Child Hood Tuberculosis

Abadi Leul (MD)

July 2017
 TB is a chronic disease which is airborne and caused by
Mycobacterium tuberculosis in most of the cases
M. tuberculosis is a pleomorphic, weakly gram-positive
and acid-fast bacillus.
M. tuberculosis complex is comprised of MTB and other
closely related mycobacterial species
M. bovis
M. africanum
M. microti
M. caprae and
M. canetti
 A hallmark of all mycobacteria is acid fastness:
The capacity to form stable mycolate complexes with
aryl methane dyes.
Mycobacteria grow slowly.
Isolation from clinical specimens on solid synthetic
media usually takes 3 to 6 weeks, and drug-
susceptibility testing requires an additional 4 weeks.
Growth can be detected in 1 to 3 weeks in selective
liquid media using radio labeled nutrients and PCR
technology
 EPIDEMIOLOGY
More than of the world's population is infected with
Mycobacterium tuberculosis.
The greatest risk for progression occurs in the 1st 2 yr
after infection.
Untreated infants with latent Tb infection (LTBI) have up
to 40% likelihood of developing tuberculosis,
About 1.3 million new cases occur in children every year
(More than 8 million new cases/yr)
450,000 children die of the disease worldwide each year .( 3
million/yr )
Natural course of tuberculosis (without HIV)
Course of tuberculosis with HIV co-infection
 Probability of progression of tuberculosis
from infection to disease in pediatrics

Age(Yr) at % of children with % of children that progress

TB pulmonary disease after to milliary or CNS disease
infection infection
<1 30 40 10 20
12 10 20 25
25 5 0.5
5 10 2 < 0.5
>10 10 -20 < 0.5
 Transmission.
Transmission of M. tuberculosis is person to person
Airborne mucus droplet nuclei
The chance of transmission increases when the patient has
AFB Positive
AFB Negative but culture positive
Unpasteurized milk ingestion
M. bovis
NB.
Young children with tuberculosis rarely infect other children
or adults.
Most adults no longer transmit the organism within several
days to 2 weeks after beginning adequate chemotherapy.
 Pathogenesis
When the bacilli enter the alveolar spaces of the lung, they are
engulfed by macrophages. Most of the bacilli are killed, but some
survive within non activated macrophages, which carry them
through lymphatic vessels to the regional lymph nodes.

The primary complex (Ghon complex) comprises

Parenchymal lesion + Regional LAP.

In sever cases there is enlargement and caseation necrosis in the

nodes and may rapture in to adjacent structure causing different
clinical manifestations
 These nodes may rapture to the Pulmonary vein
milliary tuberculosis
TB meningitis
Specific organ tuberculosis
Bronchus
Progressive pulmonary TB
Mediastinal lymph nodes may enlarge and compress regional
bronchus
leading to collapse /atelectasis or emphysema
Inflamed caseous nodes can attach to the bronchial wall
and erode through it, causing endobronchial tuberculosis
or a fistula tract.
Hilar adenopathy with right sided collapse consolidation
 Clinical Manifestations

Tuberculosis infection (latent tuberculosis)

Asymptomatic stage of infection with M. tuberculosis
The tuberculin skin test (TST) is positive
Chest radiograph is normal
Tuberculosis disease Chest findings
Clinical signs and symptoms of TBC - Signs of consolidation/cavitation/Collapse
Chronic cough ( > 3 weeks) - Signs of fluid especially on the left side
Unexplained weight loss/FTT - Localized wheezing
Unexplained fever for > 2 weeks Other signs based on the organ/organs

Failure to respond to broad involved

spectrum antibiotics
 Pulmonary tuberculosis
I. Primary pulmonary disease

70% subpleural and pleurisy very common

All lobes equally involved

Collapse-consolidation and endobronchial Tb

Calcification needs a minimum of 6-12 months to develop

II. Progressive Primary Pulmonary Disease(rare)

Primary focus enlarges steadily and develops a large caseous

center (primary cavity )

Significant signs or symptoms are common

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 Pleural Effusion.
Result from discharge of the bacilli into the pleural space from a
sub pleural pulmonary focus or caseated lymph node.

Infrequent in children <6 yr of age and rare in <2 yr of age.

Usually unilateral and more common on the left side but can be
bilateral.

Clinical onset of tuberculosis pleurisy is often sudden,

characterized by low to high fever, shortness of breath, chest pain
on deep inspiration, and diminished breath sounds.
 The pleural fluid analysis may reveal
Appearance yellow or slightly tinged with blood
The specific gravity is usually 1.0121.025,
Protein level is usually 24 g/dL,
Glucose concentration may be low (2040 mg/dL).
Cell count may vary from several hundreds to thousands.
Early polymorphonuclear cells predominate followed by
lymphocytosis.
AFB rarely positive and Culture positive in <30% of cases.
Biopsy of the pleural membrane is more likely to yield a
positive acid-fast stain or culture
 Lymph Node Disease.
Tuberculosis of the superficial lymph nodes is the most
common form of extra pulmonary tuberculosis in children.
Most cases occur within 69 mo of initial infection by M.
tuberculosis
Anterior cervical > Submandibular > supraclavicular
Firm but not hard, discrete, and nontender, often feel fixed to
underlying or overlying tissue and become matted
 TB lymphadenitis
Left untreated
May resolve spontaneously
Progresses to caseation and
necrosis.
The capsule of the node breaks
down, resulting in the spread of
infection to adjacent nodes.
Rupture of the node usually results
in a draining sinus tract that may
require surgical removal.
 DDX
Pyogenic lymphadenitis
Nontuberculous mycobacteria (NTM)
Cat scratch disease (Bartonella henselae),
Brucellosis, toxoplasmosis, tumor, branchial cleft cyst,
cystic hygroma, and Tularemia
 Tuberculosis pericarditis
Occurs when organisms from the lung or pleura spread to the
contiguous surfaces of the pericardium.

There is an accumulation of fluid with lymphocytic infiltration in the

pericardial space.

Persistent inflammations may result in a cellular immune response, with

rupture of granulomas into the pericardial space and the development
of constrictive pericarditis.

Tuberculous pericarditis is managed with antimycobacterial and

corticosteroids to decrease inflammation.
Flask shape
 Central Nervous System Disease
The most serious complication in children and is fatal
without prompt and appropriate treatment.
Tuberculous meningitis usually arises from the formation
of a metastatic caseous lesion in the cerebral cortex or
meninges that develops during the lymphohematogenous
dissemination of the primary infection.
This initial lesion increases in size and discharges small
numbers of tubercle bacilli into the subarachnoid space.
The resulting gelatinous exudate infiltrates the
corticomeningeal blood vessels, producing inflammation,
obstruction, and subsequent infarction of cerebral cortex.
 The brainstem is often the site of greatest involvement,
which accounts for the frequently associated dysfunction of
cranial nerves III, VI, and VII.
The exudates also interferes with the normal flow of
cerebrospinal fluid (CSF) in and out of the ventricular
system at the level of the basilar cisterns, leading to a
communicating hydrocephalus
The combination of vasculitis, infarction, cerebral edema,
and hydrocephalus results in the severe damage that can
occur gradually or rapidly.
Profound abnormalities in electrolyte metabolism, due to salt
wasting or the SIDH, also contribute to the path physiology
of tuberculosis meningitis.
 Tuberculous meningitis complicates about 0.3% of untreated
tuberculosis infections in children.
It is most common in children between 6 mo and 4 yr of age.
The clinical progression of tuberculosis meningitis may be rapid
or gradual.
Rapid progression tends to occur more often in infants and
young children, who may experience symptoms for only several
days before the onset of acute hydrocephalus, seizures, and
cerebral edema.
Three Stage
The 1st stage (lasts 12 wk) nonspecific symptoms, such as
fever, headache, irritability, drowsiness, and malaise.
The 2nd stage usually begins more abruptly.
Usually correlates with the development of hydrocephalus,
increased intracranial pressure, and vasculitis.
lethargy, nuchal rigidity, seizures, positive Kerning or
Brudzinski signs, hypertonia, vomiting, cranial nerve
palsies, and other focal neurologic signs.
The 3rd stage is marked by coma, hemiplegia or paraplegia,
hypertension, decerebrate posturing, deterioration of vital
signs, and eventually death.
 Prognosis correlates with the clinical stage of illness at
the time treatment is initiated and age of the patient

stage one have an excellent outcome, stage 3 carries

poor prognosis and those who survive have
permanent disabilities, including blindness, deafness,
paraplegia, diabetes insipidus, or mental retardation.

The prognosis for young infants is generally worse

than for older children.
 Diagnosis of tuberculous meningitis is difficult early in its course,
requiring a high index of suspicion on the part of the clinician.
The tuberculin skin test is nonreactive in up to 50% of cases,
2050% of children have a normal chest radiograph.
The most important laboratory test for the diagnosis of tuberculosis
meningitis is examination and culture of the lumbar CSF.
The CSF leukocyte count usually ranges from 10 to 500
cells/mm3.;Lymphocytes predominate in the majority of cases.
The CSF glucose is typically <40 mg/dL
The protein level is elevated and may be markedly high (400
5,000 mg/dL) secondary to hydrocephalus and spinal block.
 During early stage I, the CSF may resemble that of viral
aseptic meningitis only to progress to the more severe CSF
profile over several weeks.

Yield of AFB from CSF and mycobacterial culture is related

directly to the volume of the CSF sample.

Examinations or culture of small amounts of CSF are unlikely

to demonstrate M. tuberculosis.

When 510 mL of lumbar CSF can be obtained, positivity

reaches up to 30% of cases and the culture is positive in 50
70% of cases.
 Radiographic studies may aid in the diagnosis of
tuberculous meningitis.

Skull x-ray may show evidences of sutural diathesis

CT or MRI of the brain of patients with tuberculous

meningitis

May be normal during early stages of the disease.

Basilar enhancement and communicating

hydrocephalus

Signs of cerebral edema or early focal ischemia

are the most common findings.
Tuberculoma
A tumor-like mass resulting from aggregation of caseous tubercles

Presents clinically as a brain tumor.

Tuberculomas account for up to 40% of brain tumors in some

areas of the world

Un like adults most tuberculomas in children are infratentorial,

located at the base of the brain near the cerebellum.

Lesions are most often singular but may be multiple.

The most common symptoms are headache, fever, and

convulsions.
 The tuberculin skin test is usually reactive

Chest radiograph is usually normal.

On CT or MRI of the brain, tuberculomas usually

appear as discrete lesions with a significant amount of
surrounding edema and ring enhancement

Most tuberculomas resolve with medical management.

 Corticosteroids are usually administered during the 1st few
weeks of treatment to decrease cerebral edema.

the paradoxical development of tuberculomas in patients

with tuberculous meningitis who are receiving ultimately
effective chemotherapy has been recognized.

The cause and nature of such tuberculomas is unknown, but

they do not represent failure of drug treatment.

This should be considered whenever a child with tuberculous

meningitis deteriorates or develops focal neurologic findings
while on treatment
 Miliary tuberculosis
Usually complicates the primary infection, occurring within 26
mo of the initial infection.
Most common in infants and malnourished or immunosuppressed
patients
Widespread hematogenous dissemination with infection of
multiple organs.
The lesions are of roughly the same size as that of a millet seed
Characterized by fever, general malaise, weight loss,
lymphadenopathy, night sweats, and hepatosplenomegaly.
Diffuse bilateral pneumonitis is common, and meningitis may be
present.
 The chest radiograph reveals bilateral miliary infiltrates,
showing overwhelming infection. Smaller lesions may coalesce
to form larger lesions and sometimes extensive infiltrates.
The TST may be nonreactive (up to 40%) as a result of anergy.
 Diagnosis of TB in children
Diagnosis of tuberculosis in children is difficult .
Children rarely produce sputum,
Rarely form cavitary lesion
Lack the tussive power to expectorate
Usually swallow their sputum
Recommended approach to diagnose TB in children
A. History of contact with TB patient
A close contact is defined as living in the same household or
being in frequent contact with a person (e.g. caregiver) who
is smear-positive TB.
Patients who are sputum smear-negative but culture
positive are also infectious.
B. Sign and symptom complex including growth and
development
C. Tuberculin skin test
Intradermal injection of 0.1 mL containing 5 tuberculin
units of purified protein derivative (PPD) to the volar
aspect of the forearm.

The amount of induration in response to the test is

measured 4872 hr after administration.

Result is interpreted together with other criteria

D. Bacteriological confirmation whenever possible
1. Gene Expert (Xpert) MTB/RIF Assay
The preferred method in children
Can be done from Sputum or any other fluid including CSF
2. AFB stain
In areas where Xpert is not available
3. Sputum culture
Culture remains the gold standard in mycobacterial detection
because of its higher sensitivity and specificity.
It also helps to do drug sensitivity testing
 Solid culture media: (Lwenstien-Jensen) is culture media which has
several advantages
Ease of preparation, low cost, and low contamination rate.
Solid culture results may take several weeks, 21-42 days, for
growth.
Solid culture media is the gold standard for diagnosis of MTB.
The long turnaround time for result made the use of the technique
less often.
Liquid culture media: (BACTEC MGIT 960 system)
A specially enriched media for growing mycobacteria with 10 %
more sensitivity than LJ solid media
Developed to shorten the time for MTB growth to 5-10 days.
The method is prone to higher contamination rate.
 Line Probe Assay (LPA): Line Probe Assay is a rapid DST
technique using molecular technology.

It is a DNA strip test that makes use of PCR + reverse

hybridization that identify the presence or absence of specific
mutations on the genes of TB bacilli.

E. Histopathologic exam

Biopsy,FNAC,Aspiration of effusion from serous membranes

F. Chest radiography
The commonest picture of active TB is that of persistent
pulmonary abnormalities together with enlarged mediastinal
lymph nodes (primary complex).

Segmental (or lobar) consolidation /Colapse associated with

mediastinal lymphadenopathy. usually right middle lobe

Right middle lobe syndrome

A miliary pattern of shadowing in non HIV-infected children

is highly suggestive of TB.
G. Lumbar puncture when TB meningitis is suspected
H. HIV testing
AFB
Algorithm for screening Tuberculosis in HIV uninfected children
 Treatment of Tuberculosis
Treatment outcomes in children are generally good provided
that effective treatment starts promptly.
Risk of adverse events are low compared to adults
Principles of management:
Chemotherapy with Anti-TB drugs
Nutritional rehabilitation
Screening of the family(index case, other contacts) for
tuberculosis
Follow up (Adherence, response, drug side effect)
Adjuvant therapy
Health education
 Important notes of treatment of TB in children:
1. Anti-Tb drugs should be administered daily.
2. As children approach a body wt of 25 kg, Adult dosage can be used
3. Children receiving treatment must be weighed at least every month
4. Treatment doses should be adjusted as soon as a child changes
weight bands
5. Check tablet strengths regularly to avoid toxicity
6. Pyridoxine is recommended for children with severe malnutrition,
or taking ART
7. Streptomycin shouldnt be used as part of the first line treatment
regimen for children
8. Ethambutol is safe in children at a dose of 20 mg/kg (range 15 25
mg/kg) daily
 TB treatment regimen in children
TB Type TB patient registration Regimen
group Intensive Continuation
phase phase
New, Relapse, treatment All forms except CNS 2 (RHEZ) 4 (RH)
after lost to follow up and Bone Tb
Treatment Failure TB Meningitis 2 (RHEZ) 10 (RH)
Bone TB (osteo
arthritis)
MDR-TB Confirmed cases of Second line anti-TB drugs
R/M/XDR-TB

NB. In the case of relapse, treatment failure, and treatment after lost to f/up DST
must be performed.
 Drug Recommended dose

Daily
Dose and range (mg/Kg Maximum
body weight) (mg)
Isoniazid 10 (7-15) 300

Rifampicin 15 (10-20) 600

Pyrazinamide 35 (30-40) -

Ethambutol 20 (15-25) -

Children weighing 25kg and more can be treated using recommendation for adults
 The two most effective bactericidal drugs are
isoniazid (H) and rifampicin (R),
Act against:
Metabolically active bacteria that multiply
constantly and rapidly,
The semi-dormant bacilli that multiply slowly in
the macrophages.
Rifampicin also acts at a very early stage of
bacillary multiplication.
 Pyrazinamide and Streptomycin are also
bactericidal drugs that act complimentarily.
Pyrazinamide (Z) destroys intracellular bacteria
that live in an acid environment,
Streptomycin (S), is active only against
extracellular bacteria as it cannot penetrate the cell
membrane.
Ethambutol is a bacteriostatic drug
 Treatment Side Effects

Rifampin Orange body fluids ; Drug

interactions,
Hepatotoxicity; thrombocytopenia
INH Neuropathy ; Hepatotoxicity
GI intolerance
PZA Hepatotoxicity; Joint pains
GI intolerance; hyperuricemia
Ethambutol Ocular toxicity (dose related)
GI intolerance
Streptomycin Auditory and vestibular toxic effects
Nephrotoxic effects; Rash
 Indications for steroid
Endobronchial tuberculosis
Pericardial effusion
Tuberculous pleural effusion and shift of the mediastinum.
Massive pleural effusion with mediastinal compression/shift
Miliary tuberculosis with hypoxia
TB meningitis/tuberculoma
TB of the Adrenal gland
Laryngeal TB
Renal tuberculosis
Pyridoxin
HIV co infection
Malnutrition
 TB/HIV co infection
Most common opportunistic infection among HIV-infected people
Leading cause of AIDS-related deaths worldwide
1/3 of all AIDS-related deaths are due to TB
Associated with complications
Meningitis
Miliary TB
Difficult to diagnose
Poor sputum production
Low yield of gastric aspiration
Sputum induction and bronchoscopy not widely available
Limited sensitivity of Mantoux in HIV-infected children due to
immunosuppression
Multiple and varied clinical manifestations
Overlap with other disease manifestations
Diagnosis of PTB in children is nearly always presumptive
 Impact of HIV on Tuberculosis
Rapid progression of primary tuberculosis
Alters clinical manifestations of TB
Creates diagnostic challenges
Complicates treatment
Reactivation of latent TB
Increased atypical TB
Increased extra pulmonary TB
Increased risk of relapse and treatment failure
Increased risk of multidrug resistance
HIV increases risk of developing active tuberculosis
5 -10% chance per year of re-activation
9 times greater risk compared to HIV negative people
50% chance per lifetime of re-activation
 High rates of co-infection (South African study: 48% of
hospitalized children with proven TB also had HIV)
Higher rate of progression from latent to active TB as
compared with adults
Risk is greatest shortly after infection and steadily
decreases with time
Many children will become ill within one year of infection
and most within 2 years
Infants and young children have an immature immune
system and are at greater risk of developing disease (up to
20%)
HIV and malnutrition trigger progression from infection to
disease
 Impact of TB on HIV

TB infection activates T-cells, indirectly supporting HIV

replication
Active TB is associated with
Increased HIV-1 viral load
Rate of progression to AIDS
Mortality
HIV viral load decreases with successful TB therapy
TB therapy when combined with ARV has potential for drug-
drug interactions and side effects

59
 Prevention of tuberculosis
3 IS

Intensified TB case finding(ICF)

INH Preventive therapy(IPT)

Infection control for TB(IC)

Appropriate ventilation of the air around the source case.

Offices, clinics, and hospital rooms used by adults with possible

tuberculosis should have adequate ventilation,

with air exhausted to the outside (negative-pressure

ventilation).
 Bacille Calmette-Gurin (BCG) Vaccine .
A single dose administered intradermally during infancy .
Many infants who receive BCG vaccine never have a
positive tuberculin reaction.
When a reaction does occur, the induration size is usually
less than 10 mm, and the reaction wanes after several years.
It protects against the sever forms of tuberculosis
Miliary and TB meningitis
Adequate chemotherapy
Provision of comprehensive & standard patient care
Accurate Monitoring and Evaluation (M & E) of program
performance
Community participation
THANK YOU