• TB remains one of the top infectious disease killers worldwide (alongside HIV/AIDS).
• WHO 2024 Global TB Report: ~10.8 million new cases and ~1.25 million deaths annually.
• Highest burden: South-East Asia (45%), Africa (23%), Western Pacific (18%).
• Drug-resistant TB is a growing crisis: an estimated 410,000 new cases of multidrug-resistant TB (MDR-TB) or rifampicin-resistant TB (RR-TB) globally per year.

Hong Kong is classified as an intermediate TB burden area. The annual notification rate has been declining but remains significant (~4,000–5,000 cases per year, rate ~50–60 per 100,000 population), which is considerably higher than other developed regions.

• Extrapulmonary TB accounts for approximately 2/3 of cases in Hong Kong, while pulmonary TB accounts for approximately 1/3 ^[1]. This is an important local statistic that differs from global patterns where pulmonary TB dominates.
• The elderly population in HK carries a high burden of latent TB from historical infection in the pre-chemotherapy era, with reactivation disease being common.
• Non-tuberculous mycobacteria (NTM) are also increasingly recognised in HK — but these are distinct from TB (different management, no notification, no person-to-person transmission) ^[1].
• TB is a notifiable disease in Hong Kong under the Prevention and Control of Disease Ordinance.

• Globally: M > F (~1.5–2:1).
• Age: bimodal distribution — young adults (20–40 years) in high-burden settings; elderly (>65 years) in low/intermediate-burden settings (reactivation).
• In HK: elderly patients constitute a significant proportion due to reactivation.

Previous history of pulmonary tuberculosis is also a risk factor for lung cancer ^[9] — important for the oncology cross-link.

Post-primary (reactivation) TB classically affects the apico-posterior segments of the upper lobes and the apical segments of the lower lobes. Why?

1. Higher oxygen tension (PaO₂): MTB is an obligate aerobe — the apex of the upright lung has the highest ventilation-to-perfusion (V/Q) ratio, meaning relatively more oxygen and less blood flow. This creates an ideal environment for MTB growth.
2. Reduced lymphatic drainage: Less perfusion also means fewer immune cells patrolling and less efficient drainage of infected material.
3. Reduced macrophage activity: Lower blood flow = fewer recruited immune cells.

MTB disseminates via:

• Lymphatics → regional lymph nodes (forms the Ghon complex)
• Haematogenous spread → can seed virtually any organ (kidney, bone, meninges, adrenals, liver, spleen, etc.)
• Direct extension → e.g., from lung parenchyma into the pleura
• Bronchogenic spread → aspiration of cavitary contents to other lung segments or contralateral lung

Mycobacterium tuberculosis (MTB) — the principal causative agent.

• Taxonomy: Genus Mycobacterium, Family Mycobacteriaceae, Order Actinomycetales.
• MTB complex includes:
  • M. tuberculosis (the main human pathogen)
  • M. bovis (cattle → humans via unpasteurised milk; also the basis of BCG vaccine)
  • M. africanum (West Africa)
  • M. microti (voles)
  • M. canettii (rare)

• Airborne transmission via droplet nuclei (1–5 μm particles) generated when a person with active pulmonary or laryngeal TB coughs, sneezes, speaks, or sings.
• Droplet nuclei remain suspended in air for hours and can be inhaled deep into the terminal alveoli.
• NOT transmitted by fomites (casual surface contact), handshakes, or sharing utensils.
• Infectiousness depends on:
  • Sputum smear status (smear-positive >> smear-negative)
  • Presence of cavitation (cavities contain 10⁷–10⁹ bacilli)
  • Cough frequency and intensity
  • Duration of exposure
  • Ventilation of environment

Step-by-step explanation:

1. Inhalation: MTB enters via inhaled droplet nuclei → reaches terminal alveoli (must be small enough, 1–5 μm, to bypass mucociliary clearance).

2. Innate immune response: Alveolar macrophages phagocytose MTB. However, MTB has evolved mechanisms to survive intracellularly:

   • Inhibits phagolysosome fusion (prevents acidification and killing)
   • Blocks autophagy pathways
   • Resists reactive oxygen/nitrogen species

3. Initial replication: MTB multiplies within macrophages → macrophages die → bacilli released → phagocytosed by new macrophages. This creates an initial focus of infection.

4. Lymphatic spread: Bacilli spread from the initial focus via lymphatics to regional (hilar/mediastinal) lymph nodes.

   • Ghon focus: The initial parenchymal lung lesion (usually mid-zone in primary infection — NOT the apex, which is for reactivation).
   • Ghon complex = lung lesion + regional lymph node involvement ^[2].
   • If the Ghon complex calcifies → Ranke complex.

5. Acquired (adaptive) immune response (takes 2–8 weeks):

   • Dendritic cells present MTB antigens to naïve T cells in lymph nodes.
   • CD4+ T-helper 1 (Th1) cells are activated → produce IFN-γ and TNF-α.
   • IFN-γ activates macrophages → become "epithelioid cells" with enhanced killing capacity.
   • Epithelioid cells fuse → form multinucleated giant cells (Langhans giant cells) — characteristically with nuclei arranged in a horseshoe pattern at the periphery.
   • Activated macrophages, epithelioid cells, giant cells, and lymphocytes form a granuloma — the hallmark of TB.

6. Granuloma: This is the body's attempt to "wall off" the infection.

   • Centre: caseating necrosis (caseous = "cheese-like") — due to cytotoxic T-cell killing and macrophage death.
   • Surrounding: epithelioid cells, Langhans giant cells, lymphocytes, fibroblasts.
   • This is why TB is called a granulomatous disease.

7. Outcome of primary infection:

   • Majority are asymptomatic: 50% of infants and 90% of older children ^[2] successfully contain the infection → LTBI.
   • Principle: local inflammatory reaction limits progression of infection; however, disease remains latent and may reactivate in the future ^[2].

• The granuloma contains but does not eradicate MTB. Bacilli can remain dormant (metabolically quiescent) within granulomas for decades.
• The patient is not infectious and has no symptoms.
• Evidence of infection: positive TST or IGRA (indicating prior sensitisation of T cells to MTB antigens).
• Chemoprophylaxis is indicated for positive TST or IGRA ^[2] to prevent future reactivation.

The spectrum of TB pathogenesis ^[1]:

• Infection eliminated (innate immunity) → all tests negative → no treatment
• Infection eliminated (acquired immunity) → only TST/IGRA positive → no treatment
• Infection persistent:
  • Latent TB → TST/IGRA positive, preventative treatment (1–2 drug combo)
  • Subclinical TB disease → TST/IGRA positive, culture/sputum possibly positive, some symptoms, multidrug therapy
  • Active TB disease → everything positive, multidrug therapy (but interestingly, TST and IGRA can be negative during overwhelming infection or immunocompromised state)

• Occurs when host immunity wanes → dormant bacilli within granulomas begin to replicate again.
• When host is immunocompromised, reactivation may occur. It can be localised (75%) or disseminated (e.g., TB meningitis in infants and young children) ^[2].
• Classic site: apico-posterior segments of upper lobes (80–90%) and apical segments of lower lobes ^[12] — for the reasons explained in the anatomy section (high V/Q, high O₂ tension).
• More likely to cause cavitation than primary TB → more bacilli → more infectious.

• "Miliary" from Latin miliarius = resembling millet seeds — referring to the innumerable tiny (1–2 mm) granulomas scattered throughout organs.
• Results from massive haematogenous dissemination.
• Can occur during primary infection (especially in immunocompromised/infants) or during reactivation.
• Involves multiple organs: lungs, liver, spleen, bone marrow, kidneys, meninges, adrenals.
• CXR: classic "miliary pattern" — diffuse, uniformly distributed, tiny (1–3 mm) nodules throughout both lung fields.

The tissue damage in TB is predominantly immune-mediated, not directly caused by the bacillus itself.

• Type IV (delayed-type) hypersensitivity reaction: CD4+ T cells and macrophages cause caseous necrosis and fibrosis.
• This is the same reaction that underlies the tuberculin skin test (TST) — injection of PPD causes a local Type IV reaction in previously sensitised individuals.
• Cavitation occurs when caseous material liquefies and is expectorated via communication with a bronchus → leaves a cavity lined by caseous material → ideal environment for bacillary multiplication (aerobic, extracellular, nutrient-rich).

TB is called the "great imitator" because it can mimic almost any disease. The key clinical principle is:

Remember that pulmonary TB rarely presents as an acute pneumonia-like picture... usually a much more indolent presentation ^[1].

The clinical features depend on:

1. Site of disease (pulmonary vs. extrapulmonary)
2. Stage of disease (primary vs. reactivation)
3. Host immune status
4. Extent of disease (localised vs. disseminated)

From Adrian Lui Pediatrics Notes ^[2]:

• Following primary infection, a child can be:
  • Asymptomatic (majority: 50% of infants, 90% of older children) — local inflammatory reaction limits progression, but disease remains latent.
  • Symptomatic — host immune system fails to contain inhaled MTB → spread via lymphatics to regional lymph nodes → forms Ghon complex (lung lesion + LN) → immunological system usually halts further progression.
  • S/S: prolonged fever, malaise, anorexia, weight loss, cough.
• Both asymptomatic and symptomatic infections become dormant.
• When host is immunocompromised, reactivation may occur — can be localised (75%) or disseminated (e.g., TB meningitis in infants and young children).
• Children are more likely to develop progressive primary disease (especially < 5 years), miliary TB, and TB meningitis than adults.
• Children are usually paucibacillary (low bacillary load) → less likely to be smear-positive → diagnosis more challenging.

From the 2023 Fourth Summative Minicase ^[19]: A 61-year-old chronic smoker and drinker with previous pulmonary TB at age 35 (treated with 9 months anti-TB) and worked as a construction site worker since age 30 presents with progressive shortness of breath and productive cough for 3 years. Question asked for 5 differential diagnoses — highlighting that post-TB sequelae (bronchiectasis, lung fibrosis), COPD, lung cancer, silicosis/pneumoconiosis, and heart failure are all important differentials in this demographic.

Cervical and supraclavicular lymph nodes — malignancy vs tuberculosis ^[21][22].

Differential diagnosis of generalised lymphadenopathy: neoplastic (leukaemias, lymphomas), infective (viral — EBV, CMV; bacterial, mycobacterial; parasitic; dimorphic fungi), autoimmune, and drugs ^[24].

Exudates meeting Light's criteria require further analysis including cytology, cultures, and adenosine deaminase to identify causes such as malignancy, infection, or tuberculosis ^[25].

Pyogenic osteomyelitis vs TB spine ^[26]:

Other differentials for destructive spinal lesions: metastatic carcinoma (commonest malignant cause — lung, breast, prostate, thyroid, kidney), multiple myeloma, primary bone tumour, brucellosis (in endemic areas).

This is an extremely high-yield differential, especially in the HK context.

It is crucial to rule out TB infection in the diagnosis of IBD, especially because some of the biologics (i.e., anti-TNF-alpha) will suppress the host's ability to contain TB → TB reactivation ^[8].

The choice of specimen depends on the suspected site of disease. The principle is simple: get material from where the disease is.

Important investigations to perform: CXR, blood tests, sputum tests, CT thorax (HRCT vs. spiral/volumetric, with or without contrast), bronchoscopy (airway inspection, samples for microbiology and cytology, histology; alternative: percutaneous lung biopsy), sampling of other tissues (e.g., LN, pleural effusion), SaO₂ and arterial blood gases as needed ^[22].

• Test: Ziehl-Neelsen (ZN) stain — bacilli stained red against a blue background ^[20][2].
• Principle: Mycobacteria have a thick lipid-rich cell wall (mycolic acids) that retains carbol fuchsin dye even after washing with acid-alcohol (= "acid-fast"). This is the defining feature of the genus Mycobacterium.
• Name decoded: "Acid-fast bacilli" (AFB) → acid = resists acid decolorisation; fast = held firmly (from German fest = firm); bacilli = rod-shaped bacteria.

Advantages ^[20]:

• Simple, rapid, and inexpensive
• Indicates degree of infectiousness (smear-positive = "open" TB = more infectious)

Disadvantages ^[20]:

• Low sensitivity (< 50% of active PTB is positive)
• Cannot differentiate M. tuberculosis from NTM — you just see "acid-fast bacilli" but you don't know which species
• Requires ~5,000–10,000 organisms/mL to be positive (vs. culture which needs only 10–100)

Culture remains the closest thing we have to a diagnostic "gold standard" — it provides definitive species identification and drug susceptibility testing (DST).

Why culture is essential:

1. Confirms the species (MTB vs. NTM — critical difference in management)
2. Allows drug susceptibility testing for HREZ ^[20] — essential to detect MDR-TB
3. Higher sensitivity than smear (needs only 10–100 organisms/mL)

Why culture alone is insufficient as a diagnostic strategy:

• Too slow for initial clinical decision-making
• Some patients are culture-negative despite having active TB (paucibacillary disease, especially in children and EPTB)

Once positive growth is obtained, you still need to confirm the genus Mycobacterium (ZN staining), then identify the species (MALDI-TOF MS, molecular techniques) ^[1].

Molecular tests amplify MTB-specific DNA sequences, providing rapid results with high accuracy.

Examples: GeneXpert MTB/RIF (Xpert), line probe assays (GenoType MTBDRplus), in-house PCR.

Advantages ^[20]:

• Rapid diagnosis (1–2 days)
• Differentiates M. tuberculosis from NTM with species identification possible
• Detection of genes encoding drug resistance (e.g., rpoB gene mutation for rifampicin resistance in GeneXpert)

Disadvantages ^[20]:

• Expensive
• Cannot be used to monitor response to treatment — NAAT detects nucleic acid from both dead and live organisms, so it may remain positive even after successful treatment
• Does NOT replace smear and culture — culture is still required for confirmation and full DST
• A negative NAAT alone is NOT sufficient to exclude active TB or drug resistance

More sensitive than CXR for detecting subtle parenchymal disease, cavitation, lymphadenopathy, and complications.

Exudates meeting Light's criteria require further analysis including cytology, cultures, and adenosine deaminase to identify causes such as malignancy, infection, or tuberculosis ^[25].

Pleural biopsy improves diagnostic yield ^[33]:

• Bedside percutaneous (Abram's needle): first line as TB pleuritis is common in HK; has poor sensitivity for malignant pleural effusion ^[33]
• Medical thoracoscopy / pleuroscopy: allows drain + biopsy + pleurodesis; requires IV sedation ^[33]
• VATS thoracoscopy (under GA)

Technique ^[14]:

• Jamshidi needle, patient in lateral decubitus position, insert into posterior superior iliac spine
• Major complication: double puncture risk (1 in 10,000) — needle exits through opposite cortex into retroperitoneum → could puncture spleen or kidney
• Mitigation: tilt needle laterally/superiorly to stay within safe zone

Gallium scan ^[35]:

• Clinical indications include: osteomyelitis (spinal and chronic), fever of unknown origin, pulmonary infection, tuberculosis, autoimmune disorder (including retroperitoneal fibrosis and sarcoidosis), fever in immunocompromised patients, drug-induced pulmonary toxicity
• Radiopharmaceutical: ⁶⁷Ga citrate (t½ = 78 hours)
• Principle: ⁶⁷Ga is similar to Fe³⁺ in charge, atomic radius and inorganic complexes → binds to iron-containing inflammatory proteins including transferrin, lactoferrin, ferritin, and siderophores
• If urgent: do FDG-PET instead (gallium is a cyclotron product, needs to be imported)

FDG-PET/CT: Increasingly used for:

• Detecting extent of disease in extrapulmonary/miliary TB
• Assessing treatment response
• Evaluating for occult TB in FUO

• Presentation: usually non-specific. Early stage (CD4 > 200): similar to immunocompetent with upper-zone cavitating lesions. Severe immunosuppression: decreased haemoptysis, decreased zonal predominance, decreased cavitation, increased extrapulmonary disease ^[12].
• TST/IGRA not helpful in advanced HIV (false negatives due to anergy) ^[12].
• Urine lipoarabinomannan (LAM) antigen detection: detects glycolipid cell wall component of MTB. High sensitivity in HIV-infected patients with CD4 < 200 but low sensitivity in non-HIV infected patients. NOT routinely available in HK ^[20].

• Atypical presentation: increased non-specific symptoms (weight loss, dyspnoea, malaise), decreased haemoptysis, increased generalised CXR infiltrates involving lower zones ^[12].
• May have cryptic miliary TB where CXR may not show typical miliary pattern and sputum/TST are negative ^[12].
• Diagnosis often delayed or missed → consider TB in ALL cases of pyrexia of unknown origin ^[12].
• Diagnostic specimens: BAL for AFB Sm/C/NAAT, BMA, biopsy of involved organs (e.g., liver) ^[12].

Management (SAQ!): Contact tracing and report to DH. Report to Labour Department if healthcare worker or high-risk occupations ^[33].

This is the approach used by the Department of Health in HK ^[20]:

The mnemonic HRZE (sometimes with S) refers to the backbone of TB treatment. Understanding each drug from first principles helps you remember their roles, side effects, and monitoring requirements.

Name decoded — why these particular drugs work together:

• H kills the large population of rapidly dividing bacilli (brings down the bacterial load fast).
• R kills the semi-dormant persisters that H cannot reach (prevents relapse — this is why R must be continued throughout the full course).
• Z kills bacilli in acidic intracellular environments (macrophages, caseous foci) — this sterilising effect is why adding Z to the intensive phase allows treatment to be shortened from 9 to 6 months.
• E is bacteriostatic and primarily serves to prevent resistance to H and R during the initial phase when bacterial load is highest.

The WHO classifies MDR-TB drugs into Groups A, B, and C ^[12]:

Monitoring for MDR-TB treatment ^[12]:

• LFT (hepatotoxicity)
• ECG (QTc prolongation — multiple QT-prolonging agents)
• Sputum AFB Sm/C (response to treatment)
• CXR (radiological response)
• CBC (linezolid myelosuppression)
• Visual acuity (ethambutol)
• Audiometry (if aminoglycosides used)

Treatment: side effects more common, drug interactions due to polypharmacy. Rifampicin → ↑metabolism of many non-NRTI components of ART ^[12].

Anti-TNF-α is the classical example that can increase risk of developing TB, given the importance of TNF-α in confining TB to the tuberculoma ^[1].

• Mechanism: Direct extension of subpleural caseous focus into the pleural space triggers an intense delayed-type hypersensitivity reaction → high-protein, lymphocyte-predominant exudative effusion. If frank caseous material or bacilli pour into the pleural space, it becomes a tuberculous empyema (purulent pleural fluid).
• Clinical significance: Can cause dyspnoea due to compressive atelectasis; empyema is more difficult to treat and may require chest tube drainage.
• Key investigation: Pleural fluid analysis (ADA > 40 IU/L in ~90%, lymphocyte-predominant), pleural biopsy for histopathology + AFB culture.

Tuberculous empyema is characterised by purulent pleural fluid and can progress from TB pleuritis ^[20].

Rupture of peripheral cavity or subpleural caseous focus with liquefaction into pleural space. Inflammation can lead to bronchopleural fistula which may require chest tube drainage ^[20].

• Mechanism: A subpleural cavity or caseous focus erodes through the visceral pleura → air (± caseous material) enters the pleural space → pneumothorax. If the communication persists, a bronchopleural fistula (BPF) forms — air continuously leaks from airway to pleural space, making the pneumothorax persistent and difficult to manage.
• Clinical significance: Tension pneumothorax is a medical emergency. BPF requires prolonged intercostal drainage and sometimes surgical repair.

Brock's syndrome — RML collapse due to hilar LN ^[33].

• Brock's syndrome is a specific complication of primary TB in which enlarged hilar/mediastinal lymph nodes extrinsically compress the right middle lobe bronchus (the narrowest lobar bronchus, most susceptible to external compression) → distal atelectasis and RML collapse.
• Name decoded: Named after Lord Russell Brock, a British cardiothoracic surgeon.
• Why the RML? The right middle lobe bronchus is the longest and narrowest lobar bronchus, with the smallest angle of origin from the intermediate bronchus, and is surrounded by lymph nodes on both sides — making it particularly vulnerable to extrinsic compression.

Atelectasis occurs in endobronchial TB ^[20] — when granulomatous inflammation directly involves the bronchial mucosa, causing obstruction from within.

• Mechanism: Direct spread of infected sputum from the lungs to the laryngeal mucosa, or haematogenous/lymphatic spread to the larynx.
• Clinical significance:
  • Extremely infectious — the larynx is the point where air is exhaled most forcefully, aerosolising vast numbers of bacilli.
  • Presents with hoarseness, odynophagia (painful swallowing), cough.
  • Must be distinguished from laryngeal carcinoma (both cause hoarseness in middle-aged/elderly patients).

• Mechanism: Extensive bilateral parenchymal destruction, massive pleural effusion, miliary TB with diffuse interstitial involvement, or ARDS in severe cases.
• More common in miliary TB and in immunocompromised patients (HIV, elderly).
• Can be Type 1 (hypoxaemic — V/Q mismatch from destroyed/consolidated lung) or Type 2 (hypercapnic — if respiratory muscle fatigue or extensive fibrosis).

• Mechanism: Haematogenous or lymphatic spread to other organs (already discussed in clinical features section).
• When host is immunocompromised, reactivation may occur — can be localised (75%) or disseminated (e.g., TB meningitis in infants and young children) ^[2].
• Key disseminated forms: miliary TB, TB meningitis, GU TB, skeletal TB, peritoneal TB, pericardial TB, adrenal TB.

• Mechanism: Erosion of a pulmonary artery branch within a cavity wall → formation of a Rasmussen aneurysm (pseudo-aneurysm of a pulmonary artery branch). Rupture causes life-threatening haemoptysis (> 300–600 mL/24h).
• Alternatively: Erosion into bronchial arteries (high pressure, systemic circulation) by cavitary disease also causes significant haemoptysis.
• Management: Airway protection (position patient with bleeding side down), bronchial artery embolisation (BAE), surgical resection if embolisation fails.

Result of hypercoagulability ^[20].

• Mechanism: Active TB induces a systemic pro-inflammatory and procoagulant state. Chronic inflammation → elevated fibrinogen, Factor VIII, and tissue factor → hypercoagulability → DVT/PE.
• Often under-recognised as a complication of TB.

• Mechanism: Granulomatous inflammation → caseous necrosis → healing with fibrosis and scarring. The upper lobes (site of reactivation TB) are most affected → loss of volume, traction on surrounding structures.
• CXR: Upper lobe volume loss, fibrotic bands, tracheal deviation towards the affected side, elevation of hilum.
• Clinical consequence: Restrictive lung defect → reduced lung compliance → chronic dyspnoea.

Bronchiectasis is a major chronic complication of TB ^[33][20].

Three mechanisms lead to post-TB bronchiectasis ^[20]:

Look out for: Mycobacterium tuberculosis (especially reactivation in post-tuberculous bronchiectasis) and non-tuberculous mycobacteria (NTM) — which may be secondary infection in diseased lungs or primary infection causing bronchiectasis ^[38].

TB is a common underlying disease predisposing to chronic pulmonary aspergillosis ^[20]. Aspergilloma (in old TB cavity) ^[33].

• Mechanism: After TB treatment, residual cavities in the lung remain as non-collapsing air spaces. Aspergillus fumigatus (a ubiquitous environmental mould) colonises these pre-existing cavities → forms a fungal ball (mycetoma/aspergilloma) — a conglomerate of fungal hyphae, mucus, and cellular debris sitting within the cavity.
• CXR/CT: Classic "air crescent sign" — a crescent of air between the fungal ball and the cavity wall. The fungal ball moves with changes in patient position (demonstrated on decubitus films).
• Clinical significance:
  • Often asymptomatic (incidental finding on CXR)
  • Can cause haemoptysis — sometimes massive and life-threatening (erosion of cavity wall blood vessels by fungal enzymes)
  • Distinguished from invasive aspergillosis (which occurs in severely immunocompromised patients)
• Management: Observation if asymptomatic; antifungal therapy (itraconazole, voriconazole) for symptomatic or progressive disease; BAE for haemoptysis; surgical resection for recurrent massive haemoptysis

Cor pulmonale ^[33].

• Name decoded: "cor" = heart, "pulmonale" = of the lung → right heart failure caused by lung disease.
• Mechanism: Extensive pulmonary fibrosis from TB → destruction of the pulmonary vascular bed + hypoxic vasoconstriction → increased pulmonary vascular resistance → pulmonary hypertension → right ventricular hypertrophy → right heart failure.
• Clinical features: Peripheral oedema, raised JVP, hepatomegaly (from hepatic congestion), tricuspid regurgitation, loud P2.
• Why does destroyed lung cause pulmonary hypertension? Two reasons: (1) Physical destruction of pulmonary capillaries by fibrosis reduces the total cross-sectional area of the vascular bed. (2) Alveolar hypoxia in remaining lung tissue triggers hypoxic pulmonary vasoconstriction (Euler-Liljestrand reflex) → further raises pulmonary artery pressure.

Complications: basal meningeal adhesions → CN palsies (3, 4, 6, 8), hydrocephalus. Infarction due to endarteritis obliterans. Parenchymal damage. Spinal spread: myelitis, arachnoiditis (spinal cord compression by thickened meninges → paraparesis) ^[39].

• Pericardial effusion → cardiac tamponade: Rapid accumulation of inflammatory fluid → compresses cardiac chambers → impairs diastolic filling → obstructive shock.
• Constrictive pericarditis: Chronic granulomatous inflammation → pericardial fibrosis and calcification → rigid pericardium that restricts diastolic filling of both ventricles.
  • Differentiating constrictive pericarditis from restrictive cardiomyopathy is crucial because constrictive pericarditis can be successfully treated surgically (pericardiectomy) or with anti-tuberculosis treatment ^[11].

• Vertebral collapse → kyphotic deformity (gibbus)
• Pott's paraplegia: Cord compression from paravertebral abscess, caseous tissue, or vertebral collapse
• Cold abscess tracking: Paravertebral abscess can track along psoas sheath → presents as inguinal/groin swelling (psoas abscess)

• Addison's disease: Bilateral adrenal destruction by caseous necrosis → cortisol and aldosterone deficiency → hyperpigmentation, hypotension, hyperkalaemia, hyponatraemia. TB was historically the most common cause of primary adrenal insufficiency.

These have been covered in the management section, but key complications to emphasise:

TB drug-induced acute tubulointerstitial nephritis (ATIN): A 74-year-old lady started on anti-TB medications presents with fever, generalised rash, hepatosplenomegaly, lymphadenopathy. Lab: WBC 17,800 with eosinophilia, serum creatinine 560 μmol/L, urinalysis shows WBC casts. Renal ultrasound: large echogenic kidneys ^[27].

• Mechanism: Hypersensitivity reaction (Type IV or Type I) to anti-TB drugs (most commonly rifampicin, but also isoniazid and ethambutol) → immune-mediated inflammation of the renal interstitium and tubules.
• Classic triad: Fever + rash + eosinophilia (though the full triad is present in only ~10% of cases).
• Investigations: Eosinophilia, elevated creatinine, WBC casts in urine (distinguish from RBC casts in glomerulonephritis), renal USG shows enlarged kidneys (oedema).
• Management: Stop the offending drug, supportive care, consider corticosteroids in severe cases.

This is one of the most important treatment-related complications to understand.

• What it is: Clinical or radiological worsening that occurs after starting appropriate anti-TB treatment, despite microbiological improvement.
• Mechanism: Effective anti-TB therapy reduces bacillary load → "unmasked" bacillary antigens trigger an exaggerated immune response. In HIV patients, ART restores immunity → similar hyperactive response.

Return of TNF-alpha (after stopping anti-TNF-α), body mounts a massive and exaggerated response towards the TB, especially in the lymph nodes → paradoxical reaction, worsening of clinical/radiological parameters. But over time, reverts back to normal ^[1].

Management of IRIS/paradoxical reaction ^[12]:

• Supportive ± NSAID (mild)
• Prednisolone (severe)
• Stop ART transiently (if refractory)
• Do NOT change or escalate anti-TB regimen — this is an immune phenomenon, not treatment failure

Renal transplant recipients are immunocompromised → especially prone to opportunistic infections such as CMV, Pneumocystis jirovecii, BK virus, M. tuberculosis ^[7].

• Higher mortality: Atypical presentations delay diagnosis.
• Drug interactions: Rifampicin ↑metabolism of calcineurin inhibitors → transplant rejection risk.
• IRIS: Particularly severe in HIV patients starting ART.

TB prophylaxis for those with positive tuberculin skin test or IGRA blood test. Prolonged anti-tuberculosis (multi-drug regimen) for those with active TB ^[40].

• Silicosis predisposes to TB because silica particles impair alveolar macrophage function.
• Both silica and asbestos are WHO Type I carcinogens ^[40] — so patients with silicotuberculosis are at triple risk: silicosis + TB + malignancy.
• Treatment of TB in silicosis may require prolonged courses due to impaired host immunity and drug penetration into fibrotic tissue.

TB treatment with hepatotoxic drugs (H, R, Z) in HBV carriers poses a dual risk:

• Direct hepatotoxicity from anti-TB drugs
• HBV reactivation due to immune modulation or hepatocyte damage

Management: Screen with HBsAg before treatment ^[33]. If positive, consider prophylactic antiviral therapy (entecavir or tenofovir) ^[41].