Tuberculosis

Etiology:

• Caused by Mycobacterium tuberculosis, M. bovis, and M. africanum.
  • obligate aerobe organism
  • grows best in tissues with high O2 tension → lung apices, renal cortex
  • cell wall – waxy coat containing mycolic acid, LPSes → “acid fast” e.g. Ziehl-Neelsen stain  

Epidemiology in Australia:

• Among the lowest TB rates globally.
• Higher prevalence in Indigenous Australians and rising among migrants.

Transmission:

• Inhalation of aerosolized infectious droplet nuclei from active pulmonary TB patients.
• Activities such as coughing, sneezing, talking, and spitting are primary transmission methods.
• Fomites (eating utensils, clothing, bedding) do not contribute to transmission.
• Sputum smear-positive pulmonary TB (PTB) cases are major sources of transmission (30-60% infection rate among heavily exposed individuals).

Risk Factors for Infection:

• Crowded housing leading to repeated, prolonged exposure.
• High intensity of exposure.

Risk Factors for Progression to Disease:

• Most infected individuals do not develop active TB.
• Factors increasing risk of active TB include:
  • Immunocompromise, including HIV infection (highest risk)
  • Silicosis
  • End-stage renal disease
  • Malignancies (e.g., head and neck cancers, lymphomas)
  • Diabetes mellitus
  • Chronic malnutrition and rapid weight loss
  • Chronic corticosteroid or immunosuppressive therapy
  • Tobacco smoking
  • Age at infection (higher risk in infancy, adolescence, old age)

Populations at Increased Risk:

• Elderly patients (higher mid-20th century incidence, postwar European migrants, Vietnam war refugees)
• Aboriginal Australians
• Torres Strait Island residents (exposure to Papua New Guinean residents with high TB incidence)
• Migrants or refugees from high TB-burden countries (e.g., sub-Saharan Africa, India, China, other Asian countries)
• Healthcare workers in high burden countries

GPs Role in TB Management:

• Avoid diagnostic delays by sending sputum specimens for AFB examination.
• Review chest radiographs in at-risk individuals with suspicious coughs (>2 weeks) or chronic pneumonia.

 

Tuberculosis (TB) Clinical Overview

Primary TB

• Disease of first-time infection: Usually mild and often asymptomatic.
• Progression to systemic disease: Occurs if the immune response fails, leading to conditions like tuberculosis meningitis or miliary tuberculosis.

Pathophysiology

• Inhalation of aerosol droplets: Viable M. tuberculosis inhaled → transient acute inflammatory response (resistant to neutrophilic degradation).
• Spread of infection:
  • Hilar lymph nodes or
  • Bloodstream via thoracic duct.
• Immune response:
  • T lymphocyte activation: IFN-γ activates macrophages.
  • Macrophage action: Destruction of tubercle bacilli, leading to contained primary infection (not total eradication).
  • Tubercle formation: Small population of live bacilli, usually in areas of high O2 tension (lung apices), resulting in a Type IV hypersensitivity reaction.
• Granuloma formation: Small, walled-off fibrocaseous granulomas, often involving the pleura and visible as calcified scars on CXR.
• Outcome: Balance between infection extension and containment/healing.

Post-primary TB (Reactivation TB)

• Occurs years later: Often in settings of decreased immune status.
• Typical lung development:
  • Posterior segments of upper lobes
  • Superior segments of lower lobes.
• Radiographic appearance:
  • Patchy consolidation or poorly defined linear and nodular opacities.
  • Higher likelihood of cavitation (20-45% of cases) with air-fluid levels indicating airway communication and potential contagion.
  • Endobronchial spread: Well-defined 2-4 mm nodules or tree-in-bud lesions on CT.
  • Hilar nodal enlargement: Seen in about a third of cases.
  • Lobar consolidation and tuberculoma formation: Well-defined rounded masses in upper lobes (5% of cases).
  • Miliary TB: Diffuse spread of infection.

Progressive Primary TB

• Risk groups: Young children, immunocompromised individuals, elderly.
• Pathophysiology:
  • Rupture of a caseous focus into a bronchus → drainage and cavitation.
  • Increased O2 tension → mycobacterial proliferation.
  • Symptoms: Progressive and non-specific.
  • Complications: Vessel erosion in cavity walls can lead to severe, sometimes fatal haemoptysis.

with bronchial spread: – granulomatous bronchopneumonia – endobronchial TB – laryngeal TB

with lymphatic-haematogenous spread→ miliary TB – gastrointestinal TB – meningeal disease – marrow → Pott’s spine – liver, spleen – retina

Key Points for GPs

• Avoid diagnostic delays: Send sputum specimens for AFB examination and review chest radiographs for at-risk individuals with persistent cough (>2 weeks) or chronic pneumonia symptoms.
• Consider risk factors and vulnerable populations: Be aware of higher risks among certain demographic groups and individuals with specific health conditions.

Miliary Pulmonary Tuberculosis (TB)

Overview

• Uncommon but poor prognosis: Represents hematogenous dissemination of uncontrolled TB infection.
• Occurs in both primary and post-primary TB.
• Imaging: Miliary deposits appear as 1-3 mm diameter nodules, uniform in size and distribution, typically easiest to image in the lungs.
• Treatment: Successful treatment leaves no residual abnormality.

Complications

• Colonization of cavities by fungus (e.g., aspergilloma).
• Bronchiectasis.
• Empyema (tuberculous empyema).
• Fibrothorax.
• Bronchopleural fistula.
• Arterial pseudoaneurysms:
  • Bronchial artery pseudoaneurysm.
  • Pulmonary artery pseudoaneurysm (Rasmussen aneurysm).

Symptoms & Signs

Stage	Symptoms	Signs
Non-specific presentation (most common) – Fatigue – Weight loss – Cachexia – Night Sweats
Active TB	May mimic cancer presentation (Night Sweats, weight loss) May mimic community acquired Pneumonia (cough, fever, mild Chest XRay infiltrate) Exercise a low index of suspicion for testing
Primary Infection	(often asymptomatic, particularly in adults)	fever non-productive cough dyspnoea Hemoptysis (uncommon) erythema nodosum (rare)
Progressive primary TB	(non-specific symptoms; cryptic) malaise fatigue night sweats weight loss	fever of unknown origin Productive cough (typically 2-3 weeks) upper lobe cavity lesions
Post-Primary TB	cough chronic (2-3 weeks) productive of purulent sputum  night sweats weight loss anorexia insidious onset	afebrile (40-60%)
Latent Tuberculosis	is asymptomatic

Tests for Suspected Pulmonary Tuberculosis (TB)

Chest X-ray

• Views: PA (posteroanterior) and lateral.
• Typical Changes: Air space consolidation, cavitation, and fibrous contraction in one or both upper lobes or superior parts of the lower lobes.

Sputum Testing

• Gold Standard: Predicts infectiousness.
• Specimens: Three sputum specimens (preferably early morning) to maximize yield.
• In Children: Gastric aspiration is a useful surrogate.

Microscopy

• Acid-fast Microscopy: Rapid (results within 24 hours, less than an hour if urgent) and inexpensive.

Culture

• Sensitivity: Culture is the most sensitive test.
• Preferred Method: Automatic liquid cultures are more rapid and sensitive than solid culture mediums and can also test drug susceptibility.

Molecular Assays

• Function: Detect DNA specific for the Mycobacterium tuberculosis (MTB) complex.

Drug Susceptibility Testing

• First Line Agents: Isoniazid, rifampicin, ethambutol, pyrazinamide, and streptomycin.
• Second Line Drugs: Tested if resistance to first line agents is detected.
• Multidrug Resistant TB (MDR-TB): Defined by resistance to both isoniazid and rifampicin. Rifampicin-resistant strains are usually also isoniazid resistant.

Tests for Suspected Latent TB Infection (LTBI)

Diagnostic Methods

• Tuberculin Skin Test (TST) “Mantoux”: Tests immune recognition of MTB antigens.
• Interferon Gamma Release Assays (IGRA): Tests immune recognition of MTB antigens.
  • Timeframe for Positivity: 4-6 weeks after infection.
  • Note: IGRA does not diagnose active TB – microbiological tests are needed. A negative test cannot exclude active TB due to sensitivity limitations.

A comparison of tuberculin skin tests and interferon-gamma release assays

	tuberculin skin testing (TST)”Mantoux”	interferon gamma release assays IGRAs
Method	intradermal injection of 5 tuberculin units of antigen in 0.1 mL test read as the size (in mm) of palpable induration present after 48-72 hours	detects CD4+ T-cell sensitivity epitopes of wild-type TB antigen Developed by an Australian company in Victoria
Advantages	TST does not require equipment and can be done without a laboratory. It is less expensive than for IGRAs (but greater personnel time is required). Longitudinal studies have demonstrated the predictive value of TST, and randomized trials show that LTBI therapy is much more effective in those who are TST positive than TST negative.	not give false-positive results because of prior BCG vaccination.
Disadvantages	false-positive results because of prior BCG vaccination sensitization to nontuberculous mycobacteria. false-negative results because of – protein-calorie malnutrition – immunosuppression (eg, HIV or active TB) – natural waning of immunity – technical limitations (including reader variability)	false-negative/ ‘indeterminate’ result  – immunosuppression (eg, HIV or active TB) – technical variability.

 

Case Management of Tuberculosis (TB)

Therapeutic Aims

• Cure the patient.
• Prevent spread of infection to family.
• Avoid development of drug resistance.

Immunization

• BCG Vaccine: Reduces mortality rather than incidence.

Directly Observed Therapy Short-course (DOTS)

• WHO Protocol: Ensures compliance and minimizes the development of drug resistance.
• Duration: Usually around 6 months.

First-Line Anti-TB Drugs

• Isoniazid: Inhibits metabolism.
• Rifampicin: Inhibits DNA synthesis.
• Pyrazinamide.
• Ethambutol: Inhibits metabolism.
• Thiacetazone: High rate of Stevens-Johnson syndrome in HIV+ patients.
• Streptomycin.

Use in Pregnancy

• All first-line drugs except streptomycin can be used during pregnancy, as the risk of fetal TB is greater than the risk of adverse effects.

Public Health Measures

Control of Mycobacterium bovis

• Reservoir Management:
  • Case-finding in infected cattle using skin tests.
  • Destroying infected cattle.
  • Limiting transmission through milk pasteurization.

Treatment Endpoints

• Clinical Improvement: Typically noticeable within 2 weeks of appropriate treatment.
• Negative Sputum Cultures: Over 90% of patients will have negative sputum cultures within 3 months of appropriate treatment.

Follow-Up for Productive Cough

• Monthly Sputum Examinations: For those with a persistent productive cough until chemotherapy completion, then less frequently for up to 2 years.
• Two-Year Follow-Up: Sufficient if chest X-ray is stable and cultures are negative.
• Respiratory Samples: Induced sputum or bronchoscopy specimens needed only for those not responding clinically or radiologically to treatment.