dose
Infection with nontuberculous mycobacteria is the oldest of French or Danish vaccine and no difference in the
and one of the most popular hypothesis till date. results were noticed.131
According to this hypothesis, infection with certain
nontuberculous mycobacteria prevalent in the Differences in the Natural History of Infection and
environment provides some protection against Disease
tuberculosis. This naturally acquired infection can mask These series of explanations include suggestions that
any protection that may result from BCG vaccination. variation in the efficacy could be related to the differences
This hypothesis is supported by animal experiments 150 in M. tuberculosis or to differences in the pathogenesis of
and by the fact that the trials showing lowest BCG efficacy the disease. It has been found that a higher proportion of
were in the areas where the infection with nontuberculous strains of M. tuberculosis from the Chingleput area are of
mycobacteria is common; such as southeastern regions low virulence in guinea pigs than is found elsewhere in
of United States and South India. However, Comstock the world. Hence, it has been suggested that this might
and coworkers,134 in their study on Puerto Rican children, explain the low protection imparted by BCG in this region.
were unable to find evidence of lowered protection after However, laboratory data, which shows that the protection
BCG vaccination among those with intermediate level can be influenced by the challenging strain of M.
of tuberculin sensitivity (thought to be attributed to tuberculosis, has failed to show evidence for poor protection
nontuberculous mycobacteria infection). against the low virulent south Indian strain.
Explanation of this varying protective effect following Another explanation suggested is that protection
nontuberculous mycobacterial infection comes from against tuberculosis by BCG is a function of relative
another hypothesis according to which exposure to importance of the disease due to “endogenous
nontuberculous mycobacteria results into two types of reactivation versus exogenous reinfection”. Since the
immune responses; ‘Koch type’(Th-2) and ‘Listeria action of BCG is to protect against the disease due to
568
hematogenous spread of infection, protection is expected release assay testing in children during an outbreak
to be better against the serious types of tuberculosis like suggesting difference in technique of assessment may
miliary and meningitis than against pulmonary TB. These alter the outcome.165
findings seems to be responsible for variations in results
many studies. Based on the same reasoning it is BCG and Disease Outcome
postulated that BCG would protect better against
In a retrospective analysis of factors determining outcome
endogenous than exogenous pulmonary disease; thus the
of treatment of tuberculosis reported non receipt of BCG
low protection observed in the south Indian study was
during infancy as one of the significant factors responsible
due to high-risk of reinfection in that community. A high
for adverse outcome (OR=1.73, 95% CI 1.02- 2.91). The other
proportion of tuberculosis in south India is of exogenous
factors were AFB positivity and extra pulmonary
type has been inferred from the high prevalence of
tuberculosis miliary and meningeal followed by lymph
infection as elicited by tuberculin sensitivity, and low
node disease with MDR-bacilli. The beneficial effect of BCG
risk of the disease subsequent to primary infection as
in treatment outcome of TB needs to be confirmed by a
assessed by the tuberculin conversion.160
prospective study.166
Variation in Host Parameters
Other Antituberculosis Vaccines
Host genetics also have been suggested to play a role in
the efficacy of BCG vaccine. However, no statistically Vole Vaccine
significant differences have been found between racial The earliest studies of alternative to BCG as a living
groups in field trials to confirm that genetic variability is attenuated vaccine compared the “potency” of BCG to
an important factor in the development of immunity that of the vole bacillus, a strain of mycobacteria isolated
following vaccination. from naturally infected meadow mice (voles).
Chronic dietary protein deficiency in children has been Experimentally it was shown that the vaccination with
demonstrated to impair the retention of cell-mediated the vole vaccine “protected” as well, as BCG.
immune response following BCG vaccination.5-7 It was
considered that this would lead to decreased protection R1 Rv
from tuberculosis, however, data from human trials is
lacking to support nutrition as a cause of variable efficacy It is derived from attenuated strain of
from BCG vaccination. M. tuberculosis.
Age at vaccination has also been considered to be a
variable affecting BCG’s efficacy; it was greater when H37Ra
vaccine was given early in life. In the meta-analysis by Another mutant strain derived from M. tuberculosis,
Colditz and coworkers145 the protection from BCG was affords equal “protection” as compared BCG Paris.
85 percent when given at birth and it decreased to 52
percent for those vaccinated after 20 years of age. INH Resistant Vaccine
Methodological Differences in the Trials Routinely available BCG vaccine is INH susceptible. Thus
if the child who has had a close contact with a case and
Finally, the different study methodologies used in the needs to be given ATT prophylaxis with INH, the
controlled trials have been blamed for the variable results. protective effect of the vaccine if given recently will be
The major source of bias in the trials was in detection of
nullified. However, the INH resistant vaccine will
tuberculosis; e.g. detection of disease by chest X-ray of
maintain its protective effect inspite of the co-
only symptomatic persons could result in biased
administration of INH.
estimation of BCG efficacy. Besides, the trials varied
widely in their statistical precision, estimated by
Correlation of BCG Scar with Induction of Cell Mediated
calculating 95 percent confidence interval for each
Immune Response (CMIR)
efficacy value. In general the trials with narrower
confidence intervals, considered to be more precise It has been seen by Seth et al7 by in vitro estimation of
estimate of vaccine’s efficacy, have shown better CMIR after BCG vaccination that almost 12 to 15 percent
protection with BCG.164 of neonates do not develop scar but have positive CMIR.
A recent study in school children suggested that BCG The absence of scar is more conspicuous among those
vaccination was associated with a reduction of M. who were given BCG immediately after delivery. The
tuberculosis infection diagnosed by gamma interferon frequency of tuberculin reactions do not vary in children
569
with and without a scar. Mallol et al 161 and Table 38.3: Untoward reactions with BCG vaccination
Sedaghation162 had similar observations. Loco-regional complications
Simple local reactions – swelling and pain at the site of
Should the Children be Revaccinated? injection
Ulcer, abscess
Sakha et al167 evaluated the immunogenicity of neonatal Temporary swelling of regional lymph nodes
BCG-vaccination in 150 children by skin test using Purified Regional suppurative lymphadenitis
Protein Derivative (PPD) who received BCG during Complications of dissemination
neonatal period and had a scar even at the age of 7 to 8 Otitis
years. They tested children with 0.1 ml of 5-unit of PPD Retropharyngeal abscesses
Cutaneous lesions
solution. The diameter of indurated area resulted from
Metastatic subcutaneous or intramuscular abscesses
PPD-test after 72 h was less than 5 mm in 95.33% and 5 to Lesions of bones, joints and synovia
9 mm in 4.66 percent of children. There was no case with Renal and urogenital lesions
induration of 10 mm or more. Every child who developed Mesenteric adenitis
an induration area of 5 mm or more by PPD test, had a Generalized lymphadenitis/ Hepatosplenomegaly
BCG scar with the diameter of 5 mm or more. There was a Generalized disseminated disease
statistically meaningful direct correlation between size of Post-BCG syndromes
Local chronic cutaneous lesions (Keloids, histiocytoma)
neonatal-BCG scar and diameter of induration after PPD-
Acute cutaneous eruptions (erythema nodosum, rashes)
test (r = 0.21 and p = 0.008). This study shows that reactivity Ocular lesions-phylectanular conjunctivitis
to PPD test (and probably immunity against tuberculosis)
decreases as age increases. Authors recommended that
there is need to repeat BCG-vaccination in children at the The most frequent adverse reactions after BCG
age of entering primary school. vaccination are regional lymphadenitis, injection site
It is or has been the policy in many countries to abscess, osteitis and osteomyelitis.169,170 The incidence of
revaccinate with BCG at school entry or later in life. There lymphadenitis varies in different studies. Most cases tend
is no evidence that this increases protection against to occur by 5th month of vaccination. In a prospective
tuberculosis, but in Northern Malawi, it has been shown survey of 2 million infants vaccinated between 1979 and
to considerably increase protection against leprosy. Re- 1981 in six European countries the risk of lymphadenitis
vaccination schemes often fall into the lowest tuberculosis was detected to be 2.5 per lakh.59 Several factors contribute
risk period in life (age 5 to 14 years) and target a to the occurrence of lymphadenitis; the vaccine strain, the
population where protection from BCG vaccination is total number of viable and nonviable bacilli, the dose of
dubious or variable at best. the BCG, and the age at vaccination.18 When given in
It has been observed that both natural and BCG preschool or school age children the incidence of
induced tuberculin sensitivity tend to wane in the course lymphadenitis was found to be 5 to 10 times less than when
of time.163 This waning could also be associated with the vaccine was given in neonatal period.
some degree of loss of protection against exogenous Children with severe combined immune deficiency
super-infection. Seth et al7 showed that only 26.3 percent and HIV infection are at risk of developing disseminated
children were Mantoux positive after 3 to 6 years of BCG BCG disease.171
vaccination compared to 35.7 percent at 1<3 year group.
Theoretically these observations would point towards Management of Adverse Reactions due to BCG
considering revaccination in children at a later age. Vaccination
However, WHO discourages BCG revaccination on the Children with lymphadenitis due to BCG were randomly
basis of lack of evidence for additional protection to that allocated to receive either isoniazid or no treatment. There
from the first vaccination.157 was no difference in the duration of lymphadenitis
A recent report on revaccination of BCG at 19 months between the two groups, nor did isoniazid prevent the
of age in Africa observed no survival benefits of occurrence of suppuration. Similarly, children with
revaccination with BCG. In this study there was increased abscess formation were randomly assigned to receive
mortality for sometime necessitating premature stoppage either isoniazid or erythromycin (serving as placebo). The
of trial.168 response in each treatment group was the same. In
another study, comparing excision, excision plus
Adverse Reactions
isoniazid, and isoniazid alone compared to a control
Various untoward reaction with BCG vaccine are listed group without intervention; no significant differences
in Table 38.3. were observed between the various interventions, and
570
in particular, isoniazid offered no advantage. BCG Vaccination and HIV Infection

Nonsuppurative lymphadenitis is a normal reaction, and
In HIV-infected children increased frequency of
is best left without antibiotic treatment.
complications following BCG vaccination have been
Patients with suppurative lymphadenitis following
BCG vaccination were randomly assigned to treatment reported.174,175 One study has shown a relatively high rate
with simple needle aspiration, introducing the needle (10%) of post BCG lymphadenitis among the HIV infected
subcutaneously two to three centimeters distant from the children, however, the study did not include noninfected
node, versus no treatment. Regression was significantly children as control group.176 Also there are some case
faster in the treated than in the non-treated group, and reports of disseminated BCG disease developing in
spontaneous drainage was less frequent. infants following BCG vaccination.177,178 However, in a
For osteoarticular mycobacteriosis due to BCG, controlled trial infants born to HIV infected mothers had
combination therapy is indicated, but results were not no additional complications though their PPD reactivity
always favorable (both in terms of sequelae and relapses) after the vaccine was much lower compared to the infants
in a case series from Sweden. born to HIV negative mothers (33 to 83%).179
A standard course of treatment (as for clinically In a systematic review of BCG related disease in HIV
manifest tuberculosis) is also indicated in disseminated infected children including 16 studies reported a total of
mycobacteriosis due to BCG. As this is a rare 49 cases of disseminated BCG disease. Majority (41 cases)
complication, however, treatment regimens have not were reported from Cape Town Province of South Africa.
been amenable to formal study. In treatment, it should The review concludes that HIV-infected infants are at
be kept in mind that BCG is, like its parent organism, M. risk of BCG disease, but the degree of increased risk
bovis, naturally resistant to pyrazinamide. remains uncertain. Improved laboratory-based
Opinions differ on the optimal management of the surveiliance and more incidence data of confirmed cases
BCG adenitis. In most cases, it tends to resolve with time, are urgently needed. Improved population-based studies
though some cases tend to be indolent or suppurate and in areas outside sub-Saharan Africa are also required to
form fistulous tracts. Though there are no statistically inform vaccination policy. Improved knowledge of the
proved trials but erythromycin given for two weeks has potential efficacy of BCG for HIV-infected and HIV-
been shown to have beneficial effect in resolution of exposed infants in TB-endemic communities is critical
indolent lymphadenitis.172 However, its use is not to the risk-benefit analysis needed to change policy.180
recommended any more. Caglayan and coworkers164 Hesseling et al180a performed an analysis of isolates
found that when lymphadenitis develops rapidly (within of M. tuberculosis complex for the determination of the
2 months) after vaccination chances of its suppuration prevalence of bacilli Calmette-Guerin (BCG) disease
are higher. They recommend total surgical excision in among human immunodeficiency virus (HIV) – infected
such instances to prevent spontaneous drainage and children. Specification was done with polymerase chain
chronic suppuration. WHO suggests that drainage and reaction;183 isolates from mycobacterial cultures for 49
direct instillation of an antituberculosis drug into the HIV – infected patients were analyzed. The Danish M.
lesion should be considered for adherent and fistulous bovis BCG strain was isolated from 5 patients. No case of
lymph nodes but usually it is not done. Systemic Tokyo M. bovis BCG strain was detected responsible for
treatment with antituberculosis drug is ineffective.172 disease.
Osteitis also can occur after the vaccination with BCG All patients were asymptomatic at birth, <12 months
of age, and severely immunodeficient at presentation.
but its incidence is much less than the lymphadenitis. It
Four patients had regional adenitis ipsilateral to the
usually involves the epiphysis of the long bones
vaccination site, and 2 had pulmonary BCG disease.
particularly the lower limbs. Antituberculosis drugs
coupled in some cases with surgical curettage and
Characteristics of BCG disease
debridement, usually results in the healing of skeletal
lesions.173 • Ipsilateral axillary adenitis to BCG vaccination site
The most dreaded complication of BCG vaccination • Hepatosplenomegaly
is disseminated BCG disease. It is most frequently seen • Intraabdominal lymphadenopathy
in children with concomitant immunodeficiency and is • Symptomatology
usually fatal. Most cases of BCG-itis occur within - Failure to thrive
6 months of vaccination. Treatment is similar to treatment - Oral candidiasis
of active tuberculosis except that pyrazinamide is not - Generalised lymphadenopathy
used, as all strains of BCG are resistant to this - History of TB contact.
antituberculosis drug.
571
• Investigations dosing isolation and information about patient. After

- Tuberculin skin test –ve PCR speciation of M. tuberculosis complex was
- Decrease in CD 4+ cells, medinstinal lymphad- performed, the results were linked to patients’ personal
enopathy with persistent lobar consolidation, information. Maximum effort was made to trace these
bronchopneumonic opacification, pneumatocele, patients through repeat telephone calls and home visits.
bronchiectasis, diffuse alveolar opacifications or even Informed consent was obtained before clinical
mliary. information was studied. This study proposal was
- All children were asymptomatic at birth and given approved by the institutional review board (IRB) of
BCG vaccination. Stellenbosch University.
All patients with BCG – related disease were infants
after change in the vaccine policy in July 2000, when the Treatment of BCG Vaccination Induced Disease in HIV
recommendations of the Health Department of South Infected Children
Africa were changed from a percutaneous vaccine with
Recommended treatment is INH +RIF + PZA (2 months)
the Tokyo M. Bovis BCG strain. Young symptomatic HIV-
then RIF + ETH + Ethionamide + ofloxacin + Amikacin.
infected children are at risk of developing BCG – related
Treatment has to be individualized. Sensitivity testing
disease. The children who acquired HIV infection
of the isolate by BECTEC (rapid method) becomes
through vertical transmission, progress rapidly to
mandatory. Treatment needs to be done at a specialized
symptomatic HIV disease. They have also a high risk of
center rather by a pediatrician who has got expertise both
BCG – related disease. It is quite possible to have dual
in treating HIV and tuberculosis disease. Outcome is
infection with M. tuberculosis and M. bovis BCG. This is
quite poor. Response to antituberculosis (ATT) therapy
highly relevant in setting such as India where the
is ascribed to a number of host factors such of HIV-related
prevalence of tuberculosis and HIV is high and there
gastrointestinal disease with inadequate absorption.
routine BCG immunization is a part of universal program
• Surgical excision of large axillary lymphondes may
of immunization. One inference from this seems to be
be necessary for local containment of regional disease.
logical that if an infant develops ipsilateral axillary
• M. bovis species are generally resistant to
adenitis after BCG vaccination, she or he must be
pyrazinamide, and there is a possibility of resistance
screened for HIV along with the mother and father.
to other drugs as well.
Before this one must ensure that after BCG vaccination
an intradermal papule was raised and BCG was not Danish BCG strain poses a risk for localized and
accidentally given intracutaneously by not so an expert disseminated disease in infants who are infected with
vaccinator. The mycobacterial isolate form such infants HIV infection through vertical transmission, even if they
is usually resistant to INH, rifampicin and pyrazinamide. are asymptomatic at birth. It is also reporetd that Infection
with HIV severely impairs the BCG-specific T cell
Ethical Considerations response during the first year of life. BCG may, therefore
provide little, if any, vaccine-induced benefit in HIV-
The collection of gastric aspirates and other body fluids infected infants. Considering the significant risk of
for culture of M. tuberculosis complex forms part of BCGosis, these data strongly support not to give BCG to
routine clinical practice for children in whom tuberculosis HIV-infected infants.181
is suspected. The collection of mycobacterial isolates in Given the paucity of data suggesting serious effects
a sample bank was approved by the institutional review of BCG vaccination on the HIV infected, WHO
board of Stellenbosch University (Cape Town, South recommends BCG vaccination for all asymptomatic HIV
Africa). HIV testing for these patients was done in the infected children particularly those residing in the
course of routine clinical management; informed consent developing countries. WHO does not recommend BCG
was obtained, and pre- and post counseling were vaccination for those with symptomatic HIV infection
available. HIV-infected children were identified from a or for persons known or suspected to be HIV infected
confidential database maintained by the pediatric but have minimal risk of infection with M. tuberculosis.182
infectious diseases unit (PIDU) at Stellenbosch
University, which is accessible to attending physicians BCG as a Diagnostic Modality–The BCG Test
only. Standard procedures to maintain patient The importance of BCG as a diagnostic modality is out
confidentiality was maintained through coding of
now from the armamentarium of TB diagnostics. In his
mycobacterial cultures and patients’ personal
classical paper on BCG test in tuberculosis Udani et al183
information and through blinding of laboratory staff
described it in detail.
572
BCG test has the major drawback that once it is given, 2. The researchers found a gene in the organism that
the tuberculin test cannot be reliably used in near future helps adude immune system detection, and removed
to judge the difference between infection and TB disease. it from the bacterium.
Hence, the use of BCG test is not recommended. 3. It was found that vaccine extended the lives of mice
Immunologically it does not stand to scientic reason and guinea pigs and stimulated stronger immune
because the antigen load is much more and includes all responses compared to the existing vaccine.
components of tuberculous bacillus. 4. The scientists believe that if the results continue to be
positive, human studies may be possible in two to
Effects of BCG Other Than Those Directed Against three years.
Tuberculosis It is said that TB, a bacterial infection that usually
attacks the lungs, kills about 1.6 million people a year
BCG has been shown to be protective against leprosy in
globally. The increasing resistance of the TB organism to
some situations while not in others. It has also been shown
drug treatment makes creation of a truly effective vaccine
to be effective against M. ulcerans, albeit with an apparently
even more crucial.
very shortlived protection. BCG as vaccine, is also being
The existing BCG vaccine in the use for almost a
tried for prevention of leprosy. A recent doubleblind study
century despite its limited effectiveness is based on a live
in Malawi by the Karonga Prevention Trial Group (1996)186
attenuated strain of bacterium that causes TB in the cattle.
showed that initial BCG vaccination afforded 50%
In the new vaccine, use is made of a weakened version
protection against leprosy and a second vaccination added
of the bacterium that causes TB in human beings. The
appreciable (another 50%) protection without providing
basis being similar to other vaccines by trying to make
any protection against tuberculosis. Curihas et al186a has
the body’s own immune system stronger and have better
shown that here is clear evidence that BCG protects against
defenses to fight off invaders like disease causing
leprosy, but cross-immunity with environmental
bacteria. The researchers have found a gene in the
mycobacteria can interfere with vaccination protection.
organism that helps it edude immune system detection
The study was designed to estimate the vaccine
and removed it from the bacterium. This helps the vaccine
effectiveness of neonatal BCG against leprosy in Amazan
used in mice and guinea pigs whose life was extended
region in Brazil. This research indicated that neonatal BCG
and a stronger immune response was elicited as
vaccination in Brazilian Amazan elicited protection of 74%
compared to the existing BCG vaccine. However, a major
against all forms of leprosy cases. Secondly, highest
limitation is that it is still probably too infectious to give
protection was observed (93%) for multibaciliary cases. It
it to humans. It is only partially attenuated for virulence.
is inferred that the study provides evidence that BCG
Removal of additional genes may make the vaccine safer.
vaccine may have an important and overloaded impact
on the occurrence and transmission of leprosy particularly
Global Aspect
at an age when there is high incidence of leprosy.
The best known indications for BCG against other The TB organisms is present roughly in a third of the
than mycobacterial diseases are its use as an world’s population. Most infections remain latent but can
immunotherapeutic agent in the treatment of superficial become active when the immune system is weakened,
bladder cancer and nephritic syndrome in developing for example when the same person gets HIV infection in
countries and, to a lesser extent in, malignant melanoma. case of children viral infection like measles. The existing
It has also been suggested that BCG reduces the risk of BCG vaccine protects young children from tuberculosis
atopy and asthma, and reductions in the risk of intestinal but not the adolescents and adults against the type of
nematodes in children and HIV-infected patients have disease present in them.
been reported. TB can be treated effectively with drugs in many
cases, but drugs have to be given for upto six months
Newer Vaccines making treatment difficult and expensive. Many poorer
parts of the world lack the medical infrastructure to
Scientists are excited about the prospects of a new
deliver this kind of treatment, so many experts feel an
vaccine, after tests on mice and guinea pigs as it appears
effective vaccine, could be a highly valuable tool in
to be more effective than the BCG vaccine which is
combating the disease.
currently used.
A new generation of TB vaccines is presently under
The points new to this vaccine are:
development, mostly targeting the induction of cell-
1. Rather than trying to make changes in the current
mediated immunity by stimulation of CD4+/CD8+ T-
vaccine, researchers used a weakened version of the
cell. All the modern vaccination strategies are being
bacterium that causes TB in people.
573
explored, including recombinant BCG vaccines, AERAS-402 is a novel TB vaccine designed to boost
recombinant subunit vaccines, DNA vaccines, attenuated immunity primed by BCG, is the only licensed vaccine.
M. tuberculosis, viral vectors and saprophytes, as well as A study on safety and immunogenicity of AERAS-402 in
combined vaccine approaches. healthy M. tuberculosis uninfected BCG vaccinated adults
Various antigens such as MTB8.4, ESAT-6, MPT63, from a TB endemic region of South Africa reported that
MPT64, MPT83, PstS-1, MTB39, hsp60, and hsp70 have AERAS-402 is safe and immunogenic in healthy adults.
been tested in animal models and found to have some The immunity induced by the vaccine appears promising;
efficacy.187,88 In addition, there have been efforts to polyfunctional T cells are thought to be important
deliver multiple antigens of M. tuberculosis by using for protection against intracellular pathogens like
recombinant poxviruses and Salmonella as the vaccine M. tuberculosis. AERAS-402 induced a robust and
carriers.189,190 Different adjuvants have been used for durable CD8 T cell response, which appears extremely
these vaccines to improve the immunological response. promising.191
There are also efforts to develop new attenuated MVA-85A, in development by Oxford-Emergent
vaccines based on M. tuberculosis and also improve the Tuberculosis Consortium Ltd and the EU-funded
BCG vaccine. Several vaccine candidates have been research program TB-VAC, is a live attenuated viral
shown to be effective in preventing virulent TB infection vaccine expressing the immunodominant tuberculosis
in animal models. Immunization using a recombinant (TB) antigen 85A, and is intended for use in a heterologous
Ag85B protein, produced promising results by prime-boost strategy to prevent TB. MVA-85A is highly
preventing infection in lungs, spleen and increasing the immunogenic in both animals and humans, eliciting
survival time of vaccinated animals. Other vaccine strong polyfunctional CD4+ T-cell responses when
approaches, based on DNA expression of Ag85, alone or administered as a boost following BCG vaccination or
in combination with a modified vaccines Ankara (MVA) when administered to individuals previously exposed
vectors expression of the same antigen have also to TB. Animal studies have demonstrated trends toward
produced encouraging results in preventing TB infection reduced pathology and bacillary burden for animals
in animal models. Additional research is under way to vaccinated with BCG prime followed by MVA-85A boost
modulate immunogenicity of candidate vaccines by compared with BCG alone; however, these positive
addition of cytokines. Among these studies, evaluating effects appear to be modest, and interpretation is limited
adjuvant effects of granulocyte macrophage-colony by the small number of animals tested. The vaccine has an
stimulating factor (GM-CSF) on BCG-based vaccines and excellent safety profile in BCG-naïve, previously BCG-
IL-12 on DNA vaccines are showing promising results. vaccinated and TB-exposed adults, as well as in BCG-
At least seven candidate TB vaccines and their vaccinated adolescents and children. At the time of
combinations have entered human clinical trials and are publication, MVA-85A was in a more advanced stage of
aimed at replacing or improving existing vaccination and clinical development than other novel TB vaccine
treatment strategies for TB. Attenuated M. tuberculosis candidates, with a large-scale, proof of concept phase IIb
and a combination of BCG+rAg85A have been proposed clinical trial underway for the determination of safety,
to replace BCG for vaccination in children. Several immunogenicity and prevention of TB in infants.192
vaccine strategies, using either a live vaccine vector
expressing Ag85A, heat inactivated M. vaccae or fusion TB HIGHLIGHTS
protein, are currently being evaluated for their capacity to
prevent TB infection. Other vaccine approaches are aiming • Given the higher incidence of tuberculosis in most
at boosting BCG efficacy in adults or enhancing TB developing countries and the inability to control the
chemotherapy efficacy. spread of infection through prompt diagnosis and
The Korean TB vaccine research program, under the effective treatment of the infectious patients, WHO
responsibility of five national clinical research centers, is continues to recommend BCG vaccination for
pursuing various types of vaccine approaches, including; children on a worldwide basis.
recombinant BCG (Korean Institute of Tuberculosis), CFP • In the countries with high prevalence of tuberculosis
and Triton-X soluble proteins (Choongnam university), the vaccine should be given to the infants as soon as
DNA vaccines, adenovirus vector and IL-12 (Pohang possible after birth.
university); DNA vaccines and cytokines (Seoul National • In the countries with low prevalence of tuberculosis
University); gene “knock out” in mycobacteria policy regarding BCG vaccination should be adapted
(Youngnam university) peptides, recombinant proteins to the changing situations, taking in account both local
and recombinant BCG (Yonsea University). and global epidemiological trends.
• Due attention should continue to be paid to the quality
of BCG vaccine, its handling, technique of application,
574
the training of the personnel and the coverage of the • Besides, research is needed for develop-ing a more
eligible population. efficacious vaccine that would deliver uniform results
• BCG vaccination rather than being considered in in all settings.
isolation as means of tuberculosis control, should Government of Delhi, Directorate of Family Welfare
form part of a comprehensive control program that has given the following instruction sheet for BCG
includes case detection and treatment. vaccination (Annexure).
ANNEXURE
INSTRUCTION SHEET FOR BCG IMMUNIZATION SECTION
DO’s DON’ts
1. Maintain prescribed cold chain. 1. Vaccine should not be exposed to directed sunlight
2. Check the label and expiry date of vaccine before use. and care should be taken to conduct immunization
3. Ensure the hand wash with soap and water before session in a properly shade site.
starting immunization. 2. Do not store any vaccine in the door of the
4. Use the vaccine specific diluent for reconstitution. refrigerator.
5. Use the reconstituted BCG vaccine within four hours. 3. Do not send any target child back without
vaccination.
6. Use a separate sterilized needle and syringe for each
child. However, if changes of syringe are not possible, 4. Never use distilled/boiled water.
it can be used for ten children and then replaced with 5. Do not constitute more than one vial of one antigen
fresh disposable at sterilione. (vaccine) at a time.
7. Discard all opened vials of the vaccine at the end of 6. Do not freeze.
the day. 7. Do not store any vaccine in the door of the
8. Ensure that enough vaccine is available for the next refrigerator.
session.
Government of Delhi
Directorate of Family Welfare
Malkaganj, Delhi
38.2 BCG VACCINATION—FREQUENTLY ASKED QUESTIONS

Vimlesh Seth
Q 1. What does BCG stand for and how was it of 231 transplants). In 1921 the strain proved to be
invented? harmless even in highly susceptible guinea pigs; yet its
antigenic properties were unimpaired. They called this
BCG stands for bacilius Calmette-Guerin. It was prepared
bacillus Calmette and Guerin (BCG). In 1924, Calmette
by Calmette and Guerin by repeated subcultures of
declared the bacillus incapable of reverting to virulent
Mycobacterium bovis on ox bile medium. Prior to its
form. In 1928, the League of Nations declared the BCG
discovery, numerous investigators had tried to submit
strains as harmless in animals and man. Since then
the tubercle bacilli to attenuate it, in order to produce a
millions of infants and children have been BCG
vaccine for the prevention of tuberculosis. In Lille
vaccinated all over the world.
(France), Albert Calmette (a bacteriologist) and Camille
Guerin (a veterinarian) were working on the same with Q 2. Why should BCG vaccine be given at left upper
a highly virulent strain of tubercle bacilli of bovine origin, arm only? Some parents insist that it should be given
isolated a few years earlier by Nocard of Alfort from
at gluteal region to avoid visible scar at the upper arm.
tuberculous mastitis in a helfer. In 1908, these workers
Can BCG be given at sites other than left upper arm?
observed that addition of beef bile, acting like a soap,
melted the fatty surface of the bacilli and made possible It is a convention to give it on left upper arm, so that for
the dissociation of the aggregates and their division take up of the vaccine, one is sure where to look for the
almost to single units. The bacilli were then cultured and scar.
transplanted every three weeks for thirteen years (a total BCG vaccine should not be given at gluteal region,
575
because the regional lymphadenitis, there would prove Contamination can be prevented as follows:
to be more problematic. In any case, the scar of BCG is i. Separate needle must be used for each child.
very small and produces no cosmetic problems. In some ii. Reconstitution of ampoule should be done after
of the cases, it may even fade away completely. washing hands.
iii. It is far better to use disposable syringes and needles
Q 3. Why BCG ampoules are dark colored and so long rather than boiled syringes and needles.
in size while other vaccines (DPT, DT, Measles, MMR)
are supplied in clear ampoules or vials? Q 9. In which compartment of the refrigerator should
BCG be stored (undiluted and diluted) to maintain
BCG ampoules, are dark colored because the vaccine
potency?
deteriorates on exposure to light. A black paper is also
usually supplied with each pack of BCG ampoules, to Diluted vaccine is not to be retained for more than 3 to 4
achieve the same objective. hours, hence during this period it should be kept in the
vaccine carrier containing ice. However, undiluted
Q 4. Are any special precautions necessary while vaccine should be stored in the middle of the main
opening a BCG ampoule and why? compartment. The temperature in this compartment is 2
to 4° C and at this temperature freeze dried vaccine can
Ampoules of freeze dried BCG Vaccine are sealed under
be stored for upto 6 months. There is no need to put this
vacuum and there is no air or very little air in the
vaccine in a freezer.
ampoule. Thus, they have to be opened carefully to avoid
rushing in of air and spilling of powder.
Q 10. An authentic study was conducted in Chingleput
The neck of the ampoule should not be crushed or
regarding the efficacy of BCG way back in 1980. It
broken suddenly by a metallic object. It should always
be cut gradually at the junction of the neck and the body
proved its ineffectiveness in preventing pulmonary
of the ampoule, by a cutter (file) so that air goes in slowly tuberculosis. But all the vaccination schedules still
into the ampoule, and the powder is not spilled. recommend BCG immunization.
Reports from the Tuberculosis Prevention Trial
Q 5. BCG ampoules are supplied without any Chingleput, have been widely interpreted to show that
information regarding its dilution. Does this mean that BCG offers no protection against tuberculosis under any
any diluent can be used for its dilution? epidemiological conditions. This is not true as:
i. The efficacy of BCG was assessed solely by the
No, freeze dried BCG vaccine has to be reconstituted by
incidence of sputum positive pulmonary
dissolving it with normal saline as distilled water acts as
tuberculosis (secondary or adult type).
an irritant to the skin. The diluent should always be kept
ii. Extrapulmonary forms of tuberculosis, occurring in
with the vaccine in the main compartment of the
the study populations were not recorded
refrigerator or in the cold box or in the vaccine carrier. It
iii. Children under 10 years of age although vaccinated,
will ensure that it is cold enough when one needs it.
were not included in the assessment lasting for seven
and a half years.
Q 6. For how long is the reconstituted dissolved
iv. The report was written only seven and a half years
vaccine potent? after the beginning of the study and this period is
Reconstituted BCG vaccine should be used within 3 not sufficient to study the natural history of
hours. tubercular infection.
The study had only shown the ineffectiveness of BCG
Q 7. Why do the manufacturers produce BCG in vaccine to prevent adult type of tuberculosis and it is
ampoules only? Would it not be better if it is supplied not justified to extrapolate these results to infants and
in vials to avoid contamination of the diluted vaccine? children.
One must remember that even natural infection with
Once diluted, BCG has to be used within 3 hrs. so the tuberculosis does not protect against secondary type of
question of keeping it safe for a longer period in a vial tuberculosis and hence it would be futile to expect BCG
does not arise. (which provides much lesser immunity than natural
infection) to do so.
Q 8. How can the diluted vaccine be prevented from The basic mechanism by which BCG acts, is by
contamination? interfering with the silent bacillemia which follows after
576
the very first exposures to human strain of tuberculous Q 13. There is a lot of confusion regarding the optimal
bacteria and hence, it is most likely to be effective against age of vaccination. Some recommend at birth, while
hematogenous forms of primary tuberculosis. Other many others recommend at the age of one month.
studies have shown that the incidence of hematogenous Recently, it is being recommended to be given between
types of tuberculosis (the fatal form of tuberculosis) in 3 and 9 months of age. Please clarify.
infants and children is definitely lower in BCG vaccinated
children. Also some more studies from Thailand and Although some studies have shown a slightly higher
Hongkong, done after Chingleput trial have also shown tuberculin conversion rate when BCG is given at 3 months
that the incidence of tuberculosis is lower in BCG of age, most studies have shown good sensitization even
vaccinated contacts of open case of tuberculosis. It is for when BCG was given at birth. Therefore, the current
all these reasons that BCG vaccine is still included in all practice of giving BCG at birth is to be continued especially
immunization schedules. in view of the high endemicity of the disease in our
country, and because it is so much easier to get the children
Q 11. In several countries of the world (USA, UK) at birth rather than at 1 or 3 months on a nation wide scale.
routine BCG is not given, still they have a low incidence If BCG has been missed at birth, then it should be given at
of tuberculosis. Does this not mean that BCG has no the earliest contact, preferably before 9 months of age.
role in eradicating tuberculosis?
Q 14. BCG at birth may not produce any immunity. Is
Yes, it is a fact that BCG is not given in UK and USA as a this true?
routine. It is because these countries have a very low
incidence of tuberculosis and hence routine vaccination This is not true. It has been shown that cell mediated
is not indicated in these countries. This is in conformity immune response (CMIR) could be induced in a
with the basic principle that vaccination is not required comparable proportion of cases at birth (78.2%) and at 3
wherever the chances of natural infections are very low. months of age (72.5%). It is, therefore, considered that
This cannot be interpreted to show that BCG is not helpful new borns are capable of evoking CMIR at birth and the
in controlling tuberculosis. practice of giving BCG at birth should be continued.
Q 12. In UK, the BCG vaccine is given only at 12 to 13 Q 15. Can preterm babies be vaccinated at birth? If so,
year of age, while in India we give it at birth. Why is it is there any point (gestational age) below which
so? vaccination is contraindicated?
BCG vaccination policy chosen for a particular area BCG has been found to be effective in preterm infants
depends on its epidemiologic picture as suggested by also. A tuberculin conversion rate is 83% in a group of
WHO, ICMR study group. Thus, in areas of high preterm, appropriate for gestational age newborns (32-
prevalence, BCG should be given as early in life as 36 wks). However, small for gestational age babies have
possible, as the chances of a child acquiring infection early a poor tuberculin conversion following BCG vaccination.
in life is very high. Thus, it is in early life only that the
vaccine will have the greatest impact on serious sequelae Q 16. Similarly, is there any cut off point regarding birth
of primary infection. In general, where more than 5% of weight and BCG vaccination?
children aged 10 to 14 years have been infected, BCG
should be given at birth; where the rate is more than 2% No specific references are available, but probably
but less than 5% it should be given at school entry; and appropriate for gestational age 32 to 36 weeks newborns,
in places where less than 2% of children are infected at may be treated as a cut off. Babies above 2000 gm can be
10 to 14 years, BCG could be given at 12 to 13 years, thus easily vaccinated but it may be advisable to wait for some
affording maximum protection over the years of puberty. time for babies with lesser birth weight.
UK falls in the last category.
It seems that maximum BCG efficacy is seen within 1 Q 17. I am unable to give intradermal injection. Can I
to 2 years of vaccination and hence giving it just prior to give it by subcutaneous or intramuscular route? Can
the age when natural infection is most likely to occur in a BCG be given orally?
given population is the most cost effective way of giving No. BCG can not be given by subcutaneous or
vaccine. intramuscular route. Small abscesses are most likely to
occur if the vaccine is given subcutaneously and the
577
efficacy would be reduced. The vaccine cannot be given Q 22. Is rubbing at injection site of BCG, recommended
orally. soon after administration?
At present, there is no substitute for intradermal
No, it is not desirable to disperse the bacteria contained
injection for BCG and the technique must be mastered
in the vaccine from the intradermal site, otherwise the
by all those who wish to give-BCG vaccination. 26 gauge
efficacy would be compromised. The wheal produced
needle should be used for giving intradermal injection.
by BCG is not painful and would settle down in 20 to 30
minutes.
Q 18. How should the skin be cleaned before giving
BCG? Can spirit be used for this purpose?
Q 23. I have given BCG today. What should I tell the
No special preparation of the skin is necessary before mother who asked me whether she can bathe the child
giving BCG vaccination, i.e. washing with disinfectants today?
like alcohol, dettol, etc. is not to be done. In fact, their
use is contraindicated as they may destroy vaccine Since, the wheal settles in 20 to 30 minutes after
bacillus and thus affect the immune response adversely. vaccination, the mother can bathe the child the same day.
Cleaning with sterile water is enough.
Q 24. Should hot fomentation be done at the Injection
Q 19. The method of using the same needle (after site?
flaming) for BCG intradermal injection should be Though direct references are not available (in the case of
recommended or not? Can same syringe with only BCG), actions and substances which increase local
change of needles be advocated? vascularity (such as rubbing, histamine, hyaluronidase,
etc.) diminish the immune response. The same might
In mass campaigns, the needle is often passed through a
hold true for fomentation and hence, it is not
heated flame for its sterilization. The organisms contained
recommended.
in the length of the needle are killed. This practice is to
be strongly condemned and use of separate disposable Q 25. Do I need to given any other instructions to a
needles must be adhered to for every case. The same mother of a baby who has received BCG today?
syringe can however be used.
It is advisable to explain the expected reactions of
Q 20. How do I Know that BCG has been given vaccination to the mother in simplified language. The
intradermally? raised area will be absorbed in 20 to 30 minutes and
would disappear and nothing will be seen at the site of
Raising a wheal over the injection site is a sure sign of injection for some days. By about the 3rd or 4th week, an
intradermal injection. When an intradermal injection is area of hardness will be felt at the site of vaccination,
given, hair follicles are seen as small pits on the wheal which will become a lump of 6 to 10 mm by about the
produced. This wheal should be clearly seen for all 6th week. It is generally not painful but may be tender to
intradermal injections. When correct volume (0.1 ml) of touch. The lump sometimes softens with pus formation
vaccine is injected the wheal produced has a diameter of which may discharge, leaving a tiny ulcer which heals
about 8 mm. by itself. After 10 to 12 weeks all that is visible, is a tiny
scar, 5 to 7 mm size, with a little pigmentation at the site.
Q 21. What is the dose of BCG vaccine? Does it vary
The process of healing and ulceration may repeat 2 to 3
with the age or weight of the child? times over a period of 2 to 3 months.
The standard dose of BCG vaccine is 0.1 mg in 0.1 ml
volume, irrespective of age and weight of the child. The Q 26. Accidentally, I have injected 0.4 ml instead of 0.1
recommendation of reduced dose (0.05 mg in 0.05 ml) in ml of BCG vaccine. What complications are anticipated?
the first month of life is without any scientific explanation. Practically it is impossible to give 0.4 ml of BCG
A fear has been expressed by some workers that the rates intradermally. If it has been injected, it has probably gone
of regional lymphadenitis are higher when higher dose subcutaneous. The chances of local complications like
(0.1 mg) is given in infants. In controlled trials the abscess formation and suppurative lymphadenitis,
incidence was 1.3% as compared to 1% with low dose increase with higher doses of BCG and with
(not a significant difference). Further, one is not sure of subcutaneous injection. It would be preferable to wait
the efficacy of the lower dose of vaccine. Hence, the same for any complication to occur, and then if required, to
dose (i.e. 0.1mg) should be given at all. give INH therapy for 3 to 6 months. It may not be
578
advisable to give INH right at the time of overdose of In office practice, it is preferable to do Mantoux testing
injection, as it may interfere with the viability of injected before giving BCG in all age groups except in children
bacilli and hence may interfere with the immune below 1 year of age in whom BCG can be given without
response. Mantoux testing.
Q 27. How long after BCG inoculation does Mantoux Q 32. National Tuberculosis Control Program
test become positive? recommends giving BCG even in older children without
prior Mantoux testing. This is contrary to what I was
Taking responses of 5 to 6 mm as ‘converted’ in the case
taught. What is your opinion?
of newborns, 90% of the conversions will have occurred
by six weeks, and 95% by 12 weeks. In a tuberculin test survey done over a period of 5 years,
it was realized that in mass immunization program, as
Q 28. There is no indication of BCG take up even after 8 also in large number of children attending outpatient
weeks of inoculation. Is there any recommendation for services, the drop out rate is 51% for follow up if we
repeating BCG vaccination? If so, how long after this first decide to do BCG vaccination after tuberculin testing.
BCG? Thus, there was enormous waste of hospital time.
Tuberculin test could not be read in 51% cases. Thus, such
If no reaction is seen at the local site even after 12 weeks, a procedure though ideal, would be futile and impractical
it is an indication that BCG has not taken up. In such at the field level. Since the studies were conducted in 0
cases, BCG should be given again. to 14 years age group, no cut off point for tuberculin test
prior to BCG is recommended, in the national health
Q 29. Should Mantoux test be done in such a case program.
before giving the second dose of BCG? Direct BCG vaccination of even previously exposed
Yes, it would be preferable to give a Mantoux test in such (Mx+ve) children does not cause any adverse reactions
children. If no reaction (≥ 5mm) is seen with 1TU except an accelerated reaction and hence is quite safe.
tuberculin even after 12 weeks of vaccination, then only
the BCG vaccine may be given. Although it should be Q 33. A newborn is born to a mother who is an open
remembered that absence of reaction of Mantoux test case of tuberculosis (TB). How can he be protected from
does not necessarily mean that a hypersensitivity or TB. Can such a mother breast feed her child? Can BCG
immunity to tuberculosis has not been set up. In fact and antituberculosis treatment (ATT) be given
many of these children (i.e. Mx negative even after BCG) together?
show a positive reaction to more sensitive tests of cell
A rational approach would consist of:
mediated immunity like phytohemaglutinin blast
i. Treatment of the mother, and
transformation (PHA) or lymphocyte migration
ii. Protection of the newborn.
inhibition test (LMIT).
i. Treatment of the mother: The mother of such a
Q 30. If there is no take up (reaction) after BCG newborn has to be treated intensively with 3 to 4
vaccination, then what are the reasons for it? Is the drugs. There is no need to isolate the infant from
the mother. It has been demonstrated that INH
vaccine not potent or the technique faulty?
administered to newborns prevented infection even
Either of the factors, i.e. the potency of BCG and faulty when the infants remained with their mothers,
technique, may be operative when no reaction of BCG is suffering from open tuberculosis. Breast feeding is
obtained. If the instructions regarding storage, transport, not contraindicated as the infection does not spread
etc. are not followed meticulously, the vaccine may be through breast milk and would be preferable over
inactivated. If the vaccine is given subcutaneously, it may bottle feeding as in any other child. None of the
not evoke adequate cell mediated immune response, and antituberculosis drugs are excreted in sufficient
also if adequate dose is not given the vaccine may not amounts in breast milk to cause any toxicity to the
take up. Apart from potency of BCG and the technique, newborn.
certain host factors (like malnutrition, a recent attack of ii. Protection of the newborns: All the newborns born
measles, etc.) may also interfere with uptake of BCG. to infectious mothers, should be put on INH (10 mg/
kg) prophylaxis after excluding congenital
Q 31. Should Mantoux test be done prior to BCG tuberculosis. They should be observed clinically
vaccination in older children. Till what age BCG can be over the next three months, it any symptom like
given without performing a Mantoux test?
579
failure to thrive, fever, etc. develop, the child should of BCG. A six weeks gap should be there between measles
be screened for tuberculosis and treated for the same vaccine and BCG.
with 3 to 4 drugs depending upon the type of TB
the new born develops. If the child remains healthy, Q 37. Which vaccines can be given concurrently with
a Mantoux test should be given at three months. If BCG and which vaccines should not be given
it is negative, BCG is given and INH is stopped. But simultaneously with BCG?
if Mantoux at three months is positive, child is
BCG can be given with OPV or DPT at the same time.
investigated for tuberculosis and treated
Measles and MMR should not be given with BCG.
appropriately with 2 to 3 drugs as per
recommendations of WHO.
Q 38. I try to avoid giving two injections to children on
one visit. For example a two months old child is brought
Q 34. A child has already been treated for tuberculosis.
to me for vaccination. I give BCG at first visit and tell
Does this child need BCG?
them to come after few days for DPT and Polio
The fundamental purpose of BCG is to give a nonvaccination. Parents accept this practice do you agree
pathogenic primary infection, using a measured dose of with me?
an attenuated bovine mycobacterium. The primary
infection induces tuberculin hypersensitivity and There is no harm in giving DPT and Polio on the same
increase defence mechanisms so that if the recipient is day as BCG, but if for some reason, they are not given on
later exposed to reinfection with a pathogenic strain of the same day, then a gap of least 4 weeks must elapse
mycobacteria, that infection will not cause a clinical between two vaccinations. A lesser gap will interfere with
disease or if it does, then it will be localized. In other the uptake of both BCG, DPT and Polio.
world, once tuberculized naturally, the child already has
primary infection and hence would not need BCG. Q 39. An ulcer has formed at BCG inoculation site. It is
not healing even after eight weeks. Which antibiotics
Q 35. Is this not ideal to give BCG to all children who (local/parenteral) do you recommend to treat this
are Mantoux positive to protect them from flaring up condition? What is the suggested management?
of tuberculosis. In other worlds can BCG protect against Ulcer formation at BCG inoculation site is a normal
recrudescence type of secondary tuberculosis? phenomenon. The phenomenon of healing and ulceration
may repeat 2 to 3 times over a period of 8 to 12 weeks.
Mantoux positivity indicates that the person has been
Nothing needs to be done for this. Antibiotics are not
exposed to tuberculosis and has acquired at least primary
needed unless there is evidence of secondary infection
infection (clinical or subclinical). Thus, going by the
like cellulitis or abscess formation. In these cases
analogy mentioned in previous question, the role
erythromycin would be the drug of choice.
expected to be filled by BCG has already been achieved.
There is thus no need of BCG to such children. BCG
Q 40. Can ATT be tried in this case of nonhealing Ulcer?
prevents bacteremia following primary infection with M.
tuberculosis. ATT is not required for the so called non healing ulcer.
There is no evidence till now that it can help in Almost all of these ulcers would heal spontaneously within
preventing recrudescence type of tuberculosis. Further, 4 to 5 months of vaccination.
BCG in a Mantoux positive child tends to produce an
accelerated reaction with an increased incidence of local Q 41. Following BCG, an axillary lymph node has
lymphadenitis. formed. What should be done?
Local lymph node enlargement is also a normal
Q 36. Can BCG vaccine be given along with measles
component of BCG uptake, suggesting formation of a
vaccine?
primary complex. Nothing needs to be done for this if
Ideally different live vaccines should not be given at the the lymph node is less than 1.5 cm in size and is not
same time. A period of 4 to 6 weeks should elapse before suppurating. If it shows signs of suppuration, excision
the next vaccination is given. may be required in an occasional case where a sinus
It is preferable not to give these two vaccines together, formation is threatened.
Measles vaccine is known to depress cell medicated
immunity. This may, therefore interfere with the uptake Q 42. Can neck glands also enlarge in response to BCG
infection?
580
Yes, if BCG vaccination is given high up on the shoulder, becomes positive only after 6 to 8 weeks of BCG
the bacilli reach the nodes in supraclavicular or anterior administration.
triangle of the neck.
Q 48. BCG is used by some in the diagnosis of
Q 43. I get a chest X-ray done on a four year old child to tuberculosis. Do you recommend such a practice?
rule out tuberculosis. Left axilla shows calcified glands.
No. It is absolutely not required.
Can this be due to BCG vaccination given in infancy or
this may be due to tuberculosis?
Q 49. I gave BCG to a nine months old child who
Calcified left axillary gland is generally due to BCG developed measles after 10 days of inoculation. What
vaccination. Primary infection of the lung leads to either should be done?
hilar or paratracheal calcification.
Isoniazide chemoprophylaxis in a dose of 10 mg/kg/
Q 44. A two year old child has been brought with history day during risk period (for 12 weeks following measles
of definite BCG vaccination at birth but there is no scar. infection) is to be administered to children who develop
measles or whooping cough within 4 to 6 weeks of BCG
What should be done?
administration, to prevent possible dissemination.
Absence of scar, despite definite BCG vaccine, in a two year It will be advisable to ensure Mantoux conversion in
old child suggests that the child had failed to react to the such children as BCG may not take up in such
vaccination. Although theoretically, a scar once formed can circumstances.
also disappear but it is too early to do so by 2 years.
Revaccination should be considered if the child does not Q 50. Can BCG be given to children who are on long
react to a test dose of tuberculin (≥ 6 mm to 1TU). term steroids or chemotherapy (i.e. compromised
hosts)?
Q 45. In a eight years old child, there is no BCG scar.
According to the parents a scar was present initially any No. They are at increased risk of disseminated
how it has faded. Is it possible? If so, does it mean that tuberculosis if BCG is given. A minimum period of 6 to 8
weeks must elapse after stopping steroids before giving
the immunity has also decreased? What should be done
BCG.
in such a case?
Yes, BCG scars are known to disappear over a period of Q 51. Can BCG be given to a child who has received
time, but the disappearance of scar is not synonymous immunoglobulin 10 days back?
with either decrease of hypersensitivity or immunity.
Nevertheless revaccination should be done if a child does It is best avoided for another four weeks.
not react to test dose of tuberculin (≥ 6 mm to 1TU). Although it is generally agreed that cell mediated
immunity is the major component of immune reaction
with BCG, recently it has been shown that even humoral
Q 46. A five year old child with a positive BCG scar, is
immunity also plays an important part in preventing
being investigated for tuberculosis. His Mantoux test is
tubercular infection. Therefore, it is theoretically possible
negative and the rest of the investigations are also that BCG may be affected after immunoglobulin
normal. Having excluded tuberculosis, do I need give administration. It would be advisable therefore, to
BCG to this child again as his Mantoux is negative? postpone BCG for 4 to 6 weeks. If given earlier, it should
Opinion on this may differ. It is well known that LMIT be ensured that BCG has been successfully taken up by
may still be positive when the Mantoux has become demonstrating a Mantoux conversion.
negative, thus suggesting that hypersensitivity to BCG
still persists. There is no need to give BCG. Q 52. Can BCG be given to children with congenital
infections (TORCH)?
Q 47. Can BCG be administered concurrently with BCG efficacy has been in doubt in low birth weight
Mantoux test at the same sitting? Is Mantoux reaction neonates with severe intrauterine growth retardation
affected by BCG administration? who weigh less than 3rd percentile for their gestational
age. These factors and accompanying secondary
Yes, they can be given but there is no justification for
immunosuppression are often found co-existing in
such a procedure. Mantoux given on the same day as
children with congenital infections. Immunization would
BCG is not going to be affected by it. Mantoux test
depend on the presence/absence and interplay/severity
581
of these factors and in general BCG should be avoided Q 58. As per government instructions, no child should
in these neonates. be denied any vaccination and ampoule of vaccine is
to be opened even for a single child. What are your
Q 53. Can BCG be given to a child with hepatitis B comments? Will it not lead to a lot of wastage?
infection?
Cost of a wasted ampoule will always be less than that
In general, all viral infections have an effect on the immune of a full course of antituberculosis therapy which might
response of an individual which may differ from virus to be needed if immunization is withheld and the child
virus. BCG status in all these infections has not been worked develops active disease.
out. Hence, it is best to avoid BCG for a period of 4 to 6
weeks following a viral infection. An exception to this Q 59. What is the status of new BCG vaccine?
statement would be hepatitis B. BCG is a nonspecific
stimulator of cell mediated immunity and therefore BCG Scientists are excited about the prospects of a new
vaccination may be helpful as an immunomodulator in vaccine. After tests on mice and guinea pigs it appears
chronic hepatitis B infection. to be more effective than the currently used BCG vaccine.
The points new to this vaccine are:
Q 54. Can BCG be given to a child with chicken pox 1. Rather than trying to make changes in the current
whose skin lesions have already dried up? vaccine, researchers used a weakened version of the
bacterium that causes TB in people.
There is no definite data on this. It is not known whether 2. The researchers found a gene in the organism that
there are any immunological changes following chicken helps immune system detection. They removed it
pox infection but like all other viral infections, it will be from the bacterium.
preferable to wait for 4 to 6 weeks. 3. It was found that vaccine extended the lives of mice
and guinea pigs and stimulated stronger immune
Q 55. How soon BCG be given to a child after an attack responses compared to the existing vaccine.
of measles? 4. The scientists believe if the results continue to be
positive, human studies may be possible in two to
BCG can be given anytime after 12 weeks of measles
three years.
infection.
It is said that TB, a bacterial infection that usually
Q 56. Can BCG cause tuberculous disease? If so, under attacks the lungs, kills about 1.6 million people a year
what conditions? globally. The increasing resistance of the TB organism to
drug treatment makes creation of a truly effective vaccine
BCG can cause tuberculous disease dissemination in even more crucial.
following conditions: The existing BCG vaccine is in the use for almost a
i. Immunodeficiency states. century despite its limited effectiveness. It is based on a
ii. Incubation period of another infection particularly live attenuated strain of bacterium that causes TB in the
measles. cattle. In the new vaccine, use is made of a weakened
iii. HIV infected children version of the bacterium that causes TB in human beings.
The basis being similar to other vaccines by trying to
Q 57. Why BCG cannot be made available in single dose make the body’s own immune system stronger and have
ampoules? better defenses to fight off invaders like disease causing
Single dose ampoules will not be cost effective in bacteria. The researchers found a gene in the organism
countries like India where mass BCG vaccination strategy that helps it edude immune system detection and
is implemented. Also, since the same syringe can be used removed it from the bacterium. That helps the vaccine
with change of needles for different children, waste using this live weakened version of the organism, induce
incurred is hardly any. a strong immune response.
The size of BCG ampoule has been made for mass The new vaccine was tested in mice and guinea pigs
campaigns. In office, practice wastage can be minimized whose life was extended and a stronger immune response
if a separate day (once in a week/fortnight/month) is was elicited as compared to the existing BCG vaccine.
fixed for BCG vaccination. Of course, if would be still However, a major limitation is that it is still probably
better if smaller ampoules can be provided for office too infectious to be given it to humans. It is only partially
practice. attenuated for virulence. Removal of additional genes
may make the vaccine safer.
582
Global Aspect 13. Osborn TW. Changes in BCG strain. Tubercle 1983;64:1.
14. Gheorghiu M, Augier J, Lagrange PH. Maintenance and
The TB organisms infect roughly a third of the world’s control of the French BCG strain 1173-P2 (primary and
population. Most infections remain latent but can become secondary seedlots). Bull Inst Pasteur 1983;81:281-8.
active when the immune system is weakened, for 15. Behr MA, Small PM. A historical and molecular
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TB can be treated effectively with drugs in many mutation in the mma3 gene is responsible for impaired
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making treatment difficult and expensive. Many poorer BCG strains obtained after 1927. J Bacteriol 2000;182:3394-
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effective vaccine could be a highly valuable tool in
disease 22nd ed. Elk Grove Village 1991;11:AAP.
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in infants severely impairs the immune response induced old vaccine: dose BCG have a role in 21st Century
588
Canada. Int J Circumpolar Health 2004;63 Suppli 2: infected children. Clinical Infectious Diseases
230-6. 2003;37:1226-33.
6. Derrick SC, Repique C, Philop S, et al. Immuni-zation 10. Roth AE, Benn CS, Ravn H, et al. Effect of revaccination
with a DNA vaccine cocktail protects mice lacking CD4 with BCG in early childhood on mortality: randomised
cells against an aerogenic infection with mycobacterium trial in Guinea-Bissau. BMJ. 2010;340:c671.
tuberculosis. Infection and Immunity 2004;72:1685-92. 11. Sartono E, Lisse IM, Terveer EM, van de Sande PJ, Whittle
7. Haile M, Kallenius G. Recent development in tuberculosis H, Fisker AB, Roth A, Aaby P, Yazdanbakhsh M, Benn
vaccines. Curr Opin Infect Dis 2005;18:211-5. CS. Oral polio vaccine influences the immune response
8. Hatherill M, Mahomed H, Hanekom W. Novel vaccine to BCG vaccination. A natural experiment. PLoS One.
prime and selective BCG boost: A new tuberculosis 2010; 5:e10328.
vaccine strategy for infants of HIV-infected mothers. 12. Van-Dunem JC, de Alencar LC, Rodrigues LC, et al.
Vaccine. 2010 May 11. Sensitivity and specificity of BCG scar reading among
9. Hesseling AC, Schaaf HS, Hanekom WA, et al. Danish HIV-infected children. Vaccine. 2010;28:2067-9.
13. Vargas MH, ernal-Alcantara DA, Vaca MA, et al. Effect of
Bacille Calmette Guerin Vaccine induced disease in HIV
BCG vaccination in asthmatic school children. Pediatr
Allergy Immunol 2004;15:415-20.
39 Latent Tuberculosis
39.1 LATENT TUBERCULOSIS IN CHILDREN AND ADOLESCENTS

Vimlesh Seth, J Cunningham, S Kuhn
INTRODUCTION • No tuberculin skin test in infants who are not at risk

or in infants and children who are at low risk of
Tuberculosis continues to be the world’s most important infection
infectious cause of morbidity and mortality among adults. • Use only Mantoux test.
Nearly 1.6 million people develop TB disease each year, • Infants and children identified as having latent
and an estimated one million die each year. Despite this tuberculosis infection should receive treatment
enormous global burden, case detection rates are low (isoniazid (INH) for 9 months).
posing serious hurdles for TB control.
The pediatric age group is an important one in the
cycle of transmission of M. tuberculosis, for both the
DEFINITION individual and the community. Young children with
tuberculosis infection are more likely than adults to
Latent tuberculosis infection is the currently accepted develop serious forms of disease. Thus, children
term for the stage of M. tuberculosis infection that is constitute a high risk group deserving special attention.
asymptomatic, dormant and noncontagious; the patient Unfortunately, exposure at an early age to infectious
is not sick in any way and has a normal chest X-ray. A tuberculosis is common in most developing countries,
positive tuberculin skin test is the only evidence of latent and there are many children with subclinical infection.
tuberculosis infection. This stage may continue for the These children join the nearly 2 billion people in the world
patient’s entire life time or, in a matter of few weeks to 6 who are infected with the tubercle bacillus. Over time,
years, may progress to the stage of active disease called more and more new cases arise from this ever-increasing
tuberculosis. The latter can affect the lung or the other pool, with each new case representing another oppor-
parts of the body (lymph nodes, miliary, meningeal, bone tunity for continued tuberculosis (TB) transmission.1
and joint) and may be contagious to others. Treatment of Among the interventions which can curtail the spread
latent tuberculosis infection, previously called preventive of tuberculosis is “preventive chemotherapy” or
treatment or chemoprophylaxis aims to prevent the future “chemoprophylaxis.” These terms are often a source of
development of active disease. The Mantoux test confusion for patients and providers, as the majority of
recommended for screening for risk of tuberculosis candidates are infected with TB and the role for therapy
should be an essential function of primary health care is secondary rather than primary prevention.
for all children. In an effort to most accurately describe this intervention,
the American Thoracic Society (ATS) supports the
Highlights of Tuberculosis Screening replacement of both these terms with “treatment of latent
Recommendations tuberculosis infection” (LTBI).2
While case detection and cure of active disease are
• Screening for risk of tuberculosis exposure by clinical critical in reducing transmission, treatment of LTBI
history taking or tuberculosis risk questionnaire is an intervenes at an earlier point in the cycle, preventing the
essential part of routine well-child care development of tuberculosis in those who were
• Tuberculin skin test for infants and children at high previously infected. This strategy of TB control has
risk of exposure to tuberculosis received far more attention in developed countries where
• Continuing risk, test annually or every 2 to 3 years, programs can focus on TB elimination and are not sinking
depending upon type of risk beneath the case load seen in many developing countries.
• No further risk. Retest only if risk recurs Thus, international guidelines (International Union
590
Against Tuberculosis and Lung Disease [IUATLD], Physical Examination

World Health Organization [WHO]) concentrate on
strategies for case-finding, holding and treatment of active Physical examination of the study participants is
TB disease while strategies to manage LTBI are generated performed. It includes presence of BCG scar in contacts
from organizations in low prevalence countries such as and investigation for clinical signs of TB patients. Patient’s
the American Academy of Pediatrics,3 Canadian Lung nutritional status is to be assessed by body mass index
Association,4 and the British Thoracic Society.5 The (BMI) weight (kg)/(height m)2. Adults are considered
variation in strategies across these groups reflects a lack under weight if BMI is < 18.5 and severely underweight
of available and/or consistent evidence and program- if BMI < 16.
specific characteristics, priorities and resources. This
chapter will attempt to summarize the rationale behind Laboratory Procedures
these recommendations particularly as they pertain to • Ziehl–Neelsen staining of three sputum samples for
the pediatric population including those in high the presence of AFB
prevalence countries. The first challenge in addressing • TST with ITu injection of 0.1 ml of PPD
latent tuberculosis infection is making the diagnosis. • Villagers with clinical signs or symptoms of TB to be
Tuberculin skin testing is currently the most commonly X-rayed
used tool for diagnosing LTBI. This method has serious • Patients and their family receive counseling
flaws and ultimately cannot exclude the presence of TB. • Consent is to be taken from parents or care taker of
Clinical history and chest X-ray may assist interpretation. the child
The value of this test and the conditions that challenge • Ethics committee approval to be taken.
its utility will be discussed. New technology is emerging,6
but is not likely to be accessible to resource-poor countries Definitions
in the near future.
Isoniazid has a leading role to play in the treatment LTBI is defined as a positive TST in the absence of TB
of LTBI. Since its introduction in 1952, it has proven to be disease. The latter is suspected if the interviewers report
a safe, and effective agent in the treatment of tuberculosis. cough (chronic) (longer than 3 weeks), weight loss, night
Both the WHO and IUATLD recommend isoniazid for sweats and fever or if signs of extrapulmonary TB are
the treatment of LTBI in young children who are present.
household contacts of infectious cases and for PPD-
tuberculin positive persons with HIV infection. 7,8 Compliance
However, despite its low cost and ease of administration,
If a patient had taken medicines for more than 90%, he/
the intervention has not been widely accepted or
she is labeled as compliant.
implemented outside North America. However, there is
renewed interest in treatment of LTBI in both high and
low prevalence countries as a result of the impact of HIV
Degree of Contact
infection on tuberculosis epidemiology.9 Other anti- It is defined as close if patients and children usually share
tuberculous medications and combinations have also the same meal or the same bed, live in the same room.
been recommended for treatment of both drug Duration of contact is the reported time period from the
susceptible and resistant LTBI.2 onset of disease to the beginning of directly observed
therapy (DOT).
Risk of Latent Tuberculosis Infection in Children Living
in Households with Tuberculosis Patients Risk of Latent TB Infection
9a
Nguyen et al supports the importance of contact tracing Unlike adults who have 10 to 15% chance of developing
in remote settings with high prevalence TB setting. The the disease in their life time, contact children are at highest
following suggestions are made: risk of developing overt disease. It is likely that up to
50% of infants will develop the disease within 3 to 9
Study Procedure months of infection and 25% of children during 1 to 6
year of age, 15% at adolescence with in 1 to 2 years of
Study should be performed in a stipulated period say for
infection. Targeting 0 to 5 year age group has been
three months using a pretested questionnaire. Study
recommended particularly for those Nations that are
participants are interviewed for medical history,
unable to implement full scale contact investigation.
vaccination, number of missed days of treatment, degree
and duration of contact, characteristics of the household
Contact Tracing
and distance to health centers, knowledge of the
transmission of the disease and practices related to cough Contact tracing in high incident countries is generally
and spitting. given a low priority. A recent review suggests that this
591
Chapter 39 Latent Tuberculosis
strategy merits revision. Contact tracing is a means to and prednisolone in the dose of 25 mg and 2 mg/kg
improve early case detection, prevent further propagation respectively were added with intensive physiotherapy
of drug resistance and is a cost-effective method for early this resulted in expansion of both lungs. Although as a
identification of secondary cases to decrease transmission late sequelae, the child developed bronchiectasis.
of M. tuberculosis to meet case-detection target rates of
developing countries. Case 3
Clark9b has summarized the pitfalls in contact tracing
and early diagnosis of TB. Effective contact tracing and A 10-month-old male child had both an uncle and aunt
screening remain essential to prevent secondary cases and with a fully sensitive smear-positive pulmonary
are specially important for child contacts, given their tuberculosis. On screening X-ray chest and heef test were
greater susceptibility to disseminated disease and the negative. Two further heef tests one after 8 week and the
difficulty in diagnosis in this age group. other after 8 weeks of BCG were also negative. Prophy-
Tuberculosis is easily missed in children. A lactic isoniazid (10 mg/kg) was given for 4.5 months. The
combination of contact history, tuberculin testing and child developed a painless lump over hip joint after 13
radiology aid in diagnosis. Clark9b describes the following months, hip radiograph showed a lytic lesion in the neck
three cases of serious tuberculosis disease which illustrate of the right femur from which sterile pus was evacuated.
their vulnerability to the disease and problems that can Culture of the mycobacteria was not requested and the
be encountered with apparently straight forward contact family history of tuberculosis not ascertained.
tracing procedures. The lesion of the hip worsened in spite of being in
hips-pica and three months therapy with flouro-
quinolones and cloxacillin. At this time a Mantoux test
Case 1
(10 TU) produced a positive result of 17 × 17 mm indu-
A 5-month Asian girl who had been vaccinated for ration. Chest X-ray, renal ultrasound showed no
tuberculosis was seen as a contact of her grand mother. abnormality.
The latter had fully sensitive pulmonary tuberculosis. The Tuberculosis was diagnosed from the contact history,
child was well at this time and after one negative heef the clinical findings, about the positive tuberculin test
test, was given BCG vaccination and discharged. with good compliance of treatment for one year with
Six weeks later the child presented with fever, poor excellent result. There is no limp and normal limb growth.
feeding and vomiting. On referral to the hospital, she was There is resolution of lytic lesion.
found to be pale, unwell and tachypneic with widespread This is inferred that in spite of screening, these three
crepitations on auscultation but no hepatosplenomegaly. children developed serious form of tuberculosis. In
X-ray chest showed miliary shadows and a small opacity contrast to adults, tuberculosis is usually a primary
in the right mid zone. Miliary tuberculosis was diagnosed. disease in children. Early diagnosis is, therefore, very
A 9 month course of triple antituberculosis therapy cured important but difficult and at best, only 30 to 50% of cases
her. are confirmed by culture. Conventionally, two of the
following five criteria are required to make a diagnosis,
Case 2 a positive tuberculin test; positive radiology: a history of
contact with tuberculosis; compatible clinical symptoms;
A 6-year-old white girl was screened as a contact of an positive histology or culture. The tuberculin test, and
aunt who had fully sensitive smear-positive pulmonary contact history are more important for the diagnosis in
tuberculosis. Two heef test six weeks apart gave negative children as compared to adults. Close contacts of smear-
results, she was given BCG vaccination. Two weeks later positive cases, aged under 2 (previously 5) year old,
she presented with history of cough, headache, weight require prophylaxis with isoniazid for 6 months. Shorter
loss and fever. A chest X-ray film showed right middle courses of monotherpay are less effective.
lobe consolidation. Family history was not traced and The children should be treated by doctors with
initially the child was treated for bacterial pneumonia. experience in childhood tuberculosis, who are aware of
She did not improve after two weeks of antibiotic these differences and of the diagnostic criteria for the age
therapy. Repeat X-ray showed right hilar adenopathy group. It is recommended that all children should have
with right middle and lower lobe consolidation. The chest radiography irrespective of the result of tuberculin
family history was then ascertained and she was put on test.
only two drugs, isoniazid and rifampicin. She relapsed
after one month of treatment with complete right middle
The Tuberculosis Spectrum
to lower lobe collapse on chest X-ray film. Then she was
referred to specialized center. A Mantoux test (1 unit) Latent TB is defined solely by evidence of immunological
was positive at 10 × 25 mm induration, bronchoalveolar sensitization by mycobacterial proteins in the absence of
lavage showed plentiful acid fast bacilli. Pyrazinamide clinical signs and symptoms of active disease.9c TST was
592
the only method used till recently to define sensitization. IGRAs, there were a number of discordant positive results.
Drawback of TST is that PPD contains cross reactive These tests with both IGRAs may be indicated when the
antigens that are present in nonpathogenic mycobacteria, clinical suspicion of M. tuberculosis infection is high. What
resulting in false positive test in those immunized with can be concluded is that by IGRAs one would be able to
bacille Calmette-Guerine. Recent TST conversion has got demonstrate TB in children less than 12 months of age.
the major disadvantage of being negative in disseminated In QFT-GT, there is probably an inadequate T-cell
TB and those with HIV. More specific tests of sensitization response to mitogen. The latter was attributed to
are those rely on the in vitro release of interferon-γ helminthic infection in which there is polarization of
(IFN-γ) in response to specific M. tuberculosis antigens. circulating T-cells towards T-helper 2 (Th2) responses,
resulting in impaired Th1 responses, increased regulatory
Characterization of Subpopulation in Latent TB T-cell activity and lower IFN-γ responses. There is
production of immunoglobulin E (IgE) antibodies due to
The hypothesis is that latent TB is a reservoir of organisms parasitic infections, which can result in monocyte
that are encased in caseous lesions under hypoxic production, immunosuppressant factors such as
conditions, where as active TB is typified by bacilli prostaglandin E2 which inhibit T-cell proliferation. On
replicating aerobically at the margin of liquefied cavities. basis of this data the authors suggested that a strategy
that uses TST as a screening test followed by a
Immunological Basis of New Diagnostics in Latent confirmatory IGRA for positive cases as suggested by UK
Tuberculosis Infection in Adults and Children National Institute for Health and Clinical Excellence
Latorre et al9d evaluated the quantitative T-cell response (NICE) guidelines is inferior to solely IGRA based
after specific M. tuberculosis antigen stimulation in active approach.
tuberculosis (TB) and latent TB infection (LTBI) patients. Hence, it is suggested that IGRAs are the preferred
In adults the median number of T-cells after RDI antigen screening tool for LTBI in refugee children. QFT-GT
stimulation was significantly higher in active TB patients performance is compromised by inderminante results
than in LTBI patient. In children the number of responder where as the T-SPOT. TB performance is compromised by
T-cells against the specific antigen stimulation was higher the high number of failed tests specially in younger
in active TB patients than in LTBI patients, though the children. This study highlights the need for continued
difference was not significant. The authors summarized research to improve reliability of LTBI diagnosis in children
that in patients with suspected clinical TB, although there from high incidence countries.
is over lapping in the number of responder T-cells
between both groups, a T-cell count above the described Advantage of T-SPOT.TB Over Tuberculin Skin Test in
threshold could suggest active TB, especially in patients Prediction of TB Disease
with a high probability of active TB and low probability Leung CC et al10a demonstrated the better performance
of having LTBI. The results are consistent with the current of T-SPOT.TB over tuberculin test in patients with silicosis
evidence that T-cell response may indicate mycobacterial in adults. A positive T-SPOT.TB test significantly
burden and disease activity. predicted the subsequent development of active TB
(relative risk 4.50, 95% CL: 1.03-19.68) and culture/
Skin TST Status Prelude to Development of Latent TB histology-confirmed TB. (relative risk 7.80, 95% CL; 1.02-
Hussain et al 9e suggested that TST conversion is 59-63). T-SPOT.TB performs better than TST in the
associated with early increase in IFN-γ and IL-10 targeted screening of LTBI among silicosis patients.
responses and precedes latency by several months post
Advances in Latent TB Diagnosis:
exposure.
Lucas et al10 conducted a first large-scale prospective Interferon-Gamma Release Assays
study to investigate the clinical utility of currently available Until recently the diagnosis of latent TB infection (LTBI)
immunological tests for latent tuberculosis infection (LTBI) depended solely on the tuberculin skin test (TST). The
in resettled refugee children. There is lack of evidence biggest advance in recent times has been the development
regarding the optimal diagnostic test for LTBI from to T-cell-based interferon-gamma release assays
sufficiently powered cohort studies of children particularly (IGRAs).10b These are in-vitro blood tests that are based
those <5 year old. These data are essential to balance the on interferon gamma release after stimulation by TB
need for treatment of LTBI against unnecessary specific antigens (e.g. ESAT-6, and CFP-10). Two IGRAs
intervention and over treatment in this vulnerable are now commercially available—the quantiFERON-TB
population. It was meant to test the claimed superiority of Gold in-Tube Assay (Cellestis Ltd. Carnegie, Victoria,
T-SPOT. TB assay over the QFT-GT assay. Despite Australia) and the T-SPOT.TB assay (Oxford Immunotec
reasonable concordance of positive results between the Limited, Abingdon, Oxon, UK). IGRAs have very high
593
specificity and are unaffected by prior BCG vaccination infected but asymptomatic individual? Or alternatively
or sensitization to nontuberculous mycobacteria. The is it on the basis of conversion that a decision can be
sensitivity of IGRAs in active TB is 75 to 90 % and are made
more specific than TST in immunocompromised patients. • Does the specificity and/or cytokine profile of the
Their use is rapidly expanding in low incidence countries, immune response to the pathogen change over time
even though they cannot distinguish between latent and to include latency antigens? Can responses that are
active TB. Also there is limited data on their ability to characteristic of the different stages of infection be
predict the development of active TB. Despite their identified? However, these issues involve
limitations these can be of use in special groups such as interpretation of the results from existing technologies,
young children, immunocompromised persons, not the invention of new tools. Although the
individuals with smear-negative and extrapulmonary observation that IFN-γ produced in response to
disease. specific antigens increases with increasing bacterial
Several studies are undergoing in developing load seems simple enough to apply. Ultimately, the
countries to have strong evidence for making policy utility of this approach can be determined only by
decisions. testing the hypothesis in large-scale cohort studies.
Yoshiyama et al10c reported that TB incidence among These are the challenges ahead.
QFT-G-positive contacts was higher than among QFT-G- For screening of latent tuberculosis, assays based on
negative contacts. Andersen et al11 have suggested that the interferon-γ (IFN-γ) are an exciting new development. Its
development of highly specific IGRAs has enabled the usefulness in adults have been quite extensively tried,
accurate identification of TB infection, but it has not been but the data in children is limited. National Institute for
possible so far to translate this into a better or earlier Health and Clinical Excellence (NICE) guidelines
identification of contagious disease. A prognostic marker recommend their use for screening pediatric tuberculosis
that enables targeted treatment of populations in high (TB) contacts. Under NICE guidelines, patients with
endemic regions that are in the process of developing positive Mantoux results (or in whom Mantoux testing is
contagious TB would greatly contribute to the control of unreliable) undergo IFN-γ testing. Table 39.1.1 gives the
this global epidemic. They have suggested that instead of NICE guidelines used by authors.12
using IGRAs only in binary mode (infected and non infected) The following flow chart used in relation to BCG and
based on a cutoff value, the magnitude or conversion of an Mantoux status helps in diagnosing latent TB (Fig. 39.1).
IGRA response might enable the identification of individuals With the use of NICE guidelines 85% fewer children
who, although still asymptomatic are in the process of would have been given chemoprophylaxis for LTBI after
developing active TB. The issues to be resolved are: contact with TB. This would make significant reduction in
• Can an incipient disease cutoff value for IGRAs can prescribing, decreasing costs and unnecessary treatment
be established so that a single measurement of the for children. Trial of treatment in a suspect of latent or TB
IFN-γ response to ESAT-6 and CFP-10 can simplify disease is often a part of the diagnosis in children.
the clinician’s decision to treat an M. tuberculosis Indeterminate results are more often in younger children
Table 39.1.1: NICE guidelines for screening of pediatric tuberculosis contacts
Parameter NICE Guidelines

• Indications for giving three < 2 Years
drug therapy - Mantoux positive and abnormal CXR,
+ clinical evidence of TB.
> 2 Years
- Mantoux positive + IFN-γ positive + CXR + clinical evidence.
- Mantoux –ve (smear positive contact)
- IFN-γ +ve + clinical evidence
• Criteria for diagnosing latent - Mantoux +ve, + IFN-γ positive
tuberculosis infection (LTBI) + no clinical evidence of TB
+ no prior BCG vaccination
- Mantoux negative (smear positive contact) IFN-γ positive + no clinical
evidence
- Evidence of TB scars on CXR, no history of adequate treatment
• Criteria for giving BCG No prior BCG, Mantoux < 6mm < 2 year + IFN-γ negative
594
Fig. 39.1.1: Diagnosis of latent TB
due to inherent immunosuppression. The Mantoux test is administered. In earlier review of 24 studies, involving
well recognized as having good sensitivity and specificity 240243 children, false positive results (>10 mm) of
for TB disease in high prevalence population but not in tuberculin skin test attributable to BCG vaccination
those with low prevalence. occurred in 6.3% persons and only in 1% of those who
IFN-γ tests are as sensitive and specific as Mantoux tests were tested after more than 10 year. In the same review of
in adults. There is less data available in children, although 12 studies involving 12728 persons who were vaccinated
an ELISPOT IFN-γ test has shown 83% sensitivity for at 2 years of age or older, BCG was responsible for false
children in South Africa with 73% in HIV-positive children. positive in 40% of all persons and 20% of those who were
IFN-γ results do correlate better with risk factors and vaccinated after 10 or more years.
degree of exposure in contacts of MTB than the TST does. In spite of such a big cohort the authors recommend
A recent study in high TB prevalence area suggested that further research as follows:
the TST correlated better than IFN-γ test with recent 1. Independent studies need to be done to see the
exposure. reproducibility of the test. To estimate variability,
Treating LTBI on the basis of TST results decreases repeated assays should be performed on the same
the risk of active TB by 60%. The potential decrease in sample by the same technician, by different
false positive Mantoux results with the introduction of technicians in the same laboratory or in different
IFN-γ tests will significantly decrease the amount of LTBI laboratories.
treatment given to children in contact with TB. 2. To estimate biological variability repeated tests should
With in NICE guidelines, there is reliance on the be done in unexposed and under treated persons at
superiority of QFT over Mantoux test. However, as there intervals ranging from days to years. This information
is no gold standard to determine the absolute sensitivity is crucial to distinguish random variability from
and specificity of QFT in LTBI, it has limitation in the conversions attributable to new TB infection and to
diagnosis of LTBI. It is recommended to use the clinical study the effect of treatment on IGRA response.
judgment to interpret results to ensure the best 3. Tuberculin test and IGRA should be compared in HIV
management outcome for the child. +ve and –ve cases along with the other children with
Menzies et al13 have emphasized by metanalysis of new immune suppression due to other cause, such as those
tests for diagnosis of latent tuberculosis. The most consistent on long-term steroid therapy or are severely
finding in this review is the high specificity of IGRA, which malnourished.
is unaffected by BCG vaccination in all populations. This 4. Further it is recommended that large scale cohort studies
reflects that the antigens used in these assays are neither are needed that estimate risk for progression to active
present in BCG nor in certain nontuberculous disease in persons who have had both the tuberculin
Mycobacteria. It was inferred that the results of tuberculin and IGRA tests. It will be important to see those with
skin test varied with the age at which BCG was discordant results for the development of active disease.
595
Tuberculosis being a public health challenge its It is unclear whether the TST size cut-offs are
control requires the use of efficient diagnostic tools. M. appropriate for highly endemic countries as these
tuberculosis (MTB) requires a strong immune response guidelines have been based on studies of nonendemic
upon infection, a phenomenon measured by the old populations. However, models have been formulated
tuberculin skin test (TST). However, this test has many which can illustrate the predictive value of a positive or
limitations and a high rate of these in BCG vaccinated negative test at different cut-offs as a function of
subjects. Recent studies have identified several MTB- prevalence of TB infection.10b
antigens for diagnostic use, including the ESAT-6 and A new method of testing has been developed which
CFP-10 proteins. Based on these antigens, one of the most detects interferon-gamma (IFN-γ) responses in whole
significant advance is the development of diagnostic blood samples to M. antigens. While the first commer-
armamentorium for TB. These include the assays based cialized test detected responses to tuberculin purified
on IFN-determination IGRAs. The principle of these is protein derivative (PPD),6 a recent version utilizes
that T-cells of infected individuals produce IFN-gamma antigens that are more specific to M. tuberculosis.14 The
on encountering MTB antigen in vitro.13a latter has been approved by the FDA in the United States,
The two-step approach (first using TST followed by and has a specificity and sensitivity that exceeds that of
IGRA for confirmation) is the most favored strategy for the TST.14 While, it is not influenced by BCG vaccination
IGRA—use in the general population while the use of status,15 sensitivity appears to be less in those who are
IGRA alone is suggested in particular clinical settings immune-suppressed.16 Unless the methodology can be
and/or patient groups. adapted to a resource-poor setting, the technology
required will preclude routine use in most highly-
APPROACH TO LATENT TUBERCULOSIS INFECTION endemic countries.
Diagnosis
Considerations for Selected Populations
Earlier, Tuberculin skin testing (TST) was the only
commonly available tool for diagnosing LTBI. A detailed TB Programs with Limited Resources
discussion of the TST is found elsewhere in this text. As only 5 to 10% of those infected with M. tuberculosis
Immunization with BCG or infection with nontuber- will ever develop active disease, it is neither feasible nor
culous Mycobacteria can result in a falsely positive TST, cost effective to skin test everyone. However, in countries
limiting the specificity of the test. This is particularly with sufficient financial resources and tuberculosis
problematic for the diagnosis of LTBI where by definition program infrastructure, screening for latent infection in
there are no clinical and no/minimal radiologic findings those at high-risk of progression to active disease is an
to support M. tuberculosis infection. As a result, appropriate part of disease control.2,17 In the resource-
interpretation of the test is guided by a prior risk of poor setting, the WHO recommends that TST is done as
infection and/or progression to active disease if the part of the assessment of children who are household
individual is infected. The greater the high risk, the contacts of smearpositive pulmonary TB cases to identify
smaller the reaction size required to qualify as TST those with active disease.7 If tuberculosis disease is
positive (Table 39.1.2). excluded, WHO recommends that all children up to
Table 39.1.2: Criteria for positive tuberculin skin test (TST) in children and adolescents
Tuberculin skin test result (mm)

> 5* > 10 > 15†
• Close contact of active TB case High-risk of dissemination Age = 5 years and no
(age = 5§ years, various medical known risk factors
conditions)
• Immunosuppressed (e.g. HIV) High-risk of exposure

Active TB disease (resident in, migrant from,
or traveller to a high prevalence
area; exposure to high-risk adult
* Although North American authorities state that TST results should be interpreted irrespective of BCG immunization
status, some endemic countries use a minimum cut-off of 10 mm for a positive result.
†
In areas where atypical mycobacteria infections are prevalent.
§
Age cut-off varies from < 4 (AAP) to = 5 years (WHO, IUATLD, Canadian Thoracic Society).
Adapted from American Academy of Pediatrics. Red Book: 2003 Report of the Committee on Infectious Diseases (Ref. 3).
596
5 years receive prophylaxis. Breastfed children of of progression compared to HIV-negative individuals,

smearpositive mothers are considered as the highest risk with an annual risk of disease of 5 to 10 %20. Therefore, it
of all and require close follow-up. In settings where the comes as no surprise that in high-prevalence countries,
annual risk of TB infection is high, the risk of activating TB is a common disease in HIV-infected children.21 A
latent disease must be weighed against the risk of study in Zaire demonstrated the risk of tuberculosis in
reinfection following treatment. However, the high-risk HIV-infected women of child bearing age was three times
of progression to severe disease, particularly for children higher as compared to HIV-uninfected.22 Moreover, a
under 5, supports this approach for the pediatric age subnormal response to BCG compared to infants of HIV-
group if resources allow.18 negative mothers suggests an abnormality in immune
function that may also place them at increased risk of
Recipients of BCG tuberculosis.23 Older children with parents who are HIV-
infected are also at increased risk since progression of
In disease endemic countries, the majority receive HIV disease has a negative impact on the financial well-
primary prevention through BCG vaccination during being of the family. This in turn leads to poverty,
infancy. Although BCG administration usually results in malnutrition, and overcrowding which are all factors that
a positive TST, the size of the reaction wanes with time.19 increase the risk of exposure to TB.24
The relative merits of its use vis a vis TST are discussed The high rate of progression to disease justifies the
elsewhere in this text. Most authorities agree that a low threshold to treat HIV-infected children for LTBI.
positive TST result should be attributed to LTBI rather Given the high frequency of atypical and smear-negative
than BCG if there are factors present such as a history of disease in this population,25 the distinction between latent
contact with active TB, a family history of TB, residence infection and disease in HIV infected children can be
or migration from a region of high prevalence, increasing difficult, particularly where diagnostic facilities are
time since BCG (> 5 years), and TST reaction > 15 mm3. limited. Minimum investigations include a careful
One or more of these factors are likely to apply to children examination, TST, and CXR. While case-finding and
tested in resource-poor countries. Ultimately it is successful treatment of TB cases remains the highest
important to remember that the TST result is only one priority for tuberculosis programs in the setting of limited
piece of information used to make a clinical decision about resources, it has been suggested that preventive therapy
treatment. of individuals with dual HIV-TB infection may also
contribute to TB control. While the public health impact
HIV Infection
of such a policy has been questioned,26 there is no doubt
The HIV epidemic has lead to a dramatic rise in the regarding the benefit to the individual and probably even
number of adults developing active tuberculosis. more so for a young child than an adult. Regardless of
Although the impact on the TB incidence in children is the decisions made by individual National TB programs
not as well documented, the relationship with HIV for HIV-infected individuals, it is clear that an integrated
appears to be a negative one in many respects. It has been approach between HIV/AIDS and TB control programs
shown that LTBI in adults with HIV has a higher risk is beneficial27 (Table 39.1.3).
Table 39.1.3: General recommendations for treatment of LTBI in children according to

tuberculosis program resources
Limited resources Moderate resources

TST negative TST positive
• Age < 5 years or Treat for LTBI Start treatment for LTBI, Investigate for LTBI vs active
immunocompromised repeat TST in 8-12 weeks. disease. Treat according to
If +ve, investigate for active diagnosis.
TB vs LTBI and treat
accordingly. If –ve, stop
therapy unless immune-
compromised
• Age > 5 years and not Withhold No treatment Investigate for LTBI vs active
Immunocompromised treatment disease. Treatment of LTBI
depends on extent of resources
(See text)
Adapted from references 3, 4, 7, 8, and 16
597
TREATMENT OF LATENT TUBERCULOSIS INFECTION resistance, compliance with long treatment courses, and
adverse effects of INH. Rifampicin (RIF) is bactericidal
Antimycobacterial Agents for slow-metabolizing, intracellular bacilli,34,35 which may
be particularly advantageous for treatment of infection
Isoniazid without disease. In addition it has a lower rate of
Isoniazid is the most widely used of the antituberculosis spontaneous mutations. Studies in HIV-negative adults
agents. Initially, experimental studies were conducted in with silicosis have demonstrated efficacy with rifampicin
the guinea-pig model using a daily dose of 5 mg/kg. This alone.36 Data for children remains limited, although a 6
regimen demonstrated the efficacy of isoniazid to prevent months course has been studied in 157 adolescents with
active tuberculosis following infection.28 Subsequently, no failures noted.37 Adverse effects such as anorexia,
a number of human studies, conducted in both indus- nausea, fatigue and rash were not uncommon, occurring
trialized and developing countries, have shown that in about one-quarter of teenagers studied, although < 5%
isoniazid is an effective agent in treatment of LTBI. A discontinued medication. Based on these data, rifampicin
single agent is sufficient to eradicate the infection given for 6 to 9 months4,33 has been reserved as an alternate to
by the relatively small population of Mycobacteria. For INH if there is intolerance or contraindications to its use,
latent tuberculosis recommended by Blumberg et al28a is or high-risk of an INH-resistant but RIF-susceptible
continuous 9 months isoniazid therapy. Randomized, isolates. Rifampicin-containing combinations have also
placebo-controlled trials around the world demonstrated been used in an effort to reduce the duration of therapy
a protective efficacy of about 90% incompliant patients, and potentially improve compliance as a result. Short-
most of whom received isoniazid daily for a year.29 courses of multidrug therapy have been found highly
It was also found that as long as isoniazid was continued, efficacious for smear/culturenegative pulmonary disease,
even if taken irregularly, a protective benefit was present. including both two and three months courses of isoniazid,
Prolonged therapy has a negative impact on rifampicin, pyrazinamide and streptomycin.38 While
compliance, therefore, shorter durations of treatment streptomycin is not likely to be of sufficient benefit to
have been investigated. While LTBI studies in Alaska offset the risk of adverse effects and noncompliance39 in
demonstrated maximal benefit was achieved by 6 to 12 the treatment of LTBI, both isoniazid and pyrazinamide
months of therapy,30 subgroup analyses of adult trials have been studied in combination with rifampicin.
concluded that the maximal benefit of isoniazid is likely INH and RIF have been given in twice weekly doses
to be achieved by 9 months.31 In an IUATLD study, adults for 6 months as directly observed therapy in adult
with stable fiberotic lesions on CXR were randomized to Canadian aboriginal patients with LTBI and compared
3, 6, or 12 months courses of isoniazid or to placebo. with daily self-administered isoniazid for 12 months.
Tuberculosis cases were reduced by one-third, two-thirds Although the rate of adverse effects was about three times
and ~90% respectively compared to placebo. Although higher in the combination group, their completion rates
efficacy was lower for 6 compared to 12 months, hepatic were much higher (82 vs. 19%) and rate of tuberculosis
toxicity was also less, therefore, six months of INH is was only one-tenth that of the monotherapy group.40 A
considered as an acceptable regimen in adults.32 The meta-analysis examined data from 5 studies of adult
recommendations of major advisory groups for the patients with LTBI comparing RIF + INH for 3 months to
treatment of LTBI in HIV-uninfected children are 6 INH monotherapy for 6 to 12 months. The authors
(WHO, IUATLD) to 9 (American Academy of Pediatric, concluded that the two approaches were equivalent in
American Thoracic Society) months of isoniazid. terms of efficacy, proportion of severe adverse effects and
American organizations continue to recommend a mortality.41
treatment duration of 9 months given the lack of data on In the recently published guidelines of the Indian
shorter-courses in the young, their very low rate of serious Academy of Pediatrics, six months of chemoprophylaxis
adverse effects due to INH, and the greater lifetime risk (INH) is recommended for all under 6 years of age
for reactivation disease.33 The Canadian Lung Association contacts of an infectious case, irrespective of their BCG
recommends 6 to 9 months, but emphasizes the need for or nutritional status. PPD positive children over 6 years
good compliance if 6 months is given.4 Daily therapy is of age and who do not have any evidence of active disease
the preferred schedule, but intermittent regimens (two but are planned for immunosuppressive therapy (e.g.
or three days per week) are acceptable alternatives if children with nephrotic syndrome, acute leukemias, etc.)
provided as directly observed therapy (DOT).4,33 may also be given the benefit of chemoprophylaxis. While
there is evidence that HR combination can make the
prophylaxis shorter (3 months) but the group does not
Rifampicin-Containing Regimens
recommend this due to the risk of misuse of rifampicin.42
Alternate antimyicobacterial agents have been explored, Pediatric support for short-course INH plus RIF
principally in adults, due to concerns about multidrug therapy is limited to observational data in a district of
598
England with a high incidence of TB. Starting in the early months has been recommended if the isolate is susceptible
1980’s dual therapy for pediatric LTBI was introduced to both.55 (Table 39.4) Although traditionally ethambutol
and the duration gradually reduced from 9 to 3 months. has been avoided for children < 6 years, recent reports
The reduction in pediatric cases noted after a program of suggest a dose of 15 mg/kg/day is safe and does not
treatment for LTBI was instituted in 1981 has been require routine eye examinations.56 Seth et al57 evaluated
sustained in spite of the decreasing duration of therapy. the visual evoked responses (VER) in children with
Although the results suggest that this approach may be tuberculosis above the age of three years on ethambutol
useful in children, the sample size and study design limit therapy as one of the drug in the regimens these children
the conclusiveness of the findings.43 In the details of these were on. The VER; both Amplitude and Latency were
studies it is claimed to be the largest programmatic evaluated before therapy, during therapy at, 3, 6, 9 and
experience using rifampicin-based treatment of LTBI from 12 months and 6 months after stoppage of ethambutol.
Blackburn, England, where children at increased risk of The study revealed no ocular toxicity. There is quite
TB have been treated daily with rifampicin/isoniazid extensive data now on the safety of use of ethambutol in
since 1981. During 1981-86, the treatment duration was children.
shortened from 9 to 3 months, and the proportion of
Pediatric TB case-patients as a percentage of all reported
cases decreased from 25 to 4%. It is not a controlled clinical New Therapy
trial but the data suggested that this intervention has been
highly effective in reducing the rate of childhood TB in Newer Rifamycins such as
this city. Thus this regimen is currently recommended Rifapentine and Rifabutin
for the treatment of both adults and children with LTBI These are highly active against M. tuberculosis with a long
in the United Kingdom.43,44 half-life that has the advantage of potentially widely
Rifampicin has also been combined with spaced intermittent dosing. The optimal dose is being
pyrazinamide for a short 2 months course in adults with studied, 58 but weekly administration appears to be
LTBI. After efficacy and safety in HIV-infected acceptable for rifapentine as part of a multidrug treatment
adolescents and adults was shown in a large trial regimen for active disease. However, treatment failures
published in 2000,45 the combination was included as an with once weekly rifapentine/isoniazid exceed those who
option in American recommendations. However, reports use twice-weekly isoniazid/rifampicin, and appears to
of severe hepatotoxicity and some deaths in HIV- be related to low concentrations of isoniazid.59 Relapse
uninfected persons were subsequently published and the rates with rifabutin appear to be no different than those
recommendations revised as a result.46,47 Although twice with rifampicin in HIV-infected patients treated for active
weekly regimens for two and three months appear TB.60 No specific data are available for treatment of LTBI
promising, sample sizes were small and the comparison with rifapentine or rifabutin, but the latter is considered
groups used only 6 months of INH, therefore, it cannot an alternate drug to rifampicin, e.g. in some HIV-infected
be recommended as an unequivocal regimen.48, 49 patients as it has fewer interactions with antiretroviral
Increased rates of hepatitis in HIV-uninfected individuals drugs. However, drug interactions are complex due to
using this combination has been confirmed in other effects on CYP450 and guidelines must be carefully
geographic regions as well.50 Liver abnormalities have considered. There is no information on use of these agents
not been related to underlying liver disease, alcohol use, in children and, therefore, they are not considered options
or viral hepatitis.51 Therefore, although the higher for treatment of disease or LTBI at this time.
completion rates are attractive, caution is advised both
for the HIV-infected using protease inhibitors or NNRTIs
Fluoroquinolones
as well as HIV-negative individuals. US guidelines for
HIV-negative adults suggest it to be considered for There are another drug class of interest in the treatment of
contacts of isoniazid-resistant but rifampicin-susceptible tuberculosis. While levofloxacin and ofloxacin are the most
cases only.52-54 There is no data on the use of this commonly used at this time, newer agents such as
combination in children and it’s use is not recommended moxifloxacin and gatifloxacin are also being studied and
at this time by major pediatric guidelines.33 appear to have greater in vitro activity.61 Fluoroquinolones
have traditionally been avoided in young children due to
animal data suggesting deleterious effects on growing
Non-isoniazid/Rifamycin Combinations
cartilage. However, a review of human data suggests this
Treatment of LTBI for contacts of isoniazid and is not a concern, at least with ciprofloxacin and probably
rifampicin-resistant cases is problematic, given that levofloxacin.62 Nevertheless clinical studies of this class of
treatment with 2 or more active drugs is desirable. A drugs are necessary to determine their relative safety and
combination of pyrazinamide and ethambutol for 9 to 12 utility in treating LTBI.
Table 39.1.4: Therapy for treatment of latent tuberculosis infection in children
Dose Duration Comments
Drug Indications mg/kg (max) (months)
Daily Twice Daily Twice
weekly* weekly
• Isoniazid Low risk of resistance 10-20 20-40 6-9 9 Pyridoxine (vitamin B6)
(300) (900) (9-12 if HIV+) (9-12 if HIV+) if malnourished or
breastfed.
• Rifampicin Intolerant to isoniazid; 10-20 10-20 6 9 Contraindicated if using
Suspected/known (600) (600) (9-12 if HIV+) (9-12 if HIV+) protease inhibitors or
resistance to isoniazid nonnucleoside reverse
and pyrazinamide transcriptase inhibitors
intolerance (HIV+).
• Rifampicin+ See Table 39.1.5 Limited published data
isoniazid on use. Not used
Routinely in nonendemic
countries. See text.
• Rifampicin+ Not recommended due
pyrazinamide to adverse effects in
HIV—adults and
lack of pediatric data.
Should be individualized
• Other Multidrug resistant according to susceptibilities
combinations cases of index case and discussed with a
pediatrician and TB expert.
* All intermittent therapy should be administered under DOT.

Adapted from references 3,4
Ref. 3—American Academy of Pediatrics recommendations, Red Book; 2003.
Ref. 4—Canadian Lung Association—5th edition Government of Canada; 2002.
599
600
Table 39.1.5: Indian Academy of Pediatrics working group A project to study fundamental biology and drug
recommendations for preventive therapy in childhood development strategies for latent tuberculosis (TB) was
tuberculosis* initiated in 2005 as a part of a program to tackle grand
Indication for therapy Treatment regimen† challenges in global health. The project was funded jointly
by the Bill and Melinda Gates Foundation and the
• Asymptomatic TST Daily isoniazid
Welcome Trust, brought eight academic groups from four
positive <3 years and rifampicin
continents with industrial expertise provided by Novartis
for 6 months
Institute for Tropical Diseases (NITD). The project focused
• Asymptomatic TST ”
in particular the role of hypoxia in latent TB. They
positive <5 years with
organized three groups:
grades III or
IV malnutrition 1. To characterize TB lesion in freshly resected lung
tissues in humans and nonhuman primates with
• TST positive, recent ”
active and latent TB.
converter/no signs
(healed lesion-normal 2. The second component is directed towards drugs
CXR or calcification/fibrosis discovery.
3. The final component addresses strategies for the
• Children <3 years with ”
household TB contact evaluation of drugs with activity against hypoxic M.
tuberculosis by using positron emission tomography
• Children <5 years, ”
(PET) and computed tomography (CT) imaging to
grade III or IV malnutrition
with household TB contact monitor the effect of drugs on individual lesions in a
*
nonhuman primate model.
Indian Pediatr 1997;37:1093-6
†
See Table 39.1.4 for drug doses.
Assessment of Drug Activity Against Latent TB
There are interesting data showing that the IFN-γ response
Use of Combination of Rifampicin and PZA
to M. tuberculosis antigens approximately halves during
in Treating Latent TB drug treatment of latent TB. This decrease may mark
Tortazada et al68 have recommended that rifampicin and successful treatment with the chemotherapeutic
pyrazinamide combination should only be considered for reduction in the number of bacteria corresponding to a
treating latent tuberculosis when other regimens are reduced necessity to mount an immune response. There
unsuitable and intensive monitoring of liver function is was an initial doubling of IFN-γ response at 1 month
feasible. Treatment interruption due to hepatotoxicity (ALT possibly due to an increase in the antigen release
and AST > 5 times of upper limit of normal) was observed following bacillary death.
in 10% of contacts in 2RZ group and in 2.5% of the 6H group. Lee et al70 have investigated the role of QFT-GIT
Idh et al69 assessed the kinetics of the QFN and initial reversion on rifampicin prophylaxis in TB contacts. They
tuberculin test (TST) in relation to severity of disease in found that QFT-GIT reversions were achieved in 41.9%
tuberculosis (TB) endemic area. The TST, QFN, CD4+ cells of subjects (31/74) after 4 months of rifampicin treatment.
count and clinical symptoms (TB score) mere assessed The serial test results suggest the possibility that the QFT-
and followed up during treatment from baseline to 7 GIT test may be useful to monitor the response to
months of treatment, there was a significant decrease in rifampicin prophylaxis. However, the authors have
QFN activity (93.8% to 62.8% in HIV–ve 70.3% to 33.3% emphasized that further controlled studied with more
in HIV-/TB patients) down to a level of control group of participants and long-term follow-up are required to
blood donors (51.2%). QFN activity is significantly clarify these issues.
reduced at the end of treatment against active TB to the
background level of healthy blood donors and the Toxicity
agreement between TST of QFN is poor including
correlation to the severity of disease. In order to be practically and ethically acceptable,
preventive therapies should have a low level of toxicity.
Motivating patients to undergo treatment in the semblance
Discovery of Drugs Against Latent TB
of health is a challenging task. Multiple clinic visits, lengthy
The most ambitious objectives for anti-TB drug discovery waiting times and other operational factors complicate the
are to identify new drugs that effectively eradicate latent diagnostic process and a prolonged treatment course
TB infection and reduce chemotherapy of active disease further jeopardizes adherence. While a 5 to 10% lifetime
to 2 weeks. For this there is a need to kill those risk of progression to active disease has significant public
subpopulations of M. tuberculosis that are not eliminated health implications, this must be weighed carefully against
efficiently with current antibiotics. the individual’s risk of serious drug toxicity.
601
Although hepatic toxicity was not initially recognized smear-+ve or culture +ve disease after 2 months of
when isoniazid was first recommended in North America appropriate antituberculosis therapy.
in the mid-1960’s, subsequent reports noted an association Published data on treatment of MDR-LTBI in
with elevated hepatic transaminases as well as clinical children is very limited. A follow-up of preschool
hepatotoxicity and several deaths.49,63,64 Risk of hepatic children exposed to adults with MDR-TB in South Africa
toxicity is about 1%, but increases with age and alcohol compared 2 or more drugs based on the source cases
consumption.29,65 Hepatic failure due to isoniazid has susceptibility pattern for 6 months to no therapy.
been rarely reported in the pediatric age group66 and Untreated children were four times more likely to
elevation of liver enzymes is also extremely uncommon. progress to active disease (20% vs 5%).74 However, treat-
Caution should be exercised in the presence of a past history ment duration and definitions of disease may have
of adverse effects with isoniazid, concurrent medications negatively influenced the latter response rate.
with potential hepatotoxicity, underlying liver disease, or No definitive data exists for the treatment of contacts
a prior diagnosis of hepatitis.33 Routine liver tests should exposed to drug resistant TB, and there is disagreement
only be used in these patients as well as HIV-infected among experts about the optimal approach to MDR-TB
and pregnant or postpartum adolescents. Otherwise infection.75 Rifampicin and pyrazinamide combination
monthly monitoring for signs and symptoms of adverse therapy or a longer course of rifampicin monotherapy is
effects is considered sufficient. recommended for contacts of isoniazid resistant cases. A
Isoniazid neurotoxicity including peripheral neuritis, watch and wait approach is advocated by some for
optic neuritis, encephalopathy, seizures and other immunocompetent adults exposed to MDR-TB, but for
symptoms is also uncommon in children. This results those at higher risk—such as young children-tailor-made
from interference with niacin metabolism due to regimens based on susceptibility pattern of the index-case
isoniazid-induced pyridoxine (vitamin B6) deficiency. are suggested.76 Pyrazinamide plus ethambutol for 9 to
While this is unusual in industrialized countries, it is an 12 months is the combination suggested in American
important consideration for breastfeeding infants and guidelines for adults patients with MDR-LTBI,54 but if
children at risk of malnutrition and dietary deficiency of the isolate is not susceptible to one or both of these, at
vitamin B6.67 Where the standard of health and nutrition least 2 second line drugs to which the organism is sensitive
in a community is low, supplementary vitamin B6 is should be used.77 Although concerns about monitoring
recommended.71 for ocular toxicity in children have traditionally limited
Various adverse effects including gastrointestinal upset, the use of ethambutol, a review of the literature suggests
skin eruptions, hepatitis and rarely, thrombocytopenia are that ethambutol is considered safe in children of all ages at
associated with rifamycin therapy. In the Hong Kong study a dose of 15 mg/kg.56 Even in young infants ethambutol
of treatment of LTBI, monotherapy with rifampicin was not therapy can be monitored by recording visual evoked
associated with increased adverse reactions. Rifampicin responses (VER) as reported by Seth et al57 but at few
alone may be less hepatotoxic than isoniazid, but elevations centers only and not as a routine.
in hepatic transaminases and hepatotoxic reactions have
been noted when it is combined with either pyrazinamide72 Compliance
or isoniazid.36
A major obstacle to the successful treatment of LTBI is
patient compliance. Reports indicate that compliance with
Drug Resistance
isoniazid in treating LTBI varies widely, although children
The treatment of LTBI is now complicated by the are slightly better than adult patients in one study
emergence of drug resistant M. tuberculosis. The global encompassing all age groups.78 Certainly this is suggested
project on antituberculosis drug resistance surveillance by the 1990 findings of the Centers for Disease Control
(DRS) reports rates of MDR-TB ranging up to 14% in (CDC), Atlanta, in which 63% of people overall completed
several Eastern European and Central Asian countries.73 their course of preventive therapy, increasing to 76% when
Isoniazid treatment of LTBI has not been shown to only those < 15 years were considered. This suggests that
increase the risk of isoniazid-resistant tuberculosis children may benefit from the greater attention some
compared to controls if active disease is carefully parents pay to the well-being of their offspring than
excluded.29 Individuals at increased risk for drug resistant themselves.
tuberculosis infection include those who are: (i) contacts Unfortunately while efficacy increases with time, the
of a person with prior treatment for active TB; (ii) contacts reverse is true for adherence.32 How does one convince
of someone with drug resistant contagious TB disease; parents of the benefits of a prolonged course of
(iii) residents of areas where prevalence of drug-resistant medication in a child who is not clinically ill, even if the
MTB is high; (iv) contacts of a source case with medication, e.g. isoniazid is relatively free of side effects?
602
Determinants of compliance to treatment of LTBI are HIGHLIGHTS

complex and not well understood.79 Motivation through
education and incentives are two means of addressing • Children should be identified for treatment of
this problem that have been studied.80,81 One New York LTBI on the basis of risk factors determined
study in prisoners was able to demonstrate a significant by epidemiologic factors and TST reaction.
improvement in completion of preventive therapy as a Interpretation of this may vary with the use of BCG,
result of such efforts.82,83 Providers need to consider prevalence of nonmycobacterial infections, HIV-
other needs of the parents, i.e. travel costs, time away infection and malnutrition
from other children and work responsibilities. Even • Even in the absence of availability of skin test,
drug dosages can be a further limiting factor, as exposure history alone will determine the need for
intermittent regimens involve the use of larger doses treatment for presumed LTBI
which may be more difficult to administer to small – Children < 5 years
children. – Those infected with HIV
Directly observed therapy (DOT) has been increa- • Treatment of LTBI in children should be undertaken
singly used as a major component of comprehensive at least with 6 to 9 months of isoniazid
tuberculosis services to improve compliance. Ingestion • Rifampicin containing regimen maybe required in
of each dose of medication is observed, which appears to situation of exposure to drug resistance
increase completion of therapy compared to self- • Future efforts in tuberculosis research should
administered programs85 and may also be more cost include investigations and use of more than one drug
effective.86 with shorter-treatment regimens.
39.2 SYMPTOMS-BASED SCREENING OF CHILD TUBERCULOSIS

CONTACTS—IMPROVED FEASIBILITY IN RESOURCE LIMITED SETTINGS
Alexey Kruk, Robert P Gie, H Simon Schaff, Ben J Marais
INTRODUCTION than 5 years of age who are in close contact with a sputum
smearpositive source case should be screened for TB
Preventing and treating tuberculosis (TB) in children is diseae.10 These recommendations are motivated by the
often a low priority in TB-endemic countries.1 Although, increased risk of developing TB and the potential severity
child TB cases are rarely recorded with accuracy, children of disease observed in young children.11 Once TB disease
contribute substantially to the global TB disease burden.2 has been excluded in these vulnerable children,
It is estimated that of the 8.3 million new TB cases preventive chemotherapy should be provided to
diagnosed in the year 2000, out of 884. These 019 (11%) eliminate the chance of developing latent infection and
were children. 3 In high-income countries child TB to prevent progression to TB disease. The best-studied
constitutes 2 to 7% of all TB cases and is mainly found preventive chemotherapy regimen, isoniazid (INH)
among immigrant populations; in low-income countries monotherapy for 6 to 9 months, reduces the risk of
child TB exists in close association with conditions of developing TB disease in exposed children by at least two-
poverty and constitutes 15 to 20% of all TB cases.3-6 An thirds and probably by more than 90% with good
autopsy study from Zambia found TB to be leading adherence.12-14
respiratory cause of death among human Screening of child TB contacts has huge potential to
immunodeficiency virus (HIV)-infected and uninfected reduce the burden of pediatric TB worldwide. Although it
children.7 In South Africa TB has been reported as the is universally recommended, it is rarely practiced in
third most common cause of death in HIV-infected resourcelimited settings.15 This discrepancy mainly results
children admitted to hospital with a clinical diagnosis of from resource constraints that limit the availability of
acute severe pneumonia,8 a community-based survey tuberculin skin testing and chest radiography, often
recorded a child TB incidence of 407/100 000/year (in regarded as prerequisite tests for adequate contact
children <13 years of age).9 screening.16,17 Lacking the capacity to perform “man-
The World Health Organization (WHO) and most datory” screening tests, clinics in resource limited settings
National TB Programs (NTPs) advise that all children less rarely even attempt to provide preventive chemotherapy
603
to TB exposed children. WHO “Guidance for National passive case finding and managed according to the
Tuberculosis Programs on the Management of directly observed therapy, short-course (DOTS) strategy.
Tuberculosis in Children” no longer regard the tuberculin A TB source case was defined as an adult (> 15 years of
skin test (TST) and/or chest radiograph (CXR) as age) with pulmonary TB; diagnosed on sputum smear
mandatory screening tests for all children in settings where and/or culture. Child household contacts were defined as
these tests are not readily available (Fig. 39.2.1).10 Although children less than 5 years of age living and sleeping in the
access to preventive chemotherapy should be greatly- same house, or group of clustered houses on the same plot,
improved by employing simple symptom-based screening, as a newly diagnosed TB source case. In accordance with
the safety and feasibility of this approach have not been the South African National Tuberculosis Program (NTP)
evaluated in prospective studies. A single retrospective guidelines,20 all children younger than 5 years in household
study for South Africa demonstrated that symptom-based contact with a TB source case were assessed by
screening may be useful to identify the subset of children documenting symptoms suspicious of TB, as well as
who require further investigation to exclude TB disease. tuberculin skin test (TST) an chest radiograph (CXR)
This would allow the majority of vulnerable contacts who results. Children diagnosed with TB disease received
are asymptomatic at the time of screening to access standard TB treatment as directly observed therapy (DOT);
preventive chemotherapy without delay.18 However, 2 months of 3 drugs (INH, rifampicin (RMP), and
concerns have been raised regarding the safety of this pyrazinamide (PZA) followed by 4 months of 2 drugs
simplified approach. The study was aimed to evaluate the (INH, RMP), unless they were exposed to an index case
safety and feasibility of applying a symptom-based with known drug-resistant TB in which case individualized
approach to exclude TB disease among children in treatment was provided. The treating clinician acted
household contact with an adult TB index case. independently from the research clinician. According to
A prospective observational study was conducted current WHO recommendations,10 children without TB
from January 2004 through December 2004 in Cape Town, disease received unsupervised INH monotherapy for 6
South Africa. Children were recruited at 3 local clinics months, with monthly collection of tablets from the clinic.
served by Tygerberg Children’s Hospital as the referral All children in household contact with a newly
center. The study area is a well-established diagnosed tuberculosis (TB) source case (routinely
epidemiological field site within a predominantly entered into the local TB register) were identified and
“colored” community (people of mixed ethnicity) that invited to the clinic for evaluation, during a home-visit
experience a high TB incidence (adult TB incidence 845/ by the study social worker. At evaluation, study nurses
100,000), 9 with a relatively low prevalence of HIV enquired about the presence of current symptoms (fever,
infection19 (<10% of adult TB patients tested during 2004). cough, wheeze, reduced playfulness/unusual fatigue, or
Local clinics provide general primary health care services weight loss), performed a TST and arranged for a CXR to
and coordinate the diagnosis and treatment of TB be taken. Nurses recorded current symptoms using a
patients, free of charge. Adult TB cases are identified by standard data capture document, irrespective of their
duration or character. This approach must be differen-
tiated from the strict emphasis on well-defined symptoms
that have been promoted for symptom-based diag-
nosis.21,22 In TB-endemic areas, the presence of a persistent
non-remitting cough or wheeze for more than 2-4 weeks,
together with reduced playfulness/unusual fatigue and
documented failure to thrive provides good diagnostic
accuracy in immune-competent children.21,22 However,
for screening purposes the specificity of the test is less
relevant, but excellent negative predictive value is
essential to ensure optimal safety.
A Mantoux TST, using intradermal injection of 2
tuberculin units of purified protein derivative (PPD RT
23, Statens Serum Institute, Copenhagen, Denmark), was
performed on the volar aspect of the left forearm. The
transverse diameter of induration was measured in
millimeter after 48 to 72 hours; an induration of > 10 mm
(> 5 mm in HIV-infected children) provided a proxy for
Fig. 39.2.1: Suggested approach to contact management when chest
M. tuberculosis infection. The diagnosis of TB disease was
radiography and tuberculin skin testing are not readily available. Adapted primarily made on radiologic grounds. Chest radiographs
from the World Health Organization Guidance10 were read by the same expert who was blinded to all
604
clinical information; both anteroposterior and lateral Table 39.2.1: Demographics of children in household
CXR’s were performed. Findings were documented on a contact with an adult TB source case
standard report form and categorized as “certain TB”, or Characteristics Number (%)
“certain not TB.” All CXR’s judged to be “certain TB” by
• Adult TB source cases (n = 197)
the first reader were read by a second independent expert.
Sputum smear-positive 183 (93.8)
Radiologically “certain TB” was defined as agreement
Sputum smear-negative 12 (6.2)
between both independent experts. TB disease mani- culture-positive
festations were classified according to a recently proposed
• Household contacts
radiologic classification of childhood intrathoracic TB.23
< 5 years of age (n = 271)
Written informed consent was obtained from the Children with complete data set 252 (93.0)
parent/guardian in the home language of the patient. HIV (symptoms, TST* and CXR)
testing was not routinely performed, as the HIV
• Children included in the analysis
prevalence among children in this community is low. (n = 252)
Nevertheless, all children with symptoms suspicious of Male 141 (56.0)
HIV infection, known HIV exposure or a diagnosis of TB Age categories
disease were offered an HIV test, together with routine Age < 1 year 54 (21.4)
pre-and post-test counseling. A rapid test was used to Age 1-2 years 106 (42.1)
screen for HIV infection (Determine HIV ½ raid test, Age 3-5 years 92 (36.5)
Abbott, Tokyo, Japan); no confirmatory tests was requi- TST* results
red, as none of the children had a positive raid test. The TST positive (≥ 10 mm induration) 136 (54.0)
Western Cape Provincial Tuberculosis Program, the NTP TB treatment
and the City of Cape Town Health Department were Isoniazid (INH) preventive 217 (86.1)
consulted and their consent obtained. The University of chemotherapy
Stellenbosch Ethics Committee approved the study. No preventive therapy (received 2 (0.8)
Data were entered into an Excel spreadsheet. INH within the preceding year)
Descriptive analyses were done using SPSS (version 14, Treated for TB disease 33 (13.1)
SPSS Inc., Chicago, IL). The sensitivity, specificity and * TST—Tuberculin skin test
negative predictive value (NPV) of using any current
symptom to screen for active TB were calculated.
Symptom frequencies recorded in those treated for TB Table 39.2.2: Radiographic disease manifestations
compared to those not treated for TB were compared recorded in child TB contacts
using the chi-squared test. TB disease manifestation Number (%)
During the study period 357 adult TB cases [245
“Not TB” 211 (83.7)
(68.6%) sputum smearpositive; 201 (56.3%) male, 218 “Uncertain TB” 14 (6.0)
(61.1% 15-40 years of age)] were identified; 195 (54.4%) Treated as TB* 6/14 (42.9)
cases were sputum smear- and/or culture-positive cases “Certain TB” 27 (10.7)
and in household contact with children aged less than 5 “Certain TB” n = 27
years; representing 187 households with 271 children (on Uncomplicated lymph node disease 22 (81.5)
average 1.45 children < 5 years/household). Complete Complicated lymph node disease
information (symptoms, TST and CXR) was available in - parenchymal consolidation 2 (7.4)
252/271 (93.0%) children; included in the analysis. The - airway compression 1(3.7)
mean age of the children was 30 months (range 1-60 Lung cavity 1(3.7)
months). Of the child TB contacts included in the analysis, Pleural effusion 1(3.7)
240/252 (95.2%) were in contact with a sputum smear- * The treating clinician initiated TB treatment in 6 children with
positive and 12 (4.8%) with a sputum smearnegative “uncertain TB” all had positive TST (mean 19 mm) and had
culture-positive source case. In total 136/252 (54.0%) either suggestive symptoms or were less than 3 years of age.
children had a positive TST, with a mean positive
induration of 18 mm (Table 39.2.1).
TB treatment was administered to 33 (13.1%) children;
25 (75.8%) were less than 3 years of age, 32 (97.0%) had initiated TB treatment in 6 children with “uncertain TB”;
positive TST and 24 (72.7%) had a rapid HIV screening all had a positive TST (mean 19 mm) and 4 had suggestive
test; all tested negative. Table 39.2.2 reflects the TB disease symptoms, their average age was less than 3 years (35
manifestations recorded in the 27 children categorized months). None of the other children with “uncertain TB”
as “certain TB”; the majority (22/27, 81.5%) had developed symptoms suspicious of TB while on
uncomplicated hilar adenopathy. The treating clinician preventive therapy.
605
Table 39.2.3: Comparing symptoms reported in child TB contacts treated for TB versus those not treated for TB
Symptoms Total Treated for TB Not treated for TB Odds Ratio

N=252(%) N=33(%) N=219(%) (95%C1#)
Cough 62 (24.6) 18 (54.5) 44 (20.1) 4.8 (2.1-10.9)
Fever 14 (5.6) 6 (18.2) 8 (3.7) 5.9 (1.7-20.6)
Weight loss* 19 (7.5) 10 (30.3) 9 (4.1) 10.1(4.8-59.5)
Fatigue 16 (6.3) 6 (18.2) 10 (4.6) 4.6 (1.4-15.4)
Any symptom 76 (30.2) 25 (75.8) 51 (23.3) 10.3 (4.1-26.6)
# 95% C1—95% Confidence Interval
* Weight loss —Weight loss of flattening of growth trajectory documented on the road to health card
Table 39.2.4: The value of symptom-based screening to exclude TB disease in child TB contacts: calculations done
using different case definitions for TB disease
Different case definitions Sensitivity (%) Specificity (%) NPV (%)
Case definition 1
All children treated for TB 25/33 (75.8) 168/219 (76.7) 168/176 (95.5)
Case definition 2
All children with “Certain TB” on chest radiograph 22/27 (81.5) 170/225 (75.6) 170/175 (97.1)
Case definition 3#
All children with “Certain TB” on chest radiograph, 22/22 (100) 175/230 (76.1) 175/175 (100)
excluding those with asymptomatic hilar adenopathy
NPV*—negative predictive value
#
This case definition demonstrates that the only cases missed by symptom-based screening were children with uncomplicated
hilar adenopathy on chest radiography, which indicates recent primary infection
Symptoms recorded at the time of screening are Table 39.2.4 indicates the diagnostic value of symptom-
reflected in Table 39.2.3. Children completely asympto- based screening to exclude TB disease in children TB
matic were 176 (69.8%). Subjective weight loss was reported contacts. The negative predictive value of symptom-based
in 43 (16.7%) children, but failure to thrive was documented screening varied according to the case definition used,
on the road to health card in only 19 (7.4%) cases; 10 of 95.6% when using all treated for TB, 97.2% when only
whom were treated for TB. Among those not treated for children with radiologic “certain TB” were included, and
TB, worm infestation with iron deficiency anemia and/or 100% if the case definition excluded those with
food insecurity were regarded as the most common causes asymptomatic uncomplicated hilar adenopathy.
of failure to thrive, as children responded well to dewor- Nurses reported that symptom-based screening was
ming and food supplementation. A cough was the most quick and easy to perform. TST requires refrigeration of
common symptom recorded in those treated for TB, being the PPD, a diabetic needled syringe and appropriate
present in 18/33 (54.5%), but it was present in 44/244 expertise on the part of the study nurse to place and
(19.6%) children not treated for TB as well; 21 had peri- interpret the test result correctly. Performing a TST is time
hilar streakiness indicative of possible viral infection and consuming, especially when taking into consideration the
2 had symptoms and signs suggestive of bacterial need to record the result at a second visit 2-3 days later.
pneumonia. CXR was done at the local day and/or referral hospital.
Of the children treated for TB, 25/33 (75.5%) reported It places a considerable additional workload on radio-
symptoms at the time of screening. All 5 children with graphy services, particularly at the local day hospital, as
radiographic signs other than uncomplicated hilar evidenced by the fact that their annual stock of child
adenopathy were symptomatic, 3 with airway compression radiograph negative was depleted within 3 months.
reported cough and fever (2 had documented weight loss Although, it was not accurately quantified, parents/
as well), 1 with pleural effusion reported fever and fatigue, caregivers spent a considerable amount of time to get the
1 with parenchymal cavitation reported cough, fatigue and required tests done, especially when they were dependent
weight loss. On CXR the 8 asymptomatic children all had on public transport.
uncomplicated hilar adenopathy, 6 with “certain TB” and This prospective community-based study demons-
2 with “uncertain TB”; 5 were less than 3 years of age. trates that screening for TB disease is feasible using a
606
symptom-based approach. Employing a simplified TB disease, it is less of a concern in children. Children

approach has particular relevance in TB-endemic settings tend to develop pauci-bacillary disease, which reduces
with limited resources, where TST and CXR are not the likelihood of transmission and the risk of acquiring
readily available. In our study more than two thirds of drug resistance. Asymptomatic children would have even
child TB contacts were completely asymptomatic at the lower bacillary loads, posing a negligible risk of acquiring
time of screening and would have required no further INH resistance. A positive TST result provides proof of
tests to exclude TB disease. Although 8/33 (24.2%) M. tuberculosis infection, but it is less reliable in very
children treated for TB during the study were completely young, malnourished and/or immune compromised
asymptomatic, all these children had uncomplicated hilar children and may take up to 3 months to convert.24 Its
adenopathy detected on CXR only. The natural history main clinical applications would be to identify latent TB
of TB in children demonstrates that transient hilar infection (LTBI) in vulnerable groups (e.g. in oncology
adenopathy is a common finding following recent patient prior to the initiation of chemotherapy) and to
primary infection. According to the pre-chemotherapy provide supportive evidence for a TB case definition in
literature only a small percentage of these children are symptomatic children. Due to delayed TST conversion
likely to develop progressive disease, which would be TB infection can only be reliably excluded in immune
accompanied by clinical symptoms.11 This suggests that competent children 3 months after TB exposure ended,
asymptomatic hilar adenopathy is a natural component which explains why the American Thoracic Society (ATS)
of the primary (Ghon) complex, reflecting recent M. guidelines utilize the 3 months TST result to guide early
tuberculosis infection rather than active TB disease.11,12,23 termination of preventive chemotherapy.25 In resource-
By convention asymptomatic hilar adenopathy is limited settings where TST is not routinely available, the
currently treated as TB disease in most countries. The benefit versus cost (including nursing time, patient time,
current study was unable to evaluate the risk of providing transport costs, and inappropriate management due to
INH monotherapy to children with asymptomatic hilar misinterpretation) should be carefully considered. It seems
adenopathy, as all these children received full TB important to prioritize CXR access as the diagnostic test
treatment. However, early experience with INH mono- of preference to exclude TB disease in symptomatic
therapy (the US Public Health trials of the 1950’s and children;15,26 the yield in this group of children was high
1960’s) demonstrated that preventive chemotherapy (22/76, 28.9%). In the absence of objective diagnostic tests
should be sufficient in these cases.12 From a public health to confirm TB disease, symptom-based diagnosis may be
perspective it is important to balance the minimum considered, but this requires a strong emphasis on careful
potential risk experienced by children with asymptomatic symptom definition for improved diagnostic
hilar adenopathy receiving INH monotherapy, with the accuracy.21,22
high disease risk of not providing any preventive therapy The reality in most TB-endemic areas is that curative
to TB exposed children, due to an inability to screening TB services are already overburdened and clinics cannot
for TB disease. Insistence that TST and CXR are spare the resources required to screen and treat child TB
“mandatory” screening tests, severely limits the access contact. Implementing a simple symptom-based approach
of child TB contacts to preventive chemotherapy, makes screening far more feasible. Feasibility may be
especially in resource-limited settings where children are further improved by restricting the focus to those children
most likely to be exposed to TB at a young and vulnerable who stand to benefit most from the provision of preven-
age.17 The most important benefit demonstrated is the tive chemotherapy. The natural history of disease
fact that less than one third of child TB contacts reported demonstrated that very young (<3 year of age) and/or
symptoms that required additional investigation to immune-compromised children are at highest risk to
exclude TB disease. This implies that the majority of develop TB disease following exposure.11 In our study,
young and vulnerable children can receive preventive 16/22 (72.7%) children who met the case definition of TB
chemotherapy without delay, the excellent negative disease were less than 3 year of age, including all the
predictive value achieved (up to 100% with the exclusion children with complicated disease. Although, TB disease
of asymptomatic hilar adenopathy) also indicates that should be excluded in any child with symptoms
symptom-based screening seems to be safe. suspicious of TB, restricting the provision of preventive
In addition, any child who develops symptoms chemotherapy to those at highest risk following TB
suggestive of TB, even after the provisional preventive exposure (<3 years and/or immune-compromised) will
chemotherapy, should be evaluated to exclude TB drastically reduce the additional load on already
disease. This provides a safety net for those children in overburdened health care services; 36.5% of child TB
whom INH monotherapy may be ineffective. Another contacts in this study were older than 3 years of age.
concern that is frequently mentioned is the risk of Due to its cross sectional design we are unable to
encouraging the development and spread of INH comment with certainty on the safety of symptom-based
resistance. While this may be valid concern in adults who screening, however, ongoing disease surveillance
receive INH monotherapy without adequately ruling out continued in 2 of the 3 study clinics. Only 2 children who
607
received preventive chemotherapy presented with TB • All children < 5 years old in household contact with
disease during the following year; both were less than 3 an adult TB source case should be assessed by
years of age and reported poor adherence to preventive documenting current symptoms, tuberculin skin test
chemotherapy, only collecting tablets once. Additional and chest radiograph results
study limitation include potential recall bias and reporter • Current WHO recommendations, demonstrating
subjectivity, these influences were limited by the focus that symptom-based screening of child TB contacts
on current symptoms and the use of standardized data- should improve feasibility in resource-limited
capture forms that were completed prior to TST and CXR settings and seems to be safe.
evaluation. Investigator bias was further limited by the
fact that radiographs were reviewed by independent
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release assays after rifampicin prophylaxis in a tuberculosis. Int J Tuberc Lung Dis 2004; 8: 636-47.
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75. Passannante MR, Gallagher CT, Reichman LB. Preventive infection on presentation and hospital-related mortality
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76. Frieden TR, Sterling T, Pablos-Mendez, et al. The 9. Marais BJ, Hesseling AC, Gie RP, Schaaf HS, et al. The
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79. Sumartogo E. When tuberculosis treatment fails: A social
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24. Marais BJ, Pai M. New Approaches and emerging antituberculosis chemoprophylaxis and treatment in
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40 Tuberculosis Control Program in
Children—Lacunae and Experiences
Rohit Sarin, Sangeeta Sharma
INTRODUCTION reduce transmission in the community and indirectly

would also reduce the spread of disease in children.
India has the dubious distinction of contributing to over However, as majority of the children are not sputum-
1/3 of the global burden of tuberculosis and WHO has positive, they would be automatically missed in the
ranked the country as No.1 amongst the high disease priority.
burden countries.1,1a Recent estimates suggest that there
are around 8.5 million TB patients prevalent at any point
Diagnosis
of time to which 1.8 million are added every year.2 Nearly
half of this group is sputum positive and contributes to Diagnosis under the TB Control Program is from amongst
the continued transmission of the disease. It is estimated the self-reporting chest symptomatics.
that children constitute less than 7% of all cases of TB3 The definition of chest symtomatics under the TB
and only around 3% of the sputum-positive patients.4 Control Program has been “productive cough for over 2
Even though the proportion of children suffering from weeks (RNTCP).8 Children usually may not appreciate
the disease is less but they form the vulnerable group in their symptoms or bring out sputum and hence would
the context of their tendency to develop severer forms of get excluded as per this definition. Moreover, as the
pulmonary and extra pulmonary disease and the high investigation of choice for diagnosing and monitoring
mortality associated with it. WHO estimates that nearly under the RNTCP has been sputum examination, those
1.5 million new cases and 450 000 deaths from TB occur children who do not bring out sputum would face
annually amongst children in the developing countries.5,6 difficulty in diagnosis. The clinicians would then
Tuberculosis infection in children is also an indicator naturally tend to rely on chest X-rays with its known pit
of recent transmission and reflects the epidemiological falls of intra and inter reader variation.9 Further, the
status of the disease in the community. Further, it is this availability of chest X-ray is confined to Community Health
group of infected children which would form the pool Centres or Taluk Hospitals under the General Health
for the breakdown of disease in the future. The emergence Services and hence diagnosis can only be done at this level
of HIV-TB coinfection and MDR-TB further add to the rather than at Primary Health Centers (PHC). The distance,
gravity of the situation. time and costs incurred in travel would add to the barriers
In spite of the obvious importance of Tuberculosis in access for diagnosis.
Control in children, the National Tuberculosis Program The other diagnostic tool in children is Tuberculin
(1962) and the Revised National Tuberculosis Control testing, availability of which is again limited to hospital
Program (1997) have not given it the due priority. The settings rather than the PHC. Now, even the hospitals
various issues involved have been discussed in this do not have the standardized 1 TU strength as the
chapter. Government source from BCG Laboratory, Guindy has
stopped. The current availability from the private sector
ISSUES AND LACUNAE is of 2 TU and 5 TU and this needs Quality Control
The issues in the context of the Tuberculosis Control Assessment. This is more important with the 1TU PPD
Program in children can be discussed under the 6 basic recently made available in the private sector. Moreover,
headings of the Directly Observed Treatment Short- these higher strengths of tuberculin may need different
course (DOTS) strategy. guidelines for positive and negative interpretation.
Further, widespread BCG coverage also interferes with
the interpretation of results. Hence, the usefulness of this
Priority
diagnostic modality has its limitations.
The RNTCP prioritized on detecting and treating smear- The other diagnostic tools such as gastric lavage for
positive patients in order to cut the chain of transmission.7 sputum and fine needle aspiration cytology (FNAC) for
Treating smear-positive adult patients would definitely lymph nodes are not usually available under field
613
Chapter 40 Tuberculosis Control Program in Children—Lacunae and Experiences
situations in the National Program. Thus, the General schooling may pose a barrier to access. Frequent visits to
Health Services which are to implement the National health facility also brings out the issues of social stigma,
Program lack the diagnostic tools for tuberculosis. Further, especially amongst female children. The Program,
in the absence of defined diagnostic guidelines in children therefore, needs to develop a more children friendly
the only alternative left, in most situations, is to refer the approach in this regard.
child to a pediatrician at the secondary/tertiary level
institutions. To add to the problems, the pediatricians differ Monitoring of Treatment
in their diagnostic practices and, without any definite
diagnostic test, rely on the different “scoring systems”, each In the absence of sputum availability, the physician is
of which has its own limitations. Now, these are considered largely dependent on the clinical and radiological
unreliable. This is compounded by the fact that at many a improvement. Both of these have their limitations and to
times, the pediatrician may not be available even at the some extent are subjective. More objective criteria need
Secondary Health Care facility. to be developed in the program for the monitoring of
compliance and response to treatment. Presently, for
Drug Availability monitoring treatment, patient is re-examined at two
months for review of diagnosis and then finally only at
In order to ensure an uninterrupted supply of good the end of treatment. There is no system to refer the
quality drugs, the RNTCP has made a provision to patient in between, if necessary. Children, unlike adults,
procure the anti TB drugs for the pediatric age group in may deteriorate very rapidly and hence the guidelines
blister combi packs and patient-wise boxes, so that all need some modification for provision of earlier
drugs for the entire treatment duration are available for monitoring. Moreover under the Program, wherever
the patient prior to initiating the treatment. To assist in sputum examination is not possible or the sputum is
calculating required dosages and administration of anti- negative and the patient shows no improvement at two
TB drugs for children linked to the child’s weight, the months, patient is re-examined for review of diagnosis.
medication has been made available in 2 types of patient If the diagnosis is certain, intensive phase is extended for
wise-boxes (PC-13 and PC-14) for 4 weight bands (6-10,
one more month. After the extended intensive phase (total
11-17, 18-25, >26 kg body weight). The guidelines define
3 months of R3H3Z3E3 from start of treatment), child is
different combination of these boxes to cover all these
put on the continuation phase. If the patient still continues
weight bands. In India children are often malnourished
to deteriorate, the patient is declared as failure and
and neglected and during treatment gain weight and
nonresponder respectively at end of 2nd or 3rd month
move to higher weight band. However, the anti-TB drugs
respectively and put on category II. This is not being
available in blister combi packs and patient-wise boxes
accepted by many TB Experts to label a patient as failure
linked to the child’s weight often fall short as the child is
continued medicines in the lower weight band. Moreover, and non responder as early as 2 to 3 months during the
for children less than 6 kg body weight, there are no such course of treatment. Moreover, extension of continuation
treatment boxes available and they are being treated with phase for disseminated disease and miliary tuberculosis
loose drugs especially syrups or dispersible tablets. in the absence of availability of sputum has not been
Hence, this vital logistic strength of the RNTCP is diluted defined under the program.
for this highly vulnerable age group.10
Also, issues relating to drug stock outs and difficulty Special and Unique Requirements of Children
in dose titration linked to weight can arise. Further, drug Problems like visit to the DOTS center due to parental
intake in tablets/capsules for smaller children becomes preoccupation, dependency on parents, clash of school/
a problem. center timings, prolonged treatment and ignorance are
important factors for nonadherence. Options which need
Directly Observed Treatment Short-course to be made available under the program to ensure regular
One of the major strengths of the RNTCP is to ensure the drug intake and compliance are extending the center
patient taking each and every dose of medicines in the timings outside the school hours, sensitizing the health care
Intensive Phase under direct observation and weekly providers to the peculiar needs of very small children, or
supervision in the Continuation Phase. This implies that making mothers or immediate relatives as DOTS providers
the patient needs to visit the health facility for drug intake to administer drugs under supervision of community
and this becomes a major barrier for children who are by health DOTS workers. This will not only improve the
and large dependent upon the adults to take them to the compliance but also indirectly create an awareness and
health facility. Nonavailability of the parents due to work realization in the family regarding the free and prompt
commitment or nonavailability of the child due to management available under DOTS program.
614
Newer RNTCP Initiatives in Context of Children Table 40.1: Doses of individual drugs based
on body weight (kg) of child
MDR-TB and DOTS-plus
Drugs 16-25 kg 26-45 kg >45 kg
Program policy: RNTCP is routinely offering DOTS-plus Kanamycin 500 mg 500 mg 750 mg
treatment to adult MDR-TB cases in which a fixed regime Ofloxacin or 400 mg 400 mg 800 mg
of standardized drugs as Standardized Treatment Levofloxacin 200 mg 500 mg 750 mg
Regimen is given under direct supervision. However, in Ethionamide 375 mg 500 mg 750 mg
pediatric MDR cases, DOTS-plus has not yet been Pyrazinamide 500 mg 1250 mg 1500 mg
implemented although, guidelines for management of Ethambutol 400 mg 800 mg 1000 mg
pediatric MDR-TB under RNTCP have recently been Cycloserine 250 mg 500 mg 750 mg
PAS (80%B.A.)* 5 gm 10 gm 12 gm
formulated and drafted.
Once implemented under the DOTS-plus program,
only children more than 15 kg body weight with
confirmed MDR (PTB, EPTB) diagnosed by culture and TB and HIV Control Strategies
drug sensitivity will be taken into the program. After
Development of mutual TB and HIV control strategies in
confirmation of diagnosis, the patient will be given fully
children involving better co-operation between the
supervised standardized treatment regimen on the pattern
RNTCP and National AIDS Control Program will have
of DOTS-plus regimen of RNTCP in adults. But there are
an impact on growing HIV epidemic and TB treatment.
still some lacunae in the implementation of DOTS-plus
Treatment of TB in HIV positive patients should always
program in children.
be under DOTS because of risk of non-compliance in these
Diagnosis: Diagnosis of pediatric MDR-TB is often cases.
extremely delayed due to reliance on the adult case
LRS experience: Inspite of the above mentioned lacunae,
definitions of MDR-TB and children being usually
excellent success rates have been achieved for adult TB
sputum negative or sputum not available. Accordingly,
patients with WHO’s Directly Observed Treatment Short-
the criteria for initiating children on DOTS-plus treatment
course (DOTS) strategy throughout the world including
should be modified. Early diagnosis and treatment is all
India.11 DOTS strategy appears to be highly effective for
the more important in children as they are a vulnerable
pediatric pulmonary tuberculosis (PTB) and extra-
group where rapid progression of disease and mortality
pulmonary tuberculosis (EPTB) patients.12 Our studies
could be higher if left untreated. Programmatic changes
for PTB and EPTB have demonstrated remarkable
could facilitate earlier diagnosis and treatment of pediatric
recovery on DOTS. These studies also highlight the need
MDR-TB and it is likely that future measures and
of access to accurate diagnosis, effective treatment and
modifications may be necessary in order to prevent the
promoting adherence particularly in resource poor
emergence of incurable tuberculosis in children.1
endemic areas with greater burden of the disease.
Treatment: As the duration of treatment will be minimum In our study conducted over a 10 year period (January
of 24 months and there is lack of data relating to long- 1995 to July 2004) analyzing the data of 1098 pediatric PTB
term ethambutol (E) use in pediatric population, thus, patients,13 over half the patients were in the age group of
inclusion of clinical tests/markers in the follow-up 11 to 14 years and able to bring out sputum for diagnosis.
schedule of patients to detect optic neuritis is highly Further, most of the registered patients were naïve (87.7%)
recommended. and previously treated comprised only about 12%.
Also, fluoroquinolones are not yet licensed for Amongst the previously treated nearly half were treatment
pediatric use in India thus their licensing for at least use after default. Out of total cases, 414 and 404 were smear
in pediatric MDR-TB should be sorted out before the positive and negative respectively while sputum status
inclusion of this drug as part of the MDR-TB regimen. was not known in 280 patients. Sputum positivity increased
Feasibility of tablet cutters for ethionamide, with age. Hence, sputum examination was an important
levofloxacin, cycloserine, etc. should also be explored to diagnosis tool even in children. Majority of the children
facilitate weight related dosaging. were in the adolescent age group.
The recommended dosages for the different weight A total of 427 (38.9%) patients had primary complex
bands are as below: (Ghon focus with hilar lymph node and associated
Pyridoxine 50 mg and 100 mg will be given for 16-25 lymphatics) while 252, 163, 43, 24 and 189 patients had
kg and > 25 kg respectively (Table 40.1) extensive parenchymal infiltrates, cavities, apical lesions,
• PAS (para-aminosalicyclic acid) will be added if any consolidation and combination of more than one type of
of the above drug is not tolerated. radiological lesion respectively. Category I, II and III of
In case the bioavailability (BA) of PAS is 60% the treatment was started on 50.6%, 10.5% and 38.9% patients
dosage is increased to 7 gm; 14 gm and 16 gm respectively. respectively. The cure rate was 92.4% (302/327) and 92%
615
Chapter 40 Tuberculosis Control Program in Children—Lacunae and Experiences
(80/87) for the sputum positive new and retreatment mentioned above need to be suitably addressed. The
cases respectively (γ12 = 0.02, p = 0.901) but the treatment Government has only recently prioritized this issue and
completion rate amongst the smear negatives was made an effort towards developing a consensus amongst
significantly higher for new cases (97%; 636/656) than the experts for the management of children in the
retreatment cases (53.6%; 15/28) (γ12 = 100.8, p<0.001). RNTCP.10 However, to resolve the unanswered issues,
Overall success rate was 95.4% and 82.6% for new and the Government of India proposes to have similar
retreatment cases respectively (γ12 = 30.35, p<0.001). There meetings in the near future. The newer initiatives like
was an overall 3% default rate, 1.9% failure rate and 1% management of MDR-TB and HIV-TB are even more
death rate in the study. challenging in children than in adults.
In our study conducted over the same period
analyzing the data of 941 out of 975 children with EPTB, REFERENCES
there was similar age distribution as in pulmonary TB
1. World Health Organization. Global Tuberculosis Control:
lymph node TB (71.1%) was the commonest form for all
Surveillance, Planning, Financing. WHO Report 2006.
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WHO/HTM/TB 2006;362. Geneva, Switzerland: WHO
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Out of total 669 cases of lymphnode TB,14 cervical URL http://www.who.int/tb/publications/global/
tuberculous lymphadenitis (88.2%) was the commonest 2009/fullreport.pdf. Accessed April 4, 2009.
form for all ages followed by axillary lymphadenitis in 2. Central TB Division, DGHS, MOHFW, Govt of India.
3.3%. TB of other sites was seen in only 8.5% cases. Out of Expert Committee Report — Burden of Tuberculosis, 2005.
total 622, 93% cases of lymph node TB where fine needle 3. Nelson LJ, Wells CD. Global epidemiology of childhood
aspiration and/or excisional biopsy was done, it was tuberculosis. Int J Tuberc Lung Dis 2004;8:636-47.
positive in 84.2% and negative in 15.6% respectively for 4. Suryanarayana L, Suryanarayana HV, Jagannatha PS.
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in a South Indian community. Ind J Tub 1999; 46: 171-8.
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Similarly our study on 106 cases of tuberculous Tuberculosis epidemic. Geneva: WHO 1996.
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Prospective of Prevention, Diagnosis
41 and Management of Tuberculosis
in the National Program
LS Chauhan
INTRODUCTION TB kills more adults than all other infectious diseases

combined. More children are orphaned because of TB than
Tuberculosis is one of the oldest diseases known to affect due to any other infectious disease. TB was declared a
mankind as shown by the findings of tuberculous spinal global emergency by WHO in 1993, and countries round
disease in Egyptian mummies. The Greeks called the the world have intensified their measures towards TB
disease phthisis (“consumption”), emphasizing the control programs. In fact, the threat of HIV/AIDS alerted
dramatic aspect of general wasting associated with chronic them to potential danger of TB resurgence.
untreated disease. It has also been referred to in the Vedas
and ‘Ayurvedic Samhitas’ as the ‘Kshaya Rog’. The Epidemiological Basis of TB Control Activities
infectious etiology was debated until Robert Koch’s
discovery of the bacillus in 1882. Effective anti-tuberculosis The epidemiological basis of TB control activities in a
drugs were available in the middle of last century, but in community can be simplified using a model to understand
Europe and the United States, mortality rates began to the natural history of tuberculosis (Fig. 41.1).
decrease decades before the introduction of Exposure to a potentially infectious case is a
antimycobacterial drugs due to improvement in prerequisite for becoming infected. Once an individual is
socioeconomic conditions thereby establishing the fact that infected, risk factors determine the probability that an
TB and poverty are closely related. infected individual will develop tuberculosis, and some
risk factors also determine the probability that a diseased
BURDEN OF DISEASE individual will die from TB.
The major factors that determine the risk of becoming
Mycobacterium tuberculosis remains the single most serious exposed to tubercle bacilli include the number of incident
pathogen worldwide and a major global public health infectious cases in the community, the duration of their
problem in much of the developing world. Globally, it is infectiousness, and the number and nature of interactions
estimated that more than 9 million people develop active between a case and a susceptible contact per unit of time
tuberculosis (TB) disease every year of which nearly of infectiousness. The probability of becoming infected with
4 million cases are sputum smear-positive, the majority of M. tuberculosis depends on the number of infectious droplet
whom are in the developing countries.1 This is due to the nuclei per volume of air (infectious particle density) and
failure to cure a high proportion of sputum smear-positive the duration of exposure of a susceptible individual to
cases, population growth, HIV-epidemic and other that particle density. It is estimated that one infectious
socioeconomic and demographic factors (poverty, case, if not treated, on an average infects about 10 to 15
migration, etc.). Globally the HIV epidemic worsened the new persons every year.3
TB situation, increasing the number of tuberculosis cases The most important risk factor for tuber-culosis is
and accelerating the spread of the disease. It is estimated infection with tubercle bacilli. Tubercle bacilli are
that one third of the world’s AIDS cases are infected with necessary, but not a sufficient cause of tuberculosis. While
TB. HIV increases a person’s susceptibility to TB infection. the risk of becoming infected is largely exogenous in nature,
HIV is now considered the most powerful risk factor for determined by the characteristics of the source case,
the progression of TB infection to disease. environment, and duration of exposure; the risk of
Fig. 41.1: A model for tuberculosis epidemiology,2,3

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Chapter 41 Prospective of Prevention, Diagnosis and Management of Tuberculosis
developing tuberculosis, given that infection has occurred informative about the dynamics than any other
is, largely endogenous, determined by the integrity of the manifestation of the disease. TB in children always points
cellular immune system. In most instances it cannot be to recent transmission that was not curtailed in a timely
determined why a particular person does or does not fashion. Childhood TB prevalence indicates the community
develop tuberculosis after becoming infected with tubercle prevalence of sputum smear-positive pulmonary
bacilli. tuberculosis (PTB), age-related prevalence of sputum smear-
Multitude of factors has been identified which increase positive PTB, prevalence of childhood risk factors for disease
the risk of progression from subclinical infection with and stage of epidemic.
M. tuberculosis to overt tuberculosis. The three most Children as in adults acquire infection from sputum-
important of them for all practical purposes are coinfection positive infectious cases. Proper identification and
with HIV, recent infection with tubercle bacilli, and healed treatment of infectious cases will prevent childhood TB.
lesions from previous tuberculosis which was never However often childhood TB is accorded low priority
treated. Globally, low body weight or malnutrition might globally by National TB Control Programs due to
be of considerable epidemiological importance because of diagnostic difficulties, childhood TB is considered rarely
its high prevalence, particularly in low income countries. infectious, limited resources, misplaced faith in BCG and
The risk of the disease developing in the individual is lack of data on treatment.4,5 But this disregards the impact
highest shortly after getting infected. It is a strong factor, of tuberculosis on childhood morbidity and mortality.
with recent infection being 10 times more likely to produce Based on the understanding of tubercular epidemio-
a case than a long-standing infection. A common rule of the logy, the basis of any TB control activity should help to
thumb is that the lifetime risk of a newly infected young reduce risk of exposure, transmission, improve upon host
child (1-3 yrs) might be 10% and half of the risk falls within immune response to reduce risk of progression to active
the first five years following infection. The incidence of disease and treat the infected to reduce morbidity and
tuberculosis disease increases with age. This would be partly mortality.
explained by the cumulative increasing prevalence of
tuberculosis infection. There are two peaks in incidence Evolution of TB Control Program in India
observed, first in the 1 to 4 age groups, reflecting the
progression from recent infection by TB bacilli and the The evolution and progress of efforts to control tuberculosis
second in adolescents and young adults. Another factor in the country has been need-based relating to the problems
which plays a role in the development of tuberculosis disease of a technical, operational and managerial nature that
is sex. Men and women are differentially at risk. The risk is arose over time in the country. As in most of the countries,
higher for women than men in the 15 to 44 age groups the first anti-TB measures taken in India were of an
and lower in women than men beyond 44 years of age. unplanned and ad hoc nature confined mainly to the
There are several other risk factors that have been studied establishment of hospitals and Sanatoria. Attempts to
like cigarette smoking, HIV, diabetes mellitus and tackle the problem of TB through organized efforts actually
malnutrition. They adversely affect the immune system so had their origin in late 1930s. The chronology of important
could influence the tuberculosis disease incidence. Several landmarks in the history of tuberculosis (TB) control can
other medical conditions are commonly associated with be divided into three phases: the four decades prior to the
tuberculosis such as silicosis, where the risk has been shown Tuberculosis Control Program; the three decades of
to be 26 times higher to develop tuberculosis disease. It has National Tuberculosis Control Program and the current
also been found to be three times more in diabetics than phase of Revised National Tuberculosis Control Program
general population, 10 to 15 times higher in patients with (RNTCP).6
end-stage renal failure and those on hemodia-lysis and
5 times higher in male gastrectomy patients.2,3 Phase 1: The Early Days (1910-1960)
Tuberculosis case fatality is largely determined by site Before the discovery of anti-tuberculosis drugs,
and type of disease and by appropriate and timely tuberculosis treatment consisted of attempts to strengthen
intervention. Untreated sputum smear-positive the patients’ resistance to the disease. This included
tuberculosis leads to death in about 30 to 40% of cases altering local and general host factors through traditional
within one year, and cumulatively kills about 50 to 70% measures such as avoidance of physical and mental strain,
within 5 to 7 years. The extent to which tuberculosis prolonged bed rest, a rich diet, fresh air and good
continues to kill will largely depend on the extent to which ventilation, by establishment of centers of care —the TB
modern intervention strategies become available. Sanatoria. The ‘sanatorium movement’ which originated
TB in children plays a special role in the understanding in England, in the absence of chemotherapy, recommended
of the epidemiology of tuberculosis. Despite the widespread a balanced diet, fresh air and regulated exercise. The first
recognition that TB in children has a very limited impact on open air sanatorium for treatment and isolation of TB
the dynamics of the TB epidemic in a community, it is more patients in India was founded in 1906 in Tiluania, near
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Ajmer, followed by one in Almora two years later. The Adviser in TB as its head. TB was also given a prominent
United Mission Tuberculosis Sanatorium (UMTS) was place in the planning. Planning and execution of the anti-
built in 1912 at Madanapalle, South India. Dr Frimodt TB activities was greatly facilitated by this division.
Moller, its first Medical Superintendent played a large role Around the time India gained independence, effective
in India’s fight against TB through the training of TB drugs against TB began to be available (streptomycin 1944,
workers, conducting TB surveys (1939) and introduction para-aminosalicylic acid (PAS) 1946, thiacetazone 1950,
of BCG vaccination (1948). In addition, the first TB isoniazid 1952 and rifampicin 1966). The very notion that
dispensary was opened in Bombay in 1917, followed by there could be effective drugs against the tubercle bacilli
another in Madras (now Chennai). Soon anti-TB societies was so revolutionary that researchers began to experiment
were formed in Lucknow and Ajmer. on the effective dosages and combinations of drugs to be
The first concerted effort of TB control in the country as used. The issue of affordability was also considered.
a whole was through the organization of the King George Indian medical researches and health care providers had
V thanks-giving fund in 1929. The funds were utilized for pioneered several landmark clinical and community trials
preventive and educational activities, establishment of to test the efficacy of these drugs, as they became available,
clinics, training of health visitors and preparation of health using them and overcoming issues confronting them. These
education material. The provinces and states which studies revolutionized the management of TB all over the
received money started their TB associations. The TB world.
Association of India was established on the 23rd of The cost for large scale establishment for TB control
February 1939, with the objective of providing expert was not feasible at that point in time, hence attention was
advice on the development of standard methods to deal directed to prevention of TB by way of BCG vaccination,
with the disease, setting up model institutions for the which was felt to be feasible operationally and
training of TB workers, education of the public regarding economically. The International Union Against TB (IUAT)
preventive measures, and for organizing meetings and gave assistance to the BCG vaccination program in the
conferences for scientific discussions. Recognizing the country. TB demonstration and training centers were
enormity and complexity of the disease and to meet the developed for the training of the required personnel. The
needs of the large numbers of TB patients, the TB BCG campaign was introduced on a small scale in
association conceived the idea of domiciliary treatment as Madanapalli in 1948 and was extended on a mass scale
early as 1940. The association established the New Delhi in 1951. This was the first nationwide campaign against
TB clinic, now called the New Delhi TB Center, and the TB. A BCG Vaccine Production Center in Guindy, Madras
Lady Linlithgow Sanatoria in Kasauli. Research was also was set up in 1948 with the support of WHO and UNICEF.
taken up in collaboration with the Indian Research Fund
Association, now known as the Indian Council of Medical Mass BCG Campaign
Research (ICMR). India became a member of the
International Union Against Tuberculosis (IUAT) in 1929, As a part of the mass BCG campaign over 65 million children
forging international cooperation and partnerships. were vaccinated and 165 million tuberculin tests were
The Health Survey and Development committee headed administered. It was realized that TB is an equally important
by Sir Joseph Bhore, in its report in 1946 outlined a problem both in rural and urban areas. BCG campaign
conventional phased scheme for the management of TB. It helped in raising awareness of the disease as a public health
estimated that there were about 2.5 million patients in need problem not only in the minds of the medical community
of treatment and half a million deaths annually and only but also the message of health promotion and prevention of
disease to the remotest part of the country and its population.
6000 beds were available for the treatment of TB patients,
The revelation that the prevalence of TB infection was high
much below the estimated requirement of over 4,000 clinics
in most parts of the country, needed to be checked by
and 500,000 beds for TB control according to western
scientifically conducted surveys.
standards prevailing at that time. Realizing the disparity
between enormity of the TB problem and the available
resources for treatment, the committee recommended, in the National Sample Survey (1955-1958)
form of a regular program, implementation of the long A special committee of the Indian Council of Medical
accepted conventional measures by setting up TB clinics in Research (ICMR) was set up to address the issue of
the district and mobile TB clinics for rural areas. It placed obtaining detailed information of the prevalence of TB
organized domiciliary service at the forefront of the expeditiously and rationally. From 1955 to 1958, under
program. the auspices of the ICMR, a large-scale sample survey was
The key role of the government in initiating measures conducted in 6 zones of the country, covering both urban
to control the disease was strongly felt at this juncture. A and rural populations, to obtain as precise information as
TB division in the Directorate General of Health Services possible about the magnitude of TB problem in the country.
(DGHS) was established in New Delhi in 1946, with an The survey confirmed the impression of high prevalence
619
of TB morbidity in the rural areas that had earlier been respiratory diseases as well. In 1991, the LRS was
suggested by the large-scale tuberculin testing. It was upgraded into an autonomous institute and was taken
estimated that of the 8 million suffering from TB disease, over by the Ministry of Health and Family Welfare
about 80% were in the rural areas.7 With this revelation, (MoHFW), Government of India. Since the up-gradation,
the need for the development of a nationally applicable LRS has been serving as a specialized Institute of TB and
control program to tackle the problem of TB, was strongly Respiratory Diseases.
felt.
Establishment of Central TB Institutes Phase II: Development of the National

TB Control Program (1960-1990)
In 1956, the TB Chemotherapy Center (TCC), now known
as the Tuberculosis Research Center (TRC), was established The available tools for control of TB consisted of BCG
in Madras (now Chennai) under the auspices of the ICMR, vaccination for prevention, chest radiography and sputum
microscopy for case finding, and ambulatory domiciliary
with the assistance of the British Medical Research Council,
chemo-therapy for treatment. A systematic approach for
the World Health Organization (WHO) and the
formulation of sound policies for tackling the problem of
Government of India (GOI). The center was to provide
TB was urgently needed.
information on the application of mass domiciliary The development of the National TB Control Program
chemotherapy for the treatment of pulmonary TB. The TCC (NTCP) was based on a number of factors related to the
demonstrated that the time-honored virtues of sanatorium epidemiological, sociological, operational, technical and
treatment such as bed rest, well balanced diet and other administrative aspects related to TB control in India. NTI
sanatoria based measures, were unimportant provided conducted operational research studies keeping in mind
adequate chemotherapy was prescribed and fully taken. an average Indian district, its population and health facilities
Further, there was no evidence that close family contacts of available to enunciate suitable methods for the large-scale
patients treated at home incurred an increased risk of application of TB control measures. The recommendations
contracting TB. Therefore, it would be appropriate to treat that eventually emerged took the program out of the hands
infectious patients in their own homes. This finding of the specialists by integrating activities into the general
revolutionized TB treatment the world over. The discovery health services and orienting services towards the chest
of specific, potent, and readily available anti-TB drugs and symptomatics in the community who sought relief of their
the efficacy of domiciliary treatment as shown by the New suffering from the general health institutions.
Delhi TB Center and the TCC Chennai, completely changed The National Tuberculosis Institute at Bengaluru
the outlook for TB patients.8 The probability of formulating established that 95% of infectious TB patients are conscious
a comprehensive TB program to combat the disease on a of their symptoms and most report to the nearest health
community wide basis now seemed possible. institutions to seek medical aid within a few weeks of the
National Tuberculosis Institute (NTI) was established onset of their symptoms indicating that active case finding
in 1959 at Bangalore (now Bengaluru), by the GoI, with the is not necessary.9 The emphasis of the program diverted
active cooperation of the WHO, to evolve through research, attention away from the TB Sanatoria and rehabilitation
an operationally feasible, practicable TB program that could centers, towards the primary need of providing reliable
be applied to both rural and urban areas, economically and prompt diagnosis, domiciliary treatment and
affordable and which would promise a sizeable benefit to prevention services for the entire population. The NTP
the community in the foreseeable future. The NTI was was pilot tested in Anantapur district of Andhra Pradesh
expected to initiate research for the development of such a in 1961, the first model District TB Center (DTC). In the
program, create infrastructure, and train the large numbers DTC, the X-ray examination facilities were provided on
of key personnel from the various states of the country, who three days in a week and sputum examination daily.
in turn would implement and practice the methodologies Shortly after establishing the Anantapur DTC it became
developed in all parts of the country. evident that case finding could be done at any place
The Lala Ram Sarup Institute of Tuberculosis and without difficulty, but the major problem was that of
Respiratory Diseases (LRS) was established as a keeping the patients on continuous treatment.
Tuberculosis (TB) Hospital by the TB Association of India Considerable time and effort was devoted to solve the
(TAI) in 1952, with an aim to provide sanatorium treatment problem of default. The Anantapur DTC became
to TB patients. It provided both outdoor, as well as, indoor operational quickly and functioned well. Based on the
services to patients. The hospital continued to support the experiences of the pilot, the National TB Control Progam
National TB Control Program (NTP) of the country, whilst was launched in 1962, in a phased manner throughout
simultaneously began to deliver services for other the country. A DTC, which functioned as the nodal/
620
referral center for TB in the respective District was and problems faced in the implementation of the
established in nearly all the districts. program.
The program had two objectives:
1. The long-term objective of reducing tuberculosis in the Controlled Clinical Trial for Efficacy
community to a level that it ceases to be a public health of BCG Vaccine
problem, i.e.
a. One case infects less than one new person annually. BCG vaccination was the only available protective
b. The prevalence of infection in children less than 14 measure against TB. Different trials had not revealed
years of age is brought down to less than 1%, against credible proof of its efficacy. Serious concerns were raised
30 percent at the time. across the scientific community on the efficacy of BCG
and the benefits of large-scale use in the population. It
2. The short-term or operational objectives are:
was thought that it would be in the interest of the country
a. To detect maximum number of cases among the
to undertake a well designed trial to seek clear answers to
patients attending health care institutions with
the major issues confronting it. In 1968, a meticulously
symptoms of tuberculosis and treat them effectively.
designed clinical trial to test the efficacy of BCG vaccination
b. To immunize newborns and infants with BCG
was undertaken in Chingleput district of Tamil Nadu.10
vaccination.
After a period of twelve and a half years, it brought out a
c. To undertake the above objectives in an integrated
revolutionary report. It showed that BCG vaccination did
manner through the existing primary health care
not offer significant protection against TB of the lung. The
institutions in the country.
implication of this study was: Should BCG vaccination be
The national program policy as enunciated in the
given up in India? After an in-depth review, it was
introduction manual of DTP comprised:
concluded that though BCG may not protect against TB of
• Domiciliary treatment
lung which occurs mostly in adults, it could provide
• Use of a standard drug regimen of 12 to 18 months substantial protection against severe forms of TB among
duration children such as tubercular meningitis, miliary TB. The
• Treatment free of cost protective effect of BCG against these forms of TB was not
• Priority to newly diagnosed patients, over previously studied in Chingleput Trial. In India BCG vaccination
treated patients policy was revised and it was recommended to continue
• Treatment organization fully decentralized BCG vaccination in children preferably before the end of
• Efficient defaulter system/mostly self-administered the first year after birth as a part of the Expanded Program
regimen of Immunization (EPI) to give the benefit of protection
• Timely follow-up against the severe forms of childhood TB. BCG vaccination
• Chemoprophylaxis not recommended as it is policies in many other countries were also revised as a
impractical on mass basis. consequence of the Chingleput study findings.
The National TB Program was a 100% centrally
sponsored scheme and was fully integrated with the Era of Short-Course Chemotherapy
government health services of the country, thus extending
the scope of TB work to be available through its vast The conventional treatment regimens of 12 to 18 months
reaches. Over the years, nearly 600 TB clinics, 390 District were developed through chemotherapy trials, and were
TB Centers (DTC), 47,000 TB beds and 16 TB training and used in the program. However, as revealed by program
demonstration centers were established throughout the monitoring reports and observational studies conducted
country. By 1978, the NTP, which had the district level as in the field conditions, the problem of treatment compliance
its basic unit, had covered 81% (390) of the total districts in the program was a significant one. Only 66% of the TB
in the country. patients were taking drugs regularly with a defaulter rate
varying from 20 to 54%, with an overall average at 34%, as
Monitoring of the Program was observed at the Model DTC in Anantapur district of
Andhra Pradesh.
To evaluate the performance of the units of the DTPs in Chemotherapy of TB underwent revolutionary
an ongoing manner and take corrective action simul- changes in the seventies owing to the availability of two
taneously, and ultimately to improve the program well-tolerated and highly effective drugs — rifampicin and
efficiency in the long run, regular monitoring was deemed pyrazinamide. These drugs allowed short-course chemo-
essential. Till 1978, monitoring of the program was done therapy (SCC) and made it possible to simplify treatment
by northern and southern regional centers on a regional and reduce its duration. With the success of the 6 months
basis and from then by NTI only. NTI from time to time short-course chemotherapy (SCC) regimens in clinical
gave vital inputs and directions to the program based on trials, it was possible to reduce the treatment duration from
available technical, operational and managerial issues 12 down to 6 months. With the introduction of SCC
621
regimens, a new era had started in the fight against TB. In A major organizational change in RNTCP is the
1983, the TRC, Madras, pilot tested the SCC regimens in creation of the subdistrict level. The RNTCP strengthens
18 districts of the country to assess the feasibility of SCC the existing NTP infrastructure by creating a subdistrict
implementation on a larger scale. Subsequently in 1986, level supervisory team (known as the TB Unit), consisting
following successful SCC field trials by TRC and NTI, the of a fulltime treatment supervisor (Senior Treatment
GoI agreed to the introduction of SCC and SCC coverage Supervisor, STS) and a laboratory supervisor (Senior TB
was scaled-up to cover 252 districts. Laboratory Supervisor, STLS). These are new posts. In
However, this costly intervention alone could not addition, a medical officer from the general health system
improve the ground reality. Treatment compliance, even
serves as Medical Officer—TB Control at subdistrict level
with the introduction of SCC regimens, showed only a
who is specifically allocated TB control duties in addition
marginal improvement. Between 1975 and 1992, the
to his other duties. These 3 individuals constitute the
program was evaluated by three independent agencies:
the ICMR in 1975; the Institute of Communication, management unit, which is responsible for overseeing
Operations Research and Community Involvement operations in approximately a 5 lakh population
(ICORCI) in 1988; and by GOI, WHO, and SIDA in 1992. including, on an average, 5 designated microscopy centers.
These evaluations documented the already widely known To further decentralize the diagnostic and treatment
facts of the wide gap between expectations and actual services, RNTCP Designated Microscopy Centers (DMCs)
achievements of the program. are established for every 1,00,000 population. The norms
for establishments of TUs and DMCs are relaxed to 250,000
Phase III: The Revised National TB Control Program and 50,000 population respectively in hilly/difficult areas
(1992 onwards) and for tribal areas. In addition, a vast network of DOT
centers (treatment centers), all with a trained DOT provider,
Despite the NTP having been in existence since 1962, no has been established in all RNTCP areas so that patients
appreciable change in the epidemiological situation in the can have easy access to their TB treatment. At each
country had been observed. The HIV-AIDS epidemic and
microscopy center, a state-of-the-art binocular microscope,
the spread of multidrug resistance TB were threatening to
good quality reagents and new recording and reporting
further worsen the situation. In view of this, in 1992 the
proforma are available. More importantly, intensive
GOI, with WHO and SIDA, reviewed the TB situation and
modular training, supervision, and cross-checking of the
the performance of the NTP. The observations revealed
that the NTP, though technically sound, suffered from work of the laboratory technician should ensure that
managerial weaknesses, inadequate funding, an over- reliable results are obtained. Overall it is the State, District
reliance on X-ray for diagnosis, had frequent interrupted and Subdistrict staff responsible for organizing,
supplies of drugs, and low rates of treatment completion implementing and supervising RNTCP, and the success
and lack of supervision. In 1993, to rectify these lacunae, of the program largely depends on them. RNTCP shifts
the government decided to give a new thrust to TB control the responsibility of cure from the patient to the health
activities by revitalizing the NTP, with assistance from system.
the international agencies. The goal of RNTCP is to decrease mortality and
In the light of the recommendations and concerns morbidity due to TB and cut transmission of infection until
expressed by the Central Health Council, steps were TB ceases to be a major public health problem. The goal of
taken since 1993 to implement the Revised National TB RNTCP is achieved through the following objectives.
Control Program (RNTCP) in selected areas with World • To achieve and maintain a cure rate of at least 85%
Bank assistance. The Revised National TB Control among newly detected infectious (new sputum smear-
Program (RNTCP) thus formulated, adopted the positive) cases, and
internationally recommended Directly Observed • To achieve and maintain detection of at least 70% of
Treatment Short-course (DOTS) strategy, as the most such cases in the population.
systematic and cost effective approach to revitalize the Clearly, both good outcomes and high case detection
TB control program in India. rates are essential. But it was felt that it is essential that the
The RNTCP builds on the very substantial strengths system is geared up to reliably cure patients, before any
and accomplishments of the National Tuberculosis attempts are made at expanding case detection. In fact,
Program (NTP). The NTP created an extensive infra- experience clearly shows that reliably curing patients
structure for tuberculosis control, with a network of 446 results in a “recruitment effect” — wherever effective
District TB Centers, 330 TB Clinics and more than 47,600 services are offered, case detection rates steadily increase.
TB beds. The NTP also raised awareness of TB and TB Cured patients act as one of the best motivators promoting
treatment facilities, and has succeeded in placing more case detection and patient adherence to treatment. ‘Every
than 13 lakh patients on treatment on a yearly basis. cured patient is a pamphlet’.
622
The only effective means by which 85% cure rate or using directly observed treatment, and achieve high cure
more has been shown to be achievable on a program basis rates.
is by application of the DOTS strategy. It should be noted
that the principles of diagnosis of TB by sputum Systematic Monitoring and Accountability
microscopy, ambulatory treatment, and direct observation
of treatment were first established in India at the RNTCP has effectively decentralized supervision via the
Tuberculosis Research Center, Chennai and the National subdistrict TB Units, with in-built systems for monitoring
TB Institute, Bengaluru, in the 1950s and 1960s. and evaluation. There are two means of monitoring the
DOTS is a systematic strategy which has 5 components. These success of treatment. First, sputum is examined during the
are as follows: course of treatment to monitor the progress and cure of
• Political and administrative commitment patients. Second, a revised recording and reporting system
• Good quality diagnosis, primarily by sputum-smear rigorously monitors and evaluates the outcome of every
microscopy patient treated at the different levels of the health system,
• Uninterrupted supply of good quality drugs and if any area is not achieving 90% sputum conversion
• Directly observed treatment (DOT) rate at the end of 3 months and 85% cure rate, supervision
• Systematic monitoring and accountability. is intensified. For effective program implementation,
having well-trained and motivated staff is essential.
Political and Administrative Commitment
STOP TB Strategy
Since tuberculosis can be cured and the epidemic reversed,
it warrants the topmost priority, which has been accorded Global TB control has made major progress in the past
by the Government of India. This priority must be decade. The widespread implementation of the DOTS
continued and expanded at state, district, and local levels. strategy has proved to be an effective tool in controlling TB
on a mass scale and is being practiced in over 200 countries.
Maintaining the current status, the prime task for the next
Good Quality Diagnosis
decade is to achieve the Millennium Development Goals
Case detection is done primarily by sputum-microscopy (MDGs) and related STOP TB Partnership targets for TB
among chest symptomatic patients attending health control to combat HIV/AIDS, malaria and other diseases,
facilities. This policy allows effective diagnosis in the including tuberculosis. The target under MDG for
periphery and appropriate prioritization of efforts. tuberculosis is to halt and begin reversal of incidence of
tuberculosis, malaria and other major diseases by 2015.
Good Quality Drugs The indicators are to reduce the prevalence and death rates
An uninterrupted supply of good quality anti-TB drugs by 50% between 1990 and 2015.
must be available. One of the unique innovations under Meeting these targets requires a coherent control strategy.
RNTCP has been the development of Patient-Wise Boxes, The strategy should enable achievements to be sustained,
earmarked for every patient registered, which contain the effectively address the remaining constraints and
full course of treatment for one individual patient, ensuring challenges, and emphasizes the efforts to strengthen health
that treatment of that patient cannot be interrupted due to systems, alleviate poverty and advance human rights.
a lack of drugs. Hence, in RNTCP the treatment never fails The new WHO STOP TB Strategy released in 2006 lists
on account of nonavailability of medicines. six principal components to realize the global TB-related
MDGs by 2015. They are:
Short-Course Chemotherapy given • Pursuing high quality DOTS expansion and enhance-
in a Program of Direct Observation ment;
• Addressing TB/HIV, MDR-TB and other challenges;
RNTCP uses the best anti-TB medications available but • Contributing to health system strengthening;
unless patients adhere to treatment, it will fail. This is • Engaging all care providers;
why the heart of the DOTS program is “directly observed • Empowering patients and communities; and
treatment (DOT)” in which a health worker or another • Enabling and promoting research.
trained person who is not a family member, watches the The RNTCP is implementing all the components of the
patient swallow the anti-TB medicines in his/her presence. STOP TB Strategy.
However, directly observed treatment (DOT) is not just
supervised swallowing but a service to the patient. It helps Achievements of RNTCP
to develop a human bond between the patients and the
treatment observer, which increases the probability of the Starting in October 1993, the RNTCP was implemented
patient completing treatment. With short-course in a population of 2.35 million in 5 sites in different states
chemotherapy it is easier to prevent drug-resistance by (Delhi, Kerala, West Bengal, Maharashtra, and Gujarat).
623
The program was expanded to a population of 13.85 functions efficiently. Modular training has been used for all
million in 1995 and 20 million in 1996. Having proved staff from medical officers to health workers. Multipurpose
both its technical and operational feasibility, a soft loan workers are responsible for treatment observation; where
was negotiated with the World Bank in December 1996 they are not available, treatment observation is done by
and the credit agreement signed in May 1997. With this community volunteers including Anganwadi workers,
loan, it was envisaged that RNTCP would be traditional dais, and community and religious leaders.
implemented in a select number of districts in a phased Observation by a family member is not acceptable in the
manner while other districts would be strengthened as a program. In some larger cities with limited health
transitional step for introduction of the revised strategy infrastructure, the RNTCP has funded specialized, full-time
at a later stage staff for microscopy and for treatment observation.
Full nation-wide coverage was achieved in March
2006 covering over a billion populations (1114 million) Epidemiology of TB in India and
in 632 districts/reporting units. RNTCP is considered The Impact of RNTCP
the fastest expanding TB control program in the history
of DOTS. Since its inception, the program has initiated Though India is the second-most populous country in the
nearly 11 million patients on treatment by the end of 2009, world,11 India has more new TB cases annually than any
thus saving more than 1.9 million additional lives. other country. In 2007, out of the estimated global annual
Treatment success rates have tripled from 25% in the pre- incidence of 9.27 million TB cases, 1.96 million were
RNTCP era to 86% presently. TB death rates have been estimated to have occurred in India, of whom 0.87 million
cut 7-fold from 29% in the pre-RNTCP era to 4% presently. were infectious cases (Table 41.1).
The program has consistently maintained the treatment
success rate > 85% and new sputum positive (NSP) case Incidence of Tuberculosis Disease
detection rate close to the global target of 70%. From 2007 Measuring the incidence of tuberculosis disease is
onwards, RNTCP has also achieved the NSP case challenging. Long term cohort studies for direct
detection rate of more than 70% in line with the global measurement of incidence pose enormous operational
targets for TB control. In 2005 alone, 1.29 million TB difficulties, are prohibitively expensive, and have an
patients were initiated on treatment. In 2006, 1.39 million inherent risk of bias, largely due to missed or
and in 2007, 1.48 million patients have been enrolled for misclassification of cases. Measuring the impact of the
treatment. In 2008 over 1.51 million patients have been tuberculosis control program through routine surveillance
initiated on treatment. India has contributed to activities requires a consistently effective surveillance system
approximately 24% of the total global new cases detection that captures the great majority of incident cases over a
during the year 2007 as per the WHO Global Report 2009. period of years, as well as stability in underlying population
All states are currently implementing the Supervision characteristics. Estimation of disease incidence from
and Monitoring strategy — detailing guidelines, tools prevalence requires clear understanding of the duration of
and indicators for monitoring the performance from the disease. Estimates of disease incidence by any means may
be confounded by migration, urbanization, and changes in
PHI level to the national level. Quality assured diagnostic
the prevalence of comorbidities associated TB (e.g. HIV
facilities are available through a network more than
infection, diabetes, smoking, malnutrition, etc.)
12,500 designated microscopy centers across the country.
From 1960-1986, a number of community surveys and
To ensure quality, external quality assurance of sputum
active surveillance activities in mainly South India were
microscopy is being routinely conducted throughout the
conducted. Results from these surveys have been
country. This includes on-site evaluation, panel testing
summarized in a recent review article.13 These surveys
and blinded cross-checking. To improve access to tribal have suggested that the annual incidence of culture
and other marginalized groups the program has positive pulmonary tuberculosis ranged from 800–2500
developed a Tribal action plan which is being per 100,000 population.
implemented with the provision of additional TB Units Several tuberculin surveys were carried out post
and DMCs in tribal/difficult areas, additional staff, independence, estimating the Annual Risk of Tuberculosis
compensation for transportation of patient and attendant Infection (ARTI) among children <10 years as 1 to 2% per
in tribal areas and higher rate of salary to contractual year.14,15 However, many of these surveys were non-
staff, etc. standardized and carried out in limited areas mainly in
Policy direction, supervision, drugs and microscopes the southern part of India.
are provided by the central government. The funds are A nation-wide standardized tuberculin survey was
released to hire contractual staff, conduct training, POL, carried out during the period 2000-2003.16-20 For the purpose
purchase of vehicles and other items essential for performing of the survey, the country was stratified into 4 zones (north,
624
Table 41.1: Estimated burden of tuberculosis in India

Number (Millions) Rate Per 100 000Persons
(95% CI) (95% CI)
Incidence (2007 WHO estimate)1
All cases 1.962 168
AFB smear-positive 0.867 75
Period Prevalence (2000 GoI estimate)12
AFB positive 1.7 (1.3–2.1) 165 (126–204) †
Bacillary* 3.8 (2.8–4.7) 369 (272–457) †
Prevalence, all cases (2000 WHO estimate) 1 4.468 443

Prevalence, all cases (2007 WHO estimate) 1 3.304 283
* Defined as a person with at least one AFB smear positive by sputum microscopy, or at least one sputum culture positive
for M. tuberculosis
† Prevalence rate calculated from estimated number of persons with disease in 2000, divided by 2000 population estimate
Fig. 41.2: Zone-wise selection of districts — National ARTI Survey 2000-2003
west, south and east). An identical methodology of East zone part of the national survey, in which a site
sampling and tuberculin testing was used throughout the from Orissa was included. However, the Orissa state-
country. Figure 41.2 presents the 4 zones for the ARTI wide ARTI point estimate is closer to those of the Northern
surveys, and also the sampled districts. zone than to those of the Eastern zone.
Table 41.2 details the major findings, and shows Similarly a statewide survey was carried out in Kerala
interzonal and also rural/urban differences in the rates of in the year 2006–2007. The ARTI in this survey was not
transmission of infection. able to be calculated with confidence, due to the fewer
State-specific ARTI estimates are available for 2 states than expected number of infections detected. By any
in the country namely, Orissa and Kerala. The estimate measure, the ARTI for Kerala would be less than 1% per
for Orissa overlapped with the confidence limits of the annum.21
625
Table 41.2: Results of National ARTI Survey 2000-2003 for the nation as a whole was accepted then. The findings
Zone ARTI (95 % CI) of various studies, have been summarized by Chadha.14
Rural Urban Total Williams et al have suggested that the prevalence rate of
16 TB fell by 4 to 6% in India between 1990 and 2000.25
North 1.6 (1.3–2.0) 2.6 (2.3–2.9) 1.9 (1.3–2.5)
Little evidence, however, is available to inform this
East 17 1.2 (1.0–1.5) 1.7 (1.1–2.3) 1.3 (1.0–1.6) assertion. Studies in Bengaluru, 26 Tumkur, 14 and
West 18 1.5 (1.1–1.8) 2.4 (1.6–3.4) 1.6 (1.0–2.2) Chingleput27 districts in South India from the pre-RNTCP
19
South 0.8 (0.4–1.2) 1.6 (0.9–2.2) 1.0 (0.7–1.4) era showed modest to no evidence of change in the
Total 20 1.3 (1.0–1.5) 2.2 (1.8–2.6) 1.5 (1.4–1.6) prevalence of tuberculosis. One study carried out in the
BCG trial area in Thiruvallavur district, Tamil Nadu,
showed that in pre-RNTCP era, the prevalence of culture
Table 41.3: Estimated zonal ARTI and incidence of new positive tuberculosis declined by 1.8% per annum, and
smear-positive TB, 2000-2003
smear-positive tuberculosis declined by 2.1% per
Zone ARTI (95% CI) Estimated incidence new annum.28
smear-positive The prevalence of tuberculosis in India has been
TB per 100 000 (95% CI)
estimated from available ARTI data using the observed
North 1.9 (1.3–2.5) 95 (65–125) relationship between ARTI and prevalence of bacillary
East 1.3 (1.0–1.6) 65 (50–80) tuberculosis from Thiruvallavur district.12 Prevalence
West 1.6 (1.0–2.2) 80 (50–110) estimates from different sources are shown in Table 41.4.
South 1.0 (0.7–1.4) 50 (35–70) It should be noted that the Government of India
Total 1.5 (1.4–1.6) 75 (70–80)
methodology differs from that used by WHO; WHO has
estimated a prevalence of 3304 million persons for all forms
The use of the ARTI to estimate TB incidence is of tuberculosis for the year 2007.1
controversial. The frequently applied “Styblo conversion”
Mortality and Premature Death
estimate of 50 incident cases of new smear-positive
pulmonary tuberculosis per 1% annual risk of Due to Tuberculosis
tuberculosis infection22 has been criticized as no longer Perhaps more than 80% of the burden of tuberculosis
valid in the presence of a modern tuberculosis program.23 is due to premature death, as measured in terms of
This conversion, however, was recently validated in the disability-adjusted life years (DALYs) lost. 29 TB
Indian setting in a community survey in South India.24 mortality is defined by WHO as the number of TB cases
Hence using the Styblo conversion, these new smear- dying during the treatment, regardless of the cause of
positive zonal incidence estimates are used by RNTCP to their death. Case fatality rates from India prior to
calculate state-level case detection of new smear-positive RNTCP implementation were uniformly high; however,
tuberculosis for the West and North Zones (Table 41.3). prior to RNTCP, tuberculosis mortality data were not
For the South and East Zones, RNTCP has chosen for collected or analyzed systematically. Therefore, those
operational reasons to use the national ARTI estimate of figures and comparisons to RNTCP are somewhat
1.5% to calculate state-level case detection, despite the unreliable. Data from specific surveys, however,
lower incidence estimation from the ARTI surveys. suggest that case fatality rates prior to RNTCP were
Two exceptions to be noted are Orissa and Kerala. For generally greater than 20%.30
Orissa the state-specific ARTI survey estimate was 1.7%, Field surveys in the states of Andhra Pradesh and Orissa
the estimated incidence used for new smear-positive were undertaken to estimate TB specific mortality rates by
pulmonary TB case detection calculation for Orissa is 85 Tuberculosis Research Center, Chennai. Unfortunately, the
per 100,000 persons. Similarly, given the results of the results of these surveys were inconclusive due to the
Kerala state-specific ARTI survey, from the year 2007 the operational limitations of the verbal autopsy methodology
to study TB specific mortality.
ARTI estimates for the state was revised to 1% (from the
In the RNTCP era, case fatality has remained below
previously applied south-zone average of 1.5%), and the
~5% for new cases. WHO has estimated that in 2007, in
estimated incidence for NSP case detection calculation is
India 331,000 persons died of tuberculosis (rate 28 per
50 per 100,000 persons.
100,000 persons), substantially lower than the 2000
estimate of 381,000 persons (rate 38 per 100,000
Prevalence of Tuberculosis Disease persons).1
The first estimates of tuberculosis prevalence in India Lessons from the Model DOTS Project (MDP) Area
became available in the 1950s, and the figure of 4/1000 on Changes in ARTI and Prevalence of Disease
626
Table 41.4: Results of consecutive ARTI and prevalence surveys in MDP

project area, Tiruvallur District, with RNTCP implementation31,32
1999–2001 2001–2003 2004–2006 % Annual Decrease

Prevalence of Infection (95% CI) 7.8 (7.1–8.6) 6.9 (6.2–7.6) 6.0 (5.2–6.7) 5.8%
Annual Risk of TB infection (95% CI) 1.6 (1.5–1.8) 1.4 (1.3–1.6) 1.2 (1.1–1.4) 5.0%
Prevalence of TB disease
Culture-positive TB (per 100 000 pop) 609 451 311 12.6%
Smear-positive TB (per 100 000 pop) 326 257 169 12.3%
There is some evidence on the effect of RNTCP from the TB-related Millennium Development Goal
collaborative TRC/WHO MDP project area in Tiruvallur
district, Tamil Nadu. TB epidemiology in Tiruvallurhas Goal 6: To combat HIV/AIDS, malaria and other diseases.
Target 8: To have halted by 2015 and begun to reverse the
been closely evaluated by epidemiologists from the
incidence of malaria and other major diseases, including
Tuberculosis Research Centre, Chennai, for more than 30 tuberculosis.
years. RNTCP was implemented in Tiruvallur district in Indicators for Target 8 to be used to evaluate the implemen-
1999. Three sequential ARTI surveys have suggested that tation and impact of TB control:
the incidence of TB in this area has significantly decreased Indicator 23: Between 1990 and 2015, to halve the prevalence
(Table 41.4).31 Incidence again has been estimated for and death rates associated with tuberculosis; and
Indicator 24: By 2005, to detect 70% of new smear-positive TB
consistency using the Styblo conversion, although local
cases arising annually, and to successfully treat 85% of these
estimates from this area are available.22,24 The annual cases
rate of decline in the prevalence of infection in children
< 10 years old has been estimated at 5.8%, from the first With respect to the progress towards indicator 23, as
survey to the third survey. per the WHO estimates in the year 1990, the prevalence of
The consecutive ARTI surveys provided useful TB in India was 586 per 100,000 populations and the
evidence of the potential effectiveness of RNTCP in mortality due to TB was 42 per 100,000 populations. In
reducing transmission and infection rates. Additional comparison, in the year 2007, the prevalence of TB in India
supportive evidence is available from sequential disease was estimated by WHO to be 283 per 100,000 populations,
prevalence surveys in the same area (1999–2001 and and the mortality due to TB is 28 per 100,000 populations.1
2004–2006), demonstrating a change in prevalence of The estimates show that India has progressed in reducing
smear-positive tuberculosis from 326 to 169 per 100,000 the prevalence rate by 51.8% and mortality rate by 33.3%
persons.33 This corresponds to an annual decline of (Fig. 41.3).
12.3%. The rate of decline observed in 5 years of RNTCP Researchers have used modeling to demonstrate that
implementation was more than double the 4.3% rate of achieving the TB-mortality MDG target will be difficult
decline observed in the same area from 1984 to 1999, without major efforts to reduce mortality among HIV-
despite the availability of standard short-course chemo- infected TB patients.25 This interpretation has been
supported by observations from program data, where
therapy throughout.
higher case fatality rates have been observed from many
Although findings from the MDP are not necessarily
areas believed to have relatively high community HIV
applicable to the entire country, this evidence stands as
seroprevalence. Achievement of the mortality target then
proof of principle of the effectiveness of the RNTCP DOTS
may require rapid scale-up of access to interventions to
program on significantly decreasing the burden of TB in
reduce mortality in HIV-infected TB patients, particularly
the community.
antiretroviral treatment.
Progress Towards Millennium Development Goals As far as the progress towards indicator 24 is
(MDGs) with Respect to Reduction in Prevalence and concerned, the country has achieved the targets on case
Mortality Rate detection and treatment outcomes, in the year 2007 and
The indicator 23 of the MDGs mentions that between 2008 (after whole country coverage). More information
1990 and 2015 to halve prevalence of TB disease and on this indicator is detailed in the section on notification
deaths due to TB. rates.
627
Fig. 41.3: Progress towards MDG indicator 23
TB in Children and Management suggestive history of contact with a smear-positive case

of Childhood TB under RNTCP and tuberculin test. There were also problems related to
supply of drugs and pediatric formulations. Hence, the
Tuberculosis is prevalent worldwide and contagious, and
everyone is at risk of getting infected including children. main strategy was preventive, by routine vaccination with
Tuberculosis ranks among the ten major causes of mortality BCG; screening of children with suggestive symptoms
among children. The actual global disease burden of by X-ray and tuberculin, appropriate management of
childhood TB is not known, but it has been assumed that diagnosed patients; and isoniazid chemoprophylaxis
10% of the actual total TB caseload is found amongst among contacts of sputum-positive cases.
children.34 In India, the prevalence of primary tubercular Hence for RNTCP, there were the issues of under-
infection in pediatric population is alarming. The annual diagnosis andunder registration of pediatric TB cases in
risk of tubercular infection is 1.5% in the country and 40% the program. To seek consensus on improved case detection
of children by 16 years have acquired infection. Nearly and improved treatment outcomes for all diagnosed
10% of infected eventually develop the disease (5% of these pediatric TB cases, a workshop on the Formulation of
children may be expected to develop TB in the first two guidelines for diagnosis and treatment of pediatric TB cases
years of life); this large pool of infected people, means that under RNTCP was held in New Delhi on 6th and 7th
TB will continue to be a major problem in the foreseeable August 2003. In attendance were National and Inter-
future. national Pediatricians, TB experts and TB Control Program
Good data on the burden of all forms of TB amongst Managers. The consensus on diagnosis, treatment,
children in India are not available. Most surveys conducted follow-up and preventive therapy is summarized below.
have focused on pulmonary TB and no significant
population based studies on extrapulmonary TB are
Diagnosis
available. Pulmonary TB is primarily an adult disease and
it has been estimated that the 0 to 19 years old population The difficulty in obtaining sputum from children,
constitute only 7% of the total prevalent cases.35 The nonspecific radiographic findings and the paucibacillary
notification of childhood new tuberculosis cases under nature of the disease often makes the diagnosis of
the RNTCP has been approximately 6 to 7% of the total tuberculosis (TB) in children difficult. Clinicians should
new cases in the country. suspect pulmonary TB in children presenting with:
• Fever and/or cough for more than 3 weeks, with or
Prevention, Diagnosis and Management without;
of Pediatric Tuberculosis Under RNTCP • Loss of weight/no weight gain; and
In the initial phase of the NTP the major emphasis was • History of contact with a suspected or diag-nosed case
on adults, and very few guidelines are mentioned despite of active TB disease within the last 2 years.
the fact that the risk of infection and progression to Evaluations of some of the many available scoring
disease is high in children and the morbidity and systems have shown to have low specificity, which may
mortality due to severe forms of miliary TB and TB lead to over-diagnosis and unnecessary treatment of non-
meningitis is well known. Routine diagnostic tests like TB patients. Currently, it is not recommended to use such
sputum and X-ray are less sensitive and had to be relied scoring systems for the diagnosis of patients. Further
on combination of history, symptoms and signs and screening of TB suspects should be done by:
628
Bacteriological Testing Pulmonary TB, Smear-negative

Sputum examination should be done wherever possible. • TB in a patient with symptoms suggestive of TB with
Gastric lavage may be used when sputum is not available. at least three sputum-smear examinations negative
Multiple samples should be tested by both smear and for AFB and radiographic abnormalities consistent
culture, if facilities are available. with active pulmonary TB as determined by the
treating Medical Officer followed by a decision to treat
Tuberculin Test the patient with a full course of anti-tuberculosis
treatment
Mantoux test using 1 TU PPD RT 23 Tween 80 intradermal Or
should be performed in Pediatric TB suspects. The test • Diagnosis based on positive culture but negative AFB
will be read as positive if there is more than 10 mm sputum-smear examinations.
induration at 48 to 72 hours. Testing with BCG is not
recommended.
Extrapulmonary TB
Radiology Extrapulmonary tuberculosis TB of any organ other than
the lungs, such as the pleura (TB pleurisy), lymph nodes,
Chest X-ray should be taken in upright position PA view. intestines, genitourinary tract, skin, joints and bones,
Radiological lesions are not confirmatory for tuberculosis, meninges of the brain, etc. Diagnosis should be based on
as there are no pathognomonic radiological signs of TB. culture-positive specimen from the extrapulmonary site,
However, X-ray findings suggestive of TB include histological, radiological, or strong clinical evidence
mediastinal/hilar lymphadenitis with or without consistent with active extrapulmonary TB followed by
parenchymal lesions, pleural effusion, miliary and decision of the treating MO to treat with a full course of
fibrocaseous pictures. Persistent pneumonia beyond 4 anti, TB therapy. Pleurisy is classified as extrapulmonary
weeks in a symptomatic child in spite of antibiotic therapy, TB. A patient diagnosed with both sputum smear-positive
suggests probable TB. pulmonary and extrapulmonary TB should be labeled as
Diagnosis of TB in children should be made by a pulmonary TB.
Medical Officer. The existing RNTCP case definitions will
be used for all cases diagnosed. Where diagnostic Types of Cases
difficulties are faced, referral of the child should be made
to a pediatrician for further management. A high index of New: A TB patient who has never had treatment for TB or
suspicion must be maintained when the child is aged has taken anti-tuberculosis drugs for less than 1 month. A
< 1 year, there is a recent history of measles/whooping new case can be either sputum-positive, or sputum-negative
cough, immunocompromised state and steroid therapy. and extrapulmonary.
Significant superficial lymphadenopathy should be Previously treated: A TB patient who gives history of
looked for as it is present in > 40 to 50% of patients. treatment for TB or has taken anti-tuberculosis drugs for at
Children showing neurological symptoms like irritability, least 1 month from any source. A ‘previously treated’ TB patient
refusal to feed, headache, vomiting or altered sensorium may be can be either a relapse, treatment after default, failure or
suspected to have TBM. others.
The existing RNTCP case definitions given are as Relapse: A TB patient who had been declared cured or
follows: whose treatment had been completed by a physician, but
who reports back to the health service and is now found to
Disease Classification be sputum smear-positive.
Treatment after default: A TB patient who received anti-
Pulmonary TB, Smear-positive tuberculosis treatment for at least 1 month from any source
and returns to treatment after having defaulted, i.e. not
• TB in a patient with at least two initial sputum-smear
examinations (direct smear microscopy) positive for AFB taken anti-tuberculosis drugs consecutively for at least 2
Or months, and is found to be sputum smear-positive.
• TB in a patient with one sputum-smear examination Failure: Any TB patient who is smear-positive at 5 months
positive for AFB and radiographic abnormalities after starting treatment. Failure also includes a patient who
consistent with active pulmonary TB, as determined was treated with the Category II regimen but who becomes
by the treating medical officer smear-positive during treatment.
Or Others: TB patients who do not fit into the above
• TB in a patient with one sputum-smear specimen mentioned types. Reasons for putting a patient in this type
positive for AFB and culture-positive for M. tuberculosis. should be specified.
629
Transferred in: A TB patient who has been received for To assist in calculating required dosages and
treatment into a TB Unit after starting treatment in another administration of anti-TB drugs for children, the
unit where she/he had been registered. medication is made available in the form of combi-packs
in patient-wise boxes, linked to the child’s weight (Table
Treatment of Pediatric TB 41.6).
DOTS is the recommended strategy for treatment of TB

Directly Observed Treatment in Children
and all pediatric TB patients should be registered under
RNTCP. Recommended treatment regimens are given in Administration of DOTS to a child at the center means the
Table 41.5. Intermittent short-course chemotherapy given incumbent will have dependability upon either parent,
under direct observation, as advocated in the RNTCP, and could miss the school due to clash with center-timing.
should be used in children. In addition, a female child might be held from seeking
Table 41.5 indicates the treatment groups, type of treatment at a public center owing to the social stigma of
patients and regimens prescribed. disease. However, utilization of service provider’s has been
In patients with TBM on category I treatment, the four shown to result in a successful DOTS execution in TB
drugs used during the intensive phase should be HRZS patients unable to accept the treatment due to a specific
(instead of HRZE). Continuation phase of treatment in reason like inconvenient center-timing mingling with job,
TBM and spinal TB with neurological complications study and household work, unavailability of nearby DOTS
should be given for 6 to 7 months, extending the total center, social stigma or physical disability. With training
duration of treatment to 8 to 9 months. Steroids should be and supervision, the ‘mother’ could serve as a DOTS
used initially in hospitalized cases of TBM and TB provider just like the other community members such as
pericarditis and reduced gradually over 6 to 8 weeks. In neighbors, family friends or relatives.
all instances before starting a child on category II treatment,
she/he should be examined by a pediatrician or TB expert
wherever available. As recommended by WHO and in view Monitoring
of the growing evidence that the use of ethambutol in young Pediatric-focused monitoring may preferably be an integral
children is safe. Ethambutol is to be used as per RNTCP part of the program. Wherever possible, follow-up sputum
regimen for all age groups. examination is to be performed with the same frequency
Table 41.5: Treatment groups, type of patients and regimen prescribed
Treatment groups Type of patient Regimen1

Intensive Phase (IP) Continuation Phase (CP)
New Sputum smear-positive
Sputum smear-negative 2H3R3Z3E3 4H3R3
Extrapulmonary
Others Previously
Treated Smear-positive relapse
Smear-positive failure 2H3R3Z3E3S3/
Smear-positive treatment after default 1H3R3Z3E3 5H3R3E3
Others2
1
Prefix indicates month and subscript indicates thrice weekly.
Table 41.6: Suggested pediatric dosages for intermittent therapy
Drug Dosage Weight range in kilograms*

(mg/kg) 6-10 11-17 18-25 26-30
Isoniazid 10 75 150 225 300
Rifampicin 10 75 150 225 300
Pyrazinamide 30-35 250 500 750 1250
Ethambutol 30 200 400 600 1000
Streptomycin 15 – – – –
* Under RNTCP drugs are supplied in patient-wise boxes for children in different weight bands.
630
Fig. 41.4: Algorithm for clinical monitoring of childhood TB patients on treatment
as in adults. Clinical or symptomatic improvement is to be regimen but who becomes smear-positive during
assessed at the end of the intensive phase of treatment and treatment.
at the end of treatment. Improve-ment should be judged by • Defaulted: A patient who has not taken anti-TB drugs
absence of fever or cough, a decrease in the size of lymph for 2 months or more consecutively after starting
node(s) and weight gain. Radiological improvement is to treatment.
be assessed by chest X-ray examination in all smear- • Transferred out: A patient who has been transferred
negative pulmonary TB cases at the end of treatment (Fig. to another Tuberculosis Unit/District and his/her
41.4). treatment outcome is not known.
Standard treatment outcomes are given for all patients • Switched over to MDR-TB Treatment: A patient who
registered for treatment under RNTCP. The definitions of has been diagnosed as having MDR-TB by an RNTCP
these standard treatment outcomes are as follows: accredited laboratory, prior to being declared as
• Cured: Initially sputum smear-positive patient who “Failure”, and is placed on the RNTCP MDR-TB
has completed treatment and had negative sputum treatment regimen is said to have switched over to
smears, on two occasions, one of which was at the end MDR-TB treatment.
of treatment. A patient will have only one outcome. The outcome
• Treatment completed: (1) Sputum smear-positive which occurs first is considered and recorded in treatment
patient who has completed treatment, with negative card and subsequently in the TB register.
smears at the end of the intensive phase but none at the
end of treatment. (2) Sputum smear-negative TB patient Chemoprophylaxis
who has received a full course of treatment and has not Chemoprophylaxis is an effective and safe form of
become smear-positive during or at the end of treatment. prevention of tuberculosis in childhood because it aims at
(2) Extrapulmonary TB patient who has received a full the avoidance of development of TB infection into a disease
course of treatment and has not become smear-positive state. However, the correct dose of isoniazid is still
during or at the end of treatment. controversial (5 mg/kg vs. 10 mg/kg). Recent studies36-39
• Death: Patient who died during the course of treatment have shown that lower dose given for 6 months is effective
regardless of cause. and also has fewer side effects. It has been, therefore,
• Failure: Any TB patient who is smear-positive at 5 accepted under the guidelines. Developed countries have
months or more after starting treatment. Failure also already changed the nomenclature for screening to
includes a patient who was treated with Category III targeted tuberculin testing and from preventive therapy to
631
treatment of latent TB infection in both HIV infected/HIV- even when the treatment is inadequate. The only
uninfected patients for elimination of this disease. In India, definitive way of diagnosing drug-resistance is by
because of the epidemiological proportion of disease, efforts isolating the strain of M.tuberculosis and assessing its
should be made for contact screening of smear-positive susceptibility pattern, which takes up to 8 weeks with
family members especially the mothers. Such contacts (first culture and drug sensitivity testing (DST).
targets) should be given isoniazid chemoprophylaxis, so DOTS-plus services for management of MDR-TB have
that spread of the disease can be controlled in pediatric been rolled out in 2007 and full country coverage is
population. Asymptomatic children under 6 years of age, expected to be reached by 2012. Under the RNTCP’s DOTS-
exposed to an adult with infectious (smear-positive) plus strategy,41 a ‘MDR-TB suspect’ is defined as:
tuberculosis, from the same household, will be given 6 • Any TB patient who is smear-positive at 5 months or
months of isoniazid (5 mg per kg daily) chemoprophylaxis. more after starting treatment with a Cat I or Cat III
regimen (which is also the definition of the treatment
Drug-resistant Tuberculosis in Children outcome of failure), OR
• Any Cat II patient who remains smear-positive at the
The crisis of multidrug resistant TB in adults has been end of the fourth month of treatment or later, OR
well documented. However, little attention has been • A contact of a MDR case who is found to be smear-
directed at children also affected by the resurgent TB positive, regardless of prior anti-TB treatment.
epidemic. Drug resistant tuberculosis occurs mainly due Patients who meet the definition of MDR-TB suspects in
to poor treatment adherence by the patient and poor districts covered under DOTS-plus services are required to
management by physicians. Initial drug resistance to have sputum specimens referred for culture and DST. If the
isoniazid is reported to be in the range of 10 to 15% and cases are confirmed by culture and DST, then such patients
for rifampicin, range is 2 to 3%. These rates are much are treated with a combination of second line anti-TB drugs.
higher in patients who have taken prior, irregular The MDR-TB case definition is as follows:
treatment. Patterns of drug resistance in children tend to An MDR-TB suspect who is sputum-culture positive
mirror those found in adult patients in the population. and has M. tuberculosis strain resistant to isoniazid and
Proximity to adult patients with multidrug-resistant TB rifampicin, with or without resistance to other anti-
makes children prone to developing primary multidrug- tubercular drugs based on DST results from an RNTCP
resistant TB, a vulnerability documented in a South accredited laboratory.
African study.40 As it is difficult to isolate M.tuberculosis The regimen is as follows:
from children with TB, the clue to drug resistance usually • Intensive phase: 6 months of Kanamycin (inj), ofloxacin,
comes from the adult contact. Drug resistant tuberculosis ethionamide, cycloserine, pyrizinamide and etham-
should be suspected in children if the child is in contact butol (the intensive phase is extended by 3 more
with a known case of drug resistant tuberculosis; child’s months if the 4th month follow-up sputum culture is
adult contact has been on chronic irregular treatment positive)
and continues to be sputum-positive; adult contact died • Continuation phase: 18 months of ofloxacin, ethionamide,
after taking irregular treatment; and child shows initial cycloserine and ethambutol
improvement to anti-tuberculosis treatment but then • Pyridoxine 100 mg is administered to all patients on
deteriorates (clinically and radiologically). Since children RNTCP MDR-TB treatment regimen.
in general have paucibacillary TB, secondary multidrug- The dosage and weight band recommendations is given
resistant TB is considered less likely to develop in them, in Table 41.7.
Table 41.7: The dosage and weight band recommendations
S.No. Drugs 16-25 kgs 26-45 kgs >45 kgs
1. Kanamycin 500 mg 500 mg 750 mg

2. Ofloxacin 400 mg 600 mg 850 mg
(Levofloxacin) (200 mg) (500 mg) (750 mg)
3. Ethionamide 375 mg 500 mg 750 mg
4. Ethambutol 400 mg 800 mg 1000 mg
5. Pyrazinamide 500 mg 1250 mg 1500 mg
6. Cycloserine 250 mg 500 mg 750 mg
7. PAS (80% Bioavailability)* 5 mg 10 mg 12 mg
8. Pyridoxine 50 mg 100 mg 100 mg
632
Patients on treatment are followed-up during the 4. Eamranond P JE. Tuberculosis in children: Reassessing
intensive phase by monthly sputum culture and during the need for improved diagnosis in global control
continuation phase by 3 monthly sputum culture. strategies. Int J Tuberc Lung Dis 2001; 5: 594-603.
5. Arora VK. Issues in pediatric tuberculosis under DOTS
strategy (Editorial). Indian Pediatrics 2004; 41: 891-3.
TB in HIV Infected Children 6. History of Tuberculosis Control in India. Available from
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Health and Family Welfare, Government of India.
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children even more difficult than usual, for the following 9. Banerji D. A sociological study of awareness of symptoms
reasons: several HIV related diseases, including TB may among persons with pulmonary tuberculosis. Bull World
present in a similar way; the interpretation of tuberculin Health Organ 1963; 29: 665-683.
skin testing is less reliable; and compliance and completion 10. Tuberculosis Prevention Trial, Madras; Trial of BCG
vaccines in south India for tuberculosis prevention. Indian
of treatment of these children is even more difficult as they
J Med Res 1980; 72: 1-74.
may come from households where either one or both the 11. Census of India, 2006: Population Projections for India
parents may be suffering from HIV or may have died. Anti- and States, 2001-2026. New Delhi, India 2006; Office of
TB treatment is the same for HIV-infected persons as it is the Registrar General and Census Commissioner, India.
for HIV-negative TB patients. Hence they should be treated 12. Gopi PG, Subramani R, Santha T, et al. Estimation of
under the DOTS strategy. burden of tuberculosis in India for the year 2000. Indian J
Med Res 2005; 122: 243-8.
Role of BCG in Preventing TB 13. Chadha VK. Tuberculosis epidemiology in India: a
review. Int J Tuberc Lung Dis 2005; 9: 1072-82.
BCG (bacille Calmette-Guérin) is a live attenuated vaccine 14. Gothi GD, Chakraborty AK, Nair SS, et al. Prevalence of
derived from M. bovis. Studies have shown the range of tuberculosis in a South Indian district — twelve years
protection offered by BCG varied from 0 to 80% in different after the initial survey. Indian J Tuberc 1979; 26: 121-35.
parts of the world. It has been found to have a definite benefit 15. Chakraborty AK, Chaudhuri K, Sreenivas TR, et al.
in protecting young children against disseminated and Tuberculous infection in a rural population of south India:
severe TB, e.g. TB meningitis and miliary TB. BCG has little 23-year trend. Tuber Lung Dis 1992; 73: 213-8.
16. Chadha VK, Vaidyanathan PS, Jagannatha PS, et al.
or no effect in reducing the number of adult cases of pulmo-
Annual risk of tuberculous infection in the northern zone
nary TB. World Health Organization recommends BCG of India. Bull World Health Organ 2003; 81:573-80.
for all children except children with symptoms of HIV 17. Chadha VK, Kumar P, Gupta J, et al. The annual risk of
disease/AIDS in countries with high prevalence of tuberculous infection in the eastern zone of India. Int J
tuberculosis. Tuberc Lung Dis 2004; 8: 537-44.
18. Chadha VK, Vaidyanathan PS, Jagannatha PS, et al.
CONCLUSION Annual risk of tuberculous infection in the western zone
of India. Int J Tuberc Lung Dis 2003; 7: 536-42.
DOTS is effective in treating Pediatric TB, as in adults. There is 19. Kolappan C, Gopi PG, Subramani R, et al. Estimation of
a need to quickly implement the “Management Guidelines of annual risk of tuberculosis infection (ARTI) among children
Pediatric TB under RNTCP” within the country to effect the aged 1-9 years in the south zone of India. Int J Tuberc
control of childhood TB. Lung Dis 2004; 8: 418-23.
20. Chadha VK, Kumar P, Jagannatha PS, et al. Average
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29. Dye C. Global epidemiology of tuberculosis. Lancet 2006; rifampicin and isoniazid level in children with tubercular
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30. Datta M, Radhamani MP, Selvaraj R, et al. Critical 39. Seth Vimlesh, Seth SD, Beotra A, et al. Isoniazid and acetyl
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31. Gopi PG, Subramani R, Narayanan PR. Trend in the 40. Schaaf HS, Gie RP, Kennedy M, et al. Evaluation of young
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42 Frequently Asked Questions
about Tuberculosis
THE BROAD STATUS OF TUBERCULOSIS AT PRESENT IN • The case detection rate for new infectious patients has been
THE WORLD increased four folds from 20% (1997) to 91% (2006) against
Points to Ponder about the Problem of Tuberculosis the international target of 70%
• The treatment success rate of all types of TB patients
More young people from the affluent classes are falling increased from 3 folds from 30% (1996) to 87% (2006)
prey to the “poor man’s disease.” In this group immunity • Ten fold decline in the TB death rate from 20% (1996) to
gets compromised due to stress and poor diet (not due 2% (2006), therefore, averting 9507 deaths due to TB
to nonavailablity of food) in a bid to keep their weights
• Five fold increase in DOT centers from 108(1999) to 540
under control. This leads to easy susceptibility to
(2006) with fifty fold increase in NGO participation from
infection. At the rate of 2.4% new cases, in Delhi itself
3 centers (1999) to 150 centers (2006).
there is crop of 3 lakh fresh TB cases every year. Delhi is
one of the two states where the second line TB treatment
DOTS plus has been kicked off to tackle the drug resistant These above statements of figures of various aspects
TB burden. The worrying point is the young victims of of National Control Program are very encouraging.
disease. Estimation of this group is never done officially. However, the success of implementation when the
This is because of the endemic nature of the disease, all program is carried out with in the existing health
of us harbour the bug in a latent form. Stress like before program of the government, the figures do not remain
examination or crash dieting to loose weight, late night that rosy.
shifts at works place can all be the causative factor for
lowered immunity. Another surprising observation Untreatable TB Strain Causes Alarm
which is a cause of alarm that it is not the pulmonary
tuberculosis which is the commonest, brain and bone TB A survey conducted by WHO and US Center for Disease
are on the rise. Lymphnodal tuberculosis is another Control on data from 2000 to 2004 found that XDR-TB is
annoying type of disease presentation. In these types the most frequent in countries of the former Soviet Union
sputum test is often negative for AFB and xray chest is and Asia. The XDR-TB strain mixing with the AIDS virus,
often normal. Incidence of spinal tuberculosis in affluent is causing nearly 100% mortality.
young is another cause of concern. Again, the definition The above fact is a great public health threat that is
of good food, i.e. milk and milk products, fresh fruits taking alarming proportions. A virtually untreatable
and vegetables have been replaced by junkfood. This form of tuberculosis — extreme drug resistant TB (XDR-
TB) — is spreading all over the world, including India.
lowers the immunity by causing malnutrition and
South Africa is worse affected by the strain and it is being
making children more vulnerable to opportunistic
discussed at the policy level as to how to manage this
infections like TB. Upto 2006 the tackling of problem of
deadly strain. Out of 53 patients with XDR-TB, 52 died
tuberculosis was on an accelerating scale as shown in
in South Africa with in 210 days between January 2005
the following pamphlet prepared for March 24, 2007
and March 2006. Deaths occurred on an average with in
World TB Day in Delhi.
25 days even in those HIV patients who were on
antiretroviral drugs. Even in United States of America
THE SLOGAN WAS TB ANYWHERE IS TB
which has the best of medicines available, a third of those
EVERYWHERE, ONLY PEOPLE CAN STOP TB
who were diagnosed XDR-TB died. Presence of HIV/
Revised National TB Control Program, National AIDS patients in South Africa and India makes it very
Capital Territory of Delhi worrying.
• DOTS — the best strategy to control TB At present XDR-TB problem is small in India but it is
• Eight folds increase in the number of TB patients treated there. India, like South Africa has prepared its guidelines
from 5582 (1997) to an all time record number of 47,536 (2006) keeping in view the severe burden of HIV. India has taken
the initiative of undertaking a survey to guage the extent
635
Chapter 42 Frequently Asked Questions about Tuberculosis
of XDR-TB presence specially in a high HIV burden area India. An AIIMS study (Clinical Microbiology
like Mumbai. Department) has revealed that of those enrolled for the
The Government of India should: study with both HIV and TB a very high percentage were
i. Increase the number of laboratories to diagnose TB suffering from XDR-TB. All the patients died with in three
cases. months of diagnosis.
ii. Improve management of clinical cases.
iii. Strengthen basic TB care to prevent emergence of Resistance Pattern of Strains Isolated
drug-resistance.
iv. Increase collaboration between HIV and TB control Fifty four patients having HIV-TB coinfection
programs to provide necessary prevention and care investigated in 2006, 24 (44.4%) strains of tubercle bacilli
to patients infected with both. were isolated, 12(50%) of these had resistance to isoniazid
As per records of Health Ministry of India, over 3% and rifampicin (the first line drugs) where as 4 (33.3%)
of the fresh cases are suffering from XDR-TB while over were resistant to second line drugs as well. It seems from
12% of old cases undergoing treatment have developed this data that XDR-TB exists in India. The extent need to
this strain. be evaluated. This infection is a great public health threat.
The new strain is not only resistant to isoniazid and Researchers from Hinduja National Hospital in Mumbai
rifampicin, the two important drugs in the first line but first found XDR-TB in 8% of all TB patients. The sample
also to the six classes of drugs used for second-tier examined by them was pretty large (3904), in which 1274
therapy. were positive for TB. In these 32% were multidrug-
TB has also become the single largest killer of AIDS. resistant (MDR-TB) and of this 8% were XDR-TB. They
National AIDS Control Organization (NACO) recently reported only 42% mortality. This pattern of resistance
revealed that over 60% of all AIDS patients contract and is attributed to the failure of the physician to prescribe
ultimately die of TB. NACO has now decided to scale up proper treatment regimen or due to the fault of the
and integrate the National AIDS and TB control programs patient. In the latter, the patient, who is already suffering
from 2006. Every year 1.8 million new TB cases occur in from MDR-TB, does not complete lengthy course of
India of which 0.8 million are infectious. therapy.
“Unless treated properly every infectious In India, it is just in two laboratories in Gujarat and
pulmonary TB patient can infect 10 to 15 persons in a Maharashtra where MDR-TB is being diagnosed. Fifty
year. Improperly treated patient can develop resistance people have been put on DOTS Plus treatment. The
which is potentially untreatable. Since 1968, no new reports from Tuberculosis Research Center (TRC)
drugs have been discovered and the germs have started Chennai are that out of 1200 TB samples sent by
to develop drug resistances. To keep the infected laboratory in Gujarat, only 200 are MDR-TB. As
patients away from noninfected patients seems to be emphasized already 60% of all AIDS patients contract
an extreme step in South Africa, by forcibly detaining TB and India has to be prepared to face the challenge of
the patients who refuse treatment. The other measures XDR-TB before it is too late.
taken are trying to ensure better surveillance,
diagnostics and availability of drugs. This has been done Fight Against AIDS, TB Gets $100 Million Boost
because of the detection of “XDR-TB.” The clue has been (December 22, 2007)
taken from New York City Health authorities who
authorized the forcible detention of people upto two The Global Fund to Fight AIDS, Tuberculosis and
years, if required, who refused TB treatment. This led Malaria is accredited by the G-8 group of industrialized
to a significant dip in cases. It is now simpler because nations in 2002. An agreement has been signed with
of short-course strategy of treatment. Most of these the Department of Economic Affairs allocating over $100
patients had coinfection with HIV. Presence of high million to fight AIDS. This has added to the India’s
number of HIV/AIDS patients in South Africa and India becoming largest beneficiary of charity in Asia. Out of
makes it very worrying. the total funds, 80% is being used to fight AIDS. This
big grant of $100 million will help India buy second-
Status of Drug-resistant TB Cases Infecting line drugs for AIDS from UNITAID or Clinton
Foundation, purchase machines to estimate viral load,
HIV-Positive Patients in India
strengthen antiretroviral treatment programs, support
Experts who conducted this study almost warned voluntary counseling and testing services. With the
officials of TB-control program that they must stop Switzerland-headquarters International Charity’s
denying that XDR-TB cases exist in India. Extensively Support to India has provided antiretroviral treatment
drug-resistant tuberculosis (XDR-TB), the untreatable to 80,000 people having AIDS. TB treatment has been
form of TB has started to infect HIV-positive cases in given to 245,000 people.
636
Government Clubs AIDS, TB-Control Drives General Information about Tuberculosis (TB) in Children
(June 2008)
TB is a major killer of children in poor countries
Tuberculosis being the biggest killer of HIV patients in
India. To meet the challenge of double blow, India has TB kills more young people than any other single
now integrated the National AIDS and TB Control infectious disease. Every minute two children die of TB
Programs. Under this program, all patients diagnosed worldwide.
with TB will be offered free HIV testing in the country’s Tuberculosis in children is neglected: Pediatric TB does
4567 integrated counseling and testing centers (ICTC). not have a high priority in many developing countries as
Once detected with this coinfection, the patient will be fewer children than adults have the disease and children
provided a prophylactic treatment with cotrimoxazole are not usually infectious. Limited resources mean that
to prevent opportunistic infections like pneumonia. This infectious cases have priority.
has been the recommendation of WHO. The patient then Vaccination is not 100% effective: The TB vaccine, bacilli
will be referred to the closest antiretroviral (ART) center Calmette Guerin (BCG), does limit some of the severe
for treatment. forms of tuberculosis which are unique to young children,
This intensified TB/HIV services package will first but by no means prevents them all. Tens of thousands of
be rolled out in nine states with high prevalence of both “immunized” children in the developing world still
HIV/TB cases. These states are Manipur, Nagaland, suffer from tuberculous meningitis and other forms of
Tamil Nadu, Andhra Pradesh, Karnataka, Maharashtra, disease.
Meghalaya, Puducherry and Goa. Children are highly susceptible to tuberculosis: The power
In these states all TB patients irrespective of their life to resist TB infection is normally poor in the first 5 years
style, will be offered HIV testing. At the same time of life. The resistance can be further reduced by
selective testing for HIV will continue on those cases of malnutrition, human immunodeficiency virus (HIV),
diagnosed TB, if they have high risk behavior and are other childhood infections and worm infestations – all
suffering from sexually transmitted infections. Rough too common childhood conditions in poor countries. It
estimate is that 50,000 to 80,000 people suffer from HIV/ has been estimated that as many as one third of the
TB co-infection in India. One needs pretty aggressive world’s population is infected with TB, and an estimated
measures to locate them. Opening of more integrated
20 to 50% of children who live in households where an
counseling and testing centers (ICTC) will help to achieve
adult has active tuberculosis become infected. Children
this goal.
are especially vulnerable to infection from household
As per report of WHO’s consultant at the central TB
contacts as they are often held close and breathed on.
division of Ministry of Health and Family Welfare, out
The risk is particularly high in the developing world
of all known cases of TB, 1.2% are presently HIV positive.
where family size is large, living quarters are crowded
Like ICTCS, which test for HIV, India’s Revised National
and more than half the population are children.
TB Control Program (RNTCP) has 12,000 designated
Traditional diagnostic methods of TB in children are
microscopy centers (DMC). Each of these DMCs are
ineffective: A vast number of children infected remain
established for every one lakh population.
undiagnosed — creating a reservoir of future adult
HIV and TB testing facilities in all these nine states
disease. Diagnosis is difficult in children, and often fatally
are decentralized and are near to each other. Once a
delayed – early symptoms and signs of tuberculosis in
person is diagnosed for TB, he/she will be offered
children are common and easily missed. Lung TB is
voluntary free testing for HIV. If found positive she/
particularly difficult to diagnose early as children’s lungs
he will be counseled, put on prophylactic treatment for
HIV and sent to the nearest ART center on priority basis. react differently than adults, and they have little or no
Once a person is identified with coinfection it will be cough (thus not being able to provide sputum for testing).
ensured that the patients are following proper treatment Microscopic examination only occasionally reveals the
regime. Of the 2.5 million HIV infected Indians, over characteristic tubercle bacilli.
10% are expected to have full blown AIDS. Every AIDS TB can have devastating long term effects on children:
patient has 15% chance of developing TB every year. Due They can be left deaf, blind and/or totally paralysed from
to stigma attached with both the diseases, patients fail TB meningitis, even after it is cured. Spread of infection
to seek treatment. World figures for coinfection are to the bone can cause deformities of the spine
14 million. (hunchback) or other permanent disabilities.
637
TB exacerbates poverty: It makes the patient and their forms viz tuberculous meningitis (TBM). Tuberculous
family poorer because they may have to pay for treatment lymphadenitis, osteoarticular tuberculosis and TBM are
themselves, and even if TB drugs are free there is often a the extrapulmonary manifestations. The bacillary load of
cost of traveling to clinics and loss of wages for that day. tuberculosis is far less in tuberculosis in children than in
If they cannot afford this they may default from the adult type. The disease is generally noninfectious in
treatment—leading to the added complication of drug children and response to therapy is good.
resistance. Children with TB lose out the vital years of
their education, which can affect their future wage- Transmission of TB to Children
earning capacity.
The source of transmission of TB to a child is usually an
adult (usually a family member) with sputum smear-
Misconceptions about TB in Children positive pulmonary (PTB).
Childhood tuberculosis is neglected in endemic areas with
resource constraints, as children are considered to develop Public Health Importance
mild forms of disease and contribute little to the
maintenance of the tuberculosis epidemic. However, Cases of TB in children usually represent between 5 to
children contribute a significant proportion of the disease 15% of all TB cases. The frequency of childhood TB in a
burden and suffer severe tuberculosis-related morbidity given population depends on the: (i) the number of
and mortality, particularly in endemic areas. The infectious cases, (ii) the intensity of transmission, and (iii)
prechemotherapy literature that described the natural the age structure of the population. Children rarely have
history of disease in children identified three central sputum smear-positive TB. So they are less commonly
concepts: (1) the need for accurate case definitions, (2) the infectious. TB in children is, therefore due to failure of
importance of risk stratification, and (3) the diverse TB control in adults. Failure of TB control in adults means
spectrum of disease pathology, which necessitates accurate failure to cure the infectious cases (patients with sputum
disease classification. The concepts are also linked to the smear-positive PTB).
basic principles of antituberculosis treatment, providing a
simplified approach to the diagnosis and treatment of A Good TB Control Program is the Best Way to Prevent
childhood tuberculosis that is independent of resource TB in Children
constraints. The main challenges for future research are The highest priority in TB control is to cure the infectious
the development of a new BCG vaccine. It is worth cases. Children are rarely infectious. However, it is still
emphasizing that the infrastructure provided by the important to cure them. Good treatment of TB in
directly observed therapy, short course strategy, combined childhood will result in the following: (i) decreased
with well-targeted interventions, slightly improved morbidity and mortality; (ii) improved National
resources, and greatly improved political commitment, Tuberculosis Control Program credibility and reputation
may lead to a dramatic reduction in tuberculosis-related (iii) decrease in the transmission.
morbidity and mortality among children.
Risk of Infection
How is Tuberculosis in Children
Different from Adults? Risk of infection depends on two factors: (i) extent
of exposure to infectious droplet nuclei, and
It is important to realize that tuberculosis (TB) in children
(ii) susceptibility to infection. Consider an infant whose
is very different from that in adults as far as its mode
mother has sputum smear-positive PTB. The infant has a
of clinical presentation, severity of the disease,
high risk of acquiring infection: mother and infant are in
infectiousness, diagnosis, treatment and overall outcome,
very close contact; immune defences are poor. An infant
i.e. prognosis, are concerned. In nearly 80% of all
with HIV infection has an even greater susceptibility to
tuberculosis cases in children, the disease is localized as
infection with tubercle bacilli.
primary pulmonary tuberculosis. The symptoms of
tuberculosis in children are usually vague, viz. low grade
Risk of Progression of Infection to Disease
fever, cough, failure to gain weight or weight loss, poor
appetite and laziness, i.e. child is not active. The spectrum The vast majority of HIV-negative children infected with
of severity of disease ranges from the uncomplicated M. tuberculosis do not develop TB disease. In these
asymptomatic Mantoux positivity (ASMP), symptomatic healthy, asymptomatic, but TB-infected children, the
Mantoux positivity (SMP), primary pulmonary complex only evidence of infection may be a positive tuberculin
to miliary and cavitary forms of pulmonary tuberculosis, skin test. However, an infected child can develop TB
and from tuberculous lymphadenitis to disseminated disease at any time. The chance of developing disease
638
is greatest shortly after infection and then steadily tween 80, or any dose equivalent to 5 TU PPD-S is highly
decreases as time goes by. Possibility of progression indicative of tuberculous infection.
from infection to disease is very high (up to 50%) in A tuberculin test is negative when the diameter of
first year after infection in young children specifically skin induration is less than 10 mm. This is regardless of
infants. Various physical or emotional stresses may whether or not the person has had BCG. A negative
trigger progression of infection to disease. The most tuberculin skin test does not exclude TB. In other words,
important trigger is weakening of immune resistance, a negative test is of no help in deciding that the child
especially by HIV infection. Other important triggers does not have TB.
include other infections (especially measles and
whooping cough) and malnutrition. Conditions Which May Suppress
the Tuberculin Skin Test
Pathogenesis
• HIV Infection
The usual route of infection and early sequence of events • Malnutrition
in primary pulmonary infection are similar in adults and • Severe bacterial infections, including TB itself
children. TB disease in children is usually primary TB. A • Viral infections, e.g. measles, chickenpox, glandular fever
child may have asymptomatic M. tuberculosis infection: • Immunosuppressive drugs, e.g. steroids, cancer
the tubercle bacilli can lie dormant for many years. If the chemotherapy.
tubercle bacilli reactivate some years later, causing
postprimary TB, the child has usually grown into an adult
BCG and Tuberculin Skin Test Results
by then. The age when a child is infected determines the
pattern of primary disease. Up to puberty, blood-borne Tuberculin test may show some induration after BCG
spread is common. This results in disseminated (miliary vaccination for many years. This reaction is usually a
and extrapulmonary) disease. At puberty, pulmonary weaker reaction (diameter often less than 10 mm) than
spread is more common and cavitary manifestations may the reaction to natural infection with M. tuberculosis.
occur. Therefore, in a child who has not had BCG, a tuberculin
test is positive when the diameter of skin induration is
How is Tuberculosis in Children Diagnosed? 10 mm or more. In a child who has had BCG, a test may
be considered positive if the diameter of induration is 15
It is the high index of suspicion in a child pre-senting
mm or more. This too only in the first year of BCG
with vague clinical symptoms (as already mentioned)
vaccination. A positive tuberculin test is only one piece
and a history of tuberculosis in family that leads a
of evidence in favor of the diagnosis of TB. The younger
pediatrician into investigating the child for tuberculosis.
the child and the greater the diameter of induration
(above 10 to 15 mm), the stronger is that one piece of
Tuberculin Skin Test (Mantoux Test)
evidence.
Tuberculin is a purified protein derived from tubercle
bacilli. Thus, another name for tuber-culin is PPD Interferon-γγ Release Assays (IGRAs)
(Purified Protein Derivative). Following infection with
The peripheral blood sample is used for testing for these
M. tuberculosis, a person develops hypersensitivity to
assays. The sensitized T-cells from infected child release
tuberculin. Tuberculin injected into the skin of an infected
interferon-γ (IFN-γ). There are two commercial IGRAs
person produces a delayed local reaction after 24 to 48
namely Quanti FERON-γ and T-SPOT. TB are available.
hours. We quantify this reaction by measuring the
The advantage of these is that they are not interfered in
diameter of skin induration (thickening) at the site of the
individuals given BCG and those exposed to
reaction. Various conditions may suppress this reaction.
nontuberculous Mycobacterium. However, they can not
The reaction indicates hypersensitivity. In other words,
be used in isolation as the diagnostic test. Need to be
the reaction only shows that the person has at some time
considered with other tests and clinical symptomatology.
had infection with M. tuberculosis. At present these are given lot of importance in the
A tuberculin test does not measure immunity. By diagnosis of latent tuberculosis.
itself, it does not indicate the presence or extent of
tuberculosis disease; it only indicates infection.
X-ray Chest
A positive tuberculin skin reaction, i.e. the Mantoux
test, in the form of an induration and not redness, of 10 Showing a parenchymal (P) lesion, or enlarged
mm or more after 48 to 72 hours, to 2 tuberculin unit mediastinal lymph nodes (N) hilar, paratracheal,
(1TU) of purified protein derivative (PPD) RT23 with subcarinal or ductal, or a combination of them (P+N) will
639
indicate the ‘pulmonary primary complex’ (PPC). A overdiagnose TB in children. It is also easy to miss TB in
lesion showing consolidation or collapse or a children. Carefully assess all the evidence before making
combination of collapse consolidation or cavitary lesions the diagnosis.
or miliary shadows indicate a ‘progressive primary Adults with PTB usually present with cough and
disease’ (PPD) form. Calcified lesions of P, or N or P+N, sputum. Although sputum culture is the definitive test,
or fibrocalcific lesions indicate healed lesions and are in practice the readily available usual “gold standard”
termed as ‘postprimary lesions’ (PPL). test for adults with PTB is sputum-smear microscopy.
However, there is no such “gold standard” test in
Gastric Lavage/Induced Sputum children. TB in children is a general disease which may
Acid fast bacilli (AFB) can be seen in properly collected appear in any part of the body. Also, under the age of 10
early morning gastric lavage samples in nearly 1/4th of years, children with PTB rarely cough up sputum. They
cases particularly in infants and young children with usually swallow their sputum. Gastric suction and
PPD, miliary or disseminated tuberculosis. Application laryngeal swabs are generally not useful unless facilities
of new rapid laboratory techniques hasten the diagnosis are available for M. tuberculosis culture. Induced sputum
both with more sensitivity and specificity. can help in getting the specimen for smear and culture
for AFB. The diagnosis of TB in children is, therefore,
Role of Nonculture Techniques (ELISA) in nearly always presumptive. This means that bacteriological
the Diagnosis of Tuberculosis in Children confirmation is usually not possible. This situation in
children is similar to that in adults with sputum smear-
Investigations based on serological assay enzyme linked- negative PTB or extrapulmonary TB.
immunoassay (ELISA) is being used very often for The clinical features are constitutional and local
making diagnosis of TB in children thinking that ELISA (depending on the part of the body affected). The local
is the panacea for diagnosis of tuberculosis. It is a Myth. clinical features related to the site of disease are similar
The sensitivity and specificity vary with the use of in children and adults. The diagnosis rests on consistent
different antigens and there is lot of overlap. Hence, clinical features and investigation findings. If available,
ELISA is not recommended as a diagnostic tool. As it is, there a tuberculin skin test maybe helpful. In most cases of
is over-diagnosis of PPC, but with the use of ELISA as a suspected PTB, the child has usually received treatment
diagnostic test, it will add to overtreatment. with a broad-spectrum antibiotic, with no clinical
No discussion on diagnosis for tuberculosis is response. In some hospitals, helpful special diagnostic
complete without the mention of polymerase chain investigations maybe available. These may include
reactions (PCR). It is still a research tool and is not specialized X-rays, fine needle aspiration cytology,
recommended for routine use. It is very important to biopsy and histology, and TB culture.
mention because this is ‘in fashion’ investigation. In India
there are sophisticated private laboratories, which are Always look for the following two important clues
capable of doing this test at exorbitant rates. to TB in children:
Fine needle aspiration cytology (FNAC) or biopsy. AFB i. It is usually possible to identify the adult source of
staining, histopathology may establish the diagnosis of enlarged infection.
cervical/axillary or inguinal nodes. ii. Failure to thrive or weight loss (growth faltering).
CSF examination, CT scan and now, MRI study of the brain In the absence of these two clues, TB is less likely.
which show basal exudates and/or ventricular dilatation
help in the diagnosis of TBM. PRACTICAL POINT
Besides these, the features assisting in the diagnosis are: A
• Ask the mother of a child with suspected TB for the child’s
positive family history, severe proteinenergy malnutrition, and
“road to health” card (growth card). Look at the card for
history of measles or pertussis in previous 3 months. In cases
growth faltering or weight loss
where Mantoux test is negative, persistence of constitutional
• Scoring systems have no role in the diagnosis of TB in
symptoms, excessive irritability, convulsions or paresis or
children.
paralysis, a positive X-ray chest film and the lesion not
responding to antibiotic therapy for two to three weeks with
good compliance also assist in diagnosis. How should a ‘pyogenic’ parenchymal lesion in X-ray
chest be differentiated from a tuberculous one?
To Summarize Following is the Approach I would stress, particularly to general practitioners and
to Diagnose TB in Children the pediatricians, that in the presence of a positive
If you find the diagnosis of TB in children easy, you are Mantoux test, antituberculosis therapy should not be
probably over-diagnosing TB. If you find the diagnosis started right-away if an X-ray chest shows only a
of TB in children difficult, you are not alone. It is easy to parenchymal lesion. A course of suitable antibiotics in
640
adequate dosage should be given for 7 to 10 days and an c. To minimize side effects for patients (by using the
X-ray chest should be repeated after 3 to 4 weeks to see most intensive regimens only for certain cases).
the resolution of lesion. A pyogenic parenchymal lesion What determines a case definition? There are four
will either resolve completely or to a significant extent; determinants:
whereas a tuberculous lesion will remain as such. a. Site of TB
However, in presence of mediastinal adenopathy and b. Result of sputum smear
positive Mantoux test, chances of tuberculosis are high c. Previous TB treatment
and it is justified to start therapy for tuberculosis d. Severity of TB.
Clinically, a child with pyogenic infection generally
Always ask a “new” TB patient if he or she has ever had
presents with ‘acute’ onset with comparatively more
TB treatment before. The following gives a description of case
vigorous symptoms than a patient with tuberculosis. If
definitions.
the X-ray chest shows interstitial pattern, then associated
bronchial asthma and eosinophilia should be ruled out
by proper clinical examination and by absolute
Case Definitions by Site and Result of Sputum Smear
eosinophil count. A clear-cut consolidation associated PTB
with collapse is more often due to tuberculosis than
pyogenic infection unless there is associated history of Smear-positive case: At least 2 sputum smears positive for
foreign body inhalation. Thick secretions due to the AFBs OR 1 sputum smear positive for AFBs and chest
bursting of tuberculous lymph nodes into bronchi can X-ray abnormalities consistent with active TB.
result in collapse due to blockage of bronchial tree. Smear-negative case: At least 2 (and preferably 3)
sputum smears negative for AFBs and chest X-ray
What do the terms SMP and ASMP denote? abnormalities consistent with active TB. In most cases,
SMP stands for symptomatic Mantoux positive case and the patient will have had treatment with a broad-
ASMP for asymptomatic Mantoux positive case. These spectrum antibiotic, with no response.
terms are used to denote substantially large groups of The following are forms of extrapulmonary TB:
children who are Mantoux test positive but have a normal pleural effusion (pleura are outside the lungs); hilar
chest X-ray (whether symptomatic or asymptomatic). lymphadenopathy (hilar lymph nodes are outside the
lungs); miliary (TB is widespread throughout the body
Do children falling in these groups need to be treated? and not limited to the lungs).
Yes, indeed! I have studied the CT scan of chest of some
of these patients and surprisingly found that they had Case Definitions by Previous Treatment
enlarged mediastinal lymph nodes which were not
visible in the plain X-ray chest. A few of these (untreated)
New
did show hilar lymphadenopathy in the Xray film after A patient who for sure has never taken anti-TB drugs for
2 months and became symptomatic. Therefore, these more than one month.
groups, particularly those below 5 years of age and
during adolescence need adequate treatment. However, Relapse
it is mandatory to rule out other causes for the symptoms.
For symptomatic children with positive Mantoux test, A TB patient who:
appropriate category of treatment should be started. For a. Previously received treatment and was declared
asymptomatic children with positive mantoux test a cured and
chemoprophylaxis in the form of 6 months of isoniazid b. Has once again developed sputum smear-positive TB.
may be started presuming it to be a recent converter.
Treatment Failure
Questions and Answers About Case Definitions
A new TB patient who is still sputum smear-positive 5
Why make case definitions? There are two purposes: months or more after starting treatment.
a. To determine treatment.
b. For recording and reporting.
Return After Interruption of Treatment (Default)
Why do case definitions determine treatment? There
are three reasons: A new TB patient who:
a. To identify priority cases. a. Completed at least one month of treatment and
b. To make the most cost-effective use of resources (by b. Returned after at least two months interruption of
targeting resources on priority cases). treatment.
641
Transfer-in been introduced in the market. The dose of strepto-

mycin and ethambutol is 20 to 25 mg/kg/day.
A TB patient already registered for treatment in one
district who transfers to another district and continues
What is the role of quinolones in the
treatment. drug-therapy of tuberculosis in children?
Other I might remind, specially the practitioners, that quinolones

are not the first-line antituberculosis drugs. Their use is
A TB patient who does not easily fit into one of the above reserved in (i) multidrug resistant (MDR) tuberculosis;
case definitions. One example is a chronic case (a TB (ii) in conditions of drug induced hepatotoxicity while
patient who remains sputum smear-positive after treating severe tuberculosis (TBM, miliary tuberculosis)
completing a supervised re-treatment regimen). in which fluoroquinolones (ofloxacin/ moxifloxacin) may
Table 42.1 shows the severe and less severe forms of be given in addition to streptomycin and ethambutol.
extrapulmonary TB.
How safe is it to use quinolones in the pediatric age?
Children Clinical studies have shown no serious effects of using
Children and adolescents often fall into category 3 PTB ciprofloxacin in children treated for cystic fibrosis in as
in children is almost always “smear-negative” high a dose as 30 mg/kg/day for 6 months. MRI studies
(actually smear not done, since children rarely cough have not shown any detrimental effect on the cartilage of
up sputum). Young people infected during the growing child.
adolescence may develop cavitary lesion after primary
Should thiacetazone be used in children?
TB infection. This usually presents as pleural effusion or
small parenchymal lesions in the lungs. In one series of No, thiacitazone should be avoided because of the risk
adolescents with pleural effusion, without treatment of skin reaction and Stevens-Johnson syndrome which
about 25% went on to develop PTB. is more common when tuberculosis occurs in association
with HIV.
Which simple treatment regimens do you recommend
Can ethambutol be used safely in infants and younger
for different types of tuberculosis in children?
children?
Refer to Chapter on Consensus Statement of Indian Indeed, Seth et al* have studied that ethambutol in the
Academy of Pediatrics—2010. dose of 20 mg/kg/day does not produce any ocular
toxicity in children. Visual evoked response (VER) was
What about drug doses in children? measured in those above 3 years of age, both amplitude
For daily regimen INH should be prescribed in doses and latency of VER were comparable in the children on
of 5 to 10 mg/kg of body weight per day. However, ethambutol and control groups. Ethambutol has got good
this would require close monitoring if used in a daily penetration in the CSF and it helps in preventing
regimen. In intermittent regimen, this dose is well development of resistance. It is not logical to assume that
accepted. Presently, INH, rifampicin and pyrazinamide ethambutol is not safe in children below 3 years. Hence, it
combination tablets employing this dose schedule have is strongly recommended in any pediatric age where it is
indicated. Now, the VER can be measured in children less
than three years, and infants under general anesthesia, to
Table 42.1: The severe and less severe forms of have scientific and sound basis for the recommendation of
extrapulmonary TB its use in these groups, particularly cases of TBM.
Severe extra- Less severe extra- Ethambutol is also useful in multidrug resistant-tuberculosis
pulmonary TB pulmonary TB
(MDR-TB).
• meningitis lymph node
• miliary pleural effusion (unilateral) Besides therapy, what other measures are important
• pericarditis bone (excluding spine) in the management?
• peritonitis peripheral joint
• bilateral or adrenal gland All siblings of the index child should be subjected to
extensive pleural the Mantoux test and X-ray chest. Those who turn out
effusion
• spinal
* Seth Vimlesh, Khosla PK, Semwal OP, et al. Viusal evoked
• intestinal responses in tuberculosis in children on ethambutol treatment.
• genitourinary Indian Pediatr 1991; 28:713-7.
642
to be positive or are symptomatic, definitely these lesion sometimes does require more time, particularly
investigations are of immense help. Mother, father and the nodal and calcified lesions, which may take 1-1½
other adults living in the house need to be X-rayed as it years to disappear altogether. Calcification does not
has been found that many of them to have active disappear, it remains as a tell-tale mark. If there is only
tuberculosis (30%) even though they claim to be ‘healthy’. mild or no improvement, or deterioration of the lesion
This point needs to be brought to the attention of after 3 months of therapy, drug compliance should be
practitioners as their concern remains focussed on the thoroughly checked and if found satisfactory, drug
index child only. Often the physicians treating the adult resistance may be suspected which necessitates addition
tuberculosis cases fail to screen the children of an of other drug(s) to the regimen.
infectious adult for tuberculosis. By the time the children
approach the pediatrician for the symptoms, some of What about drug compliance?
them have already developed progressive primary,
This is the most important aspect of the therapy as the
disseminated disease or tuberculous meningitis.
extent of drug compliance is directly proportional to the
clinicoradiological improvement. (Pulmonary tuberculosis
How should the response to therapy in pulmonary
chapter) Seth has shown that a drug-dose compliance of
tuberculosis be monitored?
at least 80% is to be ensured to have a satisfactory response
Clinically, it should be monitored by disappearance of to the regime. Compliance may be a major problem with
symptoms of fever and cough and documentation of weight pediatric patients as they are dependent on parents for
gain. The child should become playful and gain weight. giving them the drugs. Also, the dramatic improvement
The latter is a very good criterion of response to therapy. seen in adult patients may not be evident in pediatric
Objectively, it should be monitored by evaluating the patients as they usually have fewer symptoms.
clearance of radiological lesion. For this, an X-ray chest
at the beginning of therapy and at 3 monthly intervals in What measures are needed for the infant of a lactating
the first year and six monthly in the second year is mother on antituberculosis drugs?
recommended. Then the child should be kept under
Since the drug concentrations in breast milk are
surveillance for five years. However, radiographic
subtherapeutic there are no adverse effects in the infant.
improvement of intrathoracic tuberculosis in children
At the same time, these concentrations do not provide any
occurs very slowly, and frequent monitoring with chest
protective coverage to the infant from an impending
radiographs is usually not necessary.
tuberculosis infection. No separation of baby from mother
is required. The baby should be given preventive therapy
How should the resolution of X-ray lesion be graded? with 3 HR. The general recommendation is to give
isoniazid (5 mg/kg/day) for 6 months. It is important to
To evaluate the response to therapy, the following
have periodic examination of the infant at the beginning
grading is proposed based on experience of Seth (Imaging
and after three months in the form of Mantoux test and X-
chapter)
ray chest. If both are negative, give BCG vaccination. If
Grade 1: Complete clearance of the initial tuberculous
Mantoux test is positive and child is asymptomatic
lesion.
continue therapy for another three months. If both
Grade 2: Moderate to significant clearance—1/2 to 2/3
(Mantoux test, CXR) are positive, categorise the child
clearance of lesion.
and give appropriate treatment. BCG vaccination
Grade 3: Mild improvement—only 1/3rd clearance.
is recommended after 3 months, if both the tests are
Grade 4: No improvement, or deterioration.
negative.
How helpful are these gradings in judging the response What features suggest congenital or neonatal TB?
to therapy? Three major routes for true congenital tuberculosis
In usual practice, it has been observed that, practitioners are:
keep on continuing the antituberculosis treatment for 9 a. Via the umbilical vein from the mother with
or even upto 12 months just because X-ray chest lesion lymphohematogenous spread during pregnancy.
has not completely resolved. It is stressed, on this point, b. Hematogenous dissemination leading to infection of
that if regular treatment has been taken and child has the placenta with transmission to the fetus. In either
symptomatically improved, it should be stopped at the event the bacilli first reach the fetus’s liver where the
scheduled time after completion of the regimen (6 or 9 primary complex develops leading to hepatomegaly
months) even if there is only moderate radiological or even widespread miliary disease.
clearance of the lesion. Complete clearance of radiological c. Aspiration or ingestion of infected amniotic fluid.
643
The clinical manifestations vary according to the site streptomycin and ethambutol. It should be increased to 10
and size of caseous lesion. The symptoms usually become mg/kg/day after 1 week. INH is added in the similar way,
manifest in the second or third week of life. The i.e. half dose (2.5 mg/kg) initially for 1 week than in full
presentation is in the form of respiratory distress dose. Ethambutol is continued and pyrazinamide is left out
syndrome, fever, hepatic or splenic enlargement, except in TBM and miliary tuberculosis cases. In these cases
poor feeding, lymphadenopathy, lethargy and/or pyrazinamide is reintroduced initially in half the dose (15
irritability. mg/kg) as with other drugs and then in full dose. Usually,
Diagnosis is often difficult, since the clinical features it takes 4 to 6 weeks before all antituberculosis drugs, in
can mimic those due to any bacterial infection or recommended doses, can be reintroduced. Finally extend
congenital infections like syphilis and cytomegalovirus the total duration for the period during which child
infection. The major clue to diagnosis is history of received improper regimen.
tuberculosis in the mother. The Mantoux test is mostly
negative. X-ray chest is abnormal in the majority of How do you differentiate drug-induced hepatoxicity
neonates and diagnosis is established by finding AFB in from acute viral hepatitis?
gastric and or, bone marrow aspirate, urine or liver
biopsy. The only sure way to differentiate the two is to look for
viral markers. Clinical presentation and results of liver
What should be the therapeutic approach in such cases? function tests may not help in differentiation. However,
in clinical practice this differentiation is not essential, as
Since the conditions are associated with high mortality, the management and decisions about antituberculosis
if not diagnosed in time, early and aggressive therapy is drug therapy are not different (as highlighted above).
the deciding factor. 2 HRZE, 4 HR regimen with monthly
review is recommended.
How to initiate treatment in a child with liver disease?
How do you manage a child who is in contact with a Patients with hepatic abnormality who need anti-
patient infected with tuberculosis? tuberculosis therapy should be evaluated for hepatic
tuberculosis. There may be greater potential for liver
Children below 5 years of age who are in close contact toxicity from antituberculosis drugs in patients with
with drug susceptible tuberculosis patient and are underlying liver disease. The doses of most anti-
asymptomatic, active disease ruled out by appropriate
tuberculosis drugs need not be reduced in these patients,
investigation, should be given INH for six months.
but closer monitoring of liver functions and signs and
Chemoprophylaxis for those exposed to MDR-TB is not
symptoms of toxicity is indicated.
clear. Two alternatives are suggested in such a situation.
WHO recommends that patients with established
(1) Keep the child in close follow up with 6 months of
chronic liver disease should not receive pyrazinamide.
INH prophylaxis and treat like MDR-TB on development
The recommended regimens are:
of disease. This approach is based on the premise that if
1. 2 SHRE/6 HR
we give two/ three drug prophylaxis and the bacilli
2. 2 SHE/10 HE
becomes resistant to them, we may not be left with many
In tuberculosis regime number one as given above is
drugs for treatment (2) second alternative is to give a
preferred treatment during the acute phase of viral or
combination of fluoroquinolone and ethambutol for 6 to
other hepatitis, a regimen of drugs with low potential for
12 months. The decision may be taken on case to case basis.
liver toxicity such as ethambutol and streptomycin. A
How should the drug-induced hepatotoxicity be recommended regime is 3 SE/6 HR. Other non-hepatotoxic
drugs, which can be used are aminoglycosides,
managed?
capreomycin and fluoroquinolones, preferably latter.
Drug-induced hepatotoxicity is relatively uncommon in
children, when antituberculosis drugs are given in the What are the indications for screening for HIV infection
recommended dosage schedule, INH (5 mg/kg), in children with tuberculosis?
rifampicin (10 mg/kg) and pyrazinamide (30 mg/kg). In
case a child develops jaundice or deranged liver function HIV screening should be done in the following situations:
tests (Transaminases > 5 times the normal) , they should a. Disseminated tuberculosis.
be withdrawn and substituted with streptomycin (S), b. Presence of history of blood transfusion, high risk
ethambutol and fluoroquinolones in serious tuberculosis behavior in parents.
with monitoring of liver function tests (LFT). When LFT c. Other features suggestive of immunodeficiency.
return to normal levels, rifampicin is introduced first in At present, there is no consensus about screening of
half the dose, i.e. 5 mg/kg/day with continuation of all children with tuberculosis.
644
How to differentiate tubercular meningitis from partially What are the screening procedures before start of
treated pyogenic meningitis when investigation facilities therapy for latent tuberculosis. Before isoniazid
are limited? How to manage such a case? preventive therapy is started, it is important to
undertake the following evaluations?
CSF adenosine deaminase, CSF-CRP, CSF lactate
dehydrogenase, CSF free N-acetyl neuraminic acid, 1. Exclude severe form of pulmonary tuberculosis such
immunodiagnosis, chemokine profiles in CSF and PCR as radiographically progressive primary disease
can help in distinguishing TBM from partially treated (PPD), bronchopneumonia. Every person who has
pyogenic meningitis. These tests are not readily available. a significant Mantoux test reaction positive, i.e. >10
The decision in each patient has to be individualized. In mm should have a chest radiograph. If there are
cases of doubt we end up giving both antituberculosis findings consistent with pulmonary tuberculosis,
further studies, including medical evaluation, gastric
therapy (ATT) and antipyogenic treatment and then
lavage, and comparison of the current and old
reassess the patient after two weeks.
radiographs if any should be made to exclude
progressive disease. Appropriate evaluation should
When will you withdraw antituberculosis drugs, if we be performed if extrapulmonary tuberculosis is
started so on strong suspicion of TBM or inability to suspected. Because of the risk of inducing isoniazid
differentiate TBM from viral meningoencephalitis? resistance when isoniazid is used alone in a person
Do not withdraw ATT but complete the full course. with current tuberculosis, the recommended
regimens for treatment of disease should be used
until the diagnosis is clarified. If the evaluation
Can the CSF examination be normal if a child has TBM/ confirms previous (not current) tuberculosis,
CNS tuberculosis? therapy of multidrug treatment may be stopped after
CSF can be completely normal in 5.8 to 16.5% cases of 6 months in children.
TBM with a proved diagnosis on autopsy. On the 2. Question for a history of treatment with antituber
contrary, in about 10% cases the CSF could be almost culosis drugs, or therapy for tuberculosis to exclude
simulating pyogenic meningitis. those who have been adequately treated.
There are new and/or modified clinical entities 3. Question for a history of prior isoniazid preventive
particularly in BCG vaccinated children in which the therapy to exclude those who have had an adequate
course of the drug.
child may have normal CSF but positive PCR for
4. Check for contraindications to the administration of
tuberculosis and/or tuberculosis antigen by ELISA.
isoniazid for latent tuberculosis. Theses include:
Tuberculoma, tubercular encephalopathy and intracranial
(i) Previous isoniazid-associated hepatic injury.
tubercular abscess can have normal CSF. (ii) History of severe adverse reactions to isoniazid such
as drug fever, rash, and arthritis. (iii) Acute or unstable
How do you manage child contacts of infectious adults? liver disease of any etiology. Hepatitis B surface
Children with TB may present to health units when antigen positivity per se is not a contraindication.
they are ill. However, most National TB Control 5. Identify patients for whom special precautions are
Programs also recommend active contact tracing of indicated. These include: (i) Age less than one year
children who are household contacts of infectious (ii) Concurrent use of any other medication on a long-
adults. In order to be effective, this screening must be term basis in view of possible drug interactions
(iii) History of previous discontinuation of isoniazid
systematic.The scheme below shows how to manage
because of possible, but not definite, related side
child contacts of infectious adults (with sputum smear-
effects, e.g. headaches, dizziness, nausea (iv) Although
positive PTB).
no harmful effects of isoniazid to the fetus have been
Screen all children living with a household adult observed, preventive therapy generally should be
contacts for tubercular disease. If disease is ruled out, delayed until after delivery. There does not appear
all children below 5 years of age irrespective of to be any substantial increase in tuberculosis risk for
nutritional status, BCG vaccination status, should be women as a result of pregnancy. However, for
started on INH prophylaxis for 6 to 9 months. Children pregnant women likely to have been recently infected
should be followed up every month for clinical or with high-risk medical conditions, especially HIV
screening. infection, treatment for latent tuberculosis therapy
645
should be again started when the infection is adviseable to add a second drug such as ethambutol to
documented (v) A recent report suggests an increased which the organisms is believed to be susceptible. The
risk of fatal hepatitis associated with isoniazid among drug(s) should be given in standard therapeutic doses
women, during the postpartum period. for 6 months. In situations in which there is doubt that
the infection is due to isoniazid-resistant organisms,
How should one monitor therapy for latent tuberculosis? isoniazid should not be used.
The person receiving therapy for tuberculosis or a
responsible adult in a household with children receiving
How do you manage a child with a high probability of
latent therapy should be questioned carefully at monthly infection with multidrug resistant organisms?
intervals for symptoms or signs consistent with liver In persons likely to have been infected with bacilli
damage or other adverse effects. These include any of resistant to both isoniazid and rifampicin, observation
the following: unexplained anorexia, nausea, vomiting, without therapy for latent tuberculosis has usually been
dark urine, icterus, rash, persistent paresthesias of the recommended because no other drugs have been
hands and feet, persistent fatigue, weakness or greater evaluated for latent tuberculosis. However, in persons
than 3 day duration, and/or abdominal tenderness with an especially high-risk of tuberculosis (e.g. persons
(especially right upper quadrant discomfort). with HIV infection), therapy for latent tuberculosis
If any of these or other signs or symptoms occur should be considered. If the organisms are thought to be
during preventive therapy, patients should be advised susceptible, 6 month of daily ethambutol and
to report immediately to the clinic or healthcare provider pyrazinamide at the usual therapeutic doses may be
for evaluation, including biochemical tests for hepatitis. considered. If infection is due to organisms resistant to
The use of a standardized form for interviewing will help ethambutol as well, the combination of pyrazinamide
ensure alertness to all signs and symptoms, expedite the plus a quinolone (gatifloxacin or moxifloxacin) for 6
interview process, and provide for standardized data months is recommended. Careful assessment to exclude
collection. active tuberculosis prior to the initiation of preventive
As noted, 10 to 20% of those receiving isoniazid will therapy is mandatory.
develop some mild abnormality of liver function (an
elevated aspartate aminotransferase). These abnormalities What are the complications of BCG vaccination?
tend to resolve even if isoniazid is continued. A
BCG rarely causes serious complications; osteomyelitis
transaminase measurement should be obtained prior to
and death from disseminated BCG infection have
the starting and monthly during the course of preventive
occurred in only one case per million doses administered.
therapy in a child who has had infective hepatitis and has
The frequency of side effects, most commonly prolonged
grade III of protein energy malnutrition. More careful
ulceration and local adenitis, occur in 1 to 10% of
monitoring should be considered in these groups, possibly
vaccinees, varying with the vaccine used, the intensity
including more frequent laboratory monitoring. If any of
with which adverse reactions are sought, and the
these tests exceeds three to five times the upper limit of
population vaccinated. BCG vaccination may cause
normal, discontinuation of isoniazid should be strongly
tuberculin skin test conversion, but waning of delayed
considered. Liver function tests are not a substitute for a
hypersensitivity occurs to a significant extent in the 1st
clinical evaluation at monthly intervals or for the prompt
year itself. So it does not interfere with Mantoux test
assessment of signs or symptoms of adverse reactions
interpretation.
occurring between regularly scheduled evaluations.
Inspite of these shortcomings, BCG is recommended
in the following situations.
How will you manage latent tuberculosis if a child is
1. BCG vaccine is strongly recommended for infants and
intolerant to isoniazid?
children with negative tuberculin skin test who: (i)
An approach similar to that taken for contacts of are at high-risk of intimate and prolonged exposure
isoniazid-resistant cases can be used. to persistently untreated or ineffectively treated
patients with infectious pulmonary tuberculosis, cannot
How do you manage the close contacts of isoniazid- be removed from the source of exposure, and cannot be
resistant cases? placed on long-term preventive therapy, or (ii) are
continuously exposed to persons with tuberculosis who
In the situation where there is confidence that the source have bacilli resistant to both isoniazid and rifampicin.
case has isoniazid-resistant organisms, it appears 2. BCG vaccination is also recommended for tuberculin-
reasonable to treat child contacts and those adult contacts negative infants and children in groups in which the
who appear particularly susceptible to tuberculosis (e.g. rate of new infections exceeds 1% per year and for
immunocompromised hosts) with rifampicin. It is whom the usual surveillance and treatment programs
646
have been attempted but are not operationally Bactericidal Drugs

feasible. These groups include persons without Isoniazid kills 90% of the total population of bacilli during
regular access to health care, those for whom usual the first few days of treatment. It is most effective against
health care is culturally or socially unacceptable, or the metabolically active, continuously growing bacilli.
groups who have demonstrated an inability to Rifampicin can kill the semi-dormant bacilli which
effectively use existing accessible care. In view of the isoniazid cannot. Pyrazinamide kills bacilli in an acid
recent outbreaks of multidrug resistant tuberculosis, environment inside cells, e.g. macrophages.
these recommendations are currently under review.
Vaccination should be administered only by the Sterilizing Action
route indicated in the package labeling and only in
the suggested dose. Depressed host immunity (from This means killing all the bacilli. The persisters are
illness such as HIV infection or therapy with hardest to kill. The aim of killing all the bacilli is to prevent
immunosuppressive drugs) is a contraindication to relapse. Rifampicin is the most effective sterilizing drug.
BCG administrations. Its effectiveness makes short-course chemotherapy possible.
Pyrazinamide is also a good sterilizing drug, since it kills
Which groups of children are at greater risk for the bacilli protected inside cell.
tuberculosis than others?
Preventing Drug Resistance
• Children living in a household with an adult who has
Consider a population of TB bacilli never previously
active tuberculosis
exposed to anti-TB drugs. There will be a few naturally-
• Children living in a household with an adult who is
occurring drug resistant mutant bacil1i. Faced with anti-
at high-risk for contracting TB
TB drugs, these drug-resistant mutant bacilli will grow
• Children infected with HIV or another immuno-
and replace the drug-sensitive bacilli under the following
compromising condition
circumstances:
• Children born in a country that has high prevalence
a. Inadequate anti-TB drug combinations.
of tuberculosis
b. Anti-TB drug treatment not properly applied.
• Children from communities that are medically under
Isoniazid and rifampicin are most effective in
served.
preventing resistance to other drugs. Streptomycin and
ethambutol are slightly less effective.
Should women taking antituberculosis drugs
breastfeed?
TB Treatment Regimens
Most of the commonly used antituberculosis drugs are
excreted in breast milk of nursing mother. However, only Treatment regimens have an initial (intensive) phase and
a small fraction of the adult dose appears in breast milk, a continuation phase.
and we estimate that breast fed infants would receive no
more 20% of the usual therapeutic dose for infants for New Cases
any of these dose. Based on these considerations, we
believe the risk of toxic reactions to drugs in infants of
Initial Phase (2 months)
nursing mothers receiving antituberculosis drugs is very During the initial phase, there is rapid killing of TB bacilli.
low. Infectious patients become non-infectious within about 2
weeks. Symptoms improve. The vast majority of patients
TREATMENT OF TB PATIENTS with sputum smear-positive TB become sputum smear-
negative within 2 months. Directly observed therapy
Introduction (DOT) is essential in the initial phase to ensure that the
Aims of Anti-TB Drug Treatment patient takes every single dose. Rifampicin protects against
the development of drug resistance. The risk of drug
• To cure the patient of TB resistance is higher during the early stages of anti-TB drug
• To prevent death from active TB or its late effects treatment when there are more TB bacilli.
• To prevent TB relapse
• To decrease TB transmission to others.
Continuation Phase (4 to 6 months)
Properly applied anti-TB drug treatment will achieve
these aims and prevent the emergence of drug resistant Fewer drugs are necessary, but for a longer time, in the
M. tuberculosis. Effective anti-TB drug treatment is continuation phase. The drugs eliminate the remaining
properly applied short-course chemotherapy. The course TB bacilli. Killing the persisters prevents relapse after
of a anti-TB drug treatment is long, because it is difficult completion of treatment. Directly observed therapy is the
to kill the semi-dormant TB bacilli. ideal when the patient receives rifampicin in the
647
continuation phase. If local conditions do not allow Thiacetazone

directly observed therapy, the next best is as close
supervision as possible, for example weekly supervision. • Thiacetazone is associated with a high-risk of severe,
The risk of drug resistance is less during the continuation and sometimes fatal, skin reaction in HIV-infected
phase when there are fewer TB bacilli. individuals
The patient usually receives monthly drug supplies • Use ethambutol instead of thiacetazone in patients
for self-administered treatment during a continuation with known or suspected HIV infection
phase. • At present some countries do not have the resources
to substitute ethambutol for thiacetazone. The most
Retreatment Cases effective treatment available in some countries may
In DOTS the initial phase lasts 3 months, with directly still include thiacetazone. Where it is not possible to
observed therapy. The continuation phase lasts 5 months, avoid the use of thiacetazone, it is essential to warn
with close supervision. patients about the risk of severe skin reactions. Advise
the patient to stop thiacetazone at once and report to a
health unit if itching or a skin reaction occurs.
Standard Code for TB Treatment Regimens
However, in general its use is not recommended.
There is a standard code for TB treatment regimens. Each
anti-TB drug has an abbreviation. A regimen consists of 2 TB Treatment Regimens: Questions and Answers
phases. The number before a phase is the duration
of that phase in months. A number in subscript (e.g. 3) Why use 4 drugs in the initial phase?
after a letter is the number of doses of that drug per There is a high degree of initial resistance in some
week. If there is no number in subscript after a populations. Use of a 3-drug regimen runs the risk of
letter, then treatment with that drug is daily. An alternative selecting out drug-resistant mutants. This may happen
drug (or drugs) appears as a letter (or letters) in brackets. especially in patients with high bacillary loads, e.g.
cavitary pulmonary TB.
Examples • A 4-drug regimen decreases the risks of drug
2 SHRZ/6 HR—this is a common regimen. resistance, treatment failure, and relapse.
The initial phase is 2 SHRZ. The duration of the phase
is 2 months. Drug treatment is daily (no subscript Why use pyrazinamide only in the initial phase?
number, e.g. 3 after the letters), with streptomycin (S), Pyrazinamide has its maximum sterilizing effect within
isoniazid (H), rifampicin (R) and pyrazinamide (Z). The the first 2 months. There is less benefit from longer use.
continuation phase is 6 HE. The duration of the phase is
6 months. Drug treatment is daily, with isoniazid (H) Is a 4 months continuation phase possible?
and ethambutol (E).
2 SHRZ/4 H3R3—in some countries, resources are A 4 months continuation phase is possible with
available to provide rifampicin in the continuation phase rifampicin throughout (e.g. 2 SHRZ/ 4 HR). This is
as well as in the initial phase. because isoniazid and rifampicin are both potent
bactericidal drugs.
Use of Streptomycin and Thiacetazone
Why is it so important to prevent rifampicin resistance?
in Areas of High HIV Prevalence
Rifampicin is the most effective anti-TB drug. It is
Streptomycin unlikely that a new anti-TB drug will become widely
• In high TB/HIV prevalence populations, overcrow available in the near future. If rifampicin resistance
ding is common in TB wards. There is a risk of becomes widespread, TB will be effectively untreatable.
transmission of HIV and other blood-born pathogens
between patients How do we prevent rifampicin resistance?
• Streptomycin injections are very painful in wasted Bad TB control programs, lack of supervision of anti-TB
HIV-infected TB patients treatment, bad prescribing by clinicians, and the use of
• Many National Tuberculosis Programs (NTPs) now rifampicin alone generate acquired drug resistance. The
recommend the use of ethambutol in place of best way to prevent rifampicin resistance is to strengthen
streptomycin. NTPs and ensure directly observed therapy as for
648
as possible. It is important to use methods of drug side effects the margin is too narrow between the
administration which avoid the danger of the use of therapeutic and toxic dose.
rifampicin alone. These include the use whenever
possible of fixed-dose combination tablets and of anti- Liver Disease
TB drugs supplied in blister packs.
• Most anti-TB drugs can cause liver damage. Jaundiced
What is the treatment for multidrug resistant TB? patients who develop TB should receive treatment
with the following regimen: 2 SHE/6 HE
Multidrug resistant TB arises from failure to deliver anti- • Do not give pyrazinamide to patients with liver
TB drug treatment properly. Multidrug resistance disease.
represents NTP failure. In many high TB prevalence
countries, second-line drugs are prohibitively expensive
The Role of Steroid Treatment:
and unavailable, e.g. ethionamide, cycloserine, kanamycin,
capreomycin. Multi-drug resistant TB is, therefore often
Questions and Answers
untreatable. Inadequate treatment with inappropriate
What are the indications for treatment with steroids?
antituberculosis drugs may lead to development of
extensively drug resistant tuberculosis (XDRTB). • TB meningitis (decreased consciousness, neurological
Therefore it is very important to refer to a center with defects, or spinal block)
experience in treatment of MDR tuberculosis. • TB pericarditis (with effusion or constriction)
• TB pleural effusion (when large with severe
What should we do when faced with multidrug resistant symptoms)
TB? • Hypoadrenalism (TB of adrenal glands)
• TB laryngitis (with life-threatening airway obstruction)
The cause of the problem is NTP failure. The answer is
• Severe hypersensitivity reactions to anti-TB drugs
to devote time, effort and resources in improving the
• Renal tract TB (to prevent ureteric scarring)
NTP. In some countries, one or two specialist centers may
• Massive lymph node enlargement with pressure
have the specialist expertise and second-line drugs
effects.
available to treat patients with multidrug resistant
TB. What is adjuvant steroid treatment?
Adjuvant steroid treatment is steroid treatment given in
Use of Anti-TB Drugs in Special Situation
addition to anti-TB drug treatment. Prospective
Pregnancy controlled clinical trials have confirmed the benefit of
• Streptomycin during pregnancy can cause permanent steroids in TB meningitis and pleural and pericardial
deafness in the baby TB.
• Do not give streptomycin in pregnancy. Use
What are the recommended treatment doses of
ethambutol instead.
prednisolone?
Renal Failure Rifampicin is a potent inducer of hepatic enzymes which
metabolizes steroids. The effective dose of prednisolone
• Rifampicin, isoniazid and pyrazinamide are safe
is, therefore, half the prescribed treatment dose given to
• The excretion of streptomycin is renal. The excretion
the patient. Table 42.2 shows suggested treatment doses
of ethambutol and thiacetazone is partly renal
of prednisolone.
• Avoid streptomycin and ethambutol if there are
alternatives. Otherwise give in reduced doses at less
Is steroid treatment safe in TB/HIV patients?
frequent intervals
• Use of thiacetazone is not recommended. Besides its Steroids are immunosuppressants. The worry is that
steroids may further depress immunity and increase risk
of opportunistic infections in HIV positive patients.
Table 42.2: Suggested treatment doses of prednisolone
However, on balance, TB/HIV patients are still likely to
Indication Prednisolone treatment
benefit from the use of steroids for the above indications.
TB meningitis 2 mg/kg/day for weeks 1 to 4, then
decrease over 4 to 6 weeks
Monitoring of TB Patients during Treatment
TB pericarditis 1-2 mg/kg/day for weeks 1-4, decrease
over 4 to 6 weeks Bacteriological monitoring is readily available only for
TB pleural effusion 1-2 mg/kg/day for 1 to 2 weeks patients with sputum smear-positive pulmonary TB.
Routine monitoring of treatment response by chest X-ray
649
is unnecessary and wasteful of resource. For other TB Reaction Drug responsible

patients, clinical monitoring is the usual guide to treatment • Severe rash agranulocytosis thiacetazone*
response. • Hearing loss streptomycin
• Visual disturbance (poor ethambutol
Side Effects of Anti-TB Drugs vision and color perception)
Introduction • Renal failure, shock, or rifampicin
thrombocytopenia
Most TB patients complete their treatment without any *It is used rarely now.
significant drug side effects. However, a few patients
do develop side effects. So clinical monitoring of all TB
Management of Skin Itching/Rash
patients for side effects is important during TB
treatment. Routine laboratory monitoring is not The approach depends on whether or not the patient is
necessary. receiving thiacetazone. In populations with a high TB/
HIV prevalence, thiacetazone is the drug most likely to
How do health personnel monitor patients for drug side cause skin reactions.
effects?
a. By teaching patients how to recognize symptoms of Treatment Regimen Includes Thiacetazone
common side effects and to report if they develop If a patient starts to itch, and there is no other obvious
such symptoms.
cause (e.g. scabies), stop the anti-TB drugs at once. The
b. By asking specifically about these symptoms when
itching maybe a warning sign of severe skin reaction.
they see all patients atleast monthly during
Stopping the thiacetazone at once may avert, or decrease
treatment.
the severity, of the skin reaction.
Prevention of Side Effects Give the patient intravenous fluids if the skin reaction
is severe:
Health personnel should be aware of the special
a. Exfoliative dermatitis or toxic epidermal necrolysis
situations which influence the choice and dose of anti-
b. Mucous membrane involvement
TB drugs.
c. Hypotension.
It is possible to prevent the peripheral neuropathy
caused by isoniazid. This neuropathy usually shows as a Many physicians give steroid treatment, although there
burning sensation of the feet. It occurs more commonly in is no firm evidence that this helps. A typical dose schedule
HIV-positive individuals, in adults who are drinkers consists of 1 to 2 mg/kg/day (maximum 60 mg) daily of
(alcohol), and in patients with diabetes. These patients oral prednisolone until there is some improvement. A
should receive preventive treatment with pyridoxine 10 mg gradual reduction in dose over the next few days depends
daily. on the patient’s response. Initially, if a patient is unable to
swallow, give intravenous hydrocortisone 100 to 200 mg daily
Where to Manage Drug Reactions? (instead of oral prednisolone). On recovery, restart anti-
TB drugs, replacing thiacetazone with ethambutol.
Reaction Where to Manage
• Minor, e.g. Out-patient setting
gastrointestinal Never Give a Patient Thiacetazone Again After any
joint pains Thiacetazone Reaction
• Major, e.g. Refer to district or central A severe reaction may mean stopping anti-TB treatment
jaundice severe rash Hospital for 3 to 4 weeks. A severely ill TB patient may die without
anti-TB treatment. In this case, give 2 or more previously
When to Stop Anti-TB Drugs? unused drugs until the reaction has resolved. Then
When a patient has minor drug side effects, explain the reintroduce the initial regimen (with ethambutol instead
situation, offer symptomatic treatment, and encourage of thiacetazone).
him/her to continue treatment.
When a patient has a major reaction, stop the Treatment Regimen Does Not Include Thiacetazone
suspected drug(s) responsible at once. A patient who
develops one of the following reactions must never If a patient starts to itch, exclude other obvious causes.
receive that drug again: Try treatment with anti-histamines, continue anti-TB
650
treatment and observe the patient closely. In some cases, chemotherapy (SCC). If an HIV-negative patient has had
the itching resolves. In other cases, a rash develops. In a reaction (but not a severe reaction) to isoniazid or
this case, stop the anti-TB drugs. Wait for the rash to rifampicin, it may be possible to desensitize the patient to
resolve. If the reaction is severe, the patient may need the drug.
supportive treatment as above. Start desensitization with a tenth of the normal dose.
The problem now is reintroducing TB treatment when Then increase the dose by a tenth each day, until the
we don’t know which anti-TB drug was the one patient has the full dose on the tenth day. Once drug
responsible for the reaction. The table shows the standard sensitization is over, give the drug as part of the usual
approach to reintroducing anti-TB drugs one by one after treatment regimen. If possible, while carrying out
a drug reaction. desensitization, give the patient 2 anti-TB drugs which
the patient has not had before. This is to avoid the risk of
Reintroduction of Anti-TB Drugs Following Drugs
drug resistance developing during desensitization.
Reaction Caution: However, never attempt desensitization in TB/
If possible, while the patient undergoes drug challenging, HIV patients because of the high risk of serious toxicity. The
give 2 anti-TB drugs (Table 42.3) which the patient has following method for desensitization, therefore, does not apply
not had before. The idea of drug challenging is to identify to TB/HIV patients.
the drug responsible for the reaction. Drug challenge
starts with the anti-TB drug least likely to be responsible Never Attempt Desensitization in TB/HIV Patients
for the reaction (i.e. isoniazid), start with a small challenge
dose. If a reaction occurs to a small challenge dose, it Management of Hepatitis
will not be such a bad reaction as to a full dose. Most anti-TB drugs can damage the liver. Isoniazid and
Gradually increase the dose over 3 days. Repeat the pyrazinamide are most commonly responsible.
procedure, adding in one drug at a time. A reaction after Ethambutol is rarely the causative drug. When a patient
adding a particular drug identifies that drug as the one develops hepatotoxicity during anti-TB treatment, it may
responsible for the reaction. not be the anti-TB treatment but another cause. It is often
If the drug responsible for the reaction is pyrazinamide, difficult to find out. Try to rule out other possible causes
ethambutol, or streptomycin, resume anti-TB treatment before deciding that the hepatotoxicity is drug-induced.
without the offending drug. If possible, replace the Hepatitis presents with anorexia, jaundice and often
offending drug with another drug. It maybe necessary tender liver enlargement.
to extend the treatment regimen. Consider the start of If you diagnose drug-induced hepatotoxicity, stop the
anti-TB drugs. Wait until the jaundice resolves. It is
the resumed regimen as a new start of treatment. This
strange, but fortunate, that in most cases the patient can
prolongs the total time of TB treatment, but decreases
restart the same anti-TB drugs without hepatotoxicity
the risk of recurrence.
returning. A severely ill TB patient can die without
anti-TB drugs. To avoid this, treat the patient with 2 of the
Refer Patients with Severe Drug Reactions to Specialist least hepatotoxic drugs, streptomycin and ethambutol.
Centers When the hepatotoxicity resolves, re-start usual anti-TB
Desensitization treatment as detailed earlier.
Rarely, patients develop hypersensitivity reactions to the Few Important Questions about Abdominal Tuberculosis
2 most potent anti-TB drugs, isoniazid and rifampicin. TB of the gastrointestinal tract (digestive system) and
These drugs form the corner-stone of short-course abdominal cavity is known as abdominal tuberculosis.
Table 42.3: Reintroduction of drugs after a reaction

Drug Likelihood of causing a reaction Challenging doses
Day 1 Day 2 Day 3
Isoniazid least likely 50 mg 300 mg 300 mg
Rifampicin 75 mg 300 mg Full dose
Pyrazinamide 250 mg 1 gm Full dose
Ethambutol 100 mg 500 mg Full dose
Streptomycin most likely 125 mg 500 mg Full dose
651
How does abdominal TB occur? However, other supportive tests that may be done are
Ingestion of the tuberculous germ by drinking the Mantoux test, Chest X-ray, Abdominal X-rays (with
unpasteurized milk of a cow infected with TB is one of or without barium) and scans such as ultrasound and CT
the mechanisms of abdominal TB. scan.
Abdominal TB can also occur by spread of the TB
What are the complications of abdominal TB?
bacillus from the lungs to the intestines by the blood stream.
In 2/3rd of children, there is predominant involvement of Untreated TB of the intestine may lead to intestinal
the digestive system. Involvement of the abdominal cavity obstruction, fistula or even abscess and perforation with
(peritoneum) occurs in remaining patients. Involvement of resultant peritonitis.
the lymph glands only in the abdomen is rare.
What is the treatment of abdominal TB?
What are the signs and symptoms of abdominal TB?
Abdominal TB needs to be treated with at least
Clinical feature of abdominal tuberculosis are varied. The 3 to 4 anti-TB drugs for the initial 2 months and
most common symptoms are pain in the abdomen, loss subsequently 2 anti-TB drugs for at least 7 to 10 months.
of weight, anorexia, recurrent diarrhea, low grade fever, The commonly used drugs during the initial 2 months
cough and distention of abdomen. therapy (Intensive phase) are isoniazid (INH), rifampicin,
The doctor on examination may feel a lump, fluid or a ethambutol and pyrazinamide. During the next 7 to 10
doughy feel in the abdomen. Also there may be enlarged months (continuation phase) the two drugs commonly
lymph glands elsewhere in the body. used are INH and rifampicin.
How is diagnosis of abdominal TB made? When is surgery required for abdominal TB?
Diagnosis can be confirmed by isolating the TB germ from Surgery is required whenever there is perforation,
the digestive system by either a biopsy or endoscopy. abscess or fistula formation.
43 Ethical Issues and Concerns about
Tuberculosis Research in Children
Roli Mathur, Prashant Mathur, Vimlesh Seth
INTRODUCTION aspect’.7 The clear link between TB and poverty deserves

an ethical discourse.
Tuberculosis (TB) is the most important infectious cause
of adult deaths, and persons carrying acid-fast bacilli ETHICS, HUMAN HEALTH AND RESEARCH
(AFB) in their sputum are the most infectious group in
the community.1,2 Children exposed to adults with General Issues
smear-positive pulmonary TB have a high risk for
acquiring infection, and this risk increases with the Access to adequate level of health care is recognized as a
closeness in the degree of contact.3,4 In countries with universal and fundamental human right and equity is a
high incidence of TB, risk of infection among children in fundamental principle of all health policies. Availability
of effective, accessible, affordable and locally acceptable
contact with adults with TB is 30 to 50%, which is much
health services is an ethical requirement. A meaningful
higher than that reported by industrialized countries.5
participation of communities in the development of
Although rates have fallen in industrialized countries,
health research, services and policies is the need of the
TB still remains a scourage in marginalized communities.
hour.
Despite evidence of its cost-effectiveness, program
Research in developing countries is going to become
delivery in developing countries faces several
increasingly important in order to solve the existing and
impediments in serving adults as well as children. The upcoming health problems. As a consequence it becomes
necessary health infrastructure is to be prevented from necessary to mobilize funds from national and
decay, and efficient drugs and diagnostics are to be international sources to carry on relevant research and
adequately funded.6 to harness the technical guidance from developed
Selgelid et al6 observed that though TB is second to countries. In this process it is essential that countries
HIV/AIDS as a cause of death, it still may be more develop adequate capacity in research capabilities, ethical
important for two reasons: (i) TB has been treatable and conduct of research and ethical review procedures. Major
curable for over 50 years at low cost (ii) its public health Ethical, Legal and Social Issues (ELSI) need to be
impact is even greater than HIV due to its airborne continuously debated and require attention to
transmission.
understand reasons and ways to protect autonomy,
The impact of national TB programs delivered
privacy, confidentiality, preventing stigmatization and
through the public health system was recognized by the
discrimination of research subjects. All these above
World Bank in 1990 as the most cost-effective life-saving
mentioned procedures are also required for conduct of
intervention, equal to immunization, but the international
any research in drugs, devices and vaccines, like BCG in
community was slow to scale up. As a result, poorly
the case of tuberculosis.
managed programs led to the emergence of drug-
Recent advances in science and technology have
resistant TB. The cause of extensively drug-resistant TB
brought along numerous ethical dilemmas. Advances
(XDR), often attributed to poor patient compliance, is
more likely the result of poor services, lack of infection in biotechnology, genomics, genetic engineering, organ
control, human resource shortages, delayed diagnosis, and tissue transplantation, new reproductive
poor quality drugs and treatment interruption. There is technologies, cloning, medical devices, recombinant
inadequate emphasis on children among TB studies products, surgical innovations, life support systems all
conducted in adults. The responsibility for all of this must pose challenges to the conscientious researchers and the
be widely shared, and an ethical discourse encouraged society has to evolve acceptable solutions to benefit the
addressing it. Sir William Osler (1849–1919) described majority. Each of these requires careful scrutiny by
tuberculosis (TB) as a ‘social disease with a medical appropriate scientific and ethics committees before any
653
Chapter 43 Ethical Issues and Concerns about Tuberculosis Research in Children
research is undertaken. There is no single solution to children by obtaining informed consent from the legal
any issue and decisions are taken on case-to-case basis. guardians wherever necessary and obtaining assent from
The goal of science is to explain and predict natural minors. Recruitment of those with diminished autonomy
phenomena. A discussion regarding the need to: also requires special consideration and adequate
i. Conduct research that is scientifically rigorous, and justification. Hence obtaining ‘Informed Consent’ has
ii. Accords the participants benefits and protections become the most crucial requirement in any clinical
that are due to them as human subjects is crucial. research. The principle of Justice demands that the fruit
These two goals can conflict with one another, leaving of research is equitably distributed amongst the
beneficiaries and participants of research. This has
researchers institutional ethics committees, grant
gained global importance in view of growing inter-
application review groups, and funding agencies with
national collaboration between developed and develop-
the responsibility of striking an appropriate balance.
ing countries. Selection of subjects, equitable study
Thus, both patients and healthy people become targets design and access to post-trial benefits are the hallmarks
of such studies. The practice culminates in surveillance, of this principle.
health programs and monitoring and program All clinical research involving human subjects should
evaluation. Their outputs apply to communities and take the above principles into consideration while
improve epidemiological practice, whereas clinical planning, conducting and evaluating the research and
research targets individuals or a small group of subjects during utilization of the research results. Several
to improve clinical care. In carrying out their research, international documents are available which have been
one should abstain from conduct that may injure or prepared by different agencies and these have also
jeopardize the welfare of study participants either highlighted the above.12-15
through their intentional or unintentional behavior
actions (e.g. negligence or unjustified departure from Vulnerability and Children
study protocols or standards of practice) or omissions. Biomedical research, including clinical trials and related
Consideration of risks includes attention not only to scientific research, rely on the successful recruitment of
physical risks as a result of direct contact with the human participants in order to yield meaningful results.
participants but also to psychological, economic, legal, In this sense, human participants are instrumental in
or social risks.8 securing data useful to the researcher, which is often
extrapolated to develop clinical techniques/drugs/
Principles of Biomedical Ethics methodologies applicable across a broader range of
The ethical guidelines of the Indian Council of Medical human populations. This interplay between results
Research (ICMR) were first prepared in 1980 as a Policy driven research and the necessary involvement of human
Statement9 and were subsequently revised in 200010 and participants naturally creates tension between procuring
2006.11 These documents were prepared after wide scientific data and the proper ethical treatment of research
stakeholder consultations and public debates. The participants.16
All vulnerable populations stand in unequal power
guidelines are recognized internationally.
relationships with others that typically do not
The basic principles enshrined in the Ethical
characterize ‘normal’ (or most) members of society. Such
guidelines are the following:
relationships may instantiate themselves in numerous
• Nonmaleficence – Do no harm
ways to create differing vulnerabilities across groups.
• Beneficence – Fruitful result, do good
The clinical researcher must be aware of the concerns
• Autonomy – Respect for persons specific to each vulnerable population and adjust his
• Justice – Distributive justice, equitable distribution of research protocols to compensate. Each vulnerable
risks and benefits. population deserves individual treatment according to
The purpose of research, its potential benefits to their specific circumstances. Of concern are individuals
participants, the anticipated risks and compensations for who are already disadvantaged or vulnerable to harm
the same, the unexpected consequences and steps independent of their involvement in clinical trials. Such
proposed to tackle the same, the evaluation of risk benefit participants, for whatever reasons, have been
ratio are all covered under the principles of Non- marginalized by society and are susceptible to
maleficence and Beneficence. The fundamental moral exploitation. They typically stand in unequal power
principle of “Respect for Persons” demands voluntary, relationships with others and/or possess substandard
informed consent from individuals participating in mental faculties, rendering them incompetent: key
research and is termed as the ‘Autonomy’ principle. This examples include the mentally disabled, abjectly
includes right to privacy and confidentiality and impoverished persons, prisoners/refugees, women/
obligations to protect the vulnerable groups including pregnant women, children, and ethnic minorities, etc.
654
Vulnerable populations are attractive for research required for responsible decision-making about
purposes precisely because of their vulnerability. participation by children or adolescents in experiments.
Transgressions of ethical boundaries become easier as Child health providers must always remain cognizant
does the consequent procurement of scientific data. of the link between health and human rights. 22 An
Thus, the entire field of research ethics has been built investigator’s presence in a developing country entails his
upon and refined according to examples of ‘extreme’ or her responsibility to take an interest in the general health
clinical research that have dotted modern history. and welfare of the population, emphasizing an awareness
The historical origin of current ethical principles for of nonmedical factors, such as war and drought, which
conducting research with children arises from the clearly have an impact on the health of children. An
Nuremberg Trials, which took place after the Second understanding of the determinants of health in each
World War, and the Nuremberg Code,17 which emerged unique community, combined with close collaboration
from these. The Code sets out statements of certain moral, with local health professionals, should guide the
ethical and legal principles relating to research involving development of ethical health research agendas in the
human subjects. Later, the emergence of the Declaration future.
of Helsinki14 in 1964, amended in 1989, 1996, 200818 Ethical research aims to reduce health inequities, by
includes an examination of the issue of children as serving to benefit primarily the population from which
research subjects in relation to informed consent. the study participants are recruited, and benefit
Children are a vulnerable population in even the secondarily all children on a global scale through the
richest parts of the world, yet the role of health transposition of the acquired knowledge. The second
researchers involving children in the poorest regions is factor underlying unethical priority-setting in child
a particularly pressing issue that should be addressed health research is that children have been notoriously
by the pediatric research community in a timely and ignored in the process by which new drugs are approved
meaningful manner. Ethical considerations are integral and brought to the market, a problem that has led
to all child health research throughout the world.19 investigators to characterize children as ‘Therapeutic
Research involving children has historically been Orphans’. A recent report23 reveals that the ‘drug gap’ is
discouraged on ethical grounds, and was essentially widening due to a virtual complete lack of interest of the
barred by the Nuremberg Code (1949).17 However, there
major pharmaceutical corporations in diseases that afflict
is growing recognition of the ethical imperative to include
those who are poor. Investigators involved in the design
children in research studies,20 particularly in light of
of a pediatric research project should consider three levels
evidence that child health research is not only beneficial,
at which a study may impact a society.24
but that the absence of pediatric research can be
1. The direct effect of the specific research project on
harmful.21 There is likewise the obligation to adhere to
study participants and their families.
ethical guidelines to protect the safety, human rights and
2. The impact of the study in terms of expected health
cultural integrity of the children, their families and their
outcomes among children in the community or
communities. A proactive ethical approach to global child
country in which the study is conducted.
health research serves children in two broad ways:
3. The broad effect of intervention by foreign health
1. Adherence to ethical principles leads to the
professionals on the community or region.
development of a set of rational and relevant priorities
and objectives. In relation to drug related research for TB in children,
2. Promoting ethics ensures that observational or two important aspects are:
interventional methodologies are consistent with the 1. Use of drug regimens according to the severity of
customs and needs of the specific population with disease.
whom the investigators are working, and are mindful 2. Pharmacokinetic studies of various antitubercular
of the reality within which the community exists. drugs in relation to age, nutritional and acetylator
Efforts to improve the health of children depend on phenotype (pharmacogenomics).
clinical investigations that use children as research As regards ethnic groups, people in the South of India
subjects. Children are a vulnerable population, however, are rapid acetylators and up North are slow. It is
and so are accorded special protection from research especially important in relation to drug isoniazid.
risks. Researchers in pediatrics may encounter conflicts The degree to which a child stands to benefit from a
between protecting the children who are vulnerable particular experimental intervention depends on the risk
research subjects and, developing generalizable of morbidity or mortality resulting from the illness to
knowledge to benefit children. Furthermore, there are which the intervention is targeted. Guidelines sponsored
many pitfalls for the researcher in carrying out the by the Canadian Pediatric Society state that exporting
communication with both parents and children that is research to other countries to avoid placing our own
655
children at risk neglects the social responsibility to protect reduced capacity to understand the matter to which they
and benefit all children.21 However, given the higher are assenting.
incidence of adverse outcomes of infectious diseases and The process of obtaining voluntary, informed consent
nutritional deficiencies in impoverished regions, some needs consideration. The case does not indicate the
interventions may have relatively greater benefits for socioeconomic level of the participants. If they are from
participants in these settings (e.g. zinc supplementation a low socioeconomic and educational background, there
to reduce the incidence of pneumonia).25 Therefore, a is a possibility that they will be unduly swayed by the
higher level of risk may be deemed to be acceptable if offer of free tests and modest environmental inter-
the overall risk-benefit ratio remains unchanged or ventions. Human subjects research guidelines for
improved. It is unethical, however, to locate children with children require that the permission of parents or
greater ‘background risks’ with whom to conduct a study guardians must be obtained, since children are
to justify higher-risk research.26 In general, research considered unable to give legally valid informed consent.
should not be conducted in children where: The information given to subjects and parents should
certainly include the purpose of the experiment and the
1. The information can be gained equally well in adult
risks and benefits involved. In the case of the control
volunteers;
group, it should be made clear to both parents and
2. It will expose children to significant risk that exceeds
children that their involvement is not for their own
the magnitude and likelihood of potential benefit; and
benefit but for the benefit of others. The information must
3. Suitable preliminary studies have not been conducted be made available in a manner easily understood by both
in adults first. For example, children should not usually parents and children, particularly if they are from a
be the subject of ‘first in man’ and other early phase disadvantaged population.
studies of new drugs. A process of valid informed consent is necessary in
There are clear exceptions to this principle such as almost all research settings, and assent from minors must
testing drugs or devices in diseases found most accompany consent of a legal guardian where possible.18
commonly, or exclusively in children. The intricacies of proxy consent required in pediatric
There are some situations wherein research in research is further complicated by the challenge of
children maybe warranted, e.g. obtaining valid informed consent in a developing world
1. To ensure optimal diagnosis, assessment, treatment perspective.27,28 There are at least two ways in which we
and prevention of disease during childhood; can increase the contextual suitability of informed
2. Advance the health and welfare of children; consent/assent processes, without compromising
3. Identify the determinants of child health; universal ethical standards. First, we should conduct
4. Contribute to understanding the pathophysiology of prospective, empirical studies of the informed consent
childhood disease; process in developing countries such that our practices
5. Contribute to understanding of the childhood origins will reflect evidence-based ethics. Second, we should
of adult health or disease; and/or promote the routine creation of community advisory
6. Improve the methodology of research in children. boards, which have been used successfully to facilitate
the implementation of informed consent processes that
Establishing a Valid Informed reflect the needs and wishes of study participants.29
Consent/Assent Process One of the most important ways in which ethical
research methodology promotes health equity is by
There is a long-standing moral and legal tradition that exemplifying the principle of distributive justice, which
supports parents as the primary decision-makers for their states that “studies should be designed to obtain
minor children, including the right to make proxy knowledge that benefits the class of persons of which
decisions for children about participation in research. the subjects are representative”. 30 Even if ethical
Parental decision-making is a critical factor in the study priorities exist, it is not enough to simply conduct
of pediatric research ethics, even though it is recognized pediatric research within a developing country; rather,
that parents, as well as health researchers, may have the design of every study must be such that the
interests that conflict with the best interests of the child. outcomes can be feasibly used to improve child health
Today, the legitimate role of the child in decisions within that same region. The effect of research is not
about research participation is recognized. The ethical only in the application of the knowledge acquired by
concept of assent provides a framework to assist analyzing the collected data, but also results from the
investigators and parents with efforts to incorporate the act of doing the study itself, and by the process of
views of children who are recruited as research subjects. intervening as health professionals in a foreign country.
Assent is analogous to consent where the subject has a A basic tenet of biomedical ethics, primum non-nocere
656
(do no harm), reminds us that sometimes doing nothing could be said to be acting illegally. One parent can give
at all is better than doing something potentially consent but it is preferable to have both. Where there is
damaging. Despite the ethical obligation to promote parental disagreement as to whether an ‘incompetent’
pediatric research abroad, investigators must consider child should be volunteered for research, it is possible
the overall impact of intervening and/or interfering, that one parent could apply to court to block the child’s
given the endless list of examples of failed and even participation. The Ethics Committee may in such
damaging development projects in the past.31 circumstances advice that where there is disagreement,
It is essential that the child has full information about the child should not be included in the research.
the research in order to give their ‘informed consent’ to
take part, and that consent is ‘freely volunteered’. The child Confidentiality Issues
should also know that he/she can withdraw at any time.
Information presented to the child and parent, should Confidentiality must be explained in a way that children
explain: What will happen; what is being asked of the child; can understand that his/her identity will be protected
that the child can agree – or disagree to take part – without by the investigator. The researcher present at the
adverse consequences; and may withdraw at any time; interview is rarely the only person to see the results. It
and be given in clear language at a level that the child can must therefore be made very clear who will have access
understand, using visual aids if necessary. The consent to the data and what will happen to the data when the
from a child who is a minor is called as assent. This may research is complete. The methods of removing names
be verbal or written. Generally it is expected that the and other identifying information should be explained
investigator/researcher makes an assessment of the in case the research involves anonymization. The extent
capacity of the child to give assent or not. Generally for of the anonymity and any potential areas where the
children between the ages of 7 to 12 years, only verbal confidentiality of the interview may be broken should
assent may be required. For children between 12 to 18 be explained to the child at the outset of the interview.
years, an assent form in simple language may be designed. For example, the researcher has a duty to take steps to
In dealing with children, dissent plays an important role protect the child or other children, if they are considered
too. Children who give dissent or do not agree there choice to be ‘at risk of significant harm’. The child needs to know
should be respected and they should not be enrolled. what action may be taken in the event that she discloses
However, in cases where the research is of immediate that they or others are at risk of ‘significant harm’, or
direct health benefit to the child, if the parents are willing where the researcher observes or receives information
the child may be enrolled in the study.
of incidents likely to cause harm. Arrangements need to
Under the US regulations, children should be enrolled
be made in advance, following professional advice, on
in clinical research only when it offers a compensating
agreed procedures in these cases, and for support for the
potential for benefit or poses sufficiently low risks.32-34
child. Information can be given about the storage of data
The research risks should be higher than what the
children would experience in their daily living or routine and who will have access to it, and how it will be used,
examinations.35 However, the risk varies significantly in the same clear language as used about the research. It
with age.36 Thus, Institutional Ethics Committees (IEC) can be argued that use by secondary researchers is not
could follow the options of either adopt the minimum greatly different from that of primary researchers on the
risk threshold that applies to research with children of research team, who have not been directly involved in
all ages, or adopt a different risk threshold for each stage the collection of the data. Assurances can be given about
of development, or follow a minimal risk threshold for the anonymity of the data, with the removal of names
each age. The IEC could follow either options, but this and any identifying information, to meet the concerns of
would pose a problem in multisite studies wherein IEC the child and responsible adult. It is recommended that
differences may be there. written information should always be provided for the
child and responsible adult, and a contact telephone
Parental Consent number, should they wish to contact the researchers.
Parental consent is required where it is viewed that a
child is incapable of understanding the implications of Ethical Issues in Conduct of
taking part in a study or where the child is regarded as Vaccine Trials Among Children
incompetent to give consent. Although the child’s assent
is advisable, the power to consent, in law, is that of his/ There is a recognized special need to develop TB vaccines
her parents or legal guardian. Those acting for a child appropriate to children because of the high disease
are only acting legally if participation in the project is of burden. But any clinical trial for the development of new
benefit to the child. If it is not, the parent or guardian vaccine must be closely reviewed by an appropriately
657
constituted ethics committee. The different aspects medical insurance should be in place to provide for
considered include the balance of benefits and risks, the medical care for injury or death related to the trial.
choice of control groups, the selection of participants, Compensation for participation need a special mention.
vaccine development strategies, the informed consent The amount of compensation should be commensurate
process, the appropriate standard of care, post-trial access with the expenses or loss or wages, cover for the fare.
to efficacious vaccines, trial management and oversight, However, this amount should not be so large that this
and follow-up of participants after a trial has ended.36 becomes an undue inducement to the parents to put their
Due to the special vulnerability of child participantion child/ infant to risk for obtaining the money. It is
in vaccine trials, additional safeguards should be in place preferable to either have actual reimbursements or
in any vaccine study. These safeguards include compensate in kind rather than cash by providing
identification and addressing their vulnerability and healthcare facilities. Adequate monitoring by a Data and
protecting them from any exploitation, and from mental, Safety Monitoring Board should be recommended by the
emotional and physical harm. Considering the principles Ethics committee to the sponsor.
of beneficence and justice, it is important that the choice There is growing global concern for maintaining
of the particular group of children to be included in a uniform ethical standards in biomedical research and
trial requires clear justification of the scientific need to practice all over the world in view of the exceptional
use that population, and an equitable sharing of benefits potentials of science and technology for betterment of
and risks among possible groups.37 If the targeted group mankind. There is need for review, build consensus on
belongs to a community it is advisable to include a the technical and ethical safeguards and to consider how
member of the community in the discussions of the ethics to move forward from moral reasoning to global action
committee. This would help to assess the needs and look in the interest of advancing human well being. The
at ways to fulfill the requirements of the community and challenge before all is to clarify the meaning of the rising
in addition also provide appropriate representation and ethical issues, help to assess current needs and practices
acceptability by the targeted community for the vaccine and find solutions for the same. Since 2007, there is a
trial. If the vaccine being developed is for neonates or Clinical Trials Registry of India (CTRI) funded by the
infants, it may be unethical to carry out the trials in older Department of Science and Technology (DST) and Indian
children as this may expose them to risks though they Council of Medical Research and managed at the
cannot benefit from the vaccine. However, it may be National Institute Medical Statistics under the Indian
acceptable to carry out such trials in adult participants Council of Medical Research (ICMR), Department of
who can give voluntary informed consent after Health Research, Ministry of Health and Family Welfare,
understanding the risks without any direct benefits. Govt. of India. Since 15th June, 2009, it is mandatory to
Particular care and consideration should be given to register any clinical trial approved by Drug Controller
populations that are especially vulnerable and to “over- General of India with CTRI.38 Further, a large number of
researched” populations. Another critical issue comes up medical journals have made it mandatory that they will
in the placebo controlled clinical trials. In children not publish any clinical research article unless clinical
administration of an inactive placebo by injection trials registry number is there. The clinical trials can be
involves pain and discomfort without any corresponding registered at www.ctri.in.
benefit. Therefore, it should be considered taking into
consideration the scientific validity of research if an active TUBERCULOSIS DIAGNOSIS, TREATMENT, CONTROL,
comparator that comprises an available marketed vaccine PREVENTION, ERADICATION
related or unrelated to the condition and would provide AND ETHICS
some benefit to child participants may be given as an Infectious diseases raise difficult questions about how
“active control”. While reviewing protocols for vaccine the aim to promote public health should be balanced
trials the institutional ethics committees should see and against the aim to protect human rights and liberties; and,
ensure that the trial sponsors and researchers would also because infectious diseases primarily affect the poor and
contribute to the improvement of healthcare infra- disempowered, the topic of infectious disease is closely
structure especially in the situation of low socioeconomic connected to the topic of justice. There are, furthermore,
communities that experience a high burden of disease reasons for thinking that the problem of TB is, ethically
and low standards of healthcare. A standard of care speaking, even more important than AIDS. In the vast
should be offered that improves the health conditions of majority of cases, TB drugs provide cure and they are
the trial participants and community. The IEC should much less expensive than AIDS medications. TB
also review the plans for post-trial benefits and long-term mortality is, economically speaking, much easier to
follow-up of the participating children. Preferably a prevent. Finally, being airborne, TB can be contracted
658
via casual contact and is much more contagious. In many The Public health actions around TB prevention and
ways, then, the threat to ‘innocent individuals’ control should consider the following:
particularly children under five years of age those who 1. Address principally the fundamental causes of
become immunocompromised due to infectious disease disease and requirements for health, aiming to
of infancy such as measles and malnutrition and also a prevent adverse health outcomes.
threat to the public health in general—is greater in the 2. Achieve community health in a way that respects the
case of TB. TB is arguably the most important neglected rights of individuals in the community.
topic in bioethics.7 3. Policies, programs, and priorities should be
It is well recognized that it is unethical to conduct developed and evaluated through processes that
research on children if it could be done equally well ensure an opportunity for input from community
members.
among adults. However, there is a huge disease burden
4. Advocate and work for the empowerment of
among children and a paucity of research being done
disenfranchised community members, aiming to
that directly relates to the health needs of children. It used
ensure that the basic resources and conditions
to be considered that TB in children is not a public health
necessary for health are accessible to all.
problem because it is paucibacillary, is usually not 5. Seek the information needed to implement effective
responsible for transmission of disease in the community policies and programs that protect and promote
except the adolescent who develops open TB from an health.
adult in the family (bacillary). This is a myth because 6. Programs and policies should incorporate a variety
this group with primary disease can transmit the disease of approaches that anticipate and respect diverse
in the community when as adults they develop bacillary values, beliefs, and cultures in the community.
form of pulmonary TB.1 7. Programs and policies should be implemented in a
Tuberculosis is considered a neglected disease by manner that most enhances the physical and social
Drugs for Neglected Diseases initiative (DNDi). The environment.
neglect is more pronounced in children because drugs The Institutions involved in providing care should:
available are not child-friendly and the second-line drugs 1. Provide communities with the information they have
are toxic, either hepatotoxic or more dangerous that is needed for decisions on policies or programs
nephrotoxic. Streptomycin can be neurotoxic (deafness) if and should obtain the community’s consent for their
it is used in early infancy without monitoring of ear implementation.
function for hearing. 2. Act in a timely manner on the information they have
Several ethical concepts and conflicts have been within the resources and the mandate given to them
identified around TB treatment and control.6 by the public.
a. Restriction of movement: Which involves isolation, 3. Protect the confidentiality of information that can
quarantine and migrant screening. The debate is bring harm to an individual or community if made
liberty versus utility, freedom of movement versus public. Exceptions must be justified on the basis of
public health, protection of individual versus society the high likelihood of significant harm to the
individual or others.
and responsibility for public health.
4. Institutions should ensure the professional compe-
b. National surveillance: Privacy and stigma.
tence of their employees.
c. Obligation to avoid infecting others: Duty to do not
5. Institutions and their employees should engage in
harm, legislating mortality.
collaborations and affiliations in ways that build the
d. Third party notification: Right to confidentiality versus
public’s trust and the institution’s effectiveness.
protection of the innocent, trust in healthcare system
and its implications for public health. CONCLUSION
e. Duty to treat: Professional obligations, autonomy and
The spectrum of childhood TB involves primordial
societies responsibility to promote safe working
prevention, identification of susceptible contacts of cases,
conditions.
prevention of disease transmission, management of cases,
f. Treatment exclusion: Right to healthcare, discrimi- and public health programs. Research is undertaken at
nation, primacy of patient Vs public health. these levels by local and international investigators.
g. Clinical research: Standards of care, managing third Children constitute a vulnerable population and hence
party risks. demand careful ethical introspection. Issues and concerns
h. Justice and the distribution of health resources: Right which are relevant to the overall child health research form
to healthcare access and availability, distribution of the framework for TB research and practice. Bioethics is a
research resources, rich country obligations to constantly evolving field which nourishes from changing
increase aid for self interests. scientific issues and subject vulnerability.
659
HIGHLIGHTS 16. Lott JP. Vulnerable/special participant populations.

Module Three, Developing World Bioethics, 2005. Vol 1
• Tuberculosis in children continues to be a major (5 Blackwell Publishing Ltd): 1471-8847 (online): pgs
public health problem in India. 30-54.
• Ethical considerations need to be kept in mind while 17. The Nuremberg Code. Trials of War Criminals Before
planning clinical care, research, diagnostic and the Nuremberg Military Tribunals under Control Council
therapeutic interventions in children. Law No. 10. Washington: US Government Printing
• Ethics is a constantly evolving issue and requires Office, 1949; 2: 181-2.
ongoing debate and resolution so as to protect the 18. World Medical Association. Declaration of Helsinki:
vulnerability of children. Ethical Principles for Medical Research Involving Human
Subjects. Rev. 2008 <http://www.wma. net/e/appro-
vedhelsinki.html> (Version current at September, 2009.
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44 Tuberculosis in Children:
Research Priorities
Vimlesh Seth
RESEARCH IN PEDIATRIC PRACTICE 5. International Agencies like WHO, STOP, TB, etc. also
concentrate on TB in adults; children are again a
The current status of medical research as such in children neglected lot.
in India is in an abysmal state as stated by President of
President of the Indian Academy of Pediatrics in 2007
Indian Academy of Pediatrics in 2007. He opined that
emphasized that there is an urgent need to invest in
there is dearth of good quality publications particularly
medical research, the IAP has prepared three consensus
in reputed indexed international journal.
reports on diagnosis and management of TB in children
In India with crash commercialization of health sector
the last being published in 2010 (discussed in a chapter
and entry of big corporate houses in health-care facilities,
of the book). These are merely guidelines for having
the quality medical research has suffered and lost its
uniformity in diagnosis and management of TB in
prominence. Need of investing in research seems to be a
children. These do not emphasize the areas of TB to be
non-profitable expenditure by these big business houses.
researched. The president emphasized the need to
encourage the practicing pediatricians in research. The
Reasons for Poor State of Medical Research in India pediatricians of medical colleges need to become role
model in the research. Practicing pediatrician are too busy
Lack of research culture even in medical colleges barring
providing preventive and curative services to children.
a few centers of excellence which can be counted on finger
Only a few can be motivated for research.
tips is evident. There is lack of aptitude for original
research, acknowledgment of quality research work, and Before pediatric research in office setting is to be
opportunities for those entering this field. Due to lack of started, it’s first the medical colleges (Pediatric
proper infrastructure to carryout quality research work Department) that should follow a uniform pattern of
there is a lack of research opportunities and scholar jobs. diagnosis and treatment of TB in children. In this book
Independent research avenues are glaringly few and far in the chapter on how to start a TB and HIV Pediatric
between. There are few independent bodies of clinic, various case record forms for both has been
Government of India sponsoring, facilitating and designed. Even to start with if this practice is followed
supervising research activities in the country. To name a and as DOT center being present in all medical colleges,
few these are the following: some beginning can be made. It is suggested by Seth1
1. Department of Health Research, the Indian Council that even if one DOT worker is provided to the Pediatric
of Medical Research is only one national body TB clinic in each medical college, some semblance of
significantly contributing in health research in all its uniformity of at least collection of data on TB in children
aspects, including tuberculosis in children. can be achieved.
2. Department of Science and Technology. This also In Government of India, there is a separate TB division
finances big industrial houses engaged in research with senior Deputy Director General (DG) in the Ministry
not necessarily medicine leave aside pediatrics. of Health and Family Welfare. He is responsible for
3. Council of Scientific and Industrial research. This also facilitating smooth running of Revised National
finances research in tuberculosis and also
Tuberculosis Control Program (RNTCP). Some effort is
pharmaceutical companies in drug development.
being made in the form of guidelines for diagnosis and
4. Department of Biotechnology. Its head now is a
treatment of TB in children in this program. These need
medical person and is a very positive researcher and
helps in financing big projects in medical research. to be religiously followed. Till late even 1 TU strength
However, this started about 3 to 4 years ago and PPD was not available at libitum for doing tuberculin
hopefully this will show some results. To procure test. There are lots of lacunae in the national program as
funds from this body one has to be a keen researcher discussed by program managers in another chapter in
and be able to crystalize the problems to be researched the book.
particularly in children and that too specifically in Problems of general importance such as annual risk
TB in children. of TB infection, surveillance of MDR-TB in few selected
662
areas have been the point of investigations but there is 2. Access to quality-assured sputum microscopy for all
need to give specific attention relevant to children only. cases of TB. Special attention is necessary for case
In the international forum, a research agenda for childhood detection among the HIV-infected and other high risk
tuberculosis for improving the management of childhood groups, such as household contacts of infectious cases.
tuberculosis with in National Tuberculosis Programs, research In children to have sputum for smear-microscopy is
priorities based on a literature review have been drawn. This an extremely difficult task. Recent introduction of
was done in 2007 by STOP.TB, Department of Child and induced sputum technique, for collection of sputum
Adolescent Health and World Health Organization.2 specimen seemingly has some hope but its feasibility
The points emphasized in this are discussed below: at the operational level needs a concerted effort.
which could be applicable to India. Gastric lavage though mentioned frequently is very
The main elements of the proposed research agenda infrequently practiced.
are: 3. Standardized short-course chemotherapy for all cases
1. The burden and diagnosis of childhood tuberculosis. of TB under proper case-management conditions.
2. Treatment of childhood tuberculosis. Logistics of it to be able to have access for every child
3. Roles and responsibilities. need to be worked out. Diagnosis of TB in children is
4. Recording and reporting. very difficult at the grass root level.
5. BCG vaccination in children. 4. Uninterrupted supply of quality-assured drugs with
reliable drug procurement and distribution systems.
EPIDEMIOLOGY Currently made weight wise boxes of anti TB drugs
for different age categories of children are a positive
Childhood TB is seldom confirmed under program step in this direction. However, these are not available
conditions by culture of M. tuberculosis, let alone sputum for children less than 16 kg. The latter conveniently
smear-positivity by microscopy. It is a neglected aspect excludes most vulnerable group of children under
of national TB control program. Childhood TB arises two years.
most often as a result of the inhalation of M. tuberculosis 5. Recording and reporting systems enabling outcome
bacilli expectorated by sputum smear-positive adult assessment of all children and over all performance
with pulmonary TB patient with an aerosol droplet of of program is also difficult. The case record form
5-10 µm in diameter containing 1-3 bacilli. If infection which is to be filled by a DOT worker has to be
is successfully established, a primary focus forms in extremely simple and short to be grassroot level
lung parenchyma, most often subpleural in location, and worker friendly.
bacilli spread to the regional lymph nodes and later via
the lymph and blood to organs throughout the body.
In younger children particularly those aged less than 2 DIAGNOSIS
years, progression of the various elements of the It is stated by WHO in the document on research
primary complex and overwhelming dissemination of priorities in TB in children that the diagnosis of childhood
TB are particularly likely to occur. At the other extreme TB is a critical aspect of the integration of childhood TB
of childhood, progression to adult-type pulmonary TB into national TB control program. Without the assurance
becomes much more frequent in adolescents, although of an accurate and consistent diagnosis, the precise
there is reduced propensity to disseminated TB. burden of childhood TB and its importance will remain
The document published in 2007 which lays emphasis uncertain and controversial. Many children who are
on research agenda in TB in children, has the background treated for TB may not have TB. It is further stated that
document of WHO on incidence and prevalence data on as a short term goal, there is little prospect of achieving a
tuberculosis in children though only of bacillary form. widely available, “gold standard” for diagnosis of TB in
The latest report of WHO (2009) does not mention the children either by means of culture, microscopy, poly-
problem of TB in children at all not even bacillary form. merase chain reaction (PCR) or serology. Three criteria:
So in the absence of this, action at the operational level clinical, chest radiography and tuberculin testing
for TB in children becomes difficult. DOTS strategy which suggested by WHO (2006 b) should be followed. It is
encompasses the following five aspects, should focus on estimated by using these criteria that 15 to 20 percent
children of all ages in mind. To begin with special risk children may be found to have TB in high-incidence
categories (less than 5 years and adolescent) should be communities.
given priority. Research priorities defined under the heading of
1. Sustained political commitment to increase human diagnosis are:
and financial resources and make TB control 1. Evaluation of the use of criteria suggested by WHO
(including children) a nation wide priority integral policy document (2006b) to suspect the diagnosis of
to the national health system. childhood TB and evaluate new methodologies for
663
Chapter 44 Tuberculosis in Children: Research Priorities
assisting or confirming the diagnosis of TB in children. Research Priorities

2. Evaluate Mantoux skin –test responses in HIV-
infected and non-infected children to determine • Review existing literature and identify already
sensitivity, specificity and predictive value of the existing information regarding the pharmacokinetics
suggested “cutoff points” to support the diagnosis of of antituberculosis drugs in children
M. tuberculosis infection. • Undertake pharmacokinetic studies of each of the
3. Determine the proportion of children dying of first-line antituberculosis drugs under different
suspected TB who do actively have TB, e.g. through conditions of nutrition and HIV-infection status and
postmortem studies. across a range of ages
• Undertake pharmacokinetic studies of second line
drugs. A literature review might reveal sufficient
TREATMENT information with regard to agents such as fluoro-
The lack of importance assigned to childhood TB has lead quinolones and aminoglycosides
to very few studies that have been conducted in children. • Study drug-drug interactions, particularly in HIV-
Without considering the pharmacotherapeutic basis, infected children who receive multiple drugs other
children are given the same mg/kg body weight dosages than antituberculosis agents. Study drug toxicity in
of antitubercular drugs as adults. This is called “one size this complex situation
fits all”. The body composition is very important with • Evaluate rates of treatment failure and recurrence,
regard to the drug dosage in children. The children have particularly in association with HIV/AIDS
greater extravascular fluid compartment and the • Evaluate 3 and 4 month treatment regimens in
relatively greater liver mass in proportion to body mass. paucibacillary form of childhood TB and the
In several instances it been demonstrated that children necessary longer periods of treatment in HIV-infected
receiving equivalent dose mg/kg body weight, doses of children
antituberculosis drugs result in considerably lower serum • Evaluate the treatment of drug-resistant TB in
concentrations than adults. (see chapter on anti- children and determine the most effective regimens.
tuberculosis drugs-pharmacokinetics).
Because of the diversity of disease in childhood in CONTACT-SCREENING AND MANAGEMENT
relation to age to evaluate the success of treatment, the
The value of chemoprophylaxis among children in close
studies should cover all the pediatric age groups
contact with sputum smear-positive, fully drug sensitive
(children aged < 2 years, 2-6 years and 7-14 years). Also
adults with pulmonary tuberculosis or children known
include children with HIV/AIDS and without HIV.
to be infected having positive tuberculin test is
There is now considerable literature documenting
unquestionable. Chemoprophylaxis definitely prevents
poor absorption of antituberculosis drugs in adults with
miliary tuberculosis and meningitis. This aspect is quite
TB and HIV infection. Few data are currently available
a bit neglected in the national TB programs in developing
describing the poor absorption of antituberculosis drugs
countries inspite of the recommendation of WHO (1966b)
in children with TB and with and without HIV infection.
guidelines.
This is obviously an area of research. There is one study
In relation to HIV/AIDS in developing countries,
in which malabsorption in general has been reported in
children are increasingly exposed to sputum smear-
South Indian children with TB and HIV infection.
negative cases of pulmonary tuberculosis and an accurate
assessment of impact of these contacts is needed to offer
Drug – Resistance in Childhood
rational advice concerning chemoprophylaxis. The latter
The research priorities as suggested by WHO are: has been able to reduce the incidence of disease among
1. Regular quantification of the number of children who the childhood contacts of adults with multidrug-resistant
present following contact with an adult with drug- TB but a precise delineation of the drugs, dosages and
resistant TB. duration of chemoprophylaxis is needed. Adolescents are
2. The consequences of that contact and the best options a vulnerable group both for the development of TB after
for managing the children so exposed. infection and for HIV infection if they are sexually active.
3. Surveillance of the incidence of drug resistance Pregnant teenagers might well constitute an appropriate
among children as being one of the best means of group for a targeted evaluation of the voluntary HIV-
determining the number of drug resistant strains testing and counseling and tuberculin testing and
currently circulating in the community. chemoprophylaxis.
664
Research Priorities Indian medical practioners, handles approximately 1/

6th of the world’s TB cases. Management by them is
• Carryout epidemiological studies to determine the inconsistent with National Tuberculosis Program (NTP)
number of HIV infected and non-infected children in policy and there are deficiencies both in diagnosis and
contact with both sputum smear-positive and smear- treatment. It is important that childhood TB be seen as
negative adults. This group will qualify for an integral part of evaluation of epidemiology of
chemoprophylaxis childhood tuberculosis and role of the private sector.
• Assess the value of standard isoniazid chemo-
prophylaxis (isoniazid = 5 mg/kg/day for 9 months)
and compare it to shorter multidrug chemo- Research Priorities
prophylaxis in both HIV-infected and noninfected
• Evaluate the availability of qualified staff and
children
necessary investigations at various levels of care
• Explore different methodologies to ensure adherence
under different circumstance and the accuracy of the
with recommendations for chemoprophylaxis
diagnosis of TB in children. Make sure that chest
• Study chemoprophylaxis for the childhood contacts
radiography and tuberculin testing is available to a
of adults with sputum smear-negative and smear-
satisfactory level
positive drug-resistant TB
• Study the effectiveness of family-oriented approach
• Study the concurrence of TB and HIV coinfection in
to contact tracing of the mobilization of family
pregnant teenagers and evaluate TB chemo-
members as treatment supporters
prophylaxis in those infected.
• Evaluation of the role of family centered clinics and
Roles and Responsibilities of Health Staff and Families services in managing children with TB, including those
with HIV coinfection
In developing countries, children frequently present to • Document the role of private sector in all aspects of
the health system with symptoms which lead them to management of childhood TB and the extent to which
the diagnosis of TB. When children are diagnosed as a they can be involved.
result of contact tracing activities, another family or However, seeing the past experience in India there
household member often also has TB. is need felt for private sector to participate in
Research is necessary to evaluate the effectiveness of Government run schemes.
family-oriented approach to contact tracing and mobilize
family members as treatment supporters. The esta-
blishment of family centered clinics and services could REFERENCES
make a valuable contribution in this respect.
1. Seth Vimlesh. Suggestions to get pediatric faculty
Private Sector incharge of TB and HIV clinic in children involved for
taking benefit from DOTS center for drugs particularly
It has been estimated that the private sector in India, antiretroviral and those for MDR-TB in children.
which comprises 6.4 million of the 8 million registered 2. WHO/HTM/TBM/2007.381 WHO/FCH/CAH/07.02.
Index
A Antiepileptic drugs 172 Basis of

Antigen/antibody-based tests 77 pharmacotherapy 488
Abdominal Antigens in skin test reagents 310 tuberculin test 296
adenopathy 362 Antimycobacterial BCG 477
symptoms 159 activity 431 adenitis 374
tuberculosis 128, 132, 361, 488, 650 agents 597 and tuberculin skin test results 638
ultrasound 137 drugs 449 related complications 253
Abnormal sexual development 158 Antimycobacterical activity 435 strain family 556
Absorption 428, 431, 451 Antiretroviral drugs 232 test 486, 571
Acetylator Antiretroviral therapy rollout 231 vaccinated children 153
phenotypes 472 Antitubercular vaccination 221, 235, 301, 555, 582
status and side effects of INH 473 therapy 489 against tuberculosis 318
Achievements of RNTCP 622 treatment 172 and HIV infection 570
Acquired or secondary Antituberculosis vaccine
drug-resistance 508 drugs 205, 403, 427, 449, 458 and tuberculin surveys 565
Action and pharmacokinetics 417 drugs breastfeed 646 production in India 558
Actions of antiretroviral therapy for congenital Beta-lactams with beta-lactamase
treatment 231 tuberculosis 281 inhibitors 436
Acute vaccines 568 Biopsy 202
abdomen 158 Antituberculous drugs 260 Blood 201
complications 164 Appearance of tuberculoma during B-lymphocytes 72
gastrointestinal bleeding 158 treatment of TBM 160 Bobble-head doll syndrome 161
leukemia 242 Ascitic fluid
Bone
miliary tuberculosis 257 adenosine deaminase 143
and joint infections 60
toxicity 409 analysis 141
marrow transplant recipients 244
of isoniazid 409 Assessment of
scan with TC-99m 178
viral hepatitis 643 drug activity against latent TB 600
Booster phenomenon 302
Administration of immunotherapy for
Border zone encephalitis 153
skin test 495 leprosy 319
Brain edema and hemorrhage 154
tuberculin test 300 tuberculosis 319
Breastfeeding 410, 461
Adolescent Associated molecules of cell wall 47
Bronchial
female genital tuberculosis 263 Association of nontuberculous
mycobacteria 61 disease 102, 105
tuberculosis 263 obstruction 106
and future infertility 265 Asthma 252
Autoimmune reactions 411 Bronchiectasis 228
Adrenal tuberculosis 274 Bronchopneumonic consolidation 105
Autonomic nervous system
Adult-type disease 106 Bronchoscopy and bronchoalveolar
dysfunction 158
Advantages of FDCS 460 lavage 109
Azithromycin 437
AFB positivity diagnosis 477 Burden of disease 616
Aims of anti-TB drug treatment 646
Airway obstruction 105 B
Allergic consolidation 105
C
Bacillary populations and drug-
Alternating hemiplegia 159 resistance 498 Capreomycin 439
Amikacin 439 Bacillus calmette-guerin 289, 555 Case record form pediatric
Aminoglycosides 439 Bacterial HIV clinic 546
Amnestic syndrome 159 pneumonia 228 TB clinic 529
Animal pathogenicity 54 resistance 473 Caseating consolidation. 105
Ansamycin 434 Bactericidal drugs 646 Categories and drugs-regimen
Antibacterial activity 406, 413, 415 Barium under DOTS 478
Anticancer therapy 245 enema 136 Cell
Antidote 409 study 361 death 74
666
envelope proteins 48 of vertebral tuberculosis 365 Drug

mediated immune response 113, 568 scanning 360 collection center 527
wall core 47 Cushing disease 158 regimens for pulmonary
Cement kidney 251 Cutaneous tuberculosis 116
Central and soft tissue infections 60 resistant tuberculosis 32, 497, 517
nervous system 409 syndrome 412 toxicity 235
nervous system tuberculosis 375 tuberculosis 255 resistance in children 511
Cervical lymph node tuberculosis 316 Cycloserine 438 resistant
Characteristics of BCG disease 570 Cystic tuberculosis 363 tuberculosis 511, 631
Chemoprophylaxis 491, 630 Cytokine therapy 516 virus in AIDS patients 229
Chemotherapy 202, 211, 219 Cytotoxic T-lymphocytes 71
Chicken pox 581 E
Childhood tuberculosis 541 D
Children with tuberculosis disease 514 Early bactericidal activity 397, 405, 450
Chlorpromazine 441 Daily and intermittent use of FDCS 461 Effect of migration 16
Damage to motor roots 154 Effective anti-TB drug treatment 398
Choroid
Definition of drug-resistance 505 Endometrial TB 264
plexitis 153
Deformity 209 Environmental mycobacteria 312, 566
tubercles 248
Demographic parameters 255 and disease susceptibility 314
Chronic
Demonstration of Epidemiology of
pulmonary disease 373
acid fast bacilli 371 drug-resistant tuberculosis 499
systemic disease 273
host response on exposure to HIV-tuberculosis 222
toxicity 409
M. tuberculosis 111 pediatric tuberculosis 11
Ciprofloxacin 432
M. tuberculosis or its components 109 TB in India and impact of
Circulating immune complex 113
Description of genus 42 RNTCP 623
Clarithromycin 436
Desensitization 650 tuberculosis 19
Classification of Detection of drug-resistance 510 Episodes of sensory disturbances 159
drugs 404 Determinants of Era of short-course chemotherapy 620
neurological outcomes 174 developing tuberculosis disease 31 Eradication of tuberculosis 22
NTM on basis of pigment infection and disease 30 Erythema nodosum 102
production 57 outcome of treatment of Esophageal tuberculosis 250
quinolones 431 childhood tuberculosis 118 Establishment of central TB
CNS tuberculosis 273 tuberculosis 32 institutes 619
Cold abscess 209 tuberculosis in children 21 Ethambutol 415, 465, 474, 641
Combating TB-HIV infection 230 Development of drug-resistance and Ethionamide 428
Complications of discovery of basic principles of Evidence of extraneural TB 167
abdominal TB 651 drug-resistant tuberculosis 497 Evolution of
BCG vaccination 259, 645 Development of skin test responses after BCG
LV 257 new vaccines 315 vaccination 314
spinal tuberculosis 179 tuberculous meningitis 102 TB control program in India 617
tuberculous meningitis 164 Diagnosis of Extrapulmonary tuberculosis 13, 374,
Computed tomography 169 cutaneous tuberculosis 259 478, 487
Computerized tomography 345 drug-resistant tuberculosis in Extrathoracic tuberculosis 108
Concept of DOTS plus 516 children 500
Confirm active disease 382 TB in HIV infected children 331 F
Congenital tubercular meningitis 165
and perinatal tuberculosis 377 Dihydromycoplanecin 441 Female genital tuberculosis 275
infections 580 Directly observed treatment Fine needle aspiration cytology 202, 324
tuberculosis 277, 279, 281 in children 629 Fixed
with multisystem involvement 281 short-course 613 dose
Contacts of Disadvantages of FDCS 461 drug combination for treatment
leprosy patients 317 Disease of tuberculosis 418
other mycobacterial diseases 317 burden in children 28 formulation 459
Contraindications to BCG classification 628 drug combination 293, 489
vaccination 559 Disseminated disease 60, 104 joint 206
Corticosteroids 117, 171 Distribution of Fluoroquinolones 430, 598
in tuberculosis 478 TB infection and disease 32 Focal
CSF analysis 167 tuberculosis in children 19 cerebral lesions 159
CT DNA vaccines 83 cerebritis 358
abdomen 139 Dose modification in renal failure 216 Folate antagonists 441
667
Index
Follow-up schedule for pediatric TB disease associated with K

clinic 538 mycobacterial infections 96
Frontal lobe syndrome 159 inflammatory syndrome 221 Kanamycin 439
Fusidic acid 441 status in HIV infection 226 KDA antigen 78
Future of TB research 271 test for AIDS 228 Kidney 359
Immunochemistry of tuberculin skin Korsakoff’s syndrome 157
G test 299
Immunology of L
Gas liquid chromatography 111 NTM infections 61
Gastric lavage 109 tubercular infection 241 Lactation 430
Gastrointestinal tuberculosis 66 Lacunae 612
disorders 430 tuberculous in treatment 229
tract 453 lymphadenitis 93 Large vessels 151
tuberculosis 361 meningitis 95 Late neonatal respiratory distress 281
General information about tuberculosis Immunomodulation 441 Latent tuberculosis 234, 589, 645
in children 636 Immunopathology in children and adolescents 589, 607
Genetics of mycobacteria 48 in HIV infection 225 infection 115, 595
Genital tuberculosis 275 of TB 242 children 590
Genitourinary tuberculosis 214, 375 Impact of HIV on TB 225 Length of time after acquiring
Genomics of tuberculosis 471 Incidence of tuberculosis disease 623 infection 32
Gestational age 576 Indications for tuberculin testing 303 Leprosy 316
Induced sputum 639 Leukocyte migration inhibition test 91
Ghon’s focus 104, 105
Infection with Leukotomy 159
Good TB control program 637
human immunodeficiency virus 317 Lichen scrofulosorum 258
Gouty arthralgia 414
nontuberculous Lipoarabinomannan 47, 78
Granulomas in tuberculosis 369
mycobacteria 301, 567 Live attenuated vaccines 81
Infectiousness of drug-resistant Liver
H M. Tuberculosis strains 499 and spleen 374
Inflammatory bowel disease 143 disease 643, 648
Helper T-lymphocytes 70
INH
Hematogenous spread 106 Localized meningitis on superiolateral
resistance 473
Hepatic and renal impairment 429 surface of brain 155
resistant vaccine 568
Hepatitis 414 Lomefloxacin 432
Injection technique 300
B infection 581 Long bones of extremities 362
Interaction with antiretroviral drugs 442
Hepatobilliary disorders 430 Lupus vulgaris 256
Intercurrent infection 31
Hepatotoxicity 408, 411, 473, 480 Lymph node
Interferon
High performance liquid gamma release assays 381, 487, 638 disease 105
chromatography 111 release assays 228 focus 106
History of tuberculosis 3 Internuclear ophthalmoplegia 160 involvement 346
HIV Interventions in thoracic TB 354 tuberculosis 374
and tuberculosis 34 Intestinal tuberculosis 376 Lymphadenitis 59
infection 389, 596 Intracranial Lymphadenopathy 346
and tuberculin test 303 tuberculomas 356 Lymphocytic interstitial
TB coinfection 399 tuberculosis 354 pneumonitis 227
Horizontal gaze palsy 160 Intradermal injection 576 Lymphohematogenous
Host Intramedullary tuberculoma 178 dissemination 373
immunity 21, 103 Intrathoracic tuberculosis 107
infection 242 Intravenous urography 359 M
resistance 32 Introduction to rifampicin
Human immunodeficiency virus and pharmacokinetics 455 M. bohemicum 59
drug-resistant TB 500 Isolated M. celatum type I 59
Hydrocephalus 164, 172 hepatic inferior vena cava M. elephantis 59
Hyperglycemia 158 thrombosis in case of M. genavense 59
tuberculosis 251 M. heidelbergense 59
spinal tuberculous meningitis 155 M. interjectum 59
I Isoniazid 461, 472, 597 M. lentiflavum 60
Imaging of tuberculosis 344 preventive therapy 231 Macrolides 436
Immune resistant 645 Macrophage 69
cells of body 69 Isotope scintigraphy 202 Magnetic resonance imaging 170, 345
reconstitution Issues regarding category therapy 292 Male genital tuberculosis 276
668
Management of Neonatal TB 642 Pharmacokinetics of

drug-resistant tuberculosis 501 Nerves 152 ethambutol in children 458
hepatitis 650 Nervous system disorders 430 and adults with tuberculosis 466
multidrug-resistant tuberculosis 512 Neuromuscular blockade 413 isoniazid in isoniazid resistant
neonate born to mother with Neurotuberculosis 150 tuberculosis in children 454
tuberculosis 493 Nitroimidazopyrans 441 pyrazinamide in literature 456
skin itching/rash 649 NK cells 73 Phenazines 437
tuberculosis 476 Nonhealing ulcer 579 Phenothiazines 441
Mantoux Nonisoniazid/rifamycin Phlyctenular conjunctivitis 248
test 126, 136, 201, 300, 301, combinations 598 Pituitary
323, 578, 580 Nonspecific test for monitoring 117, 480 stalk tuberculosis 252
tuberculin skin test 495 Nontuberculous tuberculoma 274
Mass BCG campaign 618 mycobacteria 57 Plasma membrane 47
MDR tuberculosis 514 mycobacterial lung disease 59 Pleural
Measles vaccine 579 NTM infection 61 disease 106
Medical management of cerebral Nutritional status of vaccines 565 effusion 487
edema 172 involvement 350
Meningeal O tuberculosis 374
exudate 151 Pneumocystis jiroveci pneumonia 227
tuberculoma 155 Ocular Poisoning 412
Methods for identification of lesions 165 Polymerase chain reaction 110, 215, 260
M. tuberculosis 109 toxicity 416, 481 in diagnosis of tuberculosis 372
Miliary Ofloxacin 432, 466 Positive tuberculin skin test 102
tuberculosis 352, 373 Orificial tuberculosis 258 Postprimary lesion 353
tuberculosis in young children 102 Osteoarticular tuberculosis 102, 200, 362 Potential causes of drug-resistance 509
Mobile joint 205 Ototoxicity 413 Pott’s
Molecular diagnosis of MDR Ovarian TB 264 disease 364
tuberculosis 474 Oxazolidinones 442
spine 177, 207
Moxifloxacin 433
PPD skin test 296
MRI scan 202 P Precocious puberty 157
Multidrug-resistant
Pancreatic tuberculosis 275 Pregnancy 648
tuberculosis 504, 519
Panophthalmitis 249 Presentation of pediatric TB 11
Multifocal
skeletal tuberculosis 252 Papulonecrotic tuberculides 259 Prevaccination skin tests 318
tuberculosis 363 Para-aminosalicylic acid 438 Prevention of drug-resistance 398
Mycobacterial Paramomycin 439 Primary
capsule 45 Parasitic disease 318 drug-resistance 508
culture of biopsy on FNA Pathologic spectrum of tuberculosis infection of conjunctiva 248
material 372 in children 368 pulmonary tuberculosis 373
disease 315 Pathophysiology of infections in tuberculous chancre 257
envelope 45 cancer 242 Principles of
genome 49 PCR test 487 disease 102
infection in children 322 Pediatric tuberculosis therapy 395
population 395 score chart 228 treatment of MDR-TB 513
species 44 under RNTCP 627 Progressive
strains 337 Percutaneous fistulogram 136 primary disease 348
Mycobacteriophages 54 Performance of tuberculin skin test 305 pulmonary tuberculosis 373
Mycobacterium Pericardial tuberculosis 374 Prophylaxis 221
tuberculosis 41, 252 Peripheral Psychomotor seizures 159
ulcerans disease 316 lymph node 142 Public health importance 637
Mycobaterial infection in nerve damage 154 Pulmonary
community 565 neuritis 409, 481 disease 105
Myelography 211 Peritoneal tuberculosis 131, 362, 376 infection 105
Persistent in childhood 102
N abnormal shadows on CXR 480 metastasis 244
pyrexia 158 primary complex 345
Natural history of Persistently negative tuberculin reactivation disease 102
HIV-infection 225 reactions 303 tuberculosis 13, 101, 115, 344,
tubercular infections 102 Pharmacogenetics of tuberculosis 471 373, 642,
Needle biopsy 211
669
Index
Pyramid of childhood tuberculosis 26 Skeletal tuberculosis 375 childhood tuberculosis 287

Pyrazinamide 414, 464, 473 Skin test and assessment of vaccine cutaneous tuberculosis 260
efficacy 314 drug-resistant
Q Small arteries 152 infection 514
Smear and culture 201 tuberculosis disease 514
Quadruple skin testing 311 Sonoenteroclysis 143 hepatotoxicity 408
Quinolones in pediatric age 641 Sparfloxacin 433 HIV-TB coinfection 233
Spinal INH-monoresistant TB 501
R tuberculosis 178 late sequelae 206
tuberculosis in children 177 latent tuberculosis infection 597
Rapid identification of tuberculous arachnoiditis 165, 179 MDR and XDR-TB 502
mycobacterium 215 Sputum smear 640 pediatric TB 629
Rare hypersensitivity reactions 412 Standard code for TB treatment polydrug-resistant TB 502
Regulatory T-cells 72 regimens 647 RMP-monoresistant TB 502
Renal Starting tuberculosis clinic for TB patients 646
failure 648 children 523 TBM 170
toxicity 413 Status of fluoroquinolones in treatment tuberculosis 291, 488
tuberculosis 251 of tuberculosis 433 Trifluoperazine 441
Reporting smear results 326 Steroids in tuberculosis 293, 489 Trimethoprim-sulfamethoxazole 221
Research in pediatric practice 661 Streptolydigin 441 Tuberactinomycin 436
Resistant tuberculosis 510 Streptomycin 412, 465, 647 Tubercular
Respiratory disease 59 Symptomatic mantoux positive brain abscess 376
Rifabutin 434 group 353 cerebrovascular disease 165
Rifampicin 463, 473 Symptoms of abdominal TB 651 disease 33
resistance 647 Syndrome of inappropriate secretion of lymphadenitis 124
Rifampin 410, 597 antidiuretic hormone 157 meningitis 273, 375, 488, 644
Rifamycin 434 Synovial fluid 201 in HIV infected children 174
Rifapentine 435 Syringomyelia 160 Tuberculides 258
Role of Tuberculin
BCG in preventing TB 632 T reaction in relation to isoniazid
bronchoscopy and bronchoalveolar therapy 303
lavage fluid examination 244 Taxonomy 41, 57 skin test 296, 323, 638
CT and MRI in tuberculous TB test 228, 296, 485, 495, 628
spondylitis 365 in children 637 Tuberculoma 488
ethnicity and genetic susceptibility in HIV infected children 236, 632 Tuberculoma of brain 175
to NTM infections 60 lymphadenitis 487 Tuberculosis 248, 273, 315, 643
nonculture techniques 639 treatment regimens 646 Tuberculosis and HIV
steroid treatment 648 TBM in children 166 clinic 522
surgery in Tests for diagnosis of HIV 229 infection 218, 237
abdominal tuberculosis 146 Thalidomide 440 Tuberculosis in
management of MDR and XDR- Therapeutic drug monitoring of adolescents 377
TB 503 rifampicin and isoniazid 466 children 661
Thiacetazone 417, 641, 647, 649 diagnosed 638
S Thioamides 427 different from adults 637
Thyroid tuberculosis 275 HIV-infected children 223
Scrofula 374 T-lymphocytes 70 Tuberculosis of
Scrofuloderma 255 Transmission of ankle and elbow 207
Second-line antituberculosis drugs 503 drug-resistance 508 breast in adolescent girl 252
Selection of FDCS 461 TB to children 637 cervix, vagina and vulva 264
Sequelae of TBM 274 Transrenal mycobacterial DNA 78 eye and
Serodiagnosis of tuberculosis 143 Treatment directed to conjunctiva 248
Serological testing in CSF 168 achieve fixed joint 206 middle ear 376
Short-course chemotherapy achieve mobile joint 206 fallopian tubes 263
and reactivation of TB 245 Treatment for spinal tuberculosis 179 hip joint 204, 364
given in program of direct Treatment of knee joint 206
observation 622 abdominal TB 651 ribs 363
with antituberculosis drugs 233 BCG sacroiliac joint 364
Simultaneous tuberculous osteomyelitis 557 short
meningoencephalitis 251 vaccination induced disease in bones of hands and feet 363
Single dose ampoules 581 HIV infected children 571 long bones 207
670
spine 207, 364 Unilateral contralateral Virtual CT

vertebral column 177 hemiballismus 157 colonoscopy 142
Tuberculous Ureters 360 enteroclysis 142
abscess 357 Urinary Virulence of M. tuberculosis
arthritis 363 bladder 360 strains 565
bronchopneumonia 351 tract tuberculosis 358 Visceral tuberculosis 362
dactylitis 363 Urine examination 215 Vitamin D 441
disease 581 Use of Volatile mycobacterial markers
lesion 353 anti-TB drugs in special situation 648 in breath 79
lymphadenitis 122 combination of rifampicin and PZA Vole vaccine 568
meningitis 160, 354 in treating latent TB 600 Vulnerability and children 653
metastatic abscesses 257
osteitis/osteomyelitis 362
V W
otitis media and mastoiditis 250
spondylitis 364 Vaccine strains 564
Wild type resistance 508
Types of drug-resistance 505 Vaccines against leprosy 318
Ventriculitis 153
U Vertebral tuberculosis 366 X
Vertical gaze palsy 160
Ultrasound 344, 361 Viral vectored vaccines 82 X-ray chest 638

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Essentials of

Vimlesh Seth MD FAMS FCAI FISCD

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

Essentials of Tuberculosis in Children

First Edition : 1997

AK Gupta MD Ashok Rattan MD BN Upendra MS

Harleen MS Grewal MD PhD DTMH LS Chauhan MD Neena Khanna MD

PM Udani (Late) MD DCH Rakesh Lodha MD S Rasool MBBS

S Mukhopadhyaya MD S Kumar IP Apollo Hospital

The appearance of the book and contents are really outstanding.

1. History of Tuberculosis ............................................................................................................... 3

2. Global Epidemiology of Pediatric Tuberculosis .................................................................. 11

3. Interaction of Epidemiological Factors................................................................................... 19

4. Epidemiology: Special Reference to Children ...................................................................... 26

Section 3: Microbiology and Immunopathogenesis

5. Mycobacterium Tuberculosis ................................................................................................... 41

6. Nontuberculous Mycobacteria ................................................................................................. 57

7. Immunology of Tuberculosis: Basic Aspects and Relevance for

8. Clinicoimmunological Profile .................................................................................................. 90

Section 4: Clinical Spectrum

9. Pulmonary Tuberculosis ......................................................................................................... 101

10. Tuberculous Lymphadenitis .................................................................................................. 122

11. Abdominal Tuberculosis ......................................................................................................... 128

• Presentation According to Site of Involvement .............................................................................................131

12. Neurotuberculosis ................................................................................................................... 150

12.2. Clinical Manifestations, Diagnosis and Management ..................................................... 161

12.3. Case Studies ............................................................................................................................... 180

13. Osteoarticular Tuberculosis ................................................................................................... 200

14. Genitourinary Tuberculosis ................................................................................................... 214

15. Tuberculosis and the HIV Infection ..................................................................................... 218

15.1. TB in HIV Infected Children.................................................................................................. 218

15.2. Tuberculosis and HIV Infection ............................................................................................ 222

16. Tuberculosis and Childhood Malignancy ........................................................................... 241

17. Unusual Manifestations of Tuberculosis............................................................................. 248

18. Cutaneous Tuberculosis .......................................................................................................... 255

19. Adolescent Tuberculosis: Prelude to Future Infertility .................................................... 263

20. Endocrine Manifestations of Tuberculosis ......................................................................... 273

21. Congenital Tuberculosis ......................................................................................................... 277

22. Pitfalls in Diagnosis and Treatment of Childhood Tuberculosis ................................... 287

23. Tuberculin Test ......................................................................................................................... 296

24. Newer Tuberculins: Profile in Developing Countries ...................................................... 310

25. Laboratory Diagnosis of Mycobacterial (Tuberculosis) Infection in Children ............ 322

25.1. Conventional Methods ............................................................................................................ 322

25.2. Molecular Diagnostic Methods .............................................................................................. 332

26. Imaging of Tuberculosis in Children ................................................................................... 344

27. Pathologic Spectrum ................................................................................................................ 368

28. New Approaches to TB Diagnosis in Children .................................................................. 380

29. Principles of Therapy ............................................................................................................... 395

30. Antituberculosis Drugs: First-line Agents ........................................................................... 403

31. Antituberculosis Drugs: Second-line and Newer Agents ................................................ 427

32. Antituberculosis Drugs: Pharmacokinetics ......................................................................... 449

33. Pharmacogenetics of Tuberculosis ........................................................................................ 471

34. Management of Tuberculosis ................................................................................................. 476

35. Consensus Statement on Childhood Tuberculosis— 2010 IAP

36. Drug-resistant Tuberculosis in Children ............................................................................. 497

36.2. Multidrug-resistant Tuberculosis ......................................................................................... 504

37. Organization of Pediatric Tuberculosis and HIV Clinic .................................................. 522

Section 7: Prevention and Control of Tuberculosis

38. Bacillus Calmette-Guerin (BCG) ........................................................................................... 555

38.2. BCG Vaccination—Frequently Asked Questions .............................................................. 574

39. Latent Tuberculosis ................................................................................................................. 589

39.1. Latent Tuberculosis in Children and Adolescents............................................................. 589

39.2. Symptoms-based Screening of Child Tuberculosis Contacts—