Pulmonary Tuberculosis
Medicine · Respiratory · lean revision notes
Pulmonary Tuberculosis
Pulmonary tuberculosis (PTB) is a chronic granulomatous infection of the lung caused by Mycobacterium tuberculosis, transmitted by airborne droplet nuclei. It remains India's single biggest infectious-disease killer, and the NEET PG examiner mines it relentlessly for NTEP regimens, drug toxicities, and diagnostic cut-offs.
Etiology & microbiology
The causative organism is Mycobacterium tuberculosis (Koch's bacillus, identified 1882), an obligate aerobe with a high lipid (mycolic acid) cell wall that makes it acid-fast (retains carbol fuchsin against acid-alcohol decolorization on Ziehl-Neelsen stain). It is a slow grower with a generation time of ~16–20 hours, hence cultures take 3–8 weeks on solid Löwenstein-Jensen (LJ) medium (egg-based, glycerol favours M. tuberculosis; pyruvate favours M. bovis).
- Transmission: inhalation of droplet nuclei (1–5 µm) generated by coughing. A single cough produces ~3000 droplet nuclei.
- Infectivity correlates with sputum smear positivity and presence of cavitation.
- M. tuberculosis is a facultative intracellular pathogen surviving within alveolar macrophages.
High-yield: Acid-fastness is due to mycolic acid. A positive ZN smear requires at least 5,000–10,000 bacilli/mL; this is why smear-negative does NOT exclude TB.
Pathophysiology & the pathology eponyms
After inhalation, bacilli are engulfed by alveolar macrophages. Cell-mediated immunity (Th1, IFN-γ, TNF-α) drives caseating granuloma formation around 3–8 weeks. The granuloma contains epithelioid cells, Langhans giant cells (peripheral horseshoe nuclei), lymphocytes, and central caseous necrosis.
Primary TB (first exposure) classically forms in the lower lobe / mid-zone (subpleural, well-ventilated regions):
- Ghon focus = subpleural parenchymal granuloma.
- Ghon complex (primary complex / Ranke complex) = Ghon focus + draining hilar lymphadenopathy + lymphangitis.
- Healed, calcified Ghon complex on later imaging = the classic radiological footprint of past primary infection.
Post-primary (secondary / reactivation) TB localizes to the apical and posterior segments of the upper lobes (high oxygen tension favours the aerobe). Reactivation foci here are called Simon foci (apical foci seeded during primary haematogenous spread that reactivate later). Progressive disease produces cavitation from liquefied caseous material draining into a bronchus.
Flow of infection: Inhalation → macrophage uptake → lymphohaematogenous spread (asymptomatic) → containment as latent TB infection (LTBI) in 90% → reactivation in ~5–10% lifetime (≈10%/yr in HIV) → active PTB → cavitation → infectious smear-positive disease.
High-yield: Apical/posterior upper-lobe cavitation = reactivation TB. Lower-zone/hilar nodal disease = primary TB. Assmann focus = an early infraclavicular reactivation infiltrate.
Clinical features
- Constitutional: evening-rise low-grade fever, drenching night sweats, anorexia, weight loss, fatigue.
- Respiratory: chronic cough >2 weeks (NTEP presumptive-TB criterion), mucopurulent sputum, haemoptysis (eroded vessel or aspergilloma in old cavity), pleuritic chest pain, breathlessness in extensive disease.
- Signs: apical crackles, amphoric/cavernous breath sounds over cavities, signs of consolidation or pleural effusion.
- Rasmussen aneurysm = dilated branch of pulmonary artery in a cavity wall → massive life-threatening haemoptysis.
High-yield: Any cough ≥2 weeks ± fever, weight loss, night sweats, or haemoptysis is a presumptive TB case under NTEP and warrants sputum testing.
Diagnosis & investigation of choice
Microbiological confirmation
| Test | Principle | Key points |
|---|---|---|
| Sputum smear (ZN / fluorescent auramine) | Detects acid-fast bacilli | Cheap; needs 5,000–10,000 bacilli/mL; cannot distinguish MTB from NTM |
| CBNAAT / GeneXpert MTB/RIF | Real-time PCR detecting MTB DNA + rpoB (rifampicin resistance) | Result in ~2 h; upfront test of choice under NTEP; detects rifampicin resistance |
| Truenat MTB | Chip-based PCR, point-of-care | NTEP-validated molecular test |
| Liquid culture (MGIT/BACTEC) | Gold standard | 1–3 weeks; enables drug-susceptibility testing (DST) |
| Solid culture (LJ medium) | Gold standard | 3–8 weeks |
| Line Probe Assay (LPA) | Detects resistance genes | First-line LPA: rpoB, katG, inhA; second-line: fluoroquinolone & aminoglycoside resistance |
High-yield: CBNAAT (GeneXpert) is the recommended initial diagnostic test under NTEP. Culture remains the gold standard, but molecular WHO-recommended rapid diagnostic tests (mWRD) are now front-line.
Latent TB infection (LTBI) tests
| Feature | Mantoux (TST) | IGRA (QuantiFERON / T-SPOT) |
|---|---|---|
| Antigen | PPD (intradermal, 5 TU, read at 48–72 h) | ESAT-6, CFP-10 (absent in BCG) |
| Affected by BCG | Yes (false positive) | No |
| Affected by NTM | Yes | Minimal |
| Reads | Transverse induration (not erythema) | IFN-γ release in vitro |
Mantoux interpretation (induration cut-offs):
- ≥5 mm: HIV, recent TB contact, immunosuppressed/organ transplant, fibrotic CXR changes.
- ≥10 mm: recent immigrants from high-burden areas, IV drug users, healthcare workers, children <4 yr, comorbidities (diabetes, CKD).
- ≥15 mm: persons with no risk factors.
High-yield: Neither Mantoux nor IGRA distinguishes latent from active TB, and both can be negative in miliary TB / anergy / HIV. They diagnose infection, not disease.
Imaging
- Upper-lobe fibronodular/cavitary infiltrates = reactivation.
- Miliary TB = innumerable uniform 1–3 mm nodules ("millet seeds") from haematogenous spread; CXR may be normal early — HRCT is more sensitive.
- Old healed disease: apical fibrosis, calcified Ghon focus, pleural calcification.
Management — the NTEP/RNTCP regimen
India's programme is now the National TB Elimination Programme (NTEP) (renamed from RNTCP), targeting elimination by 2025. Treatment uses daily fixed-dose combinations (FDC) with weight-band dosing under DOT (directly observed treatment).
Drug-sensitive TB (new case):
2 HRZE (intensive phase) → 4 HR (continuation phase) = total 6 months.
- H = Isoniazid, R = Rifampicin, Z = Pyrazinamide, E = Ethambutol.
- Previously treated/recurrent cases are evaluated for drug resistance via DST rather than the old Category II (2HRZES/1HRZE/5HRE) regimen — the streptomycin-containing retreatment regimen is obsolete under current NTEP.
- TB meningitis & osteoarticular (spinal) TB: extend continuation phase → total 9–12 months; add corticosteroids in TBM and pericardial TB.
| Drug | Mechanism | Signature toxicity (exam) |
|---|---|---|
| Isoniazid (H) | Inhibits mycolic acid synthesis (activated by KatG) | Peripheral neuropathy (give pyridoxine/B6), hepatitis, lupus-like, INH = pyridoxine antagonist |
| Rifampicin (R) | Inhibits DNA-dependent RNA polymerase (rpoB) | Orange-red secretions, hepatitis, potent CYP450 inducer (↓ OCPs, warfarin, protease inhibitors), flu-like syndrome |
| Pyrazinamide (Z) | Active in acidic phagolysosome | Hyperuricaemia/gout, hepatotoxic, arthralgia |
| Ethambutol (E) | Inhibits arabinosyl transferase | Retrobulbar (optic) neuritis → loss of red-green colour vision; dose-dependent |
| Streptomycin (S) | Aminoglycoside, 30S | Ototoxicity (vestibular), nephrotoxicity; avoid in pregnancy |
High-yield (most-tested MCQs):
- Ethambutol → optic neuritis (red-green colour blindness); test colour vision before/during therapy.
- Rifampicin → CYP450 induction causing oral-contraceptive failure and orange body fluids.
- Isoniazid → peripheral neuropathy, prevented by pyridoxine (vitamin B6).
- Pyrazinamide → hyperuricaemia.
- Streptomycin → CN VIII (vestibular) toxicity, contraindicated in pregnancy.
Mnemonic for first-line toxicity — "RIPE": Rifampicin (red urine), Isoniazid (neuropathy), Pyrazinamide (hyperuricaemia + hepatotoxic), Ethambutol (eye/optic neuritis).
Drug-induced hepatitis (DIH) approach: H, R, Z are all hepatotoxic. Stop all hepatotoxic drugs if ALT >3× ULN with symptoms or >5× without; rechallenge sequentially (R first, then H) once LFTs normalize. A non-hepatotoxic holding regimen (e.g., ethambutol + levofloxacin + an aminoglycoside) bridges severe DIH.
Drug-resistant TB
| Type | Definition |
|---|---|
| Mono-resistance | Resistance to one first-line drug |
| MDR-TB | Resistance to at least isoniazid AND rifampicin |
| Pre-XDR | MDR + resistance to any fluoroquinolone |
| XDR-TB (revised WHO 2021) | MDR/RR-TB + fluoroquinolone resistance + resistance to ≥1 Group A drug (bedaquiline or linezolid) |
| RR-TB | Rifampicin resistance (treated like MDR) |
- Group A drugs (newer regimens): Levofloxacin/Moxifloxacin, Bedaquiline, Linezolid.
- Shorter all-oral BPaLM regimen (Bedaquiline + Pretomanid + Linezolid + Moxifloxacin) over ~6 months is now recommended for eligible MDR/RR-TB.
- Bedaquiline → QT prolongation; Linezolid → myelosuppression, peripheral & optic neuropathy.
High-yield: Detection of rifampicin resistance on CBNAAT/GeneXpert (rpoB mutation) triggers referral for DST and MDR-TB management.
TB in special situations
- Pleural TB: exudative, lymphocyte-predominant effusion; adenosine deaminase (ADA) >40 IU/L is suggestive; pleural-fluid AFB smear is usually negative; pleural biopsy (caseating granuloma) has the highest yield.
- Miliary TB: disseminated haematogenous disease; choroidal tubercles on fundoscopy are pathognomonic; can cause ARDS; LFTs often deranged; treat 6–9 months.
- TB + HIV: start ATT first, then ART within 2–8 weeks (sooner if CD4 <50). Use rifabutin if on protease inhibitors; watch for IRIS.
- Pregnancy: HRE-Z generally safe; avoid streptomycin (ototoxic to fetus).
High-yield: Pleural fluid ADA >40 IU/L + lymphocytic exudate strongly suggests tubercular effusion; pleural biopsy is the confirmatory investigation of choice.
Complications
- Massive haemoptysis (Rasmussen aneurysm, bronchiectasis, aspergilloma).
- Aspergilloma (mycetoma) colonizing an old cavity → "air-crescent / monad sign".
- Cor pulmonale, chronic respiratory failure, fibrothorax, bronchiectasis.
- Immune Reconstitution Inflammatory Syndrome (IRIS): paradoxical worsening (fever, enlarging nodes, worsening infiltrates) after starting ART in TB-HIV co-infection, due to recovering immunity; continue ATT and ART, add steroids/NSAIDs, treat symptomatically — do not stop therapy unless life-threatening.
- Endobronchial TB → tracheobronchial stenosis; fibrosing mediastinitis.
High-yield: IRIS = paradoxical deterioration after immune recovery (ART start); it is not treatment failure or drug resistance.
Key differentials
- Community-acquired pneumonia / lung abscess (air-fluid level vs TB cavity which has thicker wall, upper-lobe predilection).
- Lung carcinoma (especially cavitating squamous cell) — older smoker, irregular thick-walled cavity.
- Non-tuberculous mycobacteria (NTM) e.g. M. avium complex — clinically/radiologically similar, distinguished by culture/molecular ID.
- Fungal infections — histoplasmosis, coccidioidomycosis, chronic pulmonary aspergillosis.
- Sarcoidosis — non-caseating granuloma, bilateral hilar lymphadenopathy, raised ACE, negative AFB.
- Wegener's (GPA) and other cavitating vasculitides.
Recently asked / exam angle
- CBNAAT/GeneXpert as the upfront diagnostic test and its detection of rifampicin resistance (rpoB) — repeatedly tested.
- Standard regimen written as 2HRZE + 4HR and identifying total duration (6 months).
- Ethambutol → optic neuritis / colour vision and isoniazid → neuropathy, give pyridoxine are perennial single-best-answer items.
- Definition of MDR-TB (resistance to INH + rifampicin) and the revised XDR-TB definition (loss of bedaquiline/linezolid).
- Mantoux 5 TU intradermal, read induration at 48–72 h, and zone-specific cut-offs (≥5/≥10/≥15 mm).
- Pleural fluid ADA >40 IU/L; pleural biopsy as the best diagnostic yield.
- Pathology eponyms: Ghon focus/complex, Simon foci, Assmann focus, Rasmussen aneurysm, Langhans giant cells.
- IGRA uses ESAT-6/CFP-10, unaffected by prior BCG — a favourite "which test is not affected by BCG" question.
- IRIS definition and management in TB-HIV.
- New BPaLM all-oral regimen for MDR/RR-TB and bedaquiline QT prolongation.
Rapid revision
- M. tuberculosis is an obligate aerobe; acid-fastness is due to mycolic acid (ZN stain).
- CBNAAT/GeneXpert = upfront NTEP test; detects rpoB → rifampicin resistance; culture (MGIT/LJ) is gold standard.
- Ghon complex = parenchymal focus + lymphangitis + hilar node; reactivation favours upper-lobe apical/posterior segments.
- Standard new-case regimen: 2HRZE / 4HR = 6 months; TB meningitis & spinal TB extend to 9–12 months with steroids.
- RIPE toxicities: Rifampicin → red urine + CYP450 induction; Isoniazid → neuropathy (give B6); Pyrazinamide → hyperuricaemia; Ethambutol → optic neuritis.
- Streptomycin is ototoxic and contraindicated in pregnancy.
- MDR-TB = resistance to at least INH + rifampicin; XDR = MDR + fluoroquinolone + bedaquiline/linezolid resistance (WHO 2021).
- Group A drugs: levofloxacin/moxifloxacin, bedaquiline, linezolid; BPaLM is the new short oral MDR regimen.
- Mantoux: 5 TU intradermal, read induration at 48–72 h; cut-offs 5/10/15 mm by risk.
- IGRA (ESAT-6, CFP-10) is not affected by BCG; neither IGRA nor TST separates latent from active TB.
- Pleural TB: lymphocytic exudate, ADA >40 IU/L, biopsy shows caseating granuloma; miliary TB shows choroidal tubercles.
- IRIS = paradoxical worsening after ART in TB-HIV; continue therapy, add steroids — not drug failure.