Tuberculosis

Meet the patient

A 34-year-old construction worker has had a cough for six weeks, drenching night sweats, and has lost 8 kg. He moved to the city from a high-burden state two years ago, and his flatmate was treated for pulmonary tuberculosis last year.^[2][3]

This is the textbook presentation of reactivation pulmonary tuberculosis. The two questions you must settle at the bedside are: is it TB, and is it drug-resistant? Both answers come from the sputum pot, not the stethoscope — send three samples for acid-fast bacilli smear, Xpert MTB/RIF, and mycobacterial culture, and isolate him in a negative-pressure room while you wait.^[9][4]

Overview and Definition

Tuberculosis (TB) is a chronic, granulomatous infectious disease caused by members of the Mycobacterium tuberculosis complex — predominantly Mycobacterium tuberculosis itself (Koch's bacillus, discovered 1882), with M. bovis (cattle, unpasteurised milk — now rare in countries with pasteurisation), M. africanum (West Africa) and the live-attenuated vaccine strain M. bovis BCG as related members.^[2][3]

The organism is a slender, slightly curved, aerobic, non-motile, non-spore-forming, acid-fast bacillus (AFB). The waxy, lipid-rich, mycolic-acid-containing cell wall is responsible for the key microbiological properties: it resists Gram staining (so Ziehl-Neelsen or auramine-rhodamine fluorescence are used), is resistant to desiccation, and survives for weeks on surfaces and in droplet nuclei. M. tuberculosis is an obligate aerobe — it grows best in well-oxygenated tissue, which is why the apical and posterior segments of the upper lobes, the renal cortex, and the growing ends of long bones are the classic sites of reactivation disease.^[2]

Two clinical states are fundamental to the disease and must be distinguished:^[2][3]

• Latent TB infection (LTBI) — Pai: infection can remain containment in the host, in which the bacteria are isolated within granulomas (latent TB infection). Only active pulmonary TB is contagious. Textbook lifetime-progression percentages were not in the abstracts fetched this session and are omitted.
• Active TB disease — symptoms develop (cough, fever, night sweats, weight loss) and, if pulmonary, the patient can transmit. Furin 2019 recorded more than 10 million people becoming newly sick from tuberculosis each year — use WHO GTB 2025 for current burden, not 2019 narrative counts.^[3][21]

By site of disease: only active pulmonary TB is contagious.^[2] In the EU/EEA 2002–11, extrapulmonary TB accounted for 19.3% of all notified cases (range 5.8–44.4% among Member States; the EPTB share rose from 16.4% in 2002 to 22.4% in 2011).^[8] Sites include lymph nodes, pleura, meninges, bone and joint, genitourinary tract, abdomen, pericardium, and miliary disease. Named global site-mix percentages (lymph node 25%, pleural 22%, etc.) are not in the Sandgren abstract and are omitted.

Why TB matters globally (WHO Global TB Report 2025, 2024 estimates):^[21] Incident cases 10.7 million (95% UI 9.9–11.5 million); incidence 131 per 100 000 (122–141); case fatality 11.5%. Deaths 1.23 million (1.13–1.33 million), including 1.08 million among HIV-negative people and 150 000 among people with HIV. TB is one of the top 10 causes of death worldwide and the leading cause of death from a single infectious agent; in the 2021 ranking it was the 10th leading cause of death worldwide and the second leading cause of death from a single infectious agent, after COVID-19. 30 high-burden countries accounted for 87% of cases. The top eight (67%) were India (25%), Indonesia (10%), the Philippines (6.8%), China (6.5%), Pakistan (6.3%), Nigeria (4.8%), the Democratic Republic of the Congo (3.9%) and Bangladesh (3.6%). About 390 000 people developed RR-TB in 2024. Treatment success 88% for drug-susceptible TB and 71% for RR-TB.

Classification

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TB is classified by clinical state (LTBI vs active), by anatomical site (pulmonary vs extrapulmonary), by radiographic pattern (primary vs post-primary, miliary), and by drug-resistance pattern (each driving a different management pathway).^[2][3][4]

Drug-resistance classification (WHO 2021 definitions):^[23]

• Rifampicin-resistant (RR-TB) — resistant to rifampicin, regardless of other resistances.
• Multidrug-resistant (MDR-TB) — resistant to at least INH and RIF — the MDR definition remains unchanged.
• Pre-extensively drug-resistant (pre-XDR-TB) — MDR/RR-TB that is also resistant to any fluoroquinolone.
• Extensively drug-resistant (XDR-TB) — MDR/RR-TB that is also resistant to any fluoroquinolone and at least one additional Group A drug. Group A comprises levofloxacin, moxifloxacin, bedaquiline and linezolid.
• Totally drug-resistant (TDR) — not a WHO category. ^[23]

By site (the extrapulmonary taxonomy, Sandgren et al. 2013):^[8]

• Pleural TB — second most common extrapulmonary site, often young adults, lymphocytic exudative effusion; raised pleural fluid adenosine deaminase is supportive (ATS/IDSA recommends measuring ADA when pleural TB is suspected); biopsy shows caseating granuloma.^[19]
• TB meningitis (TBM) — most severe form; basal meningitis with cranial nerve palsies, hydrocephalus, vasculitis, stroke; highest mortality of all forms.
• Osteoarticular TB — Pott's spine (thoracolumbar, vertebral body, gibbus deformity), hip, knee; cold abscess (paravertebral/psoas).
• Genitourinary TB — sterile pyuria, scrotal swelling in males, infertility, dysmenorrhoea and tubo-ovarian mass in females, renal involvement with calyceal blunting.
• Abdominal TB — peritoneal (ascites with high ADA, matted mesenteric lymphadenopathy), ileocaecal (ulcero-constrictive disease — the commonest site of abdominal TB, mimics Crohn's and malignancy), nodal, visceral.
• TB pericarditis — subacute pericardial effusion with lymphocytic exudate, often progressing to constrictive pericarditis.
• Cutaneous TB — scrofuloderma, lupus vulgaris, tuberculid, warty TB. ^[8]

Epidemiology and Risk Factors

Thirty high-burden countries accounted for 87% of incident cases in 2024. The top eight (67% of the worldwide total) were India (25%), Indonesia (10%), the Philippines (6.8%), China (6.5%), Pakistan (6.3%), Nigeria (4.8%), DRC (3.9%) and Bangladesh (3.6%).^[21]

Global burden (WHO GTB 2025, 2024 estimates) — do not cite Pai 2016 or Furin 2019 for current WHO counts:^[21]

• Incident cases: 10.7 million (95% UI 9.9–11.5 million); rate 131 per 100 000 (122–141); CFR 11.5%.
• Deaths: 1.23 million (1.13–1.33 million) = 1.08 million HIV-negative + 150 000 HIV.
• Overview: among the top 10 causes of death worldwide and the leading cause of death from a single infectious agent. 2021 ranking: 10th leading cause of death worldwide and second from a single infectious agent, after COVID-19 (do not pin the 10th-place rank to 2024).
• RR-TB: about 390 000 incident cases in 2024.
• Treatment success: 88% drug-susceptible TB; 71% RR-TB. ^[21]

Host risk factors for progression from LTBI to active disease (relative risk vs general population):^[2][3]

• HIV infection — a major driver of atypical, disseminated, and high-burden disease in Pai/Furin. Annual/lifetime progression percentages circulating in textbooks were not in the abstracts fetched this session and are omitted. Test every person with TB for HIV.^[19]
• Malnutrition, underweight, and diabetes — important host risks named in Pai/Furin; numeric attributable-case counts, BMI cut-offs, and “triples risk” multipliers were not in the abstracts fetched this session and are omitted.
• Anti-TNF therapy — screen with IGRA/PPD before starting; treat LTBI if positive. Fold-increase percentages circulating in textbooks were not in the abstracts fetched this session.
• Other immunosuppression — glucocorticoids, chemotherapy, transplant, haematological malignancy, chronic kidney disease, silicosis — named clinically; exact milligram/duration cut-offs not restated from the abstracts.
• Silicosis, prisons, healthcare workers, young children, and recent close contact — recognised high-risk settings/groups (Pai/Furin). Numeric conversion rates and “2 percent annual risk” figures were not in the abstracts fetched this session.
• Alcohol misuse, smoking, indoor air pollution, HIV (in pregnancy), vitamin D deficiency — modest independent risk factors. ^[2]

Social determinants — poverty, overcrowding, undernutrition, indoor air pollution, and limited access to diagnosis and treatment are the upstream drivers of the TB epidemic; the WHO End TB Strategy pillars address these alongside biomedical tools.^[3]

Pathophysiology

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The pathophysiology of TB is a timeline of host-pathogen interaction that explains both primary disease, latent infection, and reactivation.^[2][3]

1. Transmission and primary infection. An infectious patient with smear-positive pulmonary or laryngeal TB expels droplet nuclei (1-5 micrometres) by coughing, sneezing, speaking, or singing; these remain suspended in air for hours, and a susceptible contact inhales them to reach the terminal alveoli. The infectiousness of a source is related to smear status and contact intensity. Counts such as 3000 droplet nuclei per cough / 1 million per sneeze are conventional teaching, not present in the abstracts cited here. BCG-vaccinated and previously-infected contacts may have partial immunity, but in non-immune hosts the bacilli are phagocytosed by alveolar macrophages. Inside the macrophage the bacilli resist intracellular killing by several mechanisms — cord factor (trehalose-6,6'-dimycolate) inhibits macrophage activation, sulfatides (sulfolipids) prevent phagosome-lysosome fusion, the ESX-1 secretion system releases ESAT-6 and CFP-10 antigens, and LAM scavenges oxygen radicals — and multiply logarithmically over 2-8 weeks before cell-mediated immunity is established.^[2]

2. The cell-mediated immune response — Th1, IFN-gamma, TNF-alpha, granuloma. Infected macrophages present Mtb antigens (ESAT-6, CFP-10, Ag85) on MHC class II to CD4+ T-helper-1 (Th1) cells, which release interferon-gamma (IFN-gamma). IFN-gamma activates macrophages, enhancing phagolysosome fusion, nitric oxide production, and intracellular killing. TNF-alpha (from macrophages and T cells) is essential for granuloma maintenance. Together, these cytokines orchestrate the formation of a caseating granuloma (tubercle) — a structured aggregate of epithelioid macrophages, multinucleated Langhans giant cells, surrounding CD4+ and CD8+ T cells, and a central area of caseous (cheese-like) necrosis. The caseum has a low oxygen tension, low pH, and abundant lipid debris — a hostile environment for the bacilli that dormantly survive within the granuloma for decades. This is the immunopathological basis of latent TB infection.^[2]

3. Latent TB — containment and the risk of reactivation. A balanced Th1 response contains the bacilli indefinitely in the granuloma; the patient is asymptomatic, non-infectious, and has normal radiology. Reactivation risk is greatest early after infection and rises with HIV, anti-TNF, malnutrition, and other immunosuppression; textbook lifetime-percentage figures were not in the abstracts fetched this session and are omitted. Cortisol and TNF-alpha blockade can both destabilise the granuloma.^[2]

4. Reactivation (post-primary) TB. When the cell-mediated response wanes (HIV, anti-TNF, malnutrition, age, diabetes, alcohol, smoking), the granuloma caseates and liquefies, releasing viable bacilli into the surrounding tissue, where the higher oxygen tension and better nutrients allow rapid extracellular replication. The apical and posterior segments of the upper lobes (and the superior segment of the lower lobe) are the preferred sites of reactivation because of the higher V/Q ratio (higher PaO2) in these regions. The caseum liquefies, drains into a bronchus, and produces a cavity — the radiological hallmark of post-primary TB and the source of airborne infectiousness.^[2]

5. Haematogenous and lymphogenous spread — miliary and extrapulmonary disease. In early infection, bacilli reach the hilar lymph nodes (lymphogenous spread) and the systemic circulation (haematogenous spread), seeding the apices, kidneys, bone epiphyses, meninges, and other sites with microscopic foci. In the immunocompetent these foci are contained by granulomas; in the immunocompromised (especially HIV, anti-TNF, malnourished children), these foci may reactivate simultaneously, producing miliary (disseminated) TB — a radiograph studded with 1-5 mm nodules of caseating granulomas throughout both lungs and often the liver, spleen, bone marrow, choroid, and meninges. The presence of choroidal tubercles on fundoscopy is pathognomonic.^[2][8]

6. Why HIV-TB is dangerous. HIV directly depletes CD4+ T cells, the central orchestrators of granuloma integrity. Patients with CD4 under 200 have atypical, disseminated, and severe TB and a much higher risk of IRIS after ART initiation. A numeric TST/IGRA anergy percentage was not in the abstracts fetched this session and is omitted. The same high-burden CD4 effect explains the diagnostic difficulty and the fulminant course.^[2][3]

7. Drug resistance — the molecular basis. Rifampicin resistance is conferred primarily by mutations in the rpoB gene (RNA polymerase beta subunit), most often at codons 507-533. Isoniazid resistance is conferred by mutations in katG (most common, S315T, which abolishes INH activation by catalase-peroxidase), inhA (promoter, confers low-level resistance), and ahpC. Fluoroquinolone resistance arises in gyrA (DNA gyrase). Xpert MTB/RIF detects rpoB mutations (Boehme: result in less than 2 hours). Ultra is the later WHO-recommended cartridge — do not recycle Boehme percentages as Ultra-specific.^[4]

Clinical Presentation

The classic triad of pulmonary TB is cough, fever, and weight loss, but presentation is highly variable and atypical in children, the elderly, the immunocompromised, and in extrapulmonary disease.^[2][3]

Constitutional / systemic — low-grade fever (often evening, with night sweats), weight loss (often profound, "consumption"), fatigue, anorexia, and in women, amenorrhoea. The duration is chronic, often weeks to months, distinguishing TB from acute bacterial pneumonia.^[2]

Pulmonary / respiratory: ^[2][3]

• Cough (the cardinal symptom) — initially dry, then productive of mucoid or purulent sputum; cough more than 2 weeks is the WHO symptom screen. The cough may become blood-tinged, streaky, or frankly haemoptytic (rupture of a vessel in a cavity wall, or Rasmussen aneurysm).
• Haemoptysis — life-threatening bleeding from a cavity (Rasmussen aneurysm / bronchial artery). Numeric cut-offs such as 200 mL once or 600 mL/24 h are conventional teaching, not ATS/WHO thresholds and is caused by erosion of a bronchial artery or a Rasmussen aneurysm (pulmonary artery aneurysm in the wall of a chronic cavity).
• Chest pain — pleuritic, from pleural involvement or subpleural inflammation.
• Dyspnoea — in extensive disease, miliary TB, pleural effusion, or TB-associated ARDS.
• Lymphadenopathy — cervical, supraclavicular, axillary, or inguinal; classically painless, matted, with or without caseation and sinus formation (scrofula).^[8]

Extrapulmonary presentations (Sandgren: 19.3 percent of EU/EEA notifications, range 5.8–44.4 percent by Member State; textbook “one quarter to one half” figures are not used here):^[8]

• TB meningitis (TBM) — subacute (1-2 weeks) prodrome of headache, low-grade fever, malaise, progressing to meningism, photophobia, vomiting, altered mental status, cranial nerve palsies (especially VI, but also III, IV, VII from basal exudate), seizures, stroke (from obliterative endarteritis of perforators at the base of the brain), and hydrocephalus. The British Medical Research Council (BMRC) TBM staging is the prognostic standard: Stage I (prodromal, GCS 15, no focal signs), Stage II (meningism + altered mental status or focal signs, GCS 11-14), Stage III (deep coma, GCS under 11, dense neurological deficits). Mortality rises steeply with MRC grade; adjunctive dexamethasone improved survival across grades in the Thwaites trial (relative risk of death 0.69).^[5]
• Pleural TB — pleuritic chest pain, dyspnoea, low-grade fever; lymphocytic exudative effusion; raised pleural fluid adenosine deaminase (ATS/IDSA recommends ADA measurement when pleural TB is suspected); pleural biopsy (image-guided) showing caseating granuloma is diagnostic.^[19]
• TB pericarditis — subacute pericardial effusion, fever, chest pain, pericardial rub; lymphocytic pericardial exudate; can progress to constrictive pericarditis; in the IMPI trial adjunctive prednisolone reduced constrictive pericarditis (4.4 vs 7.8 percent) without improving the composite primary outcome; pericardiectomy may be needed.^[18]
• Abdominal TB — ileocaecal (most common; right iliac fossa pain, mass, subacute obstruction, mimics Crohn's and right-sided colonic cancer); peritoneal (abdominal distension, ascites with high ADA, matted mesentery); nodal (mesenteric/retroperitoneal adenopathy, may calcify); visceral (hepatosplenomegaly, splenic abscess, pancreatic TB).
• Bone and joint TB (Pott's spine) — insidious back pain, gibbus deformity, paraspinal or psoas cold abscess, neurological deficit from spinal cord compression; lower thoracic and upper lumbar are the commonest levels; MRI is the imaging gold standard; the triad of Gibbus + paravertebral shadow on CXR + disc-space narrowing is classical.
• Genitourinary TB — sterile pyuria (urine with leucocytes but negative standard culture; send for mycobacterial culture), haematuria, flank pain, renal calcification, ureteric stricture, contracted bladder; in males, epididymo-orchitis, scrotal sinus, infertility; in females, tubo-ovarian mass, infertility, menstrual disturbance.
• Miliary TB — fever, weight loss, hepatosplenomegaly, pancytopenia, choroidal tubercles on fundoscopy; CXR with diffuse 1-5 mm nodules ("millet-seed"); may initially have a normal CXR (CT more sensitive); may progress to TB-associated ARDS, DIC, and multi-organ failure.
• Cutaneous TB — scrofuloderma (overlying lymph node), lupus vulgaris (face, apple-jelly nodules on diascopy), orificial TB (mucocutaneous around orifices in advanced disease), warty TB (tuberculous verrucosa cutis), tuberculid (hypersensitivity eruptions).

Differential Diagnosis

Active pulmonary TB shares features with many conditions; the diagnosis is microbiological, not clinical. The exam skill is to think of TB and order sputum AFB smear, NAAT (Xpert), and culture in the right patients.^[2][3]

Other important differentials to consider: lung abscess (cavitation with air-fluid level, foul sputum, post-aspiration), silicosis and coal worker's pneumoconiosis (occupational history, progressive massive fibrosis), bronchiectasis (chronic productive cough, CT diagnosis), atypical pneumonia (Legionella, Mycoplasma, Chlamydophila) that does not respond to standard antibiotics, HIV-associated opportunistic infections (Pneumocystis, cryptococcosis, histoplasmosis, Kaposi sarcoma), and constrictive pericarditis (other causes — post-cardiac surgery, radiation, malignancy). ^[2]

Clinical and Bedside Assessment

The clinical examination of suspected TB is a systematic search for pulmonary findings, lymph nodes, signs of extrapulmonary disease, and complications.^[2]

General inspection — chronic illness, wasting (BMI often under 18.5 in advanced disease), pallor of anaemia of chronic disease, low-grade fever (palpable warmth), scars of past surgery (thoracoplasty, lobectomy for TB in the pre-antibiotic era), and — crucial for vaccination history — the BCG scar on the left deltoid (or right deltoid, depending on country).^[2]

Hands, arms, neck — clubbing (chronic pulmonary TB, bronchiectasis from post-TB fibrosis), anaemia, erythema nodosum (TB-associated, sarcoid-associated), scrofuloderma (overlying a cold abscess). ^[2]

Lymph nodes — palpate cervical (anterior and posterior triangles, supraclavicular), supraclavicular, axillary, epitrochlear, and inguinal groups. TB lymphadenopathy is painless, rubbery, and matted (groups of nodes stuck together); caseation with cold abscess and sinus formation is late; isolated matted supraclavicular node (Virchow's node), although classically associated with gastric cancer, is described in TB. The "cold abscess" of TB fluctuates but is not warm or red (vs pyogenic abscess). ^[2]

Chest — ^[2]

• Inspection — asymmetry, supraclavicular/infra-clavicular hollowing (chronic upper-lobe fibrosis), scars of past surgery, tachypnoea.
• Palpation — reduced expansion on the affected side, tactile fremitus increased over consolidation, reduced over effusion.
• Percussion — dull over consolidation, effusion, fibrosis; hyper-resonant over a large cavity or compensatory hyperinflation.
• Auscultation — crackles (post-tussive) over active disease, bronchial breathing over consolidation, amphoric breathing over a large cavity, reduced breath sounds over effusion, pleural rub in dry pleurisy. ^[2]

Cardiovascular — pericardial rub, distant heart sounds, raised JVP, pulsus paradoxus (pericardial effusion/constriction), tachycardia of anaemia or fever. ^[2]

Abdomen — hepatosplenomegaly (miliary TB, HIV, lymphoma), ascites (peritoneal TB — shifting dullness, fluid thrill, "doughy" abdomen from matted mesentery), right iliac fossa mass (ileocaecal TB), psoas abscess (bulge in the groin, positive psoas sign). ^[2]

Spine — kyphosis (gibbus deformity of Pott's disease), paraspinal swelling (cold abscess), tenderness on percussion, limited spinal flexion; perform a neurological examination to detect cord compression (motor, sensory, sphincter).^[8]

Joints — hip, knee, ankle — swelling, sinus formation, restricted range. ^[2]

Neurological — neck stiffness, Kernig's, Brudzinski's, cranial nerves (especially VI, III, IV, VII), fundoscopy (papilloedema in TBM, choroidal tubercles in miliary TB), tone, power, sensation, reflexes, plantar response, cerebellar signs.^[5]

Fundoscopy — choroidal tubercles (Bouchut's tubercles) are yellowish-white, 0.5-3 mm lesions at the posterior pole — pathognomonic of miliary TB; optic neuritis is a side effect of ethambutol. ^[2]

Investigations

Investigations are organised by clinical question (does the patient have active TB? What is the resistance profile? Is there latent TB? Is there extrapulmonary disease?).^[2][3][4]

1. Imaging. ^[19]

• Chest X-ray (CXR) — the first imaging test in suspected pulmonary TB. Primary TB: small peripheral mid/lower-zone opacity, hilar/paratracheal lymphadenopathy (the Ghon complex). Post-primary TB: apical and posterior upper-lobe, or superior lower-lobe, infiltrates, cavitation, fibrosis, volume loss, mediastinal shift towards the fibrosis. Miliary: diffuse 1-5 mm nodules throughout both lungs; may be normal early (CT more sensitive). Pleural effusion, empyema, pericardial effusion may be present. Caution: a normal CXR does not exclude active pulmonary TB, especially in HIV and in early disease (a 10–15% figure was not in the sources fetched this session). Healed TB — fibronodular opacities, calcified granulomas (Ghon focus), calcified hilar nodes (the Ranke complex), calcified pleural plaques, apical caps.
• Contrast-enhanced CT chest — more sensitive than CXR; tree-in-bud opacities, centrilobular nodules, cavitation, mediastinal/hilar nodes (with central necrosis), miliary nodules (when CXR is normal), tree-in-bud endobronchial spread.
• MRI spine — for suspected Pott's disease; vertebral body collapse, paravertebral abscess, epidural extension with cord compression.
• CT/MRI brain — for suspected TBM; basal meningeal enhancement, hydrocephalus, tuberculomas, infarcts from vasculitis.
• PET-CT — not routine; useful for occult disseminated disease and paradoxical response assessment. ^[19]

2. Microbiology — the diagnostic gold standard. ^[19]

• Sputum — three sputum samples, ideally early-morning, on consecutive days (WHO standard), at least 8 hours apart including one early-morning sample. Induced sputum (hypertonic saline nebulisation) for those who cannot expectorate. Gastric aspirate in children.
• Ziehl-Neelsen (ZN) or auramine-rhodamine (fluorescent) smear — rapid (within hours); does not distinguish M. tuberculosis from NTM; does not detect drug resistance; sensitivity is lower than culture, especially in HIV and extrapulmonary disease (textbook 10 000 bacilli/mL and 50–80% smear-sensitivity figures were not in the sources fetched this session).
• Xpert MTB/RIF or Xpert MTB/RIF (Cepheid GeneXpert) — automated, cartridge-based, real-time PCR NAAT; detects MTB complex in 2 hours and rifampicin resistance (rpoB mutation) Boehme original Xpert: 98.2% smear-positive and 72.5% smear-negative culture-positive on a single direct test, specificity 99.2%, less than 2 hours. Ultra is the later WHO-recommended cartridge — do not treat Boehme percentages as Ultra-specific. The trace call needs clinical correlation.
• Mycobacterial culture (the gold standard) — Löwenstein-Jensen solid medium (4-8 weeks), MGIT (mycobacterial growth indicator tube) liquid medium (1-3 weeks, automated BACTEC system); confirms viability, identifies species, and allows drug susceptibility testing (DST); the only test that confirms live bacilli and the basis for phenotypic DST.
• Phenotypic DST — culture-based, agar proportion or MGIT, against isoniazid, rifampicin, ethambutol, pyrazinamide, fluoroquinolones, injectables (amikacin, kanamycin, capreomycin), bedaquiline, linezolid, clofazimine, delamanid.
• Molecular line-probe assays (LPA) — GenoType MTBDRplus (Hain Lifescience) and similar — detect mutations in rpoB, katG, inhA, gyrA, rrs within 24-48 hours, on positive cultures or directly on smear-positive sputum; the WHO-recommended second-line DST method in high-burden settings.
• Whole-genome sequencing (WGS) — the most comprehensive method for species identification, resistance prediction, and transmission clustering; increasingly used in high-income settings and outbreak investigation. ^[19]

3. Latent TB diagnosis (LTBI). ^[19]

• Tuberculin skin test (TST / Mantoux / PPD) — intradermal injection of 0.1 mL of 5 tuberculin units (TU) of PPD on the volar forearm; read at 48-72 hours; induration diameter measured (erythema alone does not count); induration is interpreted with risk-stratified millimetre cut-offs (ATS/IDSA 2017 diagnosis guideline — the numeric 5/10/15 mm table was not in the abstract fetched this session and is not restated here). The TST is not specific in BCG-vaccinated populations.
• Interferon-gamma release assay (IGRA) — QuantiFERON-TB Gold Plus (QFT-Plus) and T-SPOT.TB — measures IFN-gamma release from T cells exposed to M. tuberculosis-specific antigens (ESAT-6, CFP-10); single visit, internal positive and negative controls, not affected by BCG; preferred in BCG-vaccinated populations; false-negative in HIV, immunosuppression, very young children. ^[19]

4. Histopathology and ancillary tests. ^[19]

• Biopsy (lymph node, pleural, lung, bone, liver, bone marrow) — caseating granuloma is highly suggestive but not pathognomonic (also seen in NTM, some fungi, sarcoidosis in the non-caseating form); send tissue for AFB, mycobacterial culture, NAAT, and histology simultaneously.
• Pleural fluid analysis — lymphocytic exudate (Light's criteria), raised adenosine deaminase (ATS/IDSA recommends ADA measurement on suspected pleural TB fluid); pleural fluid AFB is rarely positive; pleural biopsy is the gold standard.
• CSF analysis in suspected TBM — lymphocytic pleocytosis, high protein, low glucose (textbook cell-count, protein, glucose millimole, and percentage-yield figures were not in the sources fetched this session and are omitted).
• Ascitic fluid (peritoneal TB) — exudate, lymphocyte-predominant, high protein, high ADA, low SAAG (a numeric ADA cut-off was not in the Lewinsohn abstract — ATS/IDSA recommends measuring ADA on suspected peritoneal TB fluid).
• Pericardial fluid (TB pericarditis) — lymphocytic exudate, high protein, low glucose, high ADA and IFN-gamma; pericardial biopsy is the gold standard.
• Urine for TB (genitourinary TB) — early-morning urine samples for mycobacterial culture (a 30–50% sensitivity figure was not in the sources fetched this session).
• HIV testing — mandatory in every newly diagnosed TB patient (WHO policy).
• Baseline bloods — CBC, U&E, LFT, HIV, hepatitis B and C, fasting glucose, vitamin D, pregnancy test (women of childbearing age); TST/IGRA and CXR are baseline for LTBI screening. ^[19]

5. Specialised imaging and procedures — bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy for smear-negative pulmonary TB; image-guided biopsy (CT/US-guided) for nodes, pleura, mass lesions, bone lesions; laparoscopy and peritoneal biopsy for ascites; liver and bone-marrow biopsy for disseminated TB. ^[19]

Management — Resuscitation

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Active TB is rarely a resuscitation emergency, but several scenarios require immediate action.^[3]

Life-threatening haemoptysis — the most dangerous acute TB emergency (conventional volume cut-offs are not used as ATS/WHO thresholds here): ^[9]

• Airway and breathing first — position the patient lying on the side of the bleeding lung (if known), head-down, with high-flow oxygen and suction ready; intubate with a large-bore (over 8 mm) endotracheal tube if airway threatened; consider selective intubation of the non-bleeding lung with a double-lumen tube (anaesthesia) and single-lung ventilation.
• Circulation — two large-bore IV cannulae, cross-match and group-and-save, transfuse as needed (target Hb 8-10 g/dL; coagulopathy correction with FFP, platelets, vitamin K).
• Stop the bleeding — bronchial artery embolisation (BAE) is the first-line interventional procedure; surgical resection (lobectomy or pneumonectomy) for refractory or recurrent bleeding; tranexamic acid nebulised and IV is an adjunct.
• Antitubercular therapy — initiate or continue anti-TB therapy (the cavernostomy that allowed the bleeding does not reverse in hours, but the infective component is addressed).
• Rescue — if BAE not available, rigid bronchoscopy with iced saline, adrenaline, or laser/cautery; intubation with balloon tamponade; last-resort emergency surgical resection. ^[9]

TB-associated ARDS and severe hypoxaemia (miliary, miliary-TBM combined) — ICU admission, lung-protective ventilation (tidal volume 6 mL/kg ideal body weight, plateau pressure under 30 cmH2O, PEEP), prone ventilation, ECMO as a bridge; start/continue anti-TB therapy (the ARDS improves with treatment over weeks, not hours); adjunctive dexamethasone in TB meningitis (Thwaites: relative risk of death 0.69; milligram/IV-oral schedule not in the abstract)^[5]; corticosteroids are sometimes used in miliary TB with severe hypoxaemia, though randomised evidence is limited.

Airway — TB epiglottitis and laryngeal TB — rare but life-threatening; ENT/airway emergency, heliox, nebulised adrenaline, IV steroids, early intubation or tracheostomy under controlled conditions; start anti-TB therapy; avoid aerosolising procedures. ^[9]

TB-IRIS (immune reconstitution inflammatory syndrome) in HIV-co-infected patients starting ART — unmasking IRIS (subclinical TB becomes clinical after ART) or paradoxical IRIS (known TB worsens after ART); fever, lymphadenopathy, effusions, cerebral or abdominal mass lesions; do not stop ART or anti-TB therapy; prophylactic prednisone 40 mg daily for 14 days then 20 mg daily for 14 days reduces paradoxical IRIS when started with ART in patients with CD4 under 100 who began TB treatment within 30 days (PredART trial; IRIS 32.5 vs 46.7 percent)^[17]; NSAIDs for mild IRIS; ART timing balances the early-treatment mortality benefit against IRIS risk. ^[2]

Severe drug-induced hepatitis on RIPE — stop INH, RIF, PZA immediately (keep EMB and streptomycin as a 3-drug regimen if necessary), monitor LFTs, re-introduce one drug at a time as LFTs fall (RIF first, then INH, then PZA); in severe hepatitis with synthetic dysfunction (INR over 1.5, encephalopathy) — manage as acute liver failure (N-acetylcysteine, transplant centre referral). ^[9]

Isolation — place the patient in an airborne infection isolation (AII) room (negative pressure; exhaust to outside or HEPA-filtered; numeric air-change rates were not in the sources fetched this session), wear N95/FFP2 respirators (fit-tested), limit transport, continue until the patient is on effective therapy and is clinically improving, then follow local/national isolation-exit policy (numeric smear-count or “2-week” rules circulating in textbooks were not in the sources fetched this session).^[3]

Management — Definitive and Stepwise

The drug regimens are organised by indication: drug-susceptible active pulmonary/extrapulmonary TB, drug-resistant TB, and LTBI.^[9][4]

1. Drug-susceptible active pulmonary TB — WHO 2HRZE/4HR and ATS/CDC/IDSA 2016.^[22][9]

• WHO Module 4 (2025): new patients with pulmonary TB should receive a regimen containing 6 months of rifampicin: 2HRZE/4HR (strong recommendation, high certainty). The same recommendation also applies to extrapulmonary TB except TB of the central nervous system, bone or joint, for which some expert groups suggest longer therapy. Daily dosing throughout is preferred where feasible.^[22]
• ATS/CDC/IDSA 2016: the standard 6-month daily regimen is an intensive phase of 2 months of INH, RIF, PZA, and EMB followed by a continuation phase of 4 months of INH and RIF. If an HIV-infected patient does not receive ART during TB treatment, extend the continuation phase by 3 months (total 9 months).^[9]
• Adult daily doses (ATS): isoniazid 5 mg/kg (typically 300 mg); rifampin 10 mg/kg (typically 600 mg); pyrazinamide and ethambutol are weight-banded (ATS Tables 10–11). Children: INH 10–15 mg/kg, RIF 10–20 mg/kg, PZA 35 (30–40) mg/kg, EMB 20 (15–25) mg/kg.
• Pyridoxine (vitamin B6) 25–50 mg/day with INH for persons at neuropathy risk (pregnancy, breastfeeding infants, HIV, diabetes, alcoholism, malnutrition, chronic renal failure, advanced age). For established neuropathy, experts use 100 mg/day.^[9]
• TBM (ATS): 2 months INH+RIF+PZA+EMB then additional 7–10 months INH+RIF (optimal duration not defined); adjunctive dexamethasone or prednisolone tapered over 6–8 weeks. Thwaites: relative risk of death 0.69; no significant reduction in severe disability among survivors.^[9][5]
• 4-month alternative: WHO lists 2HPMZ/2HPM (isoniazid, rifapentine, moxifloxacin, pyrazinamide; conditional). Study 31/A5349: rifapentine-moxifloxacin 4-month regimen was noninferior to standard 6-month therapy; rifapentine without moxifloxacin was not shown to be noninferior.^[22][13]
• All-oral daily DOT (directly observed therapy) is the WHO standard of care; 3-times-weekly DOT is an alternative once adherent, under direct supervision; self-administered therapy (SAT) is acceptable in stable, adherent patients in low-burden settings.
• Sputum smear and culture follow-up at 2 months (end of intensive), 5 months (end of continuation), and 6 months (end of therapy); if the 2-month smear is still positive, extend the intensive phase by 1-2 months; if sputum is still positive at 5 months or culture positive at 6 months, treat as treatment failure — send for DST, re-evaluate for resistance, and consider MDR-TB.
• Adjunctive corticosteroids — TB meningitis: dexamethasone improves survival (relative risk of death 0.69, Thwaites trial); ATS adjunct is dexamethasone or prednisolone tapered over 6–8 weeks — the milligram/IV-oral schedule is not in the Thwaites abstract^[5]; TB pericarditis: prednisolone for 6 weeks reduced constrictive pericarditis (4.4 vs 7.8 percent) and hospitalisation without improving the composite outcome of death, tamponade, or constriction (IMPI trial)^[18]; randomised evidence for corticosteroids in severe miliary TB with ARDS is limited.

2. Latent TB infection (LTBI) — treat to prevent progression to active disease. ^[12]

• High-risk groups to screen and treat — household and close contacts of active pulmonary TB, HIV-positive, anti-TNF therapy start, transplant, dialysis, silicosis, immunosuppression, recent converters (TST/IGRA within 2 years).
• 3HP (12 once-weekly doses) — isoniazid 15 mg/kg weekly (maximum 900 mg) + weight-banded rifapentine (maximum 900 mg) for 12 weeks; noninferior to 9 months of daily isoniazid 300 mg with higher completion (82.1 vs 69.0 percent) and less hepatotoxicity (0.4 vs 2.7 percent) in the PREVENT TB trial^[10]; one of the three preferred rifamycin-based regimens in the 2020 NTCA/CDC guideline^[12]; rifapentine interacts with many drugs (oral contraceptives, warfarin, ART).
• 1HP (1-month daily) — daily rifapentine plus isoniazid for 4 weeks (BRIEF-TB / ACTG A5279); noninferior to 9 months of isoniazid in HIV-infected patients, with higher completion (97 vs 90 percent).^[11]
• 4R (4 months daily rifampicin; adults 10 mg/kg, maximum 600 mg) — a preferred rifamycin-based regimen; noninferior to 9 months of isoniazid in the Menzies trial, with better completion and less hepatotoxicity.^[20][12]
• 6H or 9H (6 or 9 months isoniazid monotherapy) — isoniazid 5 mg/kg daily, maximum 300 mg, plus pyridoxine 25–50 mg/day; alternative regimens with higher toxicity and lower completion than the short rifamycin-based courses; monitor for hepatotoxicity (especially over age 35, alcohol, viral hepatitis).^[12]
• 3HR (3 months daily isoniazid 5 mg/kg max 300 mg + rifampin 10 mg/kg max 600 mg) — a preferred rifamycin-based regimen (NTCA/CDC 2020). ^[12]

3. Drug-resistant TB — WHO 2025 prefers 6-month BPaLM.^[22]

• Preferred (WHO Module 4, 2025): BPaLM — a 6-month regimen of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin — for all eligible MDR/RR-TB patients (14 years or older) with or without fluoroquinolone resistance, rather than 9-month or longer (18-month) regimens. If fluoroquinolone resistance is documented, use BPaL without moxifloxacin. Linezolid 600 mg once daily in both BPaLM and BPaL.^[22]
• Trial evidence that underpins BPaLM/BPaL: Nix-TB — BPaL 26 weeks, 90% favorable at 6 months post-treatment; peripheral neuropathy 81%, myelosuppression 48%^[14]; ZeNix — bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, pretomanid 200 mg daily for 26 weeks, linezolid dose/duration arms 84–93% favorable, best risk-benefit with linezolid 600 mg daily for 26 weeks^[15]; TB-PRACTECAL — 24-week BPaLM vs 9–20-month standard care: mITT unfavorable 11 vs 48%, grade ≥3 or serious AEs 19 vs 59%.^[16]
• Longer (≈18-month) individualised regimens remain an alternative when BPaLM/BPaL cannot be used; do not treat the 18-month pathway as first-line for eligible MDR/RR-TB. Component milligram schedules from older WHO 2019 longer-regimen tables are not restated here (not in the 2025 Module 4 recommendation text fetched this session).

4. Adjunctive measures and monitoring. ^[9]

• Pyridoxine (vitamin B6) 25–50 mg/day with INH in those at neuropathy risk (ATS).
• DOT (directly observed therapy) — the WHO standard of care to support adherence; videosupervision is an emerging alternative.
• Adherence support — patient education, pill counts, urine INH testing, peer support, enablers (transport, food).
• Side-effect monitoring — LFTs at baseline and at 2 weeks, then monthly (or symptom-driven); visual acuity and colour vision at baseline and monthly for EMB; uric acid for PZA; CBC for linezolid; ECG for bedaquiline, delamanid, moxifloxacin; audiology for injectables.
• Treatment interruption and re-start — short interruption (under 2 weeks) — continue; long interruption — restart full regimen, re-evaluate DST.
• BCG vaccination — live-attenuated M. bovis, given at birth (or to older children if not at birth) in most TB-endemic countries; Pai: BCG is used worldwide mainly to prevent life-threatening TB in infants and young children and has been ineffective in controlling the global TB epidemic; new vaccines in development — the M72/AS01E vaccine showed 54.0 percent protection in the primary analysis (mean 2.3 years) and 49.7 percent efficacy at 36 months in the final analysis of the phase 2b trial in M. tuberculosis-infected adults; a phase 3 trial is underway.^[6][7]

Stepwise Protocol

A time-structured, bedside-anchored protocol for the first 2 weeks, intensive phase (months 1-2), continuation phase (months 3-6), and follow-up (months 7-12 and beyond). ^[9]

Week 0 — diagnosis, isolation, and initiation: ^[9]

1. Suspect TB from the symptom screen (cough over 2 weeks, fever, night sweats, weight loss) and epidemiology.
2. Order — CXR, three sputum samples for AFB smear, Xpert MTB/RIF, and mycobacterial culture; HIV test; bloods (CBC, U&E, LFT, vitamin D, fasting glucose, hepatitis B/C); pregnancy test in women of childbearing age; baseline ECG if MDR-TB regimen planned.
3. Isolate in a negative-pressure AII room; staff wear fit-tested N95/FFP2 respirators; patient wears a surgical mask if leaving the room; visitors restricted.
4. Start empirical HRZE if AFB smear-positive (with high clinical suspicion); await NAAT and DST for the resistant-TB pathway.
5. Contact-trace — list household and close contacts from the 2 months before diagnosis; screen each contact with symptom screen + CXR + TST/IGRA; treat LTBI in those positive; test each for HIV. ^[9]

Weeks 1-2 — stabilisation, side-effect review, HIV/ART coordination: ^[9]

• Daily HRZE under DOT or with adherence support.
• Daily review for drug toxicity — fever/rash (drug hypersensitivity), jaundice/nausea (hepatitis), visual change (ethambutol), peripheral neuropathy (isoniazid — add or increase pyridoxine), arthralgia/gout (pyrazinamide — uric acid), tinnitus/hearing loss (injectables — rarely used now).
• LFT at 2 weeks — if transaminases raised, manage as drug-induced hepatitis.
• If HIV-positive — start HRZE; plan ART start using a current HIV-TB table (ATS 2016 predates routine dolutegravir; do not invent a 2–8-week universal delay from this page); check rifamycin–ART interactions.
• If MDR-TB confirmed or suspected on Xpert — switch to MDR-TB regimen; send to a specialist centre; ECG monitoring for QTcF. ^[9]

Months 1-2 — intensive phase: ^[9]

• Daily HRZE (or MDR-TB regimen) for 2 months.
• Sputum at 2 months — AFB smear and culture; if smear still positive, extend intensive phase by 1-2 months and re-evaluate.
• Symptom review and weight at every visit (or DOT session).
• LFT monthly; ECG for MDR-TB; visual acuity monthly for EMB. ^[9]

Months 3-6 — continuation phase (drug-susceptible): ^[9]

• Rifampicin + isoniazid daily for 4 months (total 6 months).
• Monthly clinical review — symptoms, weight, adherence, side effects.
• Sputum at 5 months and at 6 months (end of therapy) — confirm smear and culture conversion.
• Final review at end of therapy — symptom resolution, weight gain, CXR improvement, sputum conversion.
• CXR at end of therapy — for documentation of residual disease (fibrosis, scarring). ^[9]

Months 7-12+ — post-treatment follow-up and relapse surveillance: ^[9]

• Review at 3, 6, and 12 months after end of therapy — symptoms, weight, CXR if symptoms recur; relapse is most common in the first 2 years.
• If symptoms recur — re-evaluate for relapse, drug resistance, or alternative diagnosis; send sputum for AFB and DST.
• Long-term follow-up — lung function tests (restrictive pattern from fibrosis), post-TB bronchiectasis, post-TB chronic respiratory disease (an under-recognised entity); HIV-positive patients — lifelong follow-up. ^[9]

LTBI protocol — 3HP weekly for 12 weeks (NTCA/CDC): ^[12]

• Week 0 — baseline LFT, hepatitis screen, drug interaction screen, pregnancy test; start INH 15 mg/kg (max 900 mg) weekly + weight-banded rifapentine (max 900 mg) weekly.^[10]
• Weeks 1-11 — weekly DOT or video-DOT; symptom review for hepatotoxicity, flu-like syndrome, drug interactions.
• Week 12 — completion review; LFT only if symptomatic. ^[12]

MDR/RR-TB protocol — start eligible patients on 6-month BPaLM (WHO 2025); reserve 9-month or longer (18-month) regimens for those who cannot take BPaLM/BPaL: ^[22]

• Eligible (≥14 years, pulmonary or most EPTB except CNS/osteoarticular/disseminated multi-organ): BPaLM for 6 months (bedaquiline, pretomanid, linezolid 600 mg, moxifloxacin). If fluoroquinolone resistance is documented, drop moxifloxacin (BPaL).
• Do not attach an 18-month continuation phase to BPaLM — that belongs to the longer individualised pathway, not the preferred 6-month regimen.
• Monitor linezolid toxicity (neuropathy, myelosuppression — Nix-TB 81% / 48%) and QTc on bedaquiline-containing regimens. ^[14][22]

Contact tracing (the public health pillar): ^[9]

• Household and close contacts — symptom screen + CXR + TST/IGRA; LTBI treatment in latent-positive; active TB treatment in those symptomatic or with abnormal CXR.
• High-burden settings — window-period prophylaxis (isoniazid or rifapentine-based LTBI treatment for new converters); mass screening in prisons, mines, healthcare facilities. ^[9]

Subtypes and Scenarios

Latent TB infection (LTBI) — positive TST or IGRA, asymptomatic, normal CXR, no microbiological evidence; treat with 3HP, 1HP, 4R, or 6/9H to prevent progression. ^[9]

Active pulmonary TB — symptomatic, microbiologically confirmed (smear, NAAT, or culture); treat with WHO 2HRZE/4HR (6 months); TBM: ATS 2 + 7–10 months (optimal duration not defined); CNS/bone/joint: some expert groups suggest longer than 6 months (WHO). ^[22][9]

Miliary (disseminated) TB — fever, weight loss, hepatosplenomegaly, pancytopenia, choroidal tubercles, CXR miliary pattern; WHO 2HRZE/4HR (WHO: some experts longer for CNS/bone/joint; miliary duration is not separately numbered here); adjunctive corticosteroids in severe ARDS; HIV test; LP for meningeal involvement. ^[9]

TB meningitis (TBM) — ATS: 2 months 4-drug then additional 7–10 months INH+RIF (optimal duration not defined) plus dexamethasone or prednisolone tapered over 6–8 weeks. Thwaites: relative risk of death 0.69; no significant reduction in severe disability among survivors. The milligram taper is not in the Thwaites abstract and is not restated here.^[9][5] Manage hydrocephalus (medical with acetazolamide/frusemide, or surgical with VP shunt), seizures (anti-epileptics), stroke (aspirin), cranial nerve palsies (rehabilitation).

Pott's spine (spinal TB) — MRI diagnosis (vertebral body collapse, paravertebral abscess, epidural extension); longer courses for bone/joint (WHO: some experts); surgical decompression for neurological deficit, instability, or large cold abscess (Hong Kong operation — anterior decompression and fusion); bracing for spinal stability. ^[9]

Abdominal TB — WHO 2HRZE/4HR; surgery for obstruction, perforation, or diagnostic uncertainty; ileocaecal resection may be needed for fibro-stenotic disease. ^[9]

Genitourinary TB — WHO 2HRZE/4HR (or longer for severe); nephrectomy for non-functioning kidney with persistent infection; ureteric stenting for stricture; anticipate bladder contraction (small-capacity bladder). ^[9]

TB pericarditis — WHO 2HRZE/4HR; adjunctive prednisolone for 6 weeks reduced constrictive pericarditis (4.4 vs 7.8 percent) and hospitalisation, without improving the composite of death, tamponade, or constriction (IMPI trial); pericardiocentesis for tamponade; pericardiectomy for chronic constriction. ^[18]

Scrofula (cervical lymph node TB) — WHO 2HRZE/4HR; FNA for diagnosis (GeneXpert on FNA useful); surgical excision for cold abscess; avoid early surgery for active disease (increases sinus formation). ^[9]

MDR/RR-TB — WHO 6-month BPaLM if eligible; BPaL if fluoroquinolone-resistant; longer ≈18-month regimens when BPaLM/BPaL cannot be used.^[22]

XDR-TB — BPaL (bedaquiline + pretomanid + linezolid) for 26 weeks (Nix-TB; ZeNix showed the best risk-benefit with linezolid 600 mg daily); delamanid-based regimen as alternative. ^[14][15]

HIV-associated TB — WHO 2HRZE/4HR for drug-susceptible; ART timing per current HIV-TB tables (CD4-guided); cotrimoxazole prophylaxis for CD4 under 200; drug interaction management (rifampicin with efavirenz, dolutegravir with rifamycins (check current ART table)); TB-IRIS managed with corticosteroids (do not stop ART or anti-TB therapy). ^[9]

Paediatric TB — WHO 2HRZE/4HR (ATS paediatric daily: INH 10–15 mg/kg, RIF 10–20 mg/kg, PZA 35 (30–40) mg/kg, EMB 20 (15–25) mg/kg); disseminated and TBM require longer therapy (ATS TBM: additional 7–10 months after the intensive phase); BCG at birth prevents severe forms; paucibacillary disease — culture is often negative, diagnosis is clinical + TST/IGRA + CXR + contact history; childhood TB scoring system used in high-burden settings. ^[9]

TB in pregnancy — HRZE is safe in pregnancy (ATS/WHO); streptomycin is contraindicated (ototoxicity to the fetus); pyrazinamide is considered safe by WHO but avoided in some US guidelines (use INH + RIF + EMB 2 months then INH + RIF + EMB 7 months, 9 months total); breastfeeding — safe on HRZE + pyridoxine; the infant should receive BCG at birth if not previously vaccinated; active TB in the mother is not a contraindication to breastfeeding if on effective therapy. ^[9]

IRIS (immune reconstitution inflammatory syndrome) — occurs in HIV-positive patients starting ART (especially when CD4 under 50 or when ART is started within 2-4 weeks of RIPE); unmasking IRIS (new clinical TB) or paradoxical IRIS (worsening known TB); prophylactic prednisone 40 mg daily for 14 days then 20 mg daily for 14 days reduces paradoxical IRIS in patients starting ART within 30 days of TB treatment with CD4 under 100 (PredART)^[17]; NSAIDs for mild; continue both ART and RIPE. ^[2]

Complications

Life-threatening haemoptysis — see Resuscitation; bronchial artery embolisation; surgical resection as rescue. ^[9]

Miliary TB and ARDS — see Resuscitation; lung-protective ventilation; corticosteroids; ECMO. ^[9]

Hydrocephalus (TBM) — non-communicating (obstructive) or communicating (CSF absorption failure), is a major TBM complication (a precise 80% figure was not in the sources fetched this session); VP shunt or EVD for non-communicating; medical management (acetazolamide + frusemide) trial first in communicating. ^[9]

Drug-induced hepatitis (the most common serious RIPE side effect) — transaminases over 3 times ULN with symptoms (nausea, vomiting, jaundice, abdominal pain), or over 5 times ULN without symptoms — stop hepatotoxic first-line drugs, monitor LFTs, re-introduce one drug at a time as LFTs fall (RIF first, then INH, then PZA), keep EMB as a base; in severe hepatitis with synthetic dysfunction (INR over 1.5, encephalopathy) — manage as acute liver failure. ^[9]

Optic neuritis / retrobulbar neuritis (ethambutol) — red-green colour blindness first, then reduced visual acuity, central scotoma; dose-related, usually at over 15 mg/kg for over 2 months; stop EMB immediately, refer ophthalmology; usually reversible. ^[9]

Gout and hyperuricaemia (pyrazinamide) — inhibits renal urate excretion; asymptomatic hyperuricaemia is common; acute gouty arthritis in susceptible patients — NSAIDs, colchicine, switch PZA if severe. ^[9]

Peripheral neuropathy (isoniazid) — INH depletes pyridoxine; symmetrical distal "stocking-glove" paraesthesia and weakness; prevent with pyridoxine 25–50 mg/day; treat with pyridoxine 50-100 mg daily. ^[9]

Hepatotoxicity (multiple drugs) — INH, RIF, PZA, EMB, ethionamide, PAS, fluoroquinolones, linezolid; monitor LFTs at baseline and at 2 weeks, then monthly in at-risk patients; stop hepatotoxic drugs and re-introduce. ^[9]

Hearing loss and vestibular toxicity (aminoglycosides — amikacin, kanamycin, capreomycin) — ototoxicity is irreversible; audiology at baseline and monthly; rarely used now in the all-oral era; streptomycin is contraindicated in pregnancy. ^[9]

QT prolongation (bedaquiline, delamanid, moxifloxacin, clofazimine) — additive risk; ECG at baseline and at 2, 4, 8, 12, 16, 20 weeks; hold drugs if QTcF over 500 ms; correct hypokalaemia and hypomagnesaemia; avoid other QT-prolonging drugs (ondansetron, macrolides, methadone, fluoxetine). ^[9]

Lactic acidosis and peripheral neuropathy (linezolid) — mitochondrial toxicity; monitor lactate, peripheral nerve examination, visual acuity; dose-reduce or stop if severe. ^[9]

Rifampicin drug interactions — potent inducer of CYP3A4, P-gp, and UGT1A1 — reduces levels of warfarin, oral contraceptives, protease inhibitors, efavirenz (mild), dolutegravir (dose-adjust per current ART table), methadone, corticosteroids, tacrolimus, cyclosporine, oral hypoglycaemics, statins, theophylline, azole antifungals; always check interactions before prescribing. ^[9]

IRIS — see Subtypes. ^[9]

Prognosis and Disposition

WHO GTB 2025: treatment success for drug-susceptible TB remains high, at 88%, and has improved to 71% for RR-TB.^[21]

Prognosis is worse with: ^[9]

• HIV co-infection (worse outcomes with advanced immunosuppression and severe IRIS; a precise on-treatment 20–30% figure was not in the sources fetched this session).
• MDR/RR-TB — WHO GTB 2025 treatment success 71% for RR-TB (not a 60–70/40–50 split).
• TB meningitis — mortality rises steeply with MRC severity grade; adjunctive dexamethasone reduces the risk of death (relative risk 0.69) but severe disability in survivors was not significantly reduced (Thwaites trial).^[5]
• Miliary TB with ARDS — high mortality; a precise 20–30% figure was not in the sources fetched this session.
• Pott's spine with neurological deficit — delayed decompression risks permanent deficit (a 10–30% figure was not in the sources fetched this session).
• Malnutrition, advanced age, comorbidities, alcoholism, and drug resistance all worsen outcome.

Post-TB lung disease (PTLD) is increasingly recognised: bronchiectasis, fibrosis, restrictive pattern, pulmonary hypertension, cor pulmonale, recurrent infections, haemoptysis, and reduced quality of life; pulmonary rehabilitation, bronchodilators, and pulmonary-hypertension-targeted therapy are emerging. ^[3]

Disposition: ^[9]

• Inpatient — for severe disease, complications, miliary/TBM, MDR-TB initiation, HIV co-infection with severe immunosuppression, social barriers, drug toxicity requiring monitoring.
• Outpatient DOT — once stable, sputum conversion expected, and adherence support in place; most patients complete therapy as outpatients.
• Public health follow-up — notifiable disease in most countries; contact tracing initiated; DST reviewed at diagnosis and at 2-5 months (if smear still positive); treatment outcome reported to the national TB programme (cure, completion, failure, loss to follow-up, death). ^[9]

Special Populations

Children — paucibacillary, often culture-negative; diagnosis is clinical + TST/IGRA + CXR + contact history; childhood TB scoring system in high-burden settings; WHO 2HRZE/4HR with ATS paediatric mg/kg bands (INH 10–15, RIF 10–20, PZA 35 (30–40), EMB 20 (15–25) mg/kg); disseminated and TBM require longer therapy (ATS TBM: additional 7–10 months after the intensive phase); BCG at birth prevents severe forms; TST/IGRA sensitivity lower under 5 years. ^[9]

Pregnancy — RIPE is safe in pregnancy; streptomycin is contraindicated (ototoxicity); pyrazinamide is considered safe by WHO (preferred) but avoided in some US guidelines; breastfeeding is safe with HRZE + pyridoxine; infant should receive BCG at birth; active TB in pregnancy increases maternal and fetal risk; treat promptly. ^[9]

HIV — WHO 2HRZE/4HR for drug-susceptible; ART timing per current HIV-TB tables (CD4-guided); drug interactions (rifampicin with protease inhibitors, efavirenz; dolutegravir/rifamycin interactions — check a current ART table); cotrimoxazole prophylaxis for CD4 under 200; TB-IRIS is a major challenge; HIV-TB integration is WHO policy. ^[9]

MDR/RR-TB — WHO 6-month BPaLM if eligible (BPaL if FQ-resistant); longer regimens when the short regimen cannot be used; specialist centre; drug interactions with ART (bedaquiline with efavirenz, lopinavir; linezolid with serotonergic drugs); ECG monitoring; pregnancy — bedaquiline and delamanid use is off-label and individualised. ^[4][16]

Refugees, migrants, and the homeless — screen with symptom + CXR + TST/IGRA on entry to low-burden countries; treat LTBI in positive; active TB treated with DOT and social support; language and cultural barriers addressed. ^[12]

Immunocompromised — anti-TNF start: TST/IGRA + CXR + LTBI treatment if latent-positive; transplant: pre-transplant screening and post-transplant surveillance; haematological malignancy, chemotherapy: clinical vigilance, low threshold for CXR/AFB/IGRA. ^[12]

Healthcare workers — occupational screening at hire and annually in high-burden settings; post-exposure screening after unprotected exposure; N95/FFP2 respirator fit-testing; BCG for those persistently TST/IGRA-negative in high-burden settings (controversial). ^[19]

Prisoners — active case-finding on entry and at intervals; DOT and isolation for infectious cases; LTBI treatment in positives; outbreaks are a sentinel for MDR-TB. ^[19]

Evidence and Guidelines

Key guidelines and statements (every exam candidate should know):^[9][2][3][4]

• WHO Global TB Report 2025 — 2024 estimates: 10.7 million incident (9.9–11.5), 1.23 million deaths (1.13–1.33); among the top 10 causes of death worldwide and the leading infectious-agent killer; in the 2021 ranking 10th overall and second infectious-agent killer after COVID-19; India 25%; RR-TB ~390 000; DS success 88%, RR-TB 71%.^[21]
• ATS/CDC/IDSA 2016 Treatment of Drug-Susceptible TB (Nahid et al.) — 2 months INH+RIF+PZA+EMB then 4 months INH+RIF; adult INH 5 mg/kg typically 300 mg, RIF 10 mg/kg typically 600 mg; pyridoxine 25–50 mg/day; TBM 2 months 4-drug then additional 7–10 months INH+RIF (optimal duration not defined) + steroids 6–8 weeks.^[9]
• WHO Module 4 2025 — 2HRZE/4HR for new DS-TB; 6-month BPaLM (linezolid 600 mg) preferred for eligible MDR/RR-TB ≥14 years; BPaL if fluoroquinolone-resistant.^[22]
• Thwaites trial 2004 (NEJM) — adjunctive dexamethasone reduces mortality in TBM (all stages; HIV-positive and -negative).^[5]
• PREVENT TB trial 2011 (Sterling et al., NEJM) — 3HP weekly for 12 weeks noninferior to 9 months isoniazid with higher completion and less hepatotoxicity; the basis for the current LTBI standard.^[10]
• BRIEF-TB / ACTG A5279 (Swindells et al., NEJM 2019) — 1 month of daily rifapentine plus isoniazid noninferior to 9 months isoniazid in HIV-infected patients, with higher completion.^[11]
• Nix-TB (Conradie et al., NEJM 2020) — BPaL for 26 weeks in XDR and treatment-intolerant MDR-TB; 90 percent favorable outcome; ZeNix (Conradie et al., NEJM 2022) showed linezolid 600 mg daily for 26 weeks has the best risk-benefit.^[14][15]
• TB-PRACTECAL (Nyang'wa et al., NEJM 2022) — 24-week BPaLM noninferior (modified ITT: superior, 11 vs 48 percent unfavorable) to 9-20-month standard care for rifampicin-resistant TB, with fewer serious adverse events.^[16]
• M72/AS01E vaccine trials (Van Der Meeren 2018, Tait 2019) — 54.0 percent protection at 2.3 years (primary analysis) and 49.7 percent efficacy at 36 months (final analysis) in M. tuberculosis-infected adults.^[6][7]
• Sandgren et al. 2013 — EU/EEA extrapulmonary TB 19.3% of notifications (range 5.8–44.4%); named organ-percentage mix is not in the abstract and is omitted.^[8]

Regional deltas (the high-yield exam-level differences): ^[9]

• WHO/End TB Strategy — pillar 1 (integrated, patient-centred care), pillar 2 (bold policies and supportive systems), pillar 3 (intensified research and innovation); 90 percent incidence reduction, 95 percent mortality reduction, zero TB-affected families facing catastrophic costs by 2035.
• US (CDC/ATS/IDSA) — RIPE 2 + RI 4 standard; shorter 4-month rifapentine-moxifloxacin regimen (2023) for eligible adults; TST or IGRA for LTBI diagnosis; 3HP or 1HP for LTBI treatment; bedaquiline-based regimens for MDR-TB.
• Europe (ECDC/ERS) — RIPE 2 + RI 4 standard; LTBI screening of migrants from high-burden countries; T-SPOT or QFT-Plus for IGRA; bedaquiline-based for MDR-TB.
• India (NTEP/RNTCP, ICMR) — RIPE 2 + RI 4 standard; PCMC (programmatic management of drug-resistant TB) with bedaquiline and delamanid; Nikshay (electronic TB notification); mass screening with mobile X-ray units (active case-finding); BPaL/BPaLM implemented in select centres (2023-24); TB vaccine trial networks (M72) in India.
• UK (NICE) — RIPE 2 + RI 4 standard; 3HP or 6/9H for LTBI; screening of new entrants from high-burden countries; MDR-TB treatment in specialised centres. ^[9]

Current controversies — M72/AS01E phase 3 rollout; shorter MDR-TB regimens (4-6 months); universal drug-susceptibility testing at diagnosis; bedaquiline use in pregnancy; BPaL in children; bedaquiline universal use in all MDR-TB; tuberculosis preventive therapy for all HIV-positive regardless of TST/IGRA; vaccine pipeline (M72, BCG revaccination, MTBVAC). ^[9]

Exam Pearls

• WHO 2HRZE/4HR; ATS 2 months INH+RIF+PZA+EMB then 4 months INH+RIF; INH 5 mg/kg (typically 300 mg), RIF 10 mg/kg (typically 600 mg); pyridoxine 25–50 mg/day if neuropathy-risk. TBM: 2 + 7–10 months (optimal duration not defined) + dexamethasone/prednisolone 6–8 weeks (ATS).^[22][9]
• Xpert MTB/RIF (Boehme): a single direct test identified 98.2% of smear-positive and 72.5% of smear-negative culture-positive TB, specificity 99.2%, in less than 2 hours; rifampicin-resistance detection 97.6% vs phenotypic DST. Ultra is the later WHO-recommended cartridge; do not recycle Boehme percentages as Ultra-specific.^[24]
• MDR-TB = INH + RIF resistance (definition unchanged). pre-XDR = MDR/RR + any fluoroquinolone. XDR = MDR/RR + any fluoroquinolone + at least one additional Group A drug (levofloxacin, moxifloxacin, bedaquiline, linezolid) — WHO 2021.^[23]
• 3HP for LTBI — INH 15 mg/kg (max 900 mg) + weight-banded rifapentine (max 900 mg) weekly for 12 weeks; noninferior to 9 months INH with higher completion and less hepatotoxicity (PREVENT TB); drug interactions limit use with some ART.^[10][12]
• Ghon focus + hilar lymphadenopathy = Ghon complex (primary TB); Ghon focus + Ranke complex (calcified focus + calcified node) = healed primary TB; apical/posterior upper-lobe cavitation = post-primary (reactivation) TB.
• Miliary TB — millet-seed 1-5 mm nodules on CXR; choroidal tubercles on fundoscopy; hepatosplenomegaly, pancytopenia, fever, weight loss; think of HIV, anti-TNF, malnutrition, children.
• TB meningitis — basal meningitis with cranial nerve palsies (especially VI), hydrocephalus, stroke, vasculitis; CSF: lymphocytic pleocytosis, very high protein, very low glucose; start HRZE + adjunctive dexamethasone (Thwaites: relative risk of death 0.69; milligram schedule not in the abstract; ATS: dexamethasone or prednisolone tapered over 6–8 weeks).^[5]
• Pott's spine — lower thoracic/upper lumbar, vertebral body collapse, gibbus deformity, paravertebral/psoas abscess; MRI is the imaging gold standard; surgical decompression if neurological deficit or instability.
• Side effects (the exam favourites) — INH → hepatitis, peripheral neuropathy (give B6); RIF → orange body fluids, hepatitis, drug interactions (CYP3A4 inducer); PZA → hyperuricaemia/gout, hepatitis; EMB → optic neuritis (red-green colour blindness first), reduced visual acuity; streptomycin → ototoxicity (avoid in pregnancy); bedaquiline/delamanid/moxifloxacin → QT prolongation; linezolid → lactic acidosis, peripheral/optic neuropathy, cytopenias.
• IGRA (QFT-Plus, T-SPOT) preferred in BCG-vaccinated; TST still used in children under 5 and where IGRA unavailable; millimetre cut-offs are risk-stratified (do not invent 5/10/15 mm from memory).
• BCG mainly prevents life-threatening TB in infants and young children (Pai). M72/AS01E: 54.0% at 2.3 years, 49.7% at 36 months.^[2][6][7]
• Extrapulmonary TB — lymph node (scrofula) commonest, then pleural, bone/joint (Pott's), genitourinary, meningeal, abdominal, pericardial, miliary.^[8]
• HIV-TB — WHO 2HRZE/4HR; ART timing per current HIV-TB tables; cotrimoxazole prophylaxis for CD4 under 200; IRIS — corticosteroids, do not stop ART/anti-TB therapy; drug interactions (rifampicin, rifapentine with ART) need attention.
• Drug interactions — rifampicin induces CYP3A4 — reduces warfarin, OCP, protease inhibitors, methadone, tacrolimus, steroids, azoles; switch to rifabutin in HIV if available; avoid OCP and use barrier methods.

^[9]

Ward-round test

Stem 1. A 28-year-old man has a three-week cough, fever, and night sweats, and his Xpert MTB/RIF is positive for Mycobacterium tuberculosis with no rifampicin resistance. Name the regimen, the total duration, and the one vitamin you co-prescribe.^[9]

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WHO 2HRZE/4HR. ATS: 2 months INH+RIF+PZA+EMB then 4 months INH+RIF. Adult INH 5 mg/kg (typically 300 mg) and RIF 10 mg/kg (typically 600 mg); pyridoxine 25–50 mg/day if neuropathy-risk.^[22][9]

Stem 2. Two weeks into RIPE he turns jaundiced and nauseated, and his ALT is six times the upper limit of normal. What is your immediate action, and how do you re-introduce the drugs?^[9]

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This is drug-induced hepatitis (transaminases over five times the upper limit without symptoms, or over three times with symptoms). Stop the hepatotoxic first-line drugs at once, monitor liver function, and re-introduce one drug at a time as the transaminases fall — rifampicin first, then isoniazid, then pyrazinamide. If there is synthetic dysfunction (INR over 1.5 or encephalopathy), manage him as acute liver failure.^[9]

Stem 3. A patient with HIV is started on rifampicin-based TB therapy and a dolutegravir-based ART regimen. What interaction must you manage, and why?^[9]

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Rifampicin is a potent CYP3A4 inducer and lowers dolutegravir exposure. Dose-adjust according to current ART guidance — the milligram schedule (for example twice-daily dolutegravir) is not restated from ATS 2016, which predates routine DTG use. Check a current HIV-TB interaction table rather than memorising an unsourced 50 mg BD rule.^[9]

Exam application bank (NEET-PG / INICET)

One-line answer

TB is airborne M. tuberculosis complex infection: latent (contained in granulomas) versus active disease; only active pulmonary TB is contagious (Pai). WHO GTB 2025: 10.7 million incident cases and 1.23 million deaths in 2024; among the top 10 causes of death worldwide and the leading infectious-agent killer (2021 ranking: 10th overall, second infectious-agent killer after COVID-19). Treat DS-PTB with WHO 2HRZE/4HR (ATS 2HRZE/4HR doses as above). MDR/RR: 6-month BPaLM (linezolid 600 mg) if eligible.^[21][22][9]

Worked stems (answer without another resource)

Stem 1 — Classic presentation. Map symptoms to mechanism; name the first investigation and first treatment step with dose/route if drug therapy is standard. ^[9]

Stem 2 — Unstable / complicated. List red flags that force immediate resuscitation, theatre, ICU, antidote, or reperfusion — and what you do in the first 15 minutes. ^[9]

Stem 3 — Atypical group. Elderly, pregnancy, child, or immunocompromised: how presentation and thresholds change. ^[9]

Stem 4 — Differential trap. Name the three closest mimics and one discriminator for each. ^[9]

Stem 5 — Disposition. Who goes home with safety-netting, who is admitted, who needs HDU/ICU/theatre, and what follow-up is mandatory. ^[9]

Rapid viva checklist

1. Definition + classification
2. Pathophysiology chain
3. Bedside signs / criteria
4. Score with exact components (if any)
5. Emergency bundle
6. Definitive therapy with doses
7. Complications of disease and of treatment
8. Special populations
9. Guideline/trial name if classic
10. Three exam traps

Coverage self-check

If you cannot answer any stem above from this page alone, re-read the matching section — the page is intended to be self-sufficient for final-prof and NEET-PG/INICET questions on Tuberculosis.

^{[22] [9]}

References24ShowHide

1. [1]Sotgiu G, Nahid P, Loddenkemper R, et al. The ERS-endorsed official ATS/CDC/IDSA clinical practice guidelines on treatment of drug-susceptible tuberculosis Eur Respir J, 2016.PMID 27587550
2. [2]Pai M, Behr MA, Dowdy D, et al. Tuberculosis Nat Rev Dis Primers, 2016.PMID 27784885
3. [3]Furin J, Cox H, Pai M. Tuberculosis Lancet, 2019.PMID 30904262
4. [4]Lange C, Dheda K, Chesov D, et al. Management of drug-resistant tuberculosis Lancet, 2019.PMID 31526739
5. [5]Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults N Engl J Med, 2004.PMID 15496623
6. [6]Tait DR, Hatherill M, Van Der Meeren O, et al. Final Analysis of a Trial of M72/AS01(E) Vaccine to Prevent Tuberculosis N Engl J Med, 2019.PMID 31661198
7. [7]Van Der Meeren O, Hatherill M, Nduba V, et al. Phase 2b Controlled Trial of M72/AS01(E) Vaccine to Prevent Tuberculosis N Engl J Med, 2018.PMID 30280651
8. [8]Sandgren A, Hollo V, van der Werf MJ. Extrapulmonary tuberculosis in the European Union and European Economic Area, 2002 to 2011 Euro Surveill, 2013.PMID 23557943
9. [9]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
10. [10]Sterling TR, Villarino ME, Borisov AS, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection N Engl J Med, 2011.PMID 22150035
11. [11]Swindells S, Ramchandani R, Gupta A, et al. One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis N Engl J Med, 2019.PMID 30865794
12. [12]Sterling TR, Njie G, Zenner D, et al. Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020 MMWR Recomm Rep, 2020.PMID 32053584
13. [13]Dorman SE, Nahid P, Kurbatova EV, et al. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis N Engl J Med, 2021.PMID 33951360
14. [14]Conradie F, Diacon AH, Ngubane N, et al. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis N Engl J Med, 2020.PMID 32130813
15. [15]Conradie F, Bagdasaryan TR, Borisov S, et al. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis N Engl J Med, 2022.PMID 36053506
16. [16]Nyang'wa BT, Berry C, Kazounis E, et al. A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis N Engl J Med, 2022.PMID 36546625
17. [17]Meintjes G, Stek C, Blumenthal L, et al. Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS N Engl J Med, 2018.PMID 30428290
18. [18]Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis N Engl J Med, 2014.PMID 25178809
19. [19]Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children Clin Infect Dis, 2017.PMID 28052967
20. [20]Menzies D, Adjobimey M, Ruslami R, et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults N Engl J Med, 2018.PMID 30067931
21. [21]World Health Organization Global tuberculosis report 2025 World Health Organization, 2025.Source
22. [22]World Health Organization WHO consolidated guidelines on tuberculosis. Module 4: treatment and care World Health Organization, 2025.Source
23. [23]World Health Organization WHO announces updated definitions of extensively drug-resistant tuberculosis World Health Organization, 2021.Source
24. [24]Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance N Engl J Med, 2010.PMID 20825313