Kala-azar (Visceral Leishmaniasis)

Introduction and Etiology

• Definition: Visceral Leishmaniasis (VL), known as Kala-azar (Black Sickness) in India due to characteristic hyperpigmentation, is a systemic protozoal disease caused by parasites of the Leishmania donovani complex.
• Causative Agent:
  • India/East Africa: Leishmania donovani.
  • Mediterranean/Middle East: Leishmania infantum.
  • New World (Americas): Leishmania infantum (formerly L. chagasi).
• Vector: Transmitted by the bite of the female phlebotomine sandfly. In India, the specific vector is Phlebotomus argentipes.
• Reservoir: In India, the disease is anthroponotic, meaning humans are the only known reservoir. In other regions (e.g., Mediterranean), it is a zoonosis with canine reservoirs.

Epidemiology

• Global Burden: Endemic in tropical/subtropical regions. India, Bangladesh, Nepal, Sudan, South Sudan, and Brazil account for the majority of cases.
• Indian Scenario: Endemic in Bihar, Jharkhand, West Bengal, and eastern Uttar Pradesh. Children account for approximately 50% of cases.
• Risk Factors: Poverty, malnutrition, poor housing (mud walls, cracks), and close proximity to livestock/vegetation where sandflies breed.

Pathogenesis

• Transmission: Promastigotes (flagellated form) are inoculated by the sandfly. They are engulfed by macrophages and transform into amastigotes (LD bodies).
• Dissemination: Amastigotes multiply within macrophages of the reticuloendothelial system, disseminating to the spleen, liver, bone marrow, and lymph nodes.
• Immune Response:
  • Th1 Response: Associated with protection/healing (IFN-gamma production).
  • Th2 Response: Associated with disease progression (IL-4, IL-10 production) and failure of macrophages to kill the parasite.

Clinical Features

• Incubation Period: Typically 2–6 months, but can range from 10 days to years.
• Onset: Usually insidious (chronic onset) in endemic areas; acute onset is rare.
• Cardinal Signs:
  • Fever: Prolonged, irregular, high-grade. A characteristic “double rise” (double quotidian) fever in 24 hours may be seen but is uncommon now.
  • Splenomegaly: Massive, firm, non-tender enlargement. Spleen enlarges rapidly (approx. 1 inch/month) and can cross the umbilicus.
  • Hepatomegaly: Moderate enlargement, usually soft to firm.
  • Wasting: Severe weight loss and emaciation despite a relatively preserved appetite (“starving amidst plenty”).
  • Hyperpigmentation: Darkening of skin on the face, hands, feet, and abdomen (hence “Kala-azar”).
• Other Findings:
  • Pallor (anemia).
  • Lymphadenopathy: Rare in Indian VL (<5%), but common in African VL.
  • Pedal edema/Ascites (in advanced disease).

Complications

• Severe anemia and cardiac failure.
• Secondary bacterial infections (pneumonia, sepsis).
• Bleeding diathesis (epistaxis, gingival bleeding).
• Post-Kala-azar Dermal Leishmaniasis (PKDL):
  • Occurs in 15–20% of Indian patients, often years after apparent cure.
  • Manifests as hypopigmented macules, papules, or nodules, primarily on the face and trunk.
  • Crucial epidemiologically as these patients serve as a reservoir for infection.

Laboratory Diagnosis

• Hematology: Pancytopenia is characteristic.
  • Anemia (normocytic normochromic).
  • Leukopenia (count <2,000–3,000/µL).
  • Thrombocytopenia.
  • Hypergammaglobulinemia with reversal of Albumin:Globulin ratio.
• Serology:
  • rK39 Dipstick Test: The diagnostic method of choice in field settings. It detects antibodies to the 39-amino acid repeat of L. chagasi. Sensitivity >90%, Specificity >90%. Note: It remains positive for years after cure, so it cannot diagnose relapse.
• Parasitology (Definitive Diagnosis):
  • Demonstration of LD bodies (Amastigotes): In stained smears of tissue aspirates.
  • Splenic Aspirate: Gold standard (Sensitivity >95%) but carries risk of hemorrhage.
  • Bone Marrow Aspirate: Safer but less sensitive (60–85%).
• Molecular Tests: PCR is highly sensitive but currently limited to research/tertiary settings.

Current Management

The management strategies focus on effective single-dose treatments to ensure compliance and eliminate the reservoir.

1. Supportive Therapy

• Correction of anemia (transfusions if necessary).
• Treatment of secondary bacterial infections.
• Nutritional rehabilitation.

2. Specific Antileishmanial Therapy

According to the National Vector Borne Disease Control Program (NVBDCP) and WHO guidelines for India:

• First-Line Treatment:

  • Liposomal Amphotericin B (L-AmB):
    • Dose: Single dose of 10 mg/kg IV given over 2 hours.
    • Efficacy: High cure rate (>90%), safe, and ensures 100% compliance.
    • Pregnancy: It is the drug of choice for pregnant women.

• Alternative Regimens (if L-AmB is unavailable or contraindicated):

  • Combination Therapy: Miltefosine (oral) + Paromomycin (IM) for 10 days.
  • Amphotericin B Deoxycholate: 1 mg/kg/day IV on alternate days for 15 doses (30 days). Reserved for limited settings due to toxicity (nephrotoxicity, infusion reactions).
  • Miltefosine:
    • First oral drug for VL.
    • Dose (Children 2–11 years): 2.5 mg/kg/day once daily for 28 days.
    • Dose (Children >12 years): Based on weight (<25 kg: 50 mg/day; 25–50 kg: 100 mg/day).
    • Contraindication: Strictly contraindicated in pregnancy (teratogenic).
  • Sodium Stibogluconate (SSG): Generally no longer used in India (Bihar) due to high rates of resistance (>60% failure rates).

3. Treatment of PKDL

Treatment is required to interrupt transmission. Regimens are prolonged compared to VL.

• Miltefosine: 100 mg/day (adults) or weight-based pediatric dose for 12 weeks.
• Liposomal Amphotericin B: 5 mg/kg/day, twice weekly for 3 weeks (Total dose 30 mg/kg).

4. Criteria for Cure

• Initial Cure: Absence of clinical signs/symptoms at the end of treatment.
• Definite Cure: Absence of relapse at 6 months follow-up.