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Complications of Pulmonary Tuberculosis

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Classification (Table 31.1)

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1. HAEMOPTYSIS

• Bleeding from Rasmussen's aneurysm — walls of a TB cavity become atrophic/necrotic; increased pressure → dilatation of blood vessels → aneurysm formation → rupture with coughing/exertion
• Direct erosion of capillaries or arteries by granulomatous inflammation (endarteritis, vasculitis, allergic vascular damage)
• Bleeding from TB granulomas in bronchi (bronchopulmonary communications under systemic pressure)
• Post-TB bronchiectasis
• Aspergilloma
• Broncholith/cavernolith
• Scar carcinoma

• Mild: Bed rest, sedation, resuscitative measures, broad-spectrum antibiotics for superadded infection. Anti-TB treatment if active disease.
• Massive haemoptysis (>600 mL/24 h): Blood transfusion, haemodynamic resuscitation
• Fibreoptic bronchoscopy to localise bleeding + HRCT
• Bronchial artery embolisation (BAE): Good, relatively safe procedure. Risk of re-bleeding is high in destroyed lung, chronic liver disease, anticoagulant use, elevated CRP, and fungal ball
• Surgery (resection) rarely indicated; for repeated, severe, life-threatening haemoptysis with adequate pulmonary reserve

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2. ASPERGILLOMA (MYCETOMA / "FUNGAL BALL")

• Often asymptomatic and incidental finding
• Haemoptysis: Most common symptom (5–90%); due to mechanical friction, endotoxin, anticoagulant factor from Aspergillus, local vasculitis, or direct vascular invasion
• Chronic cough, weight loss, fever, dyspnoea
• Mortality: 2–14%

• Chest X-ray: "Air crescent sign" — semicircular crescentic air shadow around a radio-opaque fungal ball in an upper lobe cavity ("clapper inside a bell"). Fungal ball is mobile (changes position with posture — confirmed by fluoroscopy/CT)
• Sputum culture: positive in ~50%
• Serum precipitins (IgG to Aspergillus): Positive in almost 100% (except with non-fumigatus species or corticosteroid therapy)
• CT chest: most sensitive

• Asymptomatic: No therapy warranted; watch and wait
• Systemic antifungal (IV amphotericin B): ineffective (cannot penetrate intra-cavitary fungi)
• Intracavitary/inhalational antifungal agents: tried with varying success
• Itraconazole: varying success
• BAE: only as a temporary measure for life-threatening haemoptysis
• Surgery (lobectomy, pneumonectomy): indicated for repeated severe haemoptysis in patients with adequate pulmonary reserve. Surgical mortality: 7–23%. Post-op complications include empyema, bronchopleural fistula, respiratory failure
• Cavernostomy: useful in complicated cases

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3. POST-TB BRONCHIECTASIS

1. Caseation necrosis + granulomatous inflammation in bronchial walls → direct extension of TB
2. Scarring → bronchial stenosis → secondary bacterial infection → retention of secretions → bronchial wall destruction/dilatation
3. Compression of bronchial lumen by enlarged lymph nodes (especially in children)
4. Penetration by calcified TB lymph node → broncholith formation
5. Healing/healed TB cavities re-lined with ciliated columnar epithelium

• Commonly in upper lobes (most affected by TB)
• "Dry" or "sicca" bronchiectasis — effective drainage by gravity, so less purulent secretion
• Presents with haemoptysis or recurrent secondary bacterial infection
• CT chest: investigation of choice (replaced bronchography)

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4. TB ENDOBRONCHITIS AND TRACHEITIS

• Found in ~one-third of pulmonary TB patients
• Spread via direct implantation of M. tuberculosis, submucosal lymphatics, haematogenous spread, or from lymph nodes
• Symptoms: Cough, haemoptysis, breathlessness, sub-sternal soreness/constriction
• Healing complication: Bronchostenosis

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5. SPONTANEOUS PNEUMOTHORAX

• Reported in 5–15% of pulmonary TB patients
• In TB-endemic countries, TB is an important cause of pneumothorax
• Mechanism: Rupture of subpleural TB cavity into pleural space; rupture of open healed cavity; rupture of bleb or bulla secondary to fibrosis/lung destruction
• Infection of pleural cavity → pyopneumothorax

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6. CALCIFICATION

• A feature of healed primary TB; may be microscopic or macroscopic
• Usually innocuous — discrete radio-opaque shadows (parenchymal) or sheet-like (pleural)
• Complications of calcification:
  • Detachment → erosion through bronchial wall/blood vessel → massive haemoptysis
  • Broncholiths/pneumoliths — patient coughs out calcified stones
  • Extensive calcification → respiratory failure or chronic cor-pulmonale

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7. "OPEN-NEGATIVE" SYNDROME

• Thin-walled cavities with epithelialisation extending from bronchioles to inner lining of cavity ("isoniazid cavities" — also seen with other anti-TB drugs)
• Complete epithelialisation prevents collapse/fibrosis → cavity remains but is bacteriologically inactive
• Radiologically: "ring shadows" with thin walls
• Hazards: Secondary infection, fungal ball formation, scar carcinoma, spontaneous pneumothorax, loss of effective lung volume

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8. SCAR CARCINOMA

• Development of lung cancer associated with old TB scars
• TB confers an 11-fold higher incidence of lung cancer vs. non-TB subjects; independent of smoking (RR 1.76–1.90)
• Proposed mechanisms: Impaired ventilation → ↑ CO₂ → hyperplasia of pulmonary neuroendocrine cells → autocrine growth factors → malignant transformation
• Most common histopathological type: NSCLC (especially adenocarcinoma)
• Old TB lesion = independent predictor of poor survival in squamous cell carcinoma (HR 1.72)
• Co-existing COPD further increases risk

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9. PULMONARY FUNCTION CHANGES

• Obstructive airways disease: 30–60% of TB cases (distinct from chronic bronchitis)
• Restrictive defect: Due to diffuse parenchymal fibrosis, pleural effusion, pleural thickening, fibrothorax
• Mixed pattern most common
• Post-MDR-TB: 96% have abnormal PFTs; 66% mixed, 19% restrictive, 11% obstructive
• Residual disability common even after successful treatment

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10. CHRONIC RESPIRATORY FAILURE

• Develops due to extensive destruction of pulmonary parenchyma → V/Q mismatch
• Associated pleural thickening/fibrothorax → thoracic wall malfunction → pump failure
• Atrophy/disuse of respiratory muscles
• Results in tachypnoea, hypoxia, hypercapnia
• Both Type I (hypoxaemic) and Type II (hypercapnic) respiratory failure can occur

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11. PULMONARY HYPERTENSION AND CHRONIC COR-PULMONALE

• Occlusion/destruction of vascular bed → ↓ cross-sectional area of pulmonary circulation (must be reduced >50% before resting PAP changes)
• Vasculitis and endarteritis → ↓ pulmonary vascular bed
• Hypoxia, acidosis with hypercapnia, polycythaemia (less relevant in malnourished/anaemic patients in developing countries)
• Normal mean PAP: 13–14 mmHg; Pulmonary hypertension: >20 mmHg

• Leg oedema, atypical chest pain, exertional dyspnoea, exercise-induced cyanosis, excessive daytime sleepiness
• Distended neck veins, peripheral oedema, cyanosis
• Accentuated pulmonic component of S2 (earliest sign of pulmonary hypertension)
• RV S3 gallop (epigastric)
• With advanced PAH: diastolic murmur of pulmonary regurgitation, pansystolic murmur of tricuspid regurgitation (accentuates on inspiration)

• CXR: Enlarged RA/RV; prominent main pulmonary arteries (right descending PA >16 mm, left >18 mm); "pruning" of peripheral vessels
• ECG: P pulmonale, S1Q3 or S1-S2-S3 pattern, right axis deviation, R:S ratio in V6 ≤1.0, rSR' in right precordial leads, dominant R or R' in V1/V3R + inverted T waves
• Echocardiography (Doppler/2D TTE): Non-invasive monitoring of PAP and RV function

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12. SECONDARY AMYLOIDOSIS

• Characterised by deposition of extracellular eosinophilic protein (amyloid A) in various organs
• Pathogenesis: Cytokines (IL-1, IL-6, TNF-α) during TB inflammation stimulate hepatic synthesis of serum amyloid A precursor
• Incidence of renal amyloidosis: 8–33% in TB
• TB is the most common cause of secondary amyloidosis in Indian patients (59.1% of cases); pulmonary TB leading cause (81.6%)
• Interval from disease onset to amyloidosis: 6 months to 43 years (mean ~6.9 years; >5 years in 67%)
• Can occur even in adequately treated TB patients
• Diagnosis: Abdominal fat pad biopsy, rectal/mucosal/liver/kidney biopsy

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13. CHRONIC EMPYEMA, BRONCHOPLEURAL FISTULA, FIBROTHORAX/DESTROYED LUNG

• Occur in chronic TB; can persist even after bacteriological cure
• Cause significant morbidity, repeated infections by non-mycobacterial organisms
• Complications: frozen shoulder, protein loss, physical/respiratory disability
• Destroyed lung/fibrothorax: All three components (parenchyma, bronchi, pleura) involved; lung shrunken and fibrosed; mediastinum pulled to same side. Features: cavities, crepitations, recurrent infections, haemoptysis
• Advanced stage → respiratory failure and cor-pulmonale
• Management: Often requires surgical intervention (lobectomy, pneumonectomy, thoracoplasty, chest tubes, muscle flap repair)

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14. TB LARYNGITIS

• Occurs in 4–40% of pulmonary TB cases; incidence ↑ with extensive/cavitary disease
• Spread: Direct implantation or via lymphatics/blood vessels
• Symptoms: Sore throat, dry hacking cough, hoarseness of voice
• Laryngoscopy: Ulcer, granuloma, paresis/paralysis, destruction of cords, stenosis; vocal cords, arytenoids, and inter-arytenoid space most commonly affected
• Sputum usually positive for M. tuberculosis

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15. NONTUBERCULOUS MYCOBACTERIAL (NTM) DISEASE

• Pulmonary NTM disease is common in patients with past pulmonary TB (especially M. avium-intracellulare)
• Colonisation vs. active disease must be differentiated
• M. avium-intracellulare infection also associated with bronchiectasis in apparently healthy individuals or those with emphysema

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Quick Summary for Exam

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Haematological Manifestations of Tuberculosis

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Overview (Table 33.1)

• Haematological changes occur in both focal and disseminated TB; more frequent and profound in disseminated TB
• Usually reversible with anti-TB treatment
• May be a direct effect of infection OR a consequence of anti-TB drugs

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1. ANAEMIA

Morphology

• Predominantly normocytic, normochromic → anaemia of chronic disease
• Less commonly microcytic or macrocytic

Pathogenesis — Multifactorial (Table 33.2)

Key Facts

• Ferritin is unreliable in TB (elevated as acute-phase reactant); cut-off of 30 µg/L correctly diagnoses 88% of iron deficiency vs. 61% at 10 µg/L
• RDW is elevated in untreated anaemic TB patients; normalises with therapy
• 81% of pulmonary TB patients have increased iron stores (decreased release + suppressed erythropoiesis)
• Anaemia at TB diagnosis = poor prognosis, 4-fold increased risk of TB recurrence, >2-fold increased risk of death (iron deficiency anaemia)
• Anti-TB treatment alone (without iron supplementation) normalises plasma iron, TIBC, and ferritin

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2. LEUCOCYTE CHANGES

Leucocytosis

• Mild leucocytosis with left shift (increased myelocytes/metamyelocytes) is the most common finding — seen in 6%–22% of patients
• Pulmonary TB more frequently causes leucocytosis
• Advanced TB → higher WBC counts
• Leukaemoid reaction can occur, especially in disseminated TB

Leucopenia

• Mild leucopenia (<4 × 10⁹/L) in 1.5%–4% of pulmonary TB
• Leucopenia and neutropenia significantly higher in disseminated TB (10%–30% with miliary TB)
• Mechanisms of neutropenia: hypersplenism, increased neutrophil demand, excessive margination, cell-mediated autoimmune mechanisms

Lymphocyte Changes

• Lymphopenia more common than lymphocytosis in pulmonary TB
• CD4+ T-lymphocyte count decreased in up to 15% of patients (more common in disseminated/miliary TB)
• Lymphopenia reflects continued recruitment of CD4+ cells to granuloma sites
• Count returns to normal with effective therapy
• Recent infection → peripheral blood lymphocytosis (both CD4+ and CD8+); pleural and ascitic fluid contains predominantly CD4+ T-lymphocytes with inverted CD45RA:CD45RO ratio

Pelger-Huet Anomaly

• Acquired Pelger-Huet anomaly described in TB — bilobed nucleus joined by thin strand, spectacle-like appearance (acquired hypo-segmentation)

Monocyte Changes

• Monocytopenia in up to 50% of patients; may correlate with disease severity
• Monocytosis also described

Basophilia

• Reported in disseminated TB

Eosinophilia

• Reported in disseminated TB
• Hypereosinophilic syndrome with organ damage also reported

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3. PLATELET ABNORMALITIES

Thrombocytosis

• Mild thrombocytosis is common in pulmonary TB — acute-phase reaction driven by IL-6 which stimulates megakaryopoiesis
• IL-6 levels correlate with AFB positivity and reactive thrombocytosis

Thrombocytopenia

• More common in disseminated TB — seen in 23%–43% of miliary TB patients
• Pathogenesis: immune-mediated — anti-platelet antibodies and platelet-associated IgG demonstrated
• Majority do not have significant bleeding
• Inverse correlation between platelet count and mean platelet volume
• Increased small platelets with shortened survival
• Thrombotic thrombocytopenic purpura (TTP) reported with lymph node and pulmonary TB — postulated mechanism: increased procoagulant activity of IL-1 on endothelial cells

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4. PANCYTOPENIA

• Infrequent — seen in only 3%–12% of cases
• Rare in pulmonary TB; may occur due to drug toxicity
• More often associated with:
  • Underlying haematological disease
  • Severe miliary/disseminated TB (splenomegaly + hypersplenism)
  • Haemophagocytosis
  • Marrow hypocellularity
• Splenomegaly in disseminated TB → hypersplenism → pancytopenia (may resolve with splenectomy)
• All haematological abnormalities including pancytopenia usually reverse with effective anti-TB therapy

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5. COAGULATION ABNORMALITIES

Disseminated Intravascular Coagulation (DIC)

• Reported in both disseminated and pulmonary TB; high mortality (~63% in one series)
• In a retrospective study of 833 culture-proven TB patients: 3.2% had TB-induced DIC; 25.9% had disseminated TB
• Coagulation profile: ↑ APTT, ↑ thrombin time, ↓ antithrombin III (AT-III) activity
• Early anti-TB treatment significantly improves survival

Deep Vein Thrombosis (DVT)

• Confirmed by venography in 3%–4% of pulmonary TB patients
• Transient protein S deficiency reported in TB with DVT
• In active pulmonary TB: ↑ fibrinogen, ↑ FDP, ↑ t-PA, ↑ PAI-1, ↓ AT-III → hypercoagulable state
• Factor VIII, fibrinogen levels normalize after treatment; fibrinogen rises during first 2 weeks of therapy then corrects within 12 weeks

Other Coagulation Abnormalities

• Acquired Factor V deficiency — variable bleeding; disappears with anti-TB treatment
• Platelet hyperaggregation — 88% of intestinal TB patients; related to elevated CRP
• Transient thrombasthenia reported in TB
• Acquired Factor XIII deficiency — associated with isoniazid (IgG antibodies modify Factor XIII antigenically → autoantibody production) → severe subcutaneous and retroperitoneal bleeding
• Bone marrow emboli reported in miliary TB
• Budd-Chiari syndrome — reported in hepatic TB
• Portal vein thrombosis — associated with abdominal TB

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6. BONE MARROW CHANGES (Table 33.3)

Granulomas

• TB granulomas show Langhans' giant cells + caseation necrosis in 60%–70%
• Caseation necrosis + AFB = diagnostic of TB
• Present in 50%–100% of miliary TB; usually absent in pulmonary TB
• In 6% of bone marrow biopsies with granulomas, TB is the cause
• AFB detectable in buffy coat (55%) and bone marrow (48.3%) in pulmonary TB patients
• PCR for Mtb in bone marrow aspirate — more sensitive than conventional culture

Diagnostic Value of Bone Marrow Examination

• In HIV-seropositive patients in high TB-prevalence countries: AFB demonstrated in 12.9% of bone marrow aspirates → bone marrow examination is a useful diagnostic tool

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7. HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) AND MACROPHAGE ACTIVATION SYNDROME (MAS)

Pathophysiology

• HLH is an under-recognised hyperinflammatory disorder characterised by:
  • Haemophagocytosis (activated macrophages engulf blood cells/precursors)
  • Cytokine storm
• TB is an important, treatable cause of secondary HLH — can be fatal if untreated

HLH-2004 Diagnostic Criteria (Table 33.4)

MAS (Macrophage Activation Syndrome)

• Now classified as a category of secondary HLH
• Clinical syndrome: pancytopenia + ↑ triglycerides + hypofibrinogenaemia + haemophagocytosis in BM/spleen/lymph nodes
• Associated lab abnormalities: hyperferritinaemia + elevated LDH
• TB-induced MAS/secondary HLH responds well to anti-TB treatment

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8. DRUG-INDUCED HAEMATOLOGICAL CHANGES (Table 33.5)

Anaemia

Leucocyte Changes

Thrombocytopenia

Coagulation

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9. HAEMATOLOGICAL MANIFESTATIONS IN HIV-TB CO-INFECTION

• Leucocytosis more common in extra-pulmonary TB without HIV; leucopenia more common in HIV
• Absolute lymphocyte count <1×10⁹/L: 80% of HIV-seropositive vs. 40% of HIV-seronegative TB patients
• ~60% have bone marrow granulomas (non-granulomatous reaction in overwhelming infection)
• Bone marrow granulomas in HIV-TB: areas of necrosis with many AFB; surrounding inflammation = polymorphonuclear cells + macrophages (unlike the usual lymphocytic component in HIV-negative TB)
• Anaemia predominantly due to anaemia of chronic disease (not iron deficiency) in HIV-TB
• High hepcidin concentrations in HIV-TB co-infection → strongly associated with disseminated disease, severe anaemia, poor prognosis
• Antiretroviral drugs (especially zidovudine) also cause haematological manifestations
• AFB demonstrated in 12.9% of bone marrow aspirates in HIV-positive patients in India → bone marrow examination is useful in high TB-prevalence settings

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Quick Summary Table for Exam