Complications of tb full details for md exam answer from this pdf
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python3 << 'EOF' import pdfplumber pdf_path = "/home/daytona/workspace/attachments/52f00355-4cca-44c9-a0a1-849f67499752/Sharma mohan latest_compressed-compressed (1).pdf" # Look at TOC pages (usually pages 20-35) with pdfplumber.open(pdf_path) as pdf: for i in range(20, 40): try: text = pdf.pages[i].extract_text() or "" print(f"\n=== PAGE {i+1} ===") print(text[:800]) except Exception as e: print(f"P{i+1}: ERROR {e}") EOF
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python3 << 'EOF' import pdfplumber pdf_path = "/home/daytona/workspace/attachments/52f00355-4cca-44c9-a0a1-849f67499752/Sharma mohan latest_compressed-compressed (1).pdf" # The book page 419 - the PDF has ~20 pages of front matter before ch1 starts # Chapter 1 starts at PDF page 26 (book page 1), so offset = 25 # Book page 419 = PDF page ~444 # Let's search around pages 440-460 with pdfplumber.open(pdf_path) as pdf: for i in range(438, 470): try: text = pdf.pages[i].extract_text() or "" if 'complication' in text.lower() or '419' in text or '420' in text or '421' in text: print(f"\n=== PDF PAGE {i+1} ===") print(text[:300]) except Exception as e: print(f"P{i+1}: ERROR {e}") EOF
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python3 << 'EOF' import pdfplumber pdf_path = "/home/daytona/workspace/attachments/52f00355-4cca-44c9-a0a1-849f67499752/Sharma mohan latest_compressed-compressed (1).pdf" with pdfplumber.open(pdf_path) as pdf: for i in range(443, 457): # PDF pages 444-457 (0-indexed: 443-456) try: text = pdf.pages[i].extract_text() or "" print(f"\n{'='*60}") print(f"PDF PAGE {i+1}") print('='*60) print(text) except Exception as e: print(f"P{i+1}: ERROR {e}") EOF
I now have the complete Chapter 31 text. Let me compile this into a comprehensive, well-structured MD exam answer.
Complications of Pulmonary Tuberculosis
(Chapter 31 — Sharma & Mohan, Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases, 3rd ed.)
Classification (Table 31.1)
| Category | Complication |
|---|---|
| Local – Pulmonary | Haemoptysis, Post-TB bronchiectasis, Aspergilloma (fungal ball), TB endobronchitis & tracheitis, Scar carcinoma, Disseminated calcification, Pulmonary function changes/obstructive airways disease, Secondary pyogenic infections, NTM disease |
| Local – Pleural | Spontaneous pneumothorax, Pleural thickening (fibrothorax), Acute and chronic empyema |
| Systemic | Secondary amyloidosis, Chronic respiratory failure (Type I & II), Pulmonary hypertension, Chronic cor-pulmonale |
1. HAEMOPTYSIS
Incidence: 30–35% of pulmonary TB patients.
Key point: Occurrence of haemoptysis does not imply active TB. It may occur as the initial manifestation, during treatment, or even after apparent cure.
Pathogenesis (Table 31.2):
- 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
Management:
- 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
2. ASPERGILLOMA (MYCETOMA / "FUNGAL BALL")
A mass of fungal hyphal material growing in a lung cavity. Most commonly caused by Aspergillus fumigatus.
Incidence: 11–17% of healed TB cavities (≥2.5 cm diameter) develop aspergilloma.
Natural history: Variable — may remain stable, increase in size, or spontaneously resolve (~10% of cases).
Clinical features:
- 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%
Poor prognostic factors: Severe underlying disease, increasing lesion size, immunocompromised state, corticosteroid therapy, increasing Aspergillus-specific IgG, recurrent large-volume haemoptysis, underlying sarcoidosis or HIV infection.
Diagnosis:
- 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
Treatment:
- 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
3. POST-TB BRONCHIECTASIS
Pathogenesis (multi-factorial):
- Caseation necrosis + granulomatous inflammation in bronchial walls → direct extension of TB
- Scarring → bronchial stenosis → secondary bacterial infection → retention of secretions → bronchial wall destruction/dilatation
- Compression of bronchial lumen by enlarged lymph nodes (especially in children)
- Penetration by calcified TB lymph node → broncholith formation
- Healing/healed TB cavities re-lined with ciliated columnar epithelium
Features:
- 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)
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
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
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
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
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
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
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
11. PULMONARY HYPERTENSION AND CHRONIC COR-PULMONALE
Definition: Cor-pulmonale = enlargement (dilatation ± hypertrophy) of the right ventricle due to increased RV afterload from intrinsic pulmonary disease (excluding left heart failure/congenital heart disease).
Pathophysiology:
- 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
Clinical features:
- 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)
Investigations:
- 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
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
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)
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
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
Quick Summary for Exam
| Complication | Key Point |
|---|---|
| Haemoptysis | 30–35%; Rasmussen's aneurysm; BAE first-line for massive |
| Aspergilloma | Air crescent sign; serum precipitins 100%; treat only if symptomatic |
| Post-TB bronchiectasis | Upper lobe "dry" bronchiectasis; multifactorial pathogenesis |
| Spontaneous pneumothorax | 5–15%; rupture of subpleural cavity or bulla |
| Scar carcinoma | 11× higher lung cancer risk; independent of smoking |
| Calcification | Healed TB; broncholiths; massive haemoptysis if eroded |
| Open-negative syndrome | Thin-walled epithelialised cavity; radiological ring shadow |
| Cor-pulmonale | PAP >20 mmHg; ECG: P pulmonale, RAD, rSR'; echo monitoring |
| Amyloidosis | TB = most common cause of 2° amyloidosis in India; renal amyloid 8–33% |
| Respiratory failure | V/Q mismatch; type I & II; pump failure from fibrothorax |
| Fibrothorax/Destroyed lung | All three compartments; surgery often needed |
Hematology complications of tb full details for md exam answer from this pdf
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python3 << 'EOF' import pdfplumber pdf_path = "/home/daytona/workspace/attachments/52f00355-4cca-44c9-a0a1-849f67499752/Sharma mohan latest_compressed-compressed (1).pdf" with pdfplumber.open(pdf_path) as pdf: for i in range(466, 478): # PDF pages 467-478 try: text = pdf.pages[i].extract_text() or "" print(f"\n{'='*60}") print(f"PDF PAGE {i+1}") print('='*60) print(text) except Exception as e: print(f"P{i+1}: ERROR {e}") EOF
I now have the complete Chapter 33 text. Let me compile the comprehensive answer.
Haematological Manifestations of Tuberculosis
(Chapter 33 — Sharma & Mohan, Textbook of Tuberculosis and Nontuberculous Mycobacterial Diseases, 3rd ed., by Shaji Kumar)
Overview (Table 33.1)
| Category | Findings |
|---|---|
| Anaemia | Anaemia of chronic disease, iron deficiency, haemolytic, sideroblastic, PRCA, aplastic, megaloblastic |
| Leucocyte changes | Leucopenia/leucocytosis, lymphocytopenia, neutropenia/neutrophilia, monocytopenia/monocytosis, leukaemoid reaction, Pelger-Huet anomaly |
| Platelet changes | Thrombocytopenia or thrombocytosis, TTP |
| Pancytopenia | Hypersplenism, haemophagocytosis, marrow aplasia |
| Coagulation | DIC, DVT, Factor V/XIII deficiency, platelet hyperaggregation, protein C/S deficiency |
| Bone marrow | Granulomas, haemophagocytosis, necrosis, myelofibrosis |
| HLH/MAS | Secondary haemophagocytic lymphohistiocytosis |
General principles:
- 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
1. ANAEMIA
Most common haematological manifestation — seen in 16%–94% of pulmonary or extra-pulmonary TB patients.
Morphology
- Predominantly normocytic, normochromic → anaemia of chronic disease
- Less commonly microcytic or macrocytic
Pathogenesis — Multifactorial (Table 33.2)
| Cause | Mechanism |
|---|---|
| Anaemia of chronic disease | TNF-α from monocytes → blunted erythropoietin response + decreased utilisation of marrow iron stores |
| Iron deficiency | Low serum iron, low TIBC; however, serum ferritin is unreliable (elevated as acute phase reactant) |
| Hepcidin role | Hepcidin (acute-phase peptide, central regulator of iron homeostasis) concentrations strongly associated with mycobacterial burden, disseminated TB, and anaemia severity |
| Nutritional deficiency | Folate, B12 deficiency (especially in vegetarians/malnourished) |
| Chronic blood loss | GI TB, haemoptysis |
| Haemolytic anaemia | Autoimmune haemolytic anaemia (AIHA) — both pulmonary & disseminated TB; disappears with treatment |
| Myelophthisic anaemia | Bone marrow infiltration by granulomas |
| Hypoplastic/aplastic anaemia | Rare; associated with severe disseminated TB |
| Pure red cell aplasia (PRCA) | Reported in children with TB |
| Sideroblastic anaemia | Ring sideroblasts in marrow; responds to pyridoxine |
| Megaloblastic | Less frequent; usually not related to B12/folate deficiency |
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
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
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
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
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
6. BONE MARROW CHANGES (Table 33.3)
| Finding | Comment |
|---|---|
| Myeloid hyperplasia | Most common; normal to increased cellularity |
| Plasmacytosis | Reactive; more common in pulmonary TB than miliary TB |
| Megaloblastoid maturation | Up to 60% of disseminated TB; not due to B12/folate deficiency |
| Hypoplasia/Aplasia | Rare |
| Haemophagocytosis | More often in disseminated TB; disappears with treatment |
| Caseating/non-caseating granulomas | Present in 50%–100% of miliary TB; absent in pulmonary TB |
| Bone marrow necrosis | Described in disseminated TB |
| Myelofibrosis | Near granulomas; increased reticulin fibres |
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
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)
Diagnosis requires molecular diagnosis of primary HLH OR ≥5 of 8 criteria:
| Criterion | Threshold |
|---|---|
| Fever | Present |
| Splenomegaly | Present |
| Cytopenias (≥2 cell lines) | Hb <9 g/dL, Plt <100×10⁹/L, Neut <1.0×10⁹/L |
| Hypertriglyceridaemia | Fasting TG ≥265 mg/dL |
| Hypofibrinogenaemia | Fibrinogen ≤1.5 g/L |
| Haemophagocytosis in BM/spleen/lymph nodes | Present |
| Low/absent NK cell activity | By local laboratory reference |
| Ferritin | ≥500 μg/L |
| Soluble CD25 (IL-2 receptor) | ≥2400 U/mL |
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
8. DRUG-INDUCED HAEMATOLOGICAL CHANGES (Table 33.5)
Anaemia
| Drug | Type of Anaemia |
|---|---|
| Isoniazid (INH) | Sideroblastic (ring sideroblasts; responds to pyridoxine), PRCA (immune-mediated; reverses on withdrawal), drug-induced AIHA |
| Rifampicin | AIHA (flu-like prodrome → intravascular haemolysis; direct Coombs' positive) |
| Streptomycin | AIHA |
| PAS | AIHA, megaloblastic anaemia (B12 malabsorption), hypothrombinemia |
| Pyrazinamide | Sideroblastic anaemia (rare) |
| BCG (disseminated) | Aplastic anaemia |
Leucocyte Changes
| Drug | Effect |
|---|---|
| INH, Rifampicin, PAS | Leucopenia, agranulocytosis, aplastic anaemia |
| PAS | Atypical lymphocytosis (simulating infectious mononucleosis) |
| Rifampicin | Eosinophilia |
| Ethambutol | Leucopenia (rare); eosinophilia |
| Anti-TB drugs (general) | Drug-induced leucopenia more common in elderly patients |
Thrombocytopenia
| Drug | Mechanism |
|---|---|
| Rifampicin | Immune-mediated — antibodies against glycoprotein Ib/IX complex; both IgG and IgM types; more frequent with twice-weekly 900 mg dose (resolves with dose reduction to 150–300 mg/day) |
| Rifampicin | TTP (rare) |
| INH | Thrombocytopenia |
| Pyrazinamide | Thrombocytopenia |
| Streptomycin, Ethambutol, PAS | Thrombocytopenia |
Coagulation
| Drug | Effect |
|---|---|
| INH + Rifampicin | DIC (rare) |
| INH | Acquired Factor XIII deficiency (IgG inhibitors) → subcutaneous/retroperitoneal bleeding |
| PAS | Hypothrombinemia |
| Rifampicin | ↑ DVT risk (cytochrome P-450 enzyme induction → altered balance of anticoagulant/coagulant proteins → hypercoagulability) |
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
Quick Summary Table for Exam
| Manifestation | Key Fact |
|---|---|
| Anaemia | 16–94%; normocytic normochromic; ACD most common; hepcidin central mediator |
| Leucocytosis | 6–22%; left shift; leukaemoid reaction possible |
| Leucopenia | More in disseminated; 10–30% miliary TB |
| CD4+ lymphopenia | Up to 15%; returns to normal with therapy |
| Pelger-Huet anomaly | Acquired; bilobed spectacle-shaped nucleus |
| Thrombocytosis | IL-6 driven; acute-phase reaction; pulmonary TB |
| Thrombocytopenia | 23–43% miliary TB; immune-mediated; anti-platelet IgG |
| TTP | IL-1 on endothelial cells; also with rifampicin |
| Pancytopenia | 3–12%; hypersplenism/haemophagocytosis/marrow aplasia |
| DIC | 3.2% of culture-proven TB; 63% mortality; early anti-TB Rx improves survival |
| DVT | 3–4%; protein S deficiency; hypercoagulable state |
| Bone marrow granulomas | 50–100% miliary TB; Langhans' giant cells + caseation = diagnostic |
| HLH/MAS | Secondary HLH; ≥5 HLH-2004 criteria; treat underlying TB |
| INH sideroblastic anaemia | Ring sideroblasts; responds to pyridoxine |
| Rifampicin AIHA | Flu-like prodrome; intravascular haemolysis; Coombs' positive |
| Rifampicin thrombocytopenia | Anti-GP Ib/IX IgG/IgM; immune-mediated |
| INH Factor XIII inhibitor | IgG autoantibody; severe subcutaneous/retroperitoneal bleeding |
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