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MILIARY TUBERCULOSIS

Definition

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Pathogenesis

Mechanism of Dissemination

1. Primary infection: M. tuberculosis is inhaled as droplet nuclei → deposited in alveoli → ingested by alveolar macrophages.
2. Containment failure: In immunocompetent hosts, a Ghon focus + caseous necrosis occurs. In susceptible individuals, the focus erodes into a blood vessel or lymphatic, releasing large numbers of bacilli.
3. Lymphohematogenous spread: Bacilli disseminate via the bloodstream → seed multiple organs simultaneously.
4. Granuloma formation: Each seeded focus develops into a discrete 1–3 mm granuloma ("millet seed" = milium).
5. Two major pathways:
   • Primary miliary TB: Progressive dissemination from a fresh primary complex (children, infants)
   • Post-primary (reactivation) miliary TB: Reactivation of a latent focus → erodes into a blood vessel → systemic spread (adults, immunocompromised)

Predisposing Factors (High-risk groups)

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Pathology

• Gross: Pinpoint yellow-white nodules (1–3 mm) scattered over organ surfaces (lung, liver, spleen, meninges)
• Histology: Epithelioid cell granuloma with central caseous necrosis, Langhans giant cells, surrounded by lymphocytes and fibroblasts
• Distribution in lungs: Random/hematogenous — nodules present in all zones uniformly (unlike post-primary TB which is upper-zone predominant)

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Clinical Features

Presentation (Three patterns)

Symptoms

• Constitutional (universal): Prolonged fever (high, persistent, unremitting), night sweats, anorexia, weight loss, fatigue
• Respiratory (50–70%): Dry cough, progressive dyspnea, tachypnea — can progress to ARDS
• Neurological (25–40%): Headache, vomiting, altered sensorium → TB meningitis (most dangerous complication)
• Abdominal (20–30%): Hepatomegaly, splenomegaly, abdominal pain, diarrhea
• Ocular (rare but pathognomonic): Choroidal tubercles (seen on fundoscopy) — bilateral, pale, discrete lesions near optic disc

Signs

• Fever (remittent/continuous)
• Hepatosplenomegaly
• Lymphadenopathy (peripheral)
• Choroidal tubercles on fundoscopy (pathognomonic — found in ~13%)
• Signs of meningism (neck rigidity, Kernig's sign) if TB meningitis present
• Crepitations on auscultation
• Skin: Papulonecrotic tuberculid, scrofuloderma (rarely)

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Investigations

1. Chest X-Ray (Key investigation)

• Classic pattern: Bilateral, symmetric, diffuse micronodular (1–3 mm) "snow-storm" or "millet-seed" pattern in all lung zones
• Nodules are uniform in size and distribution
• May be normal early in disease (first 2–3 weeks)
• Hilar/mediastinal lymphadenopathy may coexist

2. HRCT Chest (Gold standard imaging)

• Random micronodules (1–3 mm) with uniform distribution
• Nodules in relation to fissures, pleura, vessels (random distribution)
• Ground-glass opacities, interlobular septal thickening
• More sensitive than CXR; detects early disease

3. Sputum Examination

• AFB smear: Positive in only ~30% — often negative because lesions are hematogenous, not endobronchial
• Culture (Löwenstein-Jensen or MGIT liquid culture): Gold standard; takes 2–8 weeks
• Xpert MTB/RIF: Rapid molecular test, detects TB + rifampicin resistance in ~2 hours

4. Blood Investigations

• CBC: Leukopenia or leukocytosis; pancytopenia if bone marrow involved; anemia of chronic disease
• ESR: Markedly elevated
• LFTs: Elevated alkaline phosphatase, bilirubin (hepatic involvement)
• Hyponatremia: Due to SIADH (common)
• Hypoalbuminemia
• Serum ferritin: Markedly elevated in disseminated disease

5. Tuberculin Skin Test (Mantoux)

• Negative in 40–70% of miliary TB cases due to anergy (T-cell exhaustion/immunosuppression)
• A negative Mantoux does NOT exclude miliary TB

6. Interferon-Gamma Release Assays (IGRAs)

• QuantiFERON-TB Gold / T-SPOT.TB
• May be negative in active miliary TB due to immunosuppression
• Useful adjunct; does not differentiate latent from active TB

7. Bronchoalveolar Lavage (BAL)

• AFB smear + culture from BAL: Positive in 40–70%
• Transbronchial biopsy: Granuloma on histology is highly diagnostic

8. Biopsy (Most definitive diagnostic modality)

• Liver biopsy: Granulomas in ~80–90%; most accessible site
• Bone marrow biopsy: Granulomas; also reveals pancytopenia cause
• Lymph node biopsy (if lymphadenopathy present)
• Histology: Caseating/non-caseating epithelioid granulomas with Langhans giant cells + AFB on Ziehl-Neelsen stain

9. CSF Analysis (if CNS involvement suspected — always do LP)

10. Fundoscopy

• Choroidal tubercles: Bilateral, creamy-yellow, discrete lesions near optic disc — pathognomonic; seen in ~13%

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Diagnosis

1. Clinical suspicion (fever + constitutional symptoms + respiratory symptoms)
2. Classic CXR/HRCT findings (diffuse 1–3 mm nodules)
3. Bacteriological confirmation (AFB smear/culture/Xpert from any site)
4. Histological confirmation (caseating granuloma on biopsy)
5. Response to anti-TB therapy (therapeutic trial in doubtful cases)

• Confirmed: Culture/Xpert positive or histology positive
• Probable: Classic radiology + clinical features + positive TST/IGRA
• Possible: Clinical + radiological features without microbiological/histological proof

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Treatment

Anti-Tuberculosis Therapy (ATT)

Standard Regimen (WHO/RNTCP):

For miliary TB with TB meningitis involvement: total duration is 12 months

Drug Doses (Adult):

• Add Pyridoxine (Vitamin B6) 10–25 mg/day with Isoniazid to prevent peripheral neuropathy

Corticosteroids (Adjunct Therapy)

1. TB meningitis (Grade 1 evidence) — Dexamethasone 0.4 mg/kg/day tapered over 6–8 weeks
2. Miliary TB with ARDS — Prednisolone 1–2 mg/kg/day
3. Pericardial TB
4. Adrenal insufficiency (TB-related)

• Dose: Prednisolone 1–2 mg/kg/day × 4 weeks, then taper over 4–8 weeks

HIV-Coinfected Patients

• Start ATT immediately
• Start ART within 2–8 weeks of ATT (earlier in severe immunosuppression, CD4 <50)
• Use NNRTI-based ART (Efavirenz preferred); avoid Rifampicin-Protease Inhibitor combinations
• Monitor for IRIS (Immune Reconstitution Inflammatory Syndrome)

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Complications

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Prognosis

• Untreated: Nearly 100% fatal
• With treatment: Mortality ~15–20% in immunocompetent patients
• Poor prognostic factors:
  • HIV coinfection
  • TB meningitis / ARDS
  • Delayed diagnosis
  • Drug resistance (MDR-TB)
  • Very high bacillary load
  • Extremes of age
  • Organ failure at presentation
• Radiological resolution: Takes 3–6 months on treatment (as shown in imaging above)

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Differential Diagnosis of Miliary Pattern on CXR

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Summary Table for Quick Revision

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