Tuberculosis

Meet the patient

A 54-year-old man presents to the outpatient department with six weeks of worsening cough, now productive of yellow sputum streaked with blood, a fever that climbs every evening, drenching night sweats that soak his shirt, and a 6 kg weight loss. He is a smoker; his chest X-ray shows apical cavitation in the right upper lobe.^[1]

The two questions that decide his next two hours are the two that decide every TB case: is he infectious? (isolate him on suspicion — do not wait for the smear), and is the bacillus resistant to rifampicin? (Xpert MTB/RIF answers that within two hours and changes the entire regimen). Hold those two questions and the whole topic slots into place.^[1]

The airborne reflex — isolate first

TB is transmitted by the airborne route. Infectious patients generate droplet nuclei (1 to 5 micrometres) by coughing, sneezing or singing, and a single inhaled bacillus can seed infection in a susceptible contact. The public-health reflex — isolate, notify, trace contacts, and treat under direct observation — is as central to TB as the pharmacology.^[1]

The reflex is activated at the bedside, not after the smear result. Place any suspected open pulmonary TB in a negative-pressure room with N95 or FFP2 or FFP3 respirator protection for staff and a surgical mask on the patient during transport. Keep isolated until the patient is improving and smear-negative — typically after two weeks of effective therapy in drug-susceptible disease. Drug-resistant TB needs negative cultures before de-isolation, a much longer period.^[4]

Etymology for viva gold: phthisis, the old Greek name for TB, means "a wasting away" — the consumptive cachexia was the disease's visible signature for millennia. Scrofula (cervical TB lymphadenitis) was the "king's evil", believed curable by the royal touch. The names outlived the beliefs because the pathology they described was unchanged.^[1]

Latent versus active — the spectrum that runs everything

TB is classified along three axes: anatomical site, natural-history stage, and drug-susceptibility pattern. The natural-history axis is the one that runs the whole topic, because it decides who is infectious and who needs preventive therapy.^[1]

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^[1]

Pulmonary TB is the only contagious form (about 80 per cent of cases); extrapulmonary TB (about 20 per cent, higher in HIV) — lymph node, pleural, skeletal, meningeal, miliary, peritoneal, pericardial, genitourinary — is not contagious in most forms but often paucibacillary and harder to diagnose.^[1]

RIPE — the four drugs and what each does

The standard drug-susceptible regimen is 2 months of HRZE then 4 months of HR — six months total, four drugs to start, two to finish. Each of the four first-line drugs has a signature mechanism and a signature toxicity, and examiners test both.^[1]

^{[2] [15] [1]}

Why the upper lobes — the obligate aerobe

M. tuberculosis is an acid-fast, obligate aerobe with a waxy cell wall rich in mycolic acid (the basis of acid-fastness on Ziehl-Neelsen staining). The upper lobes have the highest oxygen tension — higher ventilation-perfusion ratio, less perfusion, more ventilation — favouring bacillary growth there. This is why reactivation TB classically appears as apical and posterior upper-lobe infiltrates with cavitation.^[1]

The cavity is the source of everything dangerous in pulmonary TB: it teems with bacilli (making smear-positive disease highly infectious), it is the source of haemoptysis when it erodes a bronchial artery, and it is the niche that Aspergillus colonises years later to form an aspergilloma.^[1]

Pathogenesis — the Ghon complex to the cavity

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Inhaled droplet nuclei are phagocytosed by an alveolar macrophage. The bacillus survives inside the macrophage by inhibiting phagolysosome fusion, multiplies intracellularly, and is carried to the draining hilar and mediastinal lymph nodes. Over 2 to 8 weeks a CD4+ Th1 cell-mediated immune response develops: macrophages activated by IFN-gamma and TNF-alpha transform into epithelioid cells and fuse into Langhans giant cells, organising a granuloma with central caseous necrosis.^[1]

The subpleural parenchymal focus plus the draining lymph node is the Ghon complex; once it calcifies and fibroses it becomes the Ranke complex — a radiological marker of healed primary infection. Antigen from this primary response drives the tuberculin skin test (Mantoux) positive.^[1]

Latency is the dormant state — a few bacilli survive inside macrophages in the centre of the granuloma or in old apical foci. Loss of immune containment (HIV, anti-TNF, malnutrition, diabetes, ageing) allows reactivation: the granuloma caseates, liquefies, erodes into a bronchus, and seeds the airways, producing the post-primary apical cavity that is the hallmark of contagious adult pulmonary TB.^[1]

HIV cripples the granuloma. CD4+ T-cell depletion means poorly formed granulomas, higher bacillary load, smears more often negative (paucibacillary or overwhelming), and more extrapulmonary and disseminated disease. This is why any patient with TB atypical in site or severity must be tested for HIV — bidirectional screening, every time.^[1]

The clinical picture — chronic, not acute

The cardinal symptom is a chronic cough lasting more than 2 to 3 weeks, initially dry then purulent or mucopurulent, with haemoptysis in about a third (streaks to massive). Constitutional symptoms — low-grade fever (often with an evening rise), drenching night sweats, weight loss, anorexia, fatigue and malaise — are nearly invariable.^[1]

The duration is the discriminator. Pneumonia is acute — days, not weeks; it declares itself with high fever and rigors and responds to antibiotics within 48 to 72 hours. TB is chronic — weeks to months — and does not respond to standard antibiotics. That single fact, the tempo, is the bedside fork that sends the sputum for Xpert rather than another course of amoxicillin.^[1]

Extrapulmonary TB — by site

Extrapulmonary TB presents by organ system, and the examiner expects a named site with a named distinguishing feature.^[1]

^{[2] [16] [1]}

Investigations — smear, Xpert, culture

The diagnosis rests on demonstrating the organism in a clinical sample, supported by imaging and the immune-based tests for latent infection.^[1]

Sputum Xpert MTB/RIF Ultra (NAAT) is the WHO-recommended initial test for all presumptive TB. It detects M. tuberculosis complex DNA and rifampicin resistance within about 2 hours, and is far more sensitive than smear — especially in HIV and paucibacillary disease. Two to three spot or early-morning samples.^[4][5]

Sputum smear microscopy (Ziehl-Neelsen or auramine fluorescence for AFB) is rapid and cheap but insensitive — it detects about 5000 to 10,000 bacilli per mL, so a negative smear does not exclude TB. Mycobacterial culture is the gold standard and the only test that confirms viability and allows full drug-susceptibility testing; liquid MGIT culture is faster (1 to 3 weeks) than solid Lowenstein-Jensen (2 to 6 weeks). Always send for culture even when Xpert is positive.^[1][9]

Chest X-ray patterns and what they imply: apical or posterior upper-lobe infiltrates with cavitation mean reactivation TB; hilar or mediastinal lymphadenopathy with a subpleural focus means primary TB (the Ghon complex, commoner in children); diffuse fine uniform millet-seed nodules mean miliary TB; a unilateral pleural effusion means pleural TB; lower-lobe disease should prompt consideration of diabetes, HIV, or primary progressive TB.^[1]

Tests for latent TB infection do not diagnose active disease. The tuberculin skin test (Mantoux) thresholds are 5 mm for HIV, immunosuppression, recent contacts and transplant; 10 mm for healthcare workers, migrants from endemic areas, IV drug users, prisoners, diabetes, CKD and silicosis; 15 mm for low-risk individuals. The IGRA (QuantiFERON-TB Gold, T-SPOT.TB) measures IFN-gamma release from T-cells exposed to ESAT-6 and CFP-10 — more specific than TST (not affected by BCG), single visit, but cannot distinguish latent from active TB.^[4]

2 HRZE plus 4 HR — the six-month cure

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^[2]

The standard treatment of drug-susceptible TB is a 6-month regimen of four drugs for the intensive phase (2 months) followed by two drugs for the continuation phase (4 months), given daily and under directly observed therapy (DOTS).^[2]

^[1]

Weight-based daily doses (adults):^[1]

^[1]

Extend therapy for cavitary pulmonary TB with a positive 2-month culture, TB meningitis (12 months), bone and joint TB (9 to 12 months), miliary TB (consider 9 months).^[1]

DOTS — the five components

^{[1] [2]}

Drug toxicity — the four signatures

Drug toxicity is the commonest reason to interrupt therapy, and each drug has a signature the examiner tests.^[1]

Hepatotoxicity — rifampicin, isoniazid and pyrazinamide are all hepatotoxic. Transient asymptomatic transaminitis is common and monitored; if ALT above 3 times the upper limit of normal with symptoms (jaundice, nausea, right-upper-quadrant pain) or above 5 times without symptoms, stop the offending drug or drugs — pyrazinamide is usually stopped first (most hepatotoxic), then rifampicin, then isoniazid; reintroduce sequentially once LFTs normalise.^[2]

Ethambutol optic neuritis — check acuity and red-green colour vision at baseline and monthly; stop immediately on any change (often irreversible if not caught early). Isoniazid peripheral neuropathy — prevented by pyridoxine (B6) 25 mg daily. Rifampicin — orange secretions (harmless), CYP induction (contraceptive and ART failure, warfarin dose adjustment).^[2]

TB meningitis and miliary TB — treat empirically, add steroids

TB meningitis is the most lethal form of TB. Subacute onset (1 to 3 weeks): headache, low-grade fever, malaise, then meningism, confusion, cranial-nerve palsies (III, VI, VII), and focal deficits. The Rich focus — a subpial or subependymal focus that ruptures into the subarachnoid space — is the pathogenesis. CSF shows a lymphocytic pleocytosis, high protein, low glucose, and a cobweb coagulum.^[1]

Treatment is empirical and urgent — do not wait for confirmation if the clinical picture fits: a 12-month regimen (2 months HRZE, with some centres substituting ethionamide or a fluoroquinolone for ethambutol for better CSF penetration, plus 10 months HR), and adjunctive dexamethasone tapered over 6 to 8 weeks. Mortality remains high even with optimal therapy — approaching 50 per cent in HIV co-infection in contemporary cohorts.^[13][14][6]

^[6]

Miliary TB is haematogenous dissemination — diffuse 1 to 3 mm nodules throughout both lung fields, with fever, weight loss, hepatosplenomegaly, anaemia of chronic disease, and choroidal tubercles on fundoscopy (pathognomonic). Higher in children, HIV and the elderly; look for and treat coexistent TBM.^[1]

TB-HIV — bidirectional screening, early ART

Every patient with TB must be tested for HIV, and vice versa. HIV transforms TB: more smear-negative, extrapulmonary and disseminated disease, higher mortality. The risk of progression from latent infection to active disease is amplified tenfold or more in HIV.^[1]

Start ART early — within 2 weeks of anti-TB therapy for CD4 under 50 cells per microlitre, and within 8 weeks for higher CD4. Use efavirenz-based ART with rifampicin (avoid protease inhibitors, which rifampicin wrecks by CYP3A4 induction); or substitute rifabutin for rifampicin if a protease-inhibitor regimen is needed. Watch for TB-IRIS — paradoxical worsening of TB symptoms 1 to 8 weeks after ART starts, treated with corticosteroids if severe.^[1]

MDR-TB — BPaLM for eligible cases

Rifampicin resistance on Xpert indicates multidrug-resistant TB — resistant to at least rifampicin and isoniazid. Refer for an MDR-TB regimen; do not add rifampicin-based therapy alone. Pre-XDR-TB adds resistance to any fluoroquinolone; XDR-TB adds resistance to any fluoroquinolone and at least one Group A drug (bedaquiline or linezolid).^[3]

The shorter all-oral BPaLM regimen (bedaquiline, pretomanid, linezolid, plus moxifloxacin for 6 months) is WHO-recommended for eligible MDR and pre-XDR cases; longer individualised all-oral regimens are used for the rest. No more injectables as first-line MDR therapy — the ototoxicity was unacceptable.^[3]

^[7]

Prevention — BCG, latent TB, infection control

BCG (Bacille Calmette-Guerin) is a live attenuated strain of M. bovis, given intradermally at birth in high-burden countries (including India, universal) or selectively in the UK, ANZ and US. The Colditz meta-analysis established that BCG protects against disseminated and childhood TB and TB meningitis (efficacy about 70 to 80 per cent for these severe forms) — the major benefit — with variable and modest protection against adult pulmonary TB (0 to 80 per cent, latitude-dependent). Contraindicated in the immunocompromised.^[1][12]

Latent TB infection (LTBI) preventive therapy is targeted at those most likely to progress. Regimens: 3HP (weekly rifapentine plus isoniazid for 3 months — 12 doses), 4R (daily rifampicin for 4 months), or 6H or 9H (daily isoniazid, with pyridoxine). Indications: recent contact of an infectious case, HIV-positive, before anti-TNF or transplant immunosuppression, end-stage CKD or dialysis, silicosis, fibrotic lesions on CXR from old TB. Exclude active TB first — giving monotherapy isoniazid to a patient with active disease breeds resistance.^[10][11]

Airborne precautions for all suspected or confirmed pulmonary or laryngeal TB: negative-pressure isolation, N95 or FFP2 or FFP3 respirators for staff, UV germicidal irradiation and natural ventilation in high-burden settings. De-isolate after 2 weeks of effective therapy with clinical improvement and negative smears in drug-susceptible disease.^[1]

When it goes wrong — the preventable list

• The unisolated infectious patient — protecting staff and other patients starts at the bedside, not after the smear result.^[4]
• Treating smear-negative chronic cough with repeated antibiotics without ever sending an Xpert — the recurring trainee error.^[1]
• Missing ethambutol optic neuritis by not testing red-green colour vision at baseline and monthly.^[2]
• Giving rifampicin with protease inhibitors without dose adjustment — the ART fails.^[1]
• Failing to test for HIV in every TB patient — bidirectional screening, every time.^[1]
• Missing rifampicin resistance by not sending Xpert on every patient — a single result redirects the entire regimen.^[3]
• Default and lost-to-follow-up — the single biggest driver of resistance; DOTS exists precisely to prevent it.^[2]
• Streptomycin in pregnancy — fetal ototoxicity with congenital deafness reported after first-trimester exposure; avoid, especially in the first trimester.^[17]

Special populations

In HIV, screen all people for TB at every encounter (symptom screen — cough, fever, weight loss, night sweats; if positive, Xpert and CXR). Treat TB first, then start ART early. Use efavirenz-based ART with rifampicin; or rifabutin with a protease inhibitor. Give cotrimoxazole prophylaxis. Treat latent TB in all HIV-positive patients without active disease.^[1]

In pregnancy, treat TB — first-line drugs are safe. The regimen is 2 HRZE plus 4 HR; do NOT give streptomycin (fetal ototoxicity with congenital deafness reported after in-utero exposure). Give pyridoxine with isoniazid. Treat latent TB if high-risk (HIV, recent contact); otherwise defer to the postpartum. Breastfeeding is safe on first-line therapy.^[15][17]

In children, TB is paucibacillary (smear often negative) and more often extrapulmonary; severe forms (TBM, miliary) are commoner because of immature cell-mediated immunity. Use weight-based dosing; collect gastric aspirate or induced sputum (children cannot expectorate). BCG protects against disseminated and childhood TB and TBM.^[1]

In chronic kidney disease and dialysis, adjust ethambutol and pyrazinamide dosing (ethambutol three times weekly after haemodialysis; pyrazinamide three times weekly). Rifampicin and isoniazid do not need renal adjustment. Treat latent TB in all dialysis patients with positive IGRA — dialysis is a WHO-recommended LTBI testing and treatment indication.^[15][11]

Before immunosuppression (anti-TNF, transplant), screen with IGRA and chest X-ray and treat latent TB first (3HP, 4R, or 9H) — TNF-alpha is central to granuloma containment, and anti-TNF reactivates latent TB at 5 to 10 times the baseline rate. Do not start anti-TNF until at least one month of LTBI therapy is complete.^[11]

^{[1] [8]}

The evidence — WHO, ATS, CDC, IDSA, ERS

The WHO publishes the Consolidated Guidelines on Tuberculosis (Modules 1 to 5), updated annually. Key recommendations: Xpert MTB/RIF Ultra is the initial test for all presumptive TB (replacing smear as the first test); 6 months of HRZE or HR for drug-susceptible TB with daily dosing; BPaLM for eligible MDR or pre-XDR cases; and a full preventive-therapy programme (3HP, 4R, 6H or 9H).^[4]

The ATS, CDC and IDSA treatment guidelines (Nahid 2016, Nahid 2019) codify the 6-month regimen and the drug-resistant pathway. The Boehme 2010 NEJM study established Xpert MTB/RIF as a rapid, sensitive molecular test that could be deployed at the point of care. The Thwaites 2004 RCT established dexamethasone in TB meningitis. The Conradie 2020 Nix-TB trial established BPaL for XDR and treatment-intolerant MDR-TB.^{[2][3][6][7][9]}

The mantra, and the mnemonic

^{[2] [15] [1]}

The mantra: isolate on suspicion, Xpert on every patient, 2 HRZE plus 4 HR for six months as DOTS, pyridoxine with isoniazid, watch the vision on ethambutol, watch the liver on all three, dexamethasone in TBM, never streptomycin in pregnancy.^[1][2]

^{[2] [13] [6]}

Ward-round test — three stems, thirty seconds each

Stem 1 — the patient from the top of the topic (answer)ShowHide

The 54-year-old with six weeks of cough, evening fever, night sweats, weight loss, and right upper-lobe apical cavitation. What do you do in the next two hours? Model: This is active pulmonary TB until proven otherwise — chronic tempo, constitutional symptoms, apical cavitation. Isolate immediately in a negative-pressure room with respirator protection (do not wait for the smear). Send two to three sputum samples for Xpert MTB/RIF Ultra (the initial test, which also detects rifampicin resistance), AFB smear, and mycobacterial culture. Test for HIV. Notify public health (Ni-kshay in India). Once drug-susceptible TB is confirmed, start 2 months of HRZE then 4 months of HR, daily, as DOTS, with pyridoxine 25 mg. De-isolate after 2 weeks of effective therapy with clinical improvement and negative smears.^[2][4]

Stem 2 — the rifampicin-resistant result (answer)ShowHide

The Xpert on your patient returns positive for M. tuberculosis complex DNA and rifampicin resistance. What changes? Model: This is MDR-TB — resistant to at least rifampicin and isoniazid. Do not add rifampicin-based therapy alone. Refer to the MDR-TB service for a prolonged all-oral regimen — the BPaLM regimen (bedaquiline, pretomanid, linezolid, plus moxifloxacin for 6 months) for eligible cases, or a longer individualised regimen. Send line-probe assay or whole-genome sequencing to define the full resistance pattern (fluoroquinolone, bedaquiline, linezolid). Prolong isolation — de-isolation needs negative cultures, not just clinical improvement. Counsel the patient on adherence — default in MDR-TB breeds XDR-TB.^[3][7]

Stem 3 — the comatose patient with a cobweb coagulum (answer)ShowHide

A 30-year-old presents with two weeks of headache and fever, now confused and meningitic. Lumbar puncture shows a lymphocytic pleocytosis, protein 2.5 g/L, glucose 1.5 mmol/L, and a cobweb coagulum. What is the diagnosis and what two things must you add to the standard regimen? Model: This is TB meningitis — the most lethal form. The CSF pattern (lymphocytes, high protein, low glucose, cobweb coagulum) is characteristic; Xpert MTB/RIF on CSF is the rapid test. Treat empirically and urgently — do not wait for confirmation: a 12-month regimen (2 months HRZE, with ethionamide or a fluoroquinolone substituted for ethambutol for CSF penetration, plus 10 months HR). The two additions are adjunctive dexamethasone (Thwaites 2004 — improves survival, tapered over 6 to 8 weeks) and consideration of coexistent miliary TB or hydrocephalus (CT brain). Mortality is 20 to 30 per cent even with optimal therapy.^[1][6]

References17ShowHide

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2. [2]Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis Clin Infect Dis, 2016.PMID 27516382
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