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Pulmonary Tuberculosis - Pathogenesis, Clinical Features, Lab Diagnosis, NTEP Treatment & BCG Vaccination

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CASE ANALYSIS

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1. PATHOGENESIS

Causative Agent

• Mycobacterium tuberculosis - an obligate aerobic, non-spore-forming, non-motile, acid-fast bacillus (due to high mycolic acid content in its cell wall)
• Transmission: inhalation of droplet nuclei (1-5 µm) from an infectious person

Primary (Ghon) Complex - First Infection

1. Inhaled bacilli deposit in the mid-lung zone (well-ventilated areas, usually right lower or middle lobe)
2. Bacilli are engulfed by alveolar macrophages but initially resist killing (due to inhibition of phagosome-lysosome fusion)
3. An initial focus of pneumonic consolidation forms in the lung parenchyma = Ghon's focus
4. Bacilli travel via lymphatics to hilar/mediastinal lymph nodes
5. Ghon's focus + enlarged lymph nodes = Ghon's complex (primary complex)
6. In immunocompetent individuals: CMI (cell-mediated immunity) develops in 2-8 weeks

Granuloma Formation (Core of Pathogenesis)

• Activated macrophages + CD4+ T helper cells form caseating granulomas (tubercles)
• Granuloma components:
  • Central area: caseous (cheese-like) necrosis with bacilli
  • Surrounding: epithelioid cells (modified macrophages), Langhans giant cells (multiple nuclei arranged at periphery), lymphocytes
  • Outer zone: fibroblasts and fibrous tissue
• Mycobacterium tuberculosis infection leads to development of caseating granulomas; granulomas are composed of a large percentage of CD11b+ macrophages, which produce VEGF-C leading to de novo lymphangiogenesis - Murray & Nadel's Textbook of Respiratory Medicine
• IFN-γ is a critical mediator of the interaction between MTB, macrophages and granuloma formation

Stages of Primary TB

Reactivation (Post-Primary / Secondary TB)

• Occurs due to reactivation of dormant bacilli (endogenous) or reinfection (exogenous)
• Commonly affects apices of upper lobes (high O₂ tension favors mycobacterial growth)
• Triggers: immunosuppression (HIV, diabetes, malnutrition, steroids, TNF-α inhibitors), old age
• Results in: cavitation, bronchogenic spread, haematogenous dissemination (miliary TB)

Progression in the Case

• Caseous necrosis liquefies → cavity formation → bacilli spill into airways → productive cough + haemoptysis
• Systemic spread causes constitutional symptoms: fever, night sweats, weight loss (cachexia)

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2. CLINICAL FEATURES

Constitutional (Systemic) Symptoms

• Fever: characteristically low-grade, worse at night (as in the case) - due to IL-1, IL-6, TNF-α
• Night sweats: drenching (patients may soak their clothes)
• Weight loss / anorexia: due to increased cytokines (cachexia); hence called "consumption" historically
• Fatigue, malaise

Respiratory Symptoms

• Productive cough: initially dry, then mucopurulent sputum - early hallmark
• Haemoptysis: blood in sputum - from erosion of blood vessels in cavities (Rasmussen's aneurysm) or erosion of bronchial wall
• Breathlessness / dyspnoea: in advanced disease
• Chest pain: pleuritic, if pleural involvement

Physical Signs

• Early disease: often normal examination
• Later: dullness to percussion (consolidation, effusion), bronchial breathing, amphoric breathing (over cavities), crackles (post-tussive creps)
• Clubbing in chronic disease
• Signs of complications: pleural effusion, pneumothorax, pericarditis

Complications

• Haemoptysis (massive)
• Pneumothorax / pyopneumothorax
• Pleural effusion / empyema
• Laryngeal TB (hoarseness)
• Intestinal TB (from swallowed sputum)
• Miliary TB / TB meningitis (haematogenous spread)
• Cor pulmonale (in chronic fibro-cavitary disease)
• Amyloidosis (secondary/AA)

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3. LABORATORY DIAGNOSIS

A. Sputum Examination (Most Important)

• Ziehl-Neelsen (ZN) staining: Mycobacteria stain red against blue background (acid-fast = resist decolorisation with acid-alcohol)
• At least 2 sputum specimens for AFB smear microscopy (NAAT is the preferred initial test per WHO)
• Under NTEP: sputum collected - 1 spot sample + 1 early morning sample
• Sensitivity ~60-70%; Specificity ~98%
• Fluorescent microscopy (auramine-rhodamine stain) increases sensitivity

• Grows on Lowenstein-Jensen (LJ) medium (egg-based, contains glycerol + malachite green)
• Colonies: rough, dry, cream/buff-coloured ("cauliflower colonies")
• Slow growing: 4-8 weeks
• BACTEC (liquid medium): faster - 10-14 days
• Culture confirms diagnosis, tests drug sensitivity

• Automated, self-contained real-time PCR
• Detects M. tuberculosis complex AND rifampicin resistance in 90 minutes
• WHO recommends Xpert MTB/RIF as the preferred initial diagnostic test especially in:
  • HIV-positive individuals
  • Suspected drug-resistant TB
  • Seriously ill patients
• Under NTEP: Xpert MTB/RIF is the first-line diagnostic test - Murray & Nadel's Textbook of Respiratory Medicine

B. Tuberculin Skin Test (Mantoux Test / TST)

• 0.1 ml of 5 TU PPD (purified protein derivative) injected intradermally on flexor surface of forearm
• Read at 48-72 hours: measure induration (not redness)
• Positive: ≥10 mm induration (≥5 mm in HIV patients, immunocompromised, close contacts)
• Indicates infection (past or present); does NOT differentiate active from latent TB
• False positive: BCG vaccination, NTM infection
• False negative: HIV/AIDS, miliary TB, malnutrition, immunosuppression (anergy)

C. Interferon-Gamma Release Assay (IGRA)

• Tests T-cell response to M. tuberculosis-specific antigens (ESAT-6, CFP-10)
• More specific than TST (not affected by BCG)
• Useful for latent TB infection detection

D. Chest X-Ray (CXR)

• Radiographic findings alone cannot provide a definitive diagnosis of TB - Murray & Nadel's

E. Other Tests

• CBC: normocytic normochromic anaemia, lymphocytosis (in early), neutrophilia (in bacterial superinfection)
• ESR: raised (non-specific)
• Serum ADA (Adenosine Deaminase): elevated in TB pleural effusion
• Bronchoscopy + BAL: for smear-negative cases
• Biopsy (lymph node, pleural, lung): shows caseating granulomas with Langhans giant cells

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4. NTEP (National Tuberculosis Elimination Programme) GUIDELINES ON TREATMENT

Background

• RNTCP (Revised National TB Control Programme) was renamed NTEP in 2020
• Goal: Eliminate TB by 2025 (ahead of WHO's 2030 Sustainable Development Goal)
• Key platform: Ni-Kshay (web-based case management system for TB notification)

Drug-Susceptible TB (DS-TB) Standard Regimen

• Total duration: 6 months
• Drugs given as Fixed Dose Combination (FDC) tablets - improves adherence, prevents monotherapy
• All treatment under Directly Observed Treatment (DOT) through DOTS strategy
• Nikshay Poshan Yojana: Rs. 500/month nutritional support to TB patients

Drug Mechanisms

Drug-Resistant TB (DR-TB) Regimens under NTEP 2024

• MDR-TB (RR-TB): BPaLM regimen - Bedaquiline (Bdq) + Pretomanid (Pa) + Linezolid (Lzd) + Moxifloxacin (Mfx) for 6 months (26 weeks) - fully oral, injection-free
• Alternatively: 9-11 month shorter oral Bdq-containing regimen (with Linezolid replacing Ethionamide)
• Treatment success for DS-TB: 85-87% (public and private sectors combined)

Categories of TB under NTEP

DOTS Strategy (Directly Observed Treatment, Short-course)

1. Political commitment to TB control
2. Case detection by quality sputum smear microscopy
3. Standardized short-course chemotherapy under direct observation
4. Uninterrupted supply of quality anti-TB drugs
5. Standardized recording and reporting system

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5. BCG VACCINATION

Background

• BCG = Bacillus Calmette-Guérin (named after Calmette and Guérin)
• Developed from an attenuated bovine strain of M. bovis
• First oral vaccination: 1921-1925; intradermal technique: 1927
• Globally recognized as safe in 1948
• WHO recommended strain: "Danish 1331"
• Produced at BCG Laboratory, Guindy, Chennai (since 1967, using Danish 1331 strain)
• Part of WHO Expanded Programme on Immunization (EPI)

Vaccine Type

• Live attenuated bacterial vaccine (only widely used live bacterial vaccine)
• Available as: freeze-dried (preferred - more stable) and liquid vaccine
• Storage: below 10°C, away from light; stable for several weeks at ambient tropical temperature
• Reconstitute with normal saline (not distilled water - causes irritation)
• Reconstituted vaccine must be used within 3 hours, leftover discarded

Administration

Normal Post-Vaccination Reaction

• Papule at injection site within 2-3 weeks
• Pustule → ulcer → scar (4-8 weeks)
• Scar = evidence of successful vaccination (no scar = no immunity)
• Axillary lymphadenopathy may occur (mild)

Aim

Efficacy

• Provides 70-80% protection against severe forms of childhood TB:
  • TB meningitis
  • Miliary tuberculosis
• Protection against pulmonary TB in adults: variable (0-80% in different trials)
• Despite contradictory trial evidence, BCG is of proven value in preventing severe childhood TB

Contraindications

• Symptomatic HIV infection / AIDS
• Immunocompromised states (leukemia, malignancy, high-dose corticosteroids)
• Eczema/skin disease at injection site
• Not contraindicated in asymptomatic HIV-infected infants

Tuberculin Test After BCG

• BCG vaccination gives a positive Mantoux (TST) - induration of 5-10 mm (usually <10 mm)
• Induration >15 mm after BCG suggests true infection with M. tuberculosis

BCG and NTEP

• BCG vaccination remains a fundamental component of the national tuberculosis programme
• Protects against severe disease in children most at risk
• Part of the Universal Immunization Programme (UIP) of India - given at birth

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SUMMARY TABLE - Key Points for Exam

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