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Tuberculosis
Background and pathophysiology (from lecture)

Overview
Chronic granulomatous disease from cell mediated response to mycobacterium TB (99%)
Acid fast tubercle bacilli spread via airborne particles known as droplet nuclei
Inhaled and reach alveoli of lungs via respiratory tract

Characteristics
1. Non-motile rod-shaped bacterium
2. Obligate aerobe (complex found in well-aerated upper lobes of lung)
3. Facultative intracellular parasite (of macrophages, with 15-20 hour generation time)

Cell wall
Over 60% of cell wall is lipid, containing mycolic acids
Unique alpha-branched lipids found in cell walls of myco and corynebacterium.
Strong hydrophobic molecules that form a lipid shell around organism
Affects permeability properties at cell surface.
Thought to be a significant determinant of virulence in MTB.

Mycobacterium complex
Part of mycobacterium complex which can cause tuberculosis
Mycobacterium Tb (99%)
Others include M.bovis, africanium, microti, canetti, caprae, pinnipedii, mungi

Mycobacterium bovis
Aetiologic agent of TB in cows and rarely in humans
Both cows and humans can serve as reservoirs
Humans can be infected by consumption of unpasteurized milk

Mycobacterium avum
TB like disease

Mycobacterium leprae
Leprosy

Transmission
Coughing of infectious droplets, prolonged close contact with infectious case



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Factors affecting probability of transmission
Infectiousness of person with TB (no of bacilli TB expelled into air)
Environmental factors affecting concentration of M.tb organisms
Proximity, frequency and duration of exposure (close contacts)
Susceptibility of exposed person

Can be transmitted through children, though less likely

Epidemiology
Nearly 9 million new cases of TB, with 1.4 million deaths around world in 2010
Leading cause of death amongst curable infectious diseases
High incidence South/south-east Asia, far east (China), Africa, Eastern Europe.

UK epidemiology
Increasing rate in UK due to immigrant population
Around 9000 cases of TB in UK, most cases in London, Birmingham

Children
Very susceptible to infection especially at younger ages
Children <2 may not be able to control, could cause lung + miliary TB
BCG vaccination very effective in first 2 years of life

Sites of disease
Lungs (pulmonary 99%)
o Most common site
o Usually infectious
Miliary
o Bacilli spread to all parts of body
o Rare but fatal if untreated
CNS
o Meningitis (usually)
o Can also occur in brain or spine
Extra-pulmonary
o Usually not infectious unless below
o Concomitant pulmonary disease
o Extrapulmonary disease in oral cavity or larynx
o Extrapulmonary disease with open site (esp. with aerosolized fluid)

Extrapulmonary TB may present in variety of ways (e.g. TB of spine backache in thorax +
classic TB symptoms)



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Pathogenesis (overview)
Initial infection with M.tb known as primary tuberculosis
Occurs in upper region of lung to produce a subpleural lesion known as Ghon focus
Associated caseating lesion in regional lymph n. (mediast, cervical) is Ghon complex

Detailed explanation
Droplet nuclei containing tubercle bacilli inhaled and travel to alveoli to multiply
o Initial exudation and infiltration by neutrophil
o Over 2-8 weeks, macrophages replace neutrophil and engulf bacilli
o Unable to clear, leading to recruitment of more macrophages
Forms a barrier shell known as a granuloma to contain bacilli
o Central area of caseating necrosis
o Surrounded by epithelioid and Langhans giant cells (derived from macrophage)
?Small number of tubercle bacilli enter bloodstream and spread throughout body
o Reach any areas where TB disease more likely to develop
o Includes brain, larynx, lymph node, lung, spine, bone or kidney
o ?Facilitated by migration of macrophages to lymph nodes

Sequelae
Latent TB infection (LTBI) Vast majority of people
o Granuloma keeps bacilli contained and under control (i.e. latent)
o Primary infection and lymph nodes heal completely and calcify
TB disease (post-primary)
o Latent TB infection reactivated if cant keep tubercle bacilli under control
o Begin to multiply rapidly in different areas of body (lung, kidneys, brain, bone)
Miliary tuberculosis
o Granuloma breaks down
o Leads to dissemination of primary infection

Latent TB infection (LTBI)
Can detect 2-8 weeks after infection
Immune system usually able to stop multiplication of bacilli
Use Tuberculin skin test (TST)/manthoux or interferon-gamma release assay (IGRA)

Key-point: Persons with LTBI are not infectious and dont spread organisms to others

TB disease
Granuloma breaks down; bacilli escape and multiply resulting in TB disease
Can occur soon after infection or years later
Positive M.tb culture confirms TB diagnosis

Key point: Persons with TB disease usually infectious and can spread bacteria to others

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*Comparison*




















Factors causing granuloma breakdown (latent TB disease)
Overall caused by depression of host defence system
HIV (biggest risk factor)
Steroids
Chemotherapy
Diabetes
Low vitamin D
Stress
Renal failure

Manthoux skin test
TB protein injected intradermally (PPD purified protein derivative)
No immune system (nothing)
Never exposed (nothing)
CM response 48-72hours red mark on skin, up to 15mm indicates +ve test)
o Exposed previously (and developed immunity)
o BCG vaccination
Strong positive (active infection)

False negative may occur in immunosuppression (miliary TB, sarcoid, AIDS, lymphoma)


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IGRA
Take blood from patient and add TB protein
Let immune system work on it, accurate and reliable














Risk of developing disease (normal immune system)
From infected individuals with normal immunity:
5% develop TB in first 1-2 years post-infection
5% later in life

Overall 10% develop TB at some point in life if untreated

Diagnostic tests
AFB smear, culture and sensitivity
Tuberculin skin testing and IGRA
Radiology (CXR)
Serology
Histopathology
Molecular typing (PCR)

Culture vs other methods
Other methods less sensitive and cant distinguish between myco species
Tissue response not specific to TB, but can guide towards diag if not prev suspected

AFB smear
Relies on acid-fastness of cell wall (acid-fast bacilli AFB)
Light microscope (Ziehl Neelsen stain)
Fluorescent microscope (Auramine phenol stain)



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Factors affecting detection
Operator competence
Number of smears examined
Technique
Staining method

Sensitivity and smear positive
Sensitivity 10
4
bacilli per mL
Equivalent to concentration required for transmission from sputum
Used as proxy for infectivity smear-positive, open TB.

Left Bacteria under acid-fast ZN stain
Right Auramine phenol, just look for light/dark

Cultures
Undergo prolonged incubation (up to 12 weeks on Lowen-strain-Jensen medium)
Proportion of primary specimens with positive cultures, 18-22% positive for TB

Methods
Conventional solid media (most sensitive of all)
Rapid automated liquid culture systems
o More sensitive to solid cultures
o Time to detection more rapid (smear +ve 2-10 days vs 10 weeks for culture)
Xpert MTB/RIF Direct detection by PCR

CFU = colony forming unit












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DNA reverse hybridisation line probe technology
Specific oligonucleo probes immobilised as parallel lines on nitro-cellulose membrane strips













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Serology
Detection of host antibody response to mTb antigens

Histopathology
Detects characteristic tissue responses
Caseating granulomata with giant cell formation
Specific stains for acid-fast bacteria

Molecular typing
PCR allows rapid identification of rifampicin (and likely multiple drug resistance)

Indications for molecular typing of M.TB
1. Detection of laboratory cross-contamination incidents
2. Define recurrent TB disease exogenous re-infection or reactivation
3. Confirm/refute linked/unlinked isolates in outbreak investigations
4. Detect unknown transmission events
5. Detect emergence and geographic spread of strains within patient populations
compare with national and global data









Current deficiencies in TB diagnostics
Rapid, simple and inexpensive POC test for active TB to outperform sputum smear,
without requiring complex equipment and training. ? Automated NAAT, Xpert
MTB/RIF test
Diagnostic options for smear-negative TB, especially in HIV+
Childhood TB : Need for POC diagnostics on urine, saliva, breath condensate
Accurate and rapid detection of critical patterns of drug resistance (MDR, XDR)
Biomarkers to detect LTBI with high risk of progression to active TB (10%)

Drug susceptibility tests
Antibiotic incorporation methods for 1
st
and 2
nd
line agents
o Solid media : 3/52
o Liquid media: 1-2/52
Rapid detection of rifampicin and isoniazid resistance mutations from specimens
Rapid detection of resistance mutations for rifampicin, isoniazid, ethambutol,
quinolones and aminoglycosides from cultures
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Targeted testing of atypical mycobacteria clarithromycin























Key points and clinical features

Overview
Chronic granulomatous disease from cell mediated response to myco TB (99%)
Acid fast tubercle bacilli spread via airborne particles known as droplet nuclei

History
Typically prolonged with systemic symptoms
Consider history of contact with infected individuals

Symptoms
Respiratory: Cough, purulent sputum, haemoptysis, pleuritic chest pain
Systemic: Fever, weight loss, night sweats (drenched), anorexia, lethargy)

Cough and fever typically lasting >3 weeks


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Signs
Crepitations
Wheeze
Amphoric breathing (cavitation)

Pulmonary TB
Peripheral cavitating lesion (usually apices of lung)
Hilar +/- paratracheal lymphadenopathy
Ghon focus (small calcified nodule on resolution)

Investigations and diagnosis
Latent TB
Active TB
Active non-respiratory TB

General principles
If histology and clinical picture consistent with TB, start treatment without culture results
Microbiology of pathological samples (discharged pus or biopsy material)
o Direct staining (AFB smear), culture and sensitivity
o Other methods (e.g. PCR)
Histopathological pattern of inflammation
Tuberculin skin testing
Radiographic appearance (CXR)
HIV test (all TB patients)

Latent TB
Mantoux test
If positive (or non-reliable) consider IFNGRA

Active TB (NICE guidance)
CXR : Suggestive of TB
Multiple sputum samples (x3)
o At least 3 with one early morning sample (more likely to be positive)
o Send for microscopy and culture for suspected TB before start treatment
o If cant, within 7 days of starting
Spontaneously produced sputum
o Should be obtained if possible
o Else induction of sputum or bronchoscopy and lavage should be used
Children (unable to expectorate sputum)
o Induction of sputum should be considered if can be done safely
o Gastric washings consider 3
rd
line, NG tube (survives in acid as acid fast)

CXR signs
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Consolidation
Cavitation
Fibrosis
Calcification
?Hilar lymphadenopathy

Active non-respiratory TB
Lymph node biopsy
CSF
Pus aspirated from lymph nodes
Pleural biopsy and pleural fluid
Any surgical sample sent for routine culture
Any radiological sample sent for routine culture
Histology sample
Aspiration sample
Autopsy sample

Need to have CXR to exclude co-existing respiratory TB






Principles of treatment
Requires multiple antibiotic regime
o Single drugs would give short term benefit but not long term
o Guards against development of drug resistance
Must be prolonged
o Dormant bacilli hard to kill
o Minimum of 6 months (depends on characteristics of individual antibiotics
Highly effective in eliminating infection but less effective in restoring function
Problems with non-compliance, drug resistance and side effects

Treatment
Four drugs: Isoniazid, rifampicin, pyrazinamide, ethambutol/streptomycin
Consolidation bilaterally
CXR normal, TB grown in sputum
Multiple cavitations which are hard to
sterilise. TB has destroyed lung over
months/years so quite unwell
Cavity in college student (risk of spread)
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Omit 4
th
drug if drug resistance unlikely
Given for 2 months, then INH and RMP given for 4 months

Cure rate of 98% (if tolerate drug, comply with regime, sensitive bacteria)

Starting treatment
Stress importance of compliance/concordance (helps patient, stops resistance)
Check FBC, liver and renal function
Test colour vision (Ishihara chart) and acuity (ethambutol may cause ocular toxicity)
Consider direct supervised therapy

Infection control
Confirmed or suspected cases should be nursed in a side room w ve pressure ventilation

Resistance
If inappropriately used, resistance emerges quickly
Easy to become resistance to isoniazid (most important is rifampicin)
If resistant to isoniazid and rifampicin then multiple resistant TB (cure in 60%)

Incidence of drug resistance
High in Eastern Europe

Side effects
Rifampicin: Hepatitis, orange discolouration of urine and tears, inactivation of pill
Isoniazid: Hepatitis, neuropathy, agranulocytosis
Ethambutol: Optic neuritis
Pyrazinamide: Hepatitis, arthralgia (CI acute gout, porphyria)

Control of TB
Case finding
o Active : Examination of contacts
o Passive: Education all round
Treatment services (especially supervision)
Prevention
o BCG immunisation
o Prophylactic use of chemotherapy







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