Disseminated TB

1. Introduction and Definition

Disseminated tuberculosis refers to the involvement of two or more non-contiguous sites resulting from the lymphohematogenous spread of Mycobacterium tuberculosis. Miliary tuberculosis is a specific, severe form of disseminated TB characterized by the massive hematogenous seeding of tubercle bacilli, resulting in widespread, tiny (1–2 mm), millet-seed-sized granulomas in multiple organs, particularly the lungs, liver, spleen, and bone marrow.

Historically, the term "miliary" was coined by John Jacob Manget in 1700, likening the appearance of the pathological lesions to millet seeds. While lymphohematogenous spread occurs in almost all cases of primary infection (occult dissemination), "disseminated disease" implies a failure of the host immune response to contain this spread, leading to overt clinical illness.

2. Epidemiology and Risk Factors

Disseminated TB is most frequently seen in infants and young children (< 3 years of age) due to their immature cellular immunity. It usually occurs within 2 to 6 months of the initial primary infection.

Key Risk Factors:

1. Age: Infants (< 1 year) are at the highest risk.
2. Immunosuppression:
   • HIV Infection: HIV coinfection dramatically increases the risk of rapid dissemination and mortality.
   • Malnutrition: Severe Acute Malnutrition (SAM) compromises cell-mediated immunity.
   • Post-measles/Varicella: Anergy following viral infections can precipitate dissemination.
   • Primary Immunodeficiencies: Defects in the IL-12/IFN-gamma pathway.
   • Drugs: Prolonged steroid use or immunosuppressive therapy.
3. Lack of BCG Vaccination: BCG provides 50–80% protection against severe forms like miliary TB and meningitis.

3. Etiopathogenesis

The development of disseminated TB follows a specific sequence of events:

1. Primary Infection: Inhalation of droplet nuclei leads to a primary focus (Ghon focus) in the lung and regional lymphadenopathy.
2. Lymphohematogenous Spread: Bacilli drain via lymphatics to the venous circulation and eventually the arterial system.
   • Occult Spread: In most immunocompetent hosts, small numbers of bacilli seed distant organs (apices of lungs, kidneys, bones) but are contained by macrophages and T-cells (granuloma formation).
3. Massive Dissemination (Miliary TB): This occurs when:
   • A caseous lymph node or primary focus erodes directly into a blood vessel (e.g., pulmonary vein).
   • The host immune response (Cell-Mediated Immunity) fails to contain the initial bacteremia.
4. Pathology: The massive shower of bacilli lodges in the capillaries of various organs (lungs, liver, spleen, bone marrow, choroid). They incite a granulomatous reaction. In miliary TB, these lesions are of similar age and size.
   • Macroscopic: "Millet seed" nodules.
   • Microscopic: Epithelioid granulomas with Langhans giant cells and central caseation (may be absent in anergic/HIV patients).

4. Clinical Manifestations

The clinical presentation is protean ("the great imitator"). It can range from an acute fulminant sepsis-like illness to a prolonged fever of unknown origin (FUO).

A. Systemic Symptoms

• Fever: Present in almost all cases. Often high-grade, spiking, or remittent.
• Constitutional: Anorexia, weight loss (or failure to thrive), night sweats, and malaise are prominent.
• Onset: Usually insidious, but can be explosive/acute in infants or HIV-infected children.

B. Respiratory System

• Signs may be surprisingly mild despite extensive radiological disease.
• Symptoms: Cough (often mild initially), tachypnea, and dyspnea.
• Signs: Fine crepitations may be heard but are often absent. Wheezing may occur.
• Severe Complications: In advanced cases, alveolar-capillary block can lead to frank respiratory distress, cyanosis, and hypoxia (resembling ARDS). Air-leak syndromes (pneumothorax, pneumomediastinum) are recognized complications.

C. Abdominal Findings

• Hepatosplenomegaly: Very common (50% of cases).
• Ascites: May be present if the peritoneum is seeded.
• Lymphadenopathy: Generalized superficial or deep abdominal nodes.

D. Specific Organ Involvement (Signs)

1. Choroid Tubercles:
   • Found in 13–87% of patients.
   • Appearance: Bilateral, multiple, yellowish-white, raised nodules (0.5–2 mm) near the optic disc.
   • Significance: Pathognomonic for miliary TB; detection usually implies hematogenous dissemination.
2. CNS Involvement:
   • Meningitis (TBM) or Tuberculomas occur in 20–40% of miliary TB cases.
   • Always look for neck stiffness, irritability, or bulging fontanelle.
3. Skin:
   • Papulonecrotic Tuberculids: Tiny, crusted papules, often on the trunk.
   • Purpura: Thrombocytopenia or vasculitis may cause purpuric spots.

5. Diagnostic Approach

Diagnosis requires a high index of suspicion as bacteriologic confirmation is difficult (paucibacillary).

A. Radiological Investigations

1. Chest X-ray (CXR):
   • Hallmark: Miliary mottling—diffuse, uniformly distributed, discrete, tiny (1–2 mm) nodular opacities ("snowstorm appearance") throughout both lung fields.
   • Note: It may take 1–3 weeks after symptom onset for miliary shadows to appear on CXR.
2. High-Resolution CT (HRCT) Chest:
   • More sensitive than CXR.
   • Shows randomly distributed micronodules, interlobular septal thickening, and "tree-in-bud" appearance.
3. Neuroimaging (CT/MRI):
   • Mandatory in all miliary TB cases to rule out silent TBM or tuberculomas.

B. Microbiological Confirmation

1. Respiratory Specimens: Gastric Aspirate (GA) or Induced Sputum (IS) should be collected for Upfront NAAT (CBNAAT/TrueNat) and Culture (MGIT).
   • Yield is relatively higher in miliary TB compared to primary complex due to higher bacillary load in the lungs, but still variable.
2. Blood Culture: In HIV-coinfected children or severe dissemination, M. tuberculosis can sometimes be isolated from blood (BACTEC/lysis-centrifugation).
3. Invasive Sampling (High Yield):
   • Bone Marrow Aspiration/Biopsy: Useful in cases with hematological abnormalities. Culture has a good yield.
   • Liver Biopsy: Granulomas can be demonstrated in liver tissue; high diagnostic yield if hepatomegaly is present.
   • CSF Analysis: Essential to rule out meningitis (lymphocytic pleocytosis, high protein, low sugar).

C. Supportive Investigations

1. Tuberculin Skin Test (TST):
   • Often Negative (Anergy): Up to 40–50% of children with miliary TB have a non-reactive Mantoux test due to overwhelming infection and T-cell depletion. A positive test supports the diagnosis, but a negative test does not exclude it.
2. Hematology:
   • Anemia (normocytic or aplastic).
   • Leukopenia or Leukemoid reaction (resembling leukemia).
   • Thrombocytopenia or Pancytopenia (bone marrow infiltration).
   • ESR is usually elevated.
3. Biochemistry: Hyponatremia (SIADH) is common. Liver enzymes may be elevated (hepatitis).
4. Eye Examination: Dilated fundoscopy to look for choroidal tubercles.

6. Differential Diagnosis

1. Enteric Fever: Prolonged fever, hepatosplenomegaly. (Differentiated by Widal, blood culture).
2. Disseminated Malignancy: Leukemia, Lymphoma, Neuroblastoma (metastatic).
3. Fungal Infections: Histoplasmosis (similar miliary shadows and hepatosplenomegaly).
4. Langerhans Cell Histiocytosis (LCH): Miliary shadows, hepatosplenomegaly, skin rash.
5. Viral Pneumonias: Severe viral pneumonia can mimic miliary shadows.

7. Management

Management involves antitubercular therapy, corticosteroids for specific indications, and supportive care.

A. Antitubercular Chemotherapy (NTEP 2022 Guidelines)

Miliary TB is classified under Severe Extrapulmonary TB.

• Regimen: 2 HRZE + 4 HRE
  • Intensive Phase (2 months): Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E).
  • Continuation Phase (4 months): Isoniazid (H), Rifampicin (R), Ethambutol (E).
  • Total Duration: 6 months.
• Note on Duration: While standard guidelines recommend 6 months, if there is associated meningitis, bone/joint involvement, or slow response, the treatment is extended to 12 months (2 HRZE + 10 HRE). Many experts prefer 9-12 months for disseminated disease in infants.
• Dosages (Daily):
  • Isoniazid: 10 (7–15) mg/kg
  • Rifampicin: 15 (10–20) mg/kg
  • Pyrazinamide: 35 (30–40) mg/kg
  • Ethambutol: 20 (15–25) mg/kg

B. Corticosteroids

Steroids are indicated in disseminated TB in specific situations:

1. Associated Tuberculous Meningitis: To reduce cerebral edema and vasculitis.
2. Severe Respiratory Distress: Alveolocapillary block with hypoxia.
3. Pericardial Effusion.

• Dose: Prednisolone 1–2 mg/kg/day for 4 weeks, then tapered over 4–6 weeks.

C. Supportive Care

• Nutrition: Management of severe malnutrition.
• Oxygen: For hypoxia due to miliary pneumonia.
• Hyponatremia: Fluid restriction or correction depending on cause (SIADH vs Cerebral Salt Wasting).

8. Complications and Prognosis

• Mortality: Historically 100% without treatment. With timely treatment, mortality is reduced but remains significant, especially in infants and HIV-positive children.
• Complications:
  • CNS: Hydrocephalus, infarction, neurological deficits (major cause of morbidity).
  • Respiratory: Pneumothorax, chronic lung disease (fibrosis).
  • IRIS: Immune Reconstitution Inflammatory Syndrome in HIV/non-HIV patients upon starting treatment (worsening of fever/nodes).

9. Prevention

1. BCG Vaccination: Highly effective in preventing hematogenous dissemination (miliary and meningeal TB) in young children.
2. TB Preventive Treatment (TPT): Contact tracing of adults with pulmonary TB. All child contacts <5 years (and older TBI-positive children) should receive TPT (Isoniazid or Isoniazid+Rifapentine) to prevent progression from infection to disseminated disease.