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Complete Clinical Approach to Tuberculosis (TB)

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PART 1: INITIAL APPROACH - RISK STRATIFICATION

Who Is a High-Risk TB Patient?

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PART 2: CLINICAL ASSESSMENT - HISTORY

A. Presenting Complaints (Symptom Complex)

• Fever - typically low-grade, evening predominance ("hectic fever")
• Night sweats (drenching - patient wakes soaked)
• Anorexia and weight loss (>10% body weight is a red flag)
• Fatigue, malaise

• Cough - initially dry, becomes productive over weeks; if >2-3 weeks in high-prevalence area = TB until proven otherwise
• Haemoptysis - indicates cavitary disease or Rasmussen's aneurysm erosion
• Dyspnoea - suggests extensive parenchymal disease or pleural involvement
• Pleuritic chest pain - pleural TB

• Duration of symptoms (TB is characteristically insidious, weeks to months)
• Prior TB history, prior treatment (to flag drug resistance)
• Household contact with known TB case
• BCG vaccination status in childhood

B. Epidemiological History

• Country of origin, travel to endemic areas (South/Southeast Asia, Sub-Saharan Africa, Eastern Europe)
• Occupation (healthcare workers, prison staff, miners)
• HIV status / CD4 count if known
• Any immunosuppressive therapy (biologics, steroids, chemotherapy)
• History of transplantation
• Alcohol or drug use

C. Past Medical History

• Prior TB (when? which regimen? completed?)
• Diabetes mellitus
• CKD or liver disease (affects drug selection)
• Silicosis, pneumoconiosis
• Malignancy

D. Drug History

• Anti-TB drugs taken previously (essential for resistance profiling)
• Antiretrovirals (rifampicin interactions are major)
• Hepatotoxic drugs

E. Family / Social History

• Housing conditions, ventilation, overcrowding
• Number of people sharing sleeping space

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PART 3: CLINICAL EXAMINATION

General Appearance

• Cachexia (temporal wasting, sunken eyes)
• Pallor (anaemia of chronic disease)
• Lymphadenopathy - particularly posterior cervical and supraclavicular ("scrofula")
• BCG scar on left deltoid

Respiratory System

Other Systems (Extrapulmonary Clues)

• Lymph nodes: matted, rubbery, non-tender cervical/supraclavicular nodes; fistula with cheesy material = pathognomonic
• Spine: tenderness at D10-L2 level, kyphosis (gibbus deformity) = Pott's spine
• Abdomen: ascites (doughy feel), hepatosplenomegaly, tender iliac fossa mass (ileocaecal TB)
• CNS: neck rigidity, Kernig's sign, altered sensorium, focal neurological deficits (TBM)
• Joints: monoarthritis of hip/knee, cold abscess, sinus
• Genitourinary: painless haematuria, dysuria, sterile pyuria, scrotal swelling (male)
• Skin: lupus vulgaris (red-brown papules on face), erythema nodosum (hypersensitivity reaction)
• Fundoscopy: choroidal tubercles (classic miliary TB finding - look in any febrile patient with weight loss and bilateral lung infiltrates)

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PART 4: DETERMINING WHICH STAGE / SYSTEM IS INVOLVED

Classification Framework

TB Infection
├── Latent TB Infection (LTBI) - positive TST/IGRA, no symptoms, no active disease
└── Active TB
    ├── Pulmonary TB (PTB)
    │   ├── Primary PTB
    │   ├── Post-primary (reactivation) PTB
    │   ├── Cavitary PTB
    │   └── Miliary PTB
    └── Extrapulmonary TB (EPTB)
        ├── Lymph node TB (most common EPTB)
        ├── Pleural TB
        ├── CNS TB (meningitis / tuberculoma)
        ├── Skeletal TB (Pott's spine, joint TB)
        ├── Genitourinary TB
        ├── Peritoneal / abdominal TB
        ├── Pericardial TB
        └── Disseminated / miliary TB

Distinguishing Primary vs. Reactivation TB

• Harrison's Principles of Internal Medicine 22E, p. 1424

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PART 5: INVESTIGATIONS - WARD, OPD AND EMERGENCY

Tier 1: Bedside / OPD (Always Order)

• Collect 3 sputum samples: spot, early morning, spot (or 2 early morning in sequential days)
• Sensitivity 45-80% for pulmonary TB; low in HIV, extrapulmonary, paucibacillary disease
• Positive = strongly suggestive of active TB; negative does NOT rule out TB
• Result available same day

• First-line imaging for all suspected TB patients
• Classic findings of reactivation PTB: upper lobe infiltrates (apical and posterior segments), cavitation, fibrosis/scarring, pleural effusion, "tree-in-bud" pattern, bilateral involvement
• Primary PTB: mid-zone consolidation, hilar/mediastinal lymphadenopathy, Ghon complex (calcified peripheral + hilar focus)
• Miliary TB: bilateral fine nodular ("millet seed") pattern throughout both lung fields
• Post-primary CXR patterns: infiltrates → cavities → fibrocalcific disease
• A normal CXR does NOT exclude extrapulmonary TB
• Tintinalli's Emergency Medicine, p. 493 & 497

• BCG vaccination causes false-positive; false-negatives occur in HIV, severe immunosuppression, miliary TB, recent measles vaccination, early disease
• Tintinalli's Emergency Medicine, p. 494

• Blood test; preferred over TST in BCG-vaccinated individuals
• Not affected by BCG vaccination
• More specific than TST; similar sensitivity
• Does NOT distinguish latent from active TB

Tier 2: Ward / Hospital Investigations

• Gold standard for diagnosis and drug susceptibility testing (DST)
• Solid media (Lowenstein-Jensen): 3-8 weeks for growth
• Liquid media (MGIT, BACTEC): 1-3 weeks, more sensitive but costlier
• Essential for all patients before starting therapy

• WHO-endorsed rapid test; results within 2 hours
• Detects M. tuberculosis DNA AND rifampicin resistance simultaneously
• Sensitivity:
  • Smear-positive: >95%
  • Smear-negative: 50-80%
• Recommended as first-line diagnostic in any setting - Tintinalli's Emergency Medicine, p. 495
• GeneXpert Ultra improves sensitivity for paucibacillary disease and extrapulmonary specimens
• Remains positive in treated patients (detects dead + live organisms) - use for diagnosis, not treatment monitoring

• Phenotypic DST: tests against first-line (H, R, E, Z) and second-line drugs
• Molecular DST: Line Probe Assay (LPA) detects rpoB (rifampicin resistance), inhA / katG (isoniazid resistance) within 1-2 days
• Order for all culture-positive patients; mandatory before MDR-TB regimen starts

• CBC: anaemia (normocytic normochromic); lymphocytosis; thrombocytosis
• LFTs (AST, ALT, bilirubin, ALP): baseline before hepatotoxic drugs
• Serum creatinine / urine: baseline before ethambutol (optic nerve toxicity risk) and streptomycin (renal toxicity)
• Uric acid: pyrazinamide causes hyperuricaemia
• Random blood glucose / HbA1c: screen for DM comorbidity
• HIV serology: mandatory in ALL TB patients
• CD4 count if HIV positive (guides ART timing and extrapulmonary risk)
• ESR/CRP: non-specific but tracks inflammatory response

• Sterile pyuria (pus cells without bacteria on culture) = classic finding of genitourinary TB
• If GU TB suspected: 3 consecutive early morning urine (EMU) samples for AFB culture

Tier 3: Extrapulmonary-Specific Investigations

• Fine-needle aspiration cytology (FNAC): yield up to 80%
• Excisional biopsy if FNAC inconclusive
• Histology: caseating granuloma with Langhans giant cells + AFB
• GeneXpert on aspirated material

• Thoracentesis: straw-coloured exudate; protein >3 g/dL; lymphocytes predominant (late); pH ~7.3; low glucose; ADA (adenosine deaminase) >40 U/L is highly suggestive
• AFB smear of pleural fluid: <5% sensitivity
• Pleural culture: positive in 30-40%
• Pleural biopsy (Abrams needle or VATS): yield >80% for granulomas
• ADA >70 U/L in pleural fluid = very high specificity for TB

• CSF analysis (lumbar puncture): clear/slightly turbid, cells 100-500 (lymphocytic), protein >100 mg/dL, glucose <45 mg/dL (CSF:serum ratio <0.5), AFB smear low yield (<10-40%), culture positive in 45-90%
• GeneXpert on CSF: WHO-endorsed, ~90% sensitivity
• MRI brain with contrast: meningeal enhancement, communicating hydrocephalus, tuberculomas, infarcts (basal ganglia)
• Harrison's 22E, p. 1432

• Echo: pericardial effusion; constrictive physiology
• Pericardiocentesis: exudate, ADA elevated
• ECG: low-voltage complexes, diffuse ST changes

• MRI spine: gold standard - disc space narrowing, vertebral collapse, paraspinal abscess, cord compression
• X-ray: late finding (osteolysis, vertebral collapse)
• Bone biopsy for culture

• CXR: bilateral fine nodular infiltrates (1-3 mm, "millet seed")
• CT chest: confirms miliary pattern even when CXR is normal
• Fundoscopy: choroidal tubercles (pathognomonic)
• Liver/bone marrow biopsy: granulomas (if diagnosis elusive)
• Blood culture: positive in up to 50% (HIV)

• Ascitic fluid: exudate, lymphocytic, ADA elevated (>39 U/L)
• Laparoscopy with biopsy: "rice body" nodules on peritoneum + biopsy = diagnostic
• CT abdomen: omental cake, peritoneal thickening, lymphadenopathy

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PART 6: EMERGENCY DEPARTMENT APPROACH

Emergency Presentations of TB

Emergency TB Isolation Protocol

1. Place patient in separate waiting area immediately upon suspicion
2. Provide patient with a surgical mask; instruct to cover mouth when coughing
3. Negative-pressure isolation room (if available)
4. All staff wear FFP2/N95 respirator when entering
5. Evaluate immunocompromised patients (HIV, transplant) promptly even with minimal symptoms - Tintinalli's Emergency Medicine, p. 494

Emergency Diagnosis Shortcuts

• CXR: upper lobe involvement + cavitation + haemoptysis = treat as TB until culture proves otherwise
• Key clinical clue: haemoptysis + night sweats + weight loss = TB until proven otherwise
• Do NOT delay starting anti-TB therapy waiting for culture results in very ill patients with high clinical suspicion

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PART 7: TREATMENT - REGIMENS BY TB TYPE

Fundamental Principles

• Combination therapy is mandatory (prevents resistance amplification)
• Two phases: intensive + continuation
• All regimens supervised by directly observed therapy (DOT) where compliance is a concern
• Never add a single drug to a failing regimen
• First-line drugs: HRZE (Isoniazid [H], Rifampicin [R], Pyrazinamide [Z], Ethambutol [E])

Drug Dosing (Adults, Weight-Based)

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Regimen 1: Drug-Susceptible Pulmonary TB (Standard)

• Intensive phase: HRZE x 2 months (8 weeks) daily
• Continuation phase: HR x 4 months (16 weeks) daily

• Cavitary pulmonary TB with positive sputum culture at 2 months
• Interrupted therapy (patient defaulted)

• 2HPZM/2HPM (isoniazid + rifapentine + pyrazinamide + moxifloxacin x 2 months, then isoniazid + rifapentine + moxifloxacin x 2 months)
• Non-inferior to 6-month in recent TB-SEQUEL/TBTC trials
• Not yet universally available

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Regimen 2: Pulmonary TB in HIV-Positive Patients

• Same HRZE x 2 months + HR x 4 months
• ART timing:
  • CD4 <50: start ART within 2 weeks of starting ATT
  • CD4 50-500: start ART within 2-4 weeks
  • CD4 >500: start ART after 2-4 months (immune reconstitution inflammatory syndrome (IRIS) risk is lower priority)
• Rifampicin-ART interaction: rifampicin is a strong CYP450 inducer - avoid protease inhibitors; use efavirenz-based or dolutegravir-based regimens
• Cotrimoxazole prophylaxis for all HIV-TB coinfected patients (PCP, toxoplasmosis prevention)
• Successful ART lowers the rate of TB and reduces extrapulmonary involvement - Tintinalli's Emergency Medicine, p. 497

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Regimen 3: Extrapulmonary TB (Site-Specific)

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Regimen 4: Drug-Resistant TB

Definitions

MDR-TB Treatment (WHO 2022 Guidelines)

• Bedaquiline (B) + Pretomanid (Pa) + Linezolid (L) + Moxifloxacin (M) x 6 months
• Superior efficacy vs older 18-24 month regimens; fewer adverse events
• WHO strongly recommends this as first-line for MDR-TB

• Bedaquiline + Moxifloxacin + Ethionamide (or high-dose isoniazid) + Ethambutol + Pyrazinamide + Clofazimine
• 4-month intensive + 5-month continuation

• Group A drugs (prioritise): Levofloxacin/Moxifloxacin, Bedaquiline, Linezolid
• Group B drugs (add next): Clofazimine, Cycloserine/Terizidone
• Group C drugs (add if needed): Ethambutol, Delamanid, Pyrazinamide, Imipenem-cilastatin, Amikacin, Ethionamide, PAS

• Linezolid: monthly CBC (myelosuppression, anaemia), peripheral neuropathy
• Bedaquiline: ECG monthly (QTc prolongation)
• Moxifloxacin: ECG (QTc)
• Delamanid: ECG

INH-Resistant TB (HR-resistant):

• 6RZES or 6RZE (no isoniazid)
• Or add fluoroquinolone to the regimen

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Regimen 5: Latent TB Infection (LTBI)

• Indications: positive TST/IGRA + any risk factor for progression (HIV, immunosuppression, close contact, diabetes, recent conversion, high-risk occupation)
• Exclude active TB before starting (clinical assessment + CXR mandatory)

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Regimen 6: Paediatric TB

• WHO/ATS 2022 strong recommendation: 4-month regimen
• 2HRZE / 2HR (2 months HRZE + 2 months HR)
• Superior adherence vs 6 months; non-inferior efficacy

• 2HRZE / 10HR (12 months total)
• Ethambutol: use with caution in children too young to report visual changes (substitute streptomycin if needed)
• Dexamethasone mandatory for TBM

• Same regimen; adjust ART timing; nevirapine-based ART preferred over efavirenz in young children

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Regimen 7: Pregnancy

• Rifampicin, Isoniazid, Ethambutol: safe in pregnancy
• Pyrazinamide: WHO endorses use in pregnancy; ACOG historically cautious but evidence supports safety
• Standard 2HRZE / 4HR regimen is used
• Give pyridoxine (Vitamin B6) throughout to prevent INH-induced neuropathy
• Streptomycin and amikacin: contraindicated (ototoxicity to foetus)
• Fluoroquinolones: avoid if possible (teratogenicity concerns)
• Breastfeeding: safe on ATT; INH-exposed infants get pyridoxine supplement

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Regimen 8: Renal Impairment

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Regimen 9: Liver Disease / Hepatotoxicity

• Baseline LFTs before starting
• Recheck at 2 weeks, 4 weeks, then monthly
• Symptomatic monitoring: instruct patients to report jaundice, nausea, abdominal pain, dark urine

• Stop all ATT if:
  • Symptomatic hepatitis + any LFT rise
  • Asymptomatic LFT > 3x ULN (some guidelines: 5x)
• Sequence of reintroduction after recovery: R → H → Z (in order from least to most hepatotoxic)
• If cannot tolerate full regimen: use combinations of Ethambutol + Fluoroquinolone + Aminoglycoside
• Chronic liver disease: prefer regimens without pyrazinamide if LFTs are already elevated

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PART 8: MONITORING ON TREATMENT

Sputum Monitoring

• Sputum smear and culture at: 0 (baseline), 2 months, 5 months, end of treatment
• Smear still positive at 2 months = extend intensive phase by 1 month; repeat DST
• Culture conversion at 2 months is a key predictor of treatment success

Clinical Monitoring

• Weight (should gain weight on treatment)
• Symptom resolution (fever, sweats should resolve within 2-4 weeks of starting ATT)
• Ethambutol: monthly visual acuity and colour vision testing
• Streptomycin: audiometry and renal function monthly
• Linezolid (MDR-TB): CBC monthly
• Bedaquiline/Moxifloxacin: ECG monthly (QTc)

Drug Interactions (Rifampicin - Critical)

• Antiretrovirals (avoid protease inhibitors; use efavirenz/dolutegravir)
• Oral contraceptives (advise barrier contraception)
• Warfarin (INR monitoring required)
• Phenytoin, digoxin, methadone, antifungals, corticosteroids

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PART 9: SUMMARY CLINICAL FLOWCHART

Suspected TB Patient
        |
        ├── Isolate (surgical mask + negative pressure if available)
        ├── History + Examination (see above)
        ├── CXR + Sputum AFB smear x3 + GeneXpert MTB/RIF
        ├── HIV test + Baseline LFTs/RFTs/CBC
        |
        ├── HIGH CLINICAL SUSPICION (even if smear negative)
        |       └── START ATT empirically, confirm with culture
        |
        ├── GeneXpert POSITIVE, RIF-sensitive
        |       └── HRZE x 2 months + HR x 4 months
        |
        ├── GeneXpert POSITIVE, RIF-resistant
        |       └── Refer MDR-TB unit + BPaLM regimen (WHO 2022)
        |
        ├── GeneXpert NEGATIVE, strong clinical suspicion
        |       └── Culture, LPA; treat empirically if very ill
        |
        └── Extrapulmonary TB suspected
                └── Site-specific investigations (see above)
                └── Adjust duration/steroids per site

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Key References

• Harrison's Principles of Internal Medicine 22E (2025), Chapter 183 - Tuberculosis (Raviglione & Gori), pp. 1424-1443
• Tintinalli's Emergency Medicine, Chapter 67 - Tuberculosis, pp. 493-499
• Murray & Nadel's Textbook of Respiratory Medicine - Chapter 53: Tuberculosis, pp. 1164-1253
• WHO Consolidated Guidelines on Tuberculosis: Module 4 - Drug-Resistant TB Treatment, 2022 Update
• ATS/IDSA/CDC 2022 Updated TB Treatment Guidelines