MILIARY TUBERCULOSIS — 15-Mark MD Exam Answer

DEFINITION

EPIDEMIOLOGY AND RISK FACTORS

• Accounts for ~1–2% of all TB cases but contributes disproportionately to TB mortality
• High-risk groups:
  • Children < 5 years (impaired cellular immunity)
  • Elderly
  • HIV-infected individuals (most important risk factor in modern era)
  • Immunocompromised: organ transplant recipients, haematological malignancies, lymphoma
  • Those on corticosteroids, anti-TNF agents, immunosuppressives
  • Alcohol use disorder, cirrhosis, end-stage renal disease
  • Pregnancy, malnutrition, diabetes mellitus, silicosis

PATHOGENESIS

1. Primary infection: M. tuberculosis inhaled → phagocytosed by alveolar macrophages → Ghon focus formed
2. Bacteraemia: organisms drain to regional lymph nodes → lympho-haematogenous dissemination → seeding of multiple organs (lungs, liver, spleen, bone marrow, CNS, kidneys, adrenals)
3. Failure of containment: when host cell-mediated immunity (CMI) is impaired, contained foci reactivate or primary infection progresses without control
4. Granuloma formation: in each seeded site, non-caseating or caseating granulomas form; in miliary disease these granulomas are tiny (< 2 mm) and uniform — the pathological hallmark
5. Two mechanisms of miliary TB:
   • Primary miliary TB: massive dissemination shortly after initial infection (common in infants/immunocompromised)
   • Reactivation miliary TB: reactivation of dormant foci with subsequent haematogenous spread (common in elderly/HIV)

PATHOLOGY

• Gross: Lungs and affected organs studded with tiny (1–3 mm) yellowish-white firm nodules, resembling millet seeds
• Histology: Multiple discrete epithelioid cell granulomas with Langhans giant cells; may show central caseation; acid-fast bacilli demonstrable on Ziehl-Neelsen (ZN) stain
• Organs involved: Lungs (most prominent), liver, spleen, bone marrow, meninges, adrenals, kidneys, choroid of eye

CLINICAL FEATURES

General / Constitutional

Respiratory

• Dry cough (may be minimal)
• Progressive dyspnoea
• ARDS in fulminant form

Specific Signs

• Hepatosplenomegaly (granulomatous infiltration)
• Lymphadenopathy (generalised)
• Choroidal tubercles on fundoscopy — PATHOGNOMONIC for miliary TB (seen in ~13–87% of cases; bilateral, yellowish-white lesions near disc)
• Cutaneous lesions (more common in HIV): papules/vesiculopapules (tuberculosis cutis miliaris disseminata or tuberculosis cutis acuta generalisata)
• Signs of meningeal irritation if TB meningitis supervenes

Complications

• TB meningitis (most serious; occurs in ~30% of miliary TB)
• ARDS (fulminant miliary TB)
• Disseminated intravascular coagulation (DIC)
• SIADH → hyponatraemia
• Adrenal insufficiency (bilateral adrenal involvement)
• Pancytopenia (bone marrow infiltration)

DIAGNOSIS

1. Chest X-Ray (CXR)

• Classic finding: diffuse bilateral micronodular (1–3 mm) shadows uniformly distributed throughout both lung fields — the "snowstorm" pattern
• May be absent in up to 50% of cases in early disease — do not exclude miliary TB on the basis of a normal CXR

(A) Chest radiograph showing diffuse bilateral micronodular disease; (B) Coronal CT chest showing extensive micronodular disease with peripheral consolidation — Goldman-Cecil Medicine

2. HRCT Chest

• More sensitive than plain CXR
• Shows random distribution of 1–3 mm nodules throughout both lungs (as opposed to perilymphatic or centrilobular in other conditions)

3. Sputum Smear & Culture

• AFB smear positive in only 20–40% of miliary TB cases
• M. tuberculosis culture remains the gold standard (6–8 weeks; BACTEC MGIT: 2–3 weeks)
• Bronchoscopy with BAL and transbronchial biopsy increases yield when sputum is inadequate

4. Tuberculin Skin Test (TST / Mantoux)

• Often negative (anergy) in miliary TB due to severe immunosuppression — do not use to exclude disease

5. IGRA (Interferon-γ Release Assay)

• More specific than TST but sensitivity similar; may yield indeterminate results in miliary TB
• A negative TST or IGRA does NOT exclude miliary TB

6. Blood Tests

• CBC: anaemia (normocytic/normochromic), leukopenia or leukocytosis, thrombocytopenia (if bone marrow involved)
• ESR elevated
• LFTs: elevated ALP, transaminases (hepatic granulomas)
• Serum Na⁺: hyponatraemia due to SIADH (common, especially if meningitis present)
• LDH elevated

7. Fundoscopy

• Choroidal tubercles — pathognomonic; bilateral, pale/yellow, discrete lesions adjacent to optic disc

8. Biopsy (Highest Diagnostic Yield in Difficult Cases)

• All biopsies show epithelioid granulomas with or without caseation; ZN stain for AFB

9. Lumbar Puncture

• Mandatory if meningism suspected
• CSF: lymphocytic pleocytosis, raised protein, low glucose (CSF:serum glucose < 0.5), AFB smear/culture

10. Nucleic Acid Amplification Tests (NAAT/PCR)

• GeneXpert MTB/RIF on sputum or BAL — detects M. tuberculosis DNA within 2 hours; also detects rifampicin resistance
• Mycobacterial PCR on biopsied tissue shortens time to diagnosis

DIFFERENTIAL DIAGNOSIS OF MILIARY PATTERN ON CXR

TREATMENT

Regimen (Same as Other Forms of Active TB)

• Standard TB: 4 months HR
• Miliary TB: 7–10 months total (extended due to severity)
• CNS/meningeal involvement: minimum 12 months total

Corticosteroids

• Indicated in: miliary TB with meningitis, ARDS, severe hypoxia, adrenal insufficiency, pericarditis
• Prednisolone 1–2 mg/kg/day × 4–6 weeks, then taper
• Reduces complications and mortality in TB meningitis

Pyridoxine (Vitamin B6)

• 10–25 mg/day with isoniazid to prevent peripheral neuropathy

Supportive Care

• Nutritional support
• Correction of hyponatraemia (fluid restriction for SIADH)
• Respiratory support (oxygen, mechanical ventilation in ARDS)
• Treatment of adrenal insufficiency with hydrocortisone

Key Principle

Initiate treatment immediately on clinical suspicion — do NOT wait for microbiological confirmation. Delay in treatment is the leading cause of the high mortality (~21%) in miliary TB.

PROGNOSIS

• Mortality: ~21% even in the antibiotic era (higher with delayed treatment, CNS involvement, ARDS, or DIC)
• With prompt treatment: good response expected in most immunocompetent patients
• HIV co-infection worsens prognosis
• Fulminant miliary TB with ARDS/DIC carries very high mortality

SUMMARY TABLE — MILIARY TB AT A GLANCE