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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 can’t 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 don’t 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 can’t 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 can’t, 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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