Preparatory Mindset
Tuberculosis is a chronic contagious disease that always comes back in exams — the classic vignette is the patient with hemoptysis, productive cough, night sweats, weight loss (often diabetic), a right upper lobe cavitary infiltrate on CXR, and AFB-positive sputum. The exam skills are: (1) recognise the clinical patterns (primary vs secondary reactivation, miliary, pleuritis, extrapulmonary), (2) interpret the diagnostic tests correctly — smear, culture, PPD, IGRA, Xpert PCR, mNGS — including their false-positive/negative caveats, and (3) know the standard short-course regimen 2HRZE/4HR, each first-line drug's mechanism and adverse effects, and the HK/LMCHK specifics: statutory notification and directly observed therapy (DOT).
Core Concepts
Definition & etiologic agent
- Tuberculosis = chronic, potentially lifelong infection caused by bacteria of the Mycobacterium tuberculosis complex; isolated by Robert Koch in 1882; lungs primarily involved but any organ can be affected; characterised by formation of tubercular granulomas.
- Untreated, fatal within 5 years in >50% of cases; drug-susceptible TB is curable in virtually all cases if properly treated.
- M. tuberculosis: rod-shaped, aerobic, non-motile, non-spore-forming, high lipid content, acid-alcohol fast (AFB) — Ziehl-Neelsen stain (bright red rods on blue background) or fluorescent stain (luminescent yellow-green on dark background); grows slowly; cannot tolerate heat but survives in humid/dry/cold surroundings.
Epidemiology
- ~1/3 of the world's population (≈2 billion) has been infected with M. tuberculosis.
- 2021: ~6.4 million new TB cases worldwide (400,000 in HIV-positive, 6.7%); ~1.6 million deaths (187,000 HIV-positive); ~450,000 new rifampicin-resistant (RR-TB) cases with only ~60% treatment success.
- China 2019: 833,000 new cases (incidence 58/100,000); declining trend since 2008.
- Transmission: airborne droplet nuclei aerosolised by coughing, sneezing, speaking; rarely GI tract, skin, placenta. Probability of transmission depends on: infectiousness of the source, environment, length of exposure, virulence.
- Risk factors for progression to disease: recent infection, diabetes mellitus, prolonged corticosteroid/immunosuppressive therapy, head & neck cancer, haematologic diseases, ESRD, gastrectomy/intestinal bypass, malabsorption, low body weight (<10% below ideal), substance abuse, HIV, alcoholism.
Pathogenesis & immunity
- Immunity to TB is cell-mediated: macrophages phagocytose bacilli and present antigens to T lymphocytes (CD4+), which produce lymphokines → protection.
- Cytokine roles: IL-1 → fever; IL-6 → hyperglobulinaemia; TNF → killing of mycobacteria + granuloma formation; IL-4/IL-5/IL-10 → humoral immunity. Genetic factors influence innate resistance/susceptibility.
- Three basic pathologic changes (may coexist): exudative (acute pneumonia-like), proliferative (granuloma: epithelioid cells, Langhans giant cells, lymphocytes, plasma cells), necrosis/caseation (+ ulceration or calcification). When host defense is overwhelmed → caseating ulceration; when host defense predominates → hyperplasia/calcification.
- Koch phenomenon: primary infection vs reinfection show different reactions (primary: 10–14 days to local swelling/ulceration; reinfection: 3–6 weeks, more intense, can spread — reflects hypersensitivity).
Clinical patterns of tuberculosis
- Primary pulmonary TB (primary complex / bronchial lymph-node TB) — first exposure, typically children; inhaled bacilli implant in alveoli → acute inflammatory response → Ghon nodule (granuloma); nodule + hilar lymphadenopathy = Ghon complex / primary complex (dumbbell shape on CXR). Usually self-limited; primary progressive TB (~10%, immunosuppressed/malnourished children) → miliary TB and meningitis.
- Miliary TB — haematogenous dissemination; acute: uniformly distributed ~2 mm nodules ("size, distribution, density uniform"); subacute/chronic: heterogeneous.
- Secondary (reactivation/postprimary) TB — endogenous reactivation (or reinfection) in adults; predilection: apical & posterior segments of upper lobes, dorsal & posterior basal segments of lower lobes; polymorphic lesions (infiltrates, cavities, satellite lesions, caseous pneumonia, fibrosis, calcification). Forms: infiltrative PTB, tuberculoma, caseous pneumonia ("worm-eaten cavities"), chronic fibro-cavernous PTB (thick-walled cavity, upward retraction of hilar markings, mediastinal shift, compensatory emphysema, recurrent symptoms, smear+).
- Tuberculous pleuritis — fibrinous pleurisy, TB poisoning symptoms, usually unilateral pleural effusion (visible when >300 mL).
- Tracheobronchial TB.
- Extrapulmonary TB — sites of high oxygen tension: kidneys, spine, long bones, genital tract, brain/meninges, joints, regional lymph nodes.
Clinical manifestations
- Systemic: fatigue, weight loss, anorexia, low-grade afternoon fever, night sweats.
- Pulmonary: dry cough → bloody sputum → purulent sputum, chest pain, dyspnoea; or asymptomatic.
- Physical signs: non-specific (rhonchi, amphoric breath sounds, consolidation).
Diagnosis
Key diagnostic tests (confirmed by aetiology/pathology — smear, culture, Xpert, mNGS/tNGS, or caseous granuloma on biopsy):
| Test | Points |
|---|---|
| CXR | Patchy/nodular shadows (upper lobe), hilar/paratracheal adenopathy (Ghon complex), cavity ± air-fluid level, segmental atelectasis, calcification/fibrosis; miliary = uniformly distributed micronodules; chronic fibro-cavernous = thick-walled cavity + retraction |
| Sputum smear (AFB) | Direct smear positive only when >5×10³–10⁴ bacilli/mL; negative smear does not exclude TB; does not confirm M. tuberculosis (NTM can colonise); 3 consecutive morning specimens, mouth rinse first, sputum induction if needed |
| Sputum culture | Differentiates M. tuberculosis from other AFB; identifies drug resistance; slow — 2–8 weeks, not routine for early diagnosis |
| Tuberculin skin test (PPD/Mantoux) | 0.1 mL of 5 TU intradermal, read induration at 48–72 h in mm; <5 mm (−), 5–9 (+), 10–19 (++), ≥20 mm or blister (+++); positive = prior infection with or without disease; most useful in children, limited in older adults; false negatives (anergy): concurrent infection, malnutrition, old age, immunosuppression/steroids, CRF, fulminant TB, technique; false positives: NTM |
| IGRA (T-SPOT.TB / QuantiFERON) | Whole-blood ELISPOT detecting IFN-γ from sensitised T cells; detects infection incl. latent TB; useful even with low immune function; false +/- possible; positive = infection with or without disease |
| Xpert MTB/RIF (real-time PCR) | Early diagnosis; high sensitivity/specificity; 2–4 h; also detects rifampicin resistance; used for therapeutic evaluation |
| mNGS / tNGS | Metagenomic/targeted NGS; sensitive for difficult cases; false +/- if technique improper |
| TB antibody | Positive = infection, cannot distinguish past/present; not recommended for clinical diagnosis |
| Pathology | Caseous granuloma with Langhans giant cells; bronchoscopy brushing/BAL/transbronchial biopsy, percutaneous lung biopsy |
Essentials of diagnosis: clinical (fatigue, weight loss, fever, night sweats, cough, hemoptysis) + apical infiltrate on CXR + positive PPD (most cases) + confirmation by aetiology/pathology. Differential diagnosis: acute bacterial pneumonia (sputum and antibiotic response differ; images change faster), lung cancer (isolated coin lesion, endobronchial tumour with distal inflammation, cavitating mass — irregular cavity wall suggests necrotic neoplasm), bronchiectasis (chronic cough/sputum/hemoptysis; distinguished by CXR/CT).
Treatment
Principles of chemotherapy: early, combined, regular/consistent, adequate dosage, full course; combination therapy reduces resistance and relapse; surgery and supportive therapy are adjuncts.
- Standard regimen — 6 months: 2HRZE / 4HR (2 months intensive: isoniazid + rifampicin + pyrazinamide + ethambutol; 4 months continuation: isoniazid + rifampicin).
- First-line drugs: Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), Streptomycin (S).
- Second-line: kanamycin, amikacin, capreomycin, PAS, quinolones, rifabutin, ethionamide; newer: rifapentine, moxifloxacin, linezolid, clarithromycin.
| Drug | Key facts | Main adverse effects |
|---|---|---|
| Isoniazid (INH) | The best/principal bactericidal agent, in all regimens unless resistant; 5 mg/kg (300 mg daily); well tolerated (~5% adverse effects) | Hepatitis, peripheral neuropathy (give vitamin B6 ≥10 mg/d in malnutrition, pregnancy, DM, alcoholism, CRF, HIV), encephalopathy/convulsions; interacts with phenytoin & carbamazepine |
| Rifampicin (RIF) | Most potent sterilising agent; intra- + extracellular; oral/IV | Hepatitis (alcoholics/elderly), GI upset, orange discoloration of body fluids, flu-like syndrome, thrombocytopenia, rash; potent enzyme inducer — reduces OCP efficacy (counsel young women), interacts with many drugs |
| Pyrazinamide (PZA) | Kills intracellular bacilli in acidic environment; excellent CSF penetration; short-course essential; 15–30 mg/kg (max 2 g/d) | Arthralgia/gout (hyperuricaemia), hepatitis, anorexia/nausea, flushing, photosensitivity |
| Ethambutol (EMB) | Supplemental, protects against resistance; 15 mg/kg | Retrobulbar optic neuritis (most serious) — assess baseline visual acuity, monitor, ophthalmology consult; arthralgia |
| Streptomycin (SM) | Injectable; dose by age/weight | Ototoxicity (giddiness, tinnitus, vertigo, deafness), nephrotoxicity, hypersensitivity |
- Extended duration beyond 6 months: some extrapulmonary TB, silico-tuberculosis, diabetes mellitus, immunocompromised patients; adjust regimen to susceptibility results.
- Severe hemoptysis/large volume: manage airway, consider bronchial artery embolisation; oxygen for hypoxia; mechanical ventilation for acute ventilatory failure.
HKHA Handbook (LMCHK) — Key Points
- 2HRZ(E or S)7 / 4HR7 (when started in hospital or 3×/week not tolerated) - 2HRZ(E or S)7 / 4HR3 - 2HRZ(E or S)3 / 4HR3 (Government Chest Clinic regimen)
- Notification is statutory: active pulmonary TB must be notified promptly to the Department of Health (once treatment started); health-care workers / relevant occupations → also notify the Labour Department under the Occupational Safety and Health Ordinance.
- Pretreatment bloods: liver function, renal function, HBsAg and HIV antibody (after counselling and consent).
- Short-course chemotherapy is standard; give Directly Observed Treatment (DOT) as far as possible.
- Uncomplicated new cases — 6 months total (HK notations: leading number = months; subscript 7 = daily, 3 = thrice weekly; "/" separates phases):
- Retreatment cases — 9 months total:
3 (or 4) HRZES7 / 6 (or 5) HR ± E7. - Drug doses (HK): H 300 mg daily (or 10–15 mg/kg 3×/week; elderly/malnourished may need 200 mg); R 450 mg (<50 kg) / 600 mg (≥50 kg) daily; Z 1–1.5 g (<50 kg) / 1.5–2 g (≥50 kg) daily (2 g/2.5 g 3×/week); E 15 mg/kg daily; S age/weight-adjusted.
- Adverse-reaction call-outs: INH → peripheral neuropathy (give B6); RIF → drug interactions + OCP failure (alternative contraception); EMB → retrobulbar neuritis (baseline + serial visual checks); PZA → hyperuricaemia/gout; S → ototoxicity.
- Extended duration for DM and immunocompromised patients; adjust to susceptibility results.
High-Yield Points
- Classic presentation: hemoptysis + cough + night sweats + weight loss + upper lobe cavitary infiltrate + AFB+ sputum (diabetes is a key risk factor).
- AFB smear negative ≠ no TB; culture takes 2–8 weeks; Xpert MTB/RIF = rapid + rifampicin resistance.
- PPD positive = infection with or without disease; limited value in older adults; IGRA good for latent TB.
- Primary TB: children, Ghon complex; Secondary: adults, upper lobes, cavitation, reactivation.
- Standard regimen: 2HRZE/4HR (6 months).
- INH → hepatitis + neuropathy (B6); RIF → orange body fluids + enzyme inducer (OCP failure); EMB → optic neuritis; PZA → gout.
- HK: statutory notification + DOT; HBsAg/HIV + LFT/RFT before treatment.
Topic Summary
TB is a chronic granulomatous infection spread by airborne droplet nuclei; most cases reflect reactivation of latent infection in adults (secondary TB, upper-lobe cavitation). Diagnosis rests on clinical features, apical infiltrates on CXR, and aetiological confirmation (AFB smear/culture, Xpert, mNGS, or caseous granuloma on biopsy). Treatment is combination chemotherapy — the 6-month regimen 2HRZE/4HR — with close attention to each drug's toxicity (INH neuropathy, RIF interactions, EMB optic neuritis, PZA gout). For LMCHK, the HKHA Handbook adds the mandatory elements: statutory notification, DOT, pretreatment HBsAg/HIV/LFT/RFT, and the HK regimen notations — all high-yield for the written and clinical examinations.