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Diagnosis of Tuberculosis (TB)

Comprehensive Answer — MD Examination (15 Marks)

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1. DEFINITION

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2. CLINICAL DIAGNOSIS

A. Symptoms (Cardinal Features)

B. Signs on Examination

• Pallor, cachexia, clubbing (rare, in fibrocystic disease)
• Chest: Dullness on percussion over apex, crackles (post-tussive crepitations), bronchial breathing, amphoric breath sounds (cavity)
• Cervical lymphadenopathy (scrofula) — extrapulmonary TB
• Signs of pleural effusion: Stony dull percussion, absent breath sounds

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3. RADIOLOGICAL DIAGNOSIS

A. Chest X-Ray (CXR) — First-line Investigation

B. CT Chest (High-Resolution CT)

• More sensitive than CXR
• Shows tree-in-bud pattern, centrilobular nodules, cavities, bronchiectasis
• Useful when CXR is inconclusive, or in immunocompromised patients
• Detects mediastinal lymphadenopathy

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4. MICROBIOLOGICAL DIAGNOSIS

A. Sputum Specimen Collection

• 3 specimens recommended: spot → early morning → spot (or 3 consecutive early morning)
• Volume: at least 3 mL (optimal 5–10 mL)
• For smear-negative or unable to expectorate: induced sputum, bronchoscopy (BAL), gastric lavage (children)

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B. AFB Smear Microscopy

• Ziehl–Neelsen (ZN) stain — detects acid-fast bacilli (appears red on blue background)
• Auramine-rhodamine fluorescence stain — more sensitive, preferred
• Grading (WHO):

Limitations: Sensitivity 40–60%; requires ~10,000 organisms/mL; cannot distinguish M. tuberculosis from NTM. False negatives common — a negative smear does NOT exclude TB. (ATS/IDSA Guidelines, Diagnosis of TB in Adults and Children, p. 2)

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C. Mycobacterial Culture — Gold Standard

• Liquid culture (MGIT — Mycobacteria Growth Indicator Tube): results in 2–3 weeks; more sensitive
• Solid culture (Lowenstein-Jensen medium): results in 4–8 weeks; allows colony morphology
• Recommendation: Both liquid AND solid culture on all specimens (ATS/IDSA Guidelines, p. 2)
• Confirmatory identification per CLSI guidelines
• Enables DST (Drug Susceptibility Testing)

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D. Nucleic Acid Amplification Tests (NAAT)

• Xpert MTB/RIF (GeneXpert) — WHO-endorsed rapid molecular test
  • Detects M. tuberculosis DNA AND rifampicin resistance (surrogate for MDR-TB) simultaneously
  • Result in <2 hours
  • Sensitivity: ~89% in smear-positive; ~67% in smear-negative
  • Specificity: >99%
• Xpert MTB/RIF Ultra — more sensitive, especially for paucibacillary disease
• Line Probe Assay (LPA / Hain GenoType MTBDRplus): Detects resistance to INH and RIF rapidly
• Recommended on initial respiratory specimen in suspected pulmonary TB (ATS/IDSA Guidelines, p. 2)
• A positive NAAT with negative smear = probable TB, confirmed by culture
• A negative NAAT with positive smear = unlikely M. tuberculosis (consider NTM)

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5. IMMUNOLOGICAL TESTS

A. Tuberculin Skin Test (TST / Mantoux Test)

• Method: 5 TU (tuberculin units) of PPD (Purified Protein Derivative) intradermally into volar forearm; read at 48–72 hours
• Interpretation (induration in mm):

• Limitations:
  • False positive: BCG vaccination, NTM infection
  • False negative: Anergy (HIV, malnutrition, steroids, miliary TB), recent viral illness, improper technique
  • Cannot distinguish latent TB infection (LTBI) from active TB
  • Booster phenomenon (two-step testing in elderly)

B. Interferon-Gamma Release Assays (IGRAs)

• Types: QuantiFERON-TB Gold Plus (QFT-Plus), T-SPOT.TB
• Principle: Blood test measuring IFN-γ released by sensitized T-cells after stimulation with M. tuberculosis-specific antigens (ESAT-6, CFP-10)
• Advantages over TST:
  • Not affected by BCG vaccination
  • Single-visit test (no 48–72 hr return needed)
  • More specific
• Indications: Same as TST; preferred in BCG-vaccinated individuals
• Interpretation: Positive IGRA = evidence of M. tuberculosis infection (latent or active)
• Cannot distinguish LTBI from active TB (same as TST)

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6. ADDITIONAL / SUPPORTIVE INVESTIGATIONS

A. Routine Blood Tests

B. Pleural Fluid Analysis (Pleural TB)

C. Adenosine Deaminase (ADA)

• Produced by activated T-lymphocytes
• ADA >40 U/L in pleural fluid strongly suggests TB pleuritis
• Also used in CSF (TB meningitis) and ascitic fluid (TB peritonitis)

D. Bronchoscopy

• BAL for AFB smear + culture in smear-negative cases
• Transbronchial biopsy for endobronchial TB
• Bronchoscopic findings: mucosal hyperemia, ulceration, granulomas

E. Histopathology / Tissue Biopsy

• Caseating granuloma with Langhans' giant cells = pathognomonic of TB
• Specimens: Pleural biopsy, lymph node biopsy (FNAC/excision), liver biopsy, bone marrow biopsy (miliary TB), transbronchial biopsy

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7. DIAGNOSIS OF SPECIAL FORMS

A. Smear-Negative Pulmonary TB

1. Symptoms compatible with TB
2. CXR consistent with TB
3. No response to broad-spectrum antibiotics
4. Clinical decision to treat for TB
5. Positive NAAT or culture on at least one specimen

B. Latent TB Infection (LTBI)

• Positive TST or IGRA
• No clinical symptoms of active TB
• Normal CXR (or stable, old healed lesion)
• Culture negative

C. Extrapulmonary TB

D. Miliary TB

• CXR: Bilateral diffuse 1–2 mm nodules (miliary pattern)
• HRCT chest more sensitive
• Fundoscopy: Choroidal tubercles (pathognomonic)
• Bone marrow biopsy: Granulomas with AFB

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8. DIAGNOSTIC ALGORITHM (SUMMARY)

Suspected Pulmonary TB
        ↓
Clinical Evaluation (symptoms + signs)
        ↓
Chest X-Ray
        ↓
Sputum: AFB Smear (×3) + Xpert MTB/RIF (NAAT) + Culture (liquid + solid)
        ↓
┌─────────────────────────────────────────────────────────────┐
│ Smear Positive + NAAT Positive → CONFIRMED TB — Start ATT   │
│ Smear Positive + NAAT Negative → Likely NTM or inhibitor    │
│ Smear Negative + NAAT Positive → Probable TB — Treat        │
│ Smear Negative + NAAT Negative → Culture (wait) + TST/IGRA  │
│   Clinical TB (if culture negative) → Treat empirically      │
└─────────────────────────────────────────────────────────────┘
        ↓
HIV testing (all patients)
DST (all culture-positive patients)

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9. RNTCP / NTEP CLASSIFICATION (India-specific)

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10. KEY EXAM POINTS

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References

• Diagnosis of Tuberculosis in Adults and Children — ATS/IDSA Clinical Practice Guidelines, p. 2
• Treatment of Drug-Susceptible Tuberculosis — ATS/CDC/IDSA, p. 18
• Harrison's Principles of Internal Medicine, 21st Edition
• WHO Consolidated Guidelines on Tuberculosis (2022)
• NTEP (National TB Elimination Programme) India Guidelines