Visceral leishmaniasis (VL) is a potentially fatal systemic protozoan infection caused by the Leishmania donovani complex, transmitted by female phlebotomine sandflies, and characterized by persistent fever, hepatosplenomegaly, pancytopenia, and wasting. [1-3] Without treatment, mortality exceeds 95%. [4]
1. History
- Travel/residence history is paramount — endemic areas include India, East Africa (Ethiopia, Sudan, South Sudan), Brazil, and the Mediterranean. Latent infection can reactivate years to decades after exposure. [1][3][5]
- Onset is usually subacute or chronic (weeks to months), but can be acute. [3][5]
- Characterize fever: typically persistent, irregular, or remittent with twice-daily spikes; duration >2 weeks unresponsive to antibiotics. [5-6]
- Ask about weight loss, fatigue, malaise, loss of appetite, abdominal distension (from organomegaly). [5][7]
- In children: diarrhea, cough, abdominal pain, growth retardation. [7]
- Incubation period: 2 weeks to 8 months, but can be much longer. [3][8]
- Exposure routes: sandfly bite, needle sharing, blood transfusion, organ transplant, congenital/perinatal transmission (rare). [5][9]
2. Alarm Features
- Massive splenomegaly with risk of splenic rupture
- Severe pancytopenia — bleeding (epistaxis, petechiae), severe anemia (Hb <10 g/dL), neutropenic sepsis [6][9]
- Hemophagocytic lymphohistiocytosis (HLH) — VL can trigger or mimic HLH; consider in patients with hyperferritinemia, hypertriglyceridemia, and cytopenias [10-11]
- Secondary bacterial infections — a major cause of death in untreated VL [7]
- Cachexia and severe malnutrition — associated with high parasite burden [3]
- HIV coinfection — atypical presentations, lower cure rates, higher relapse and mortality [9]
- Multi-organ failure in advanced untreated disease [8]
3. Medications
First-line treatment
- Liposomal amphotericin B (AmBisome) — FDA-approved for VL [5][12]
- Immunocompetent: 3 mg/kg/day IV on days 1–5, then day 14 and day 21 (FDA-approved regimen); or 10 mg/kg single dose (WHO recommendation for Indian subcontinent) [4-5][13]
- HIV-coinfected: Total dose 20–60 mg/kg via daily or interrupted schedule (e.g., 4 mg/kg on days 1–5, 10, 17, 24, 31, 38) [9]
Oral option
- Miltefosine (Impavido) — FDA-approved for L. donovani VL in patients ≥12 years, ≥30 kg [11-12]
- Dose: ~2.5 mg/kg/day (max 150 mg/day) for 28 days [9]
- Contraindicated in pregnancy — teratogenic; effective contraception required during and for 5 months after treatment [9][11]
- GI side effects (nausea, vomiting), potential ocular toxicity [1]
- Not recommended as monotherapy for L. infantum (Americas/Europe) due to lower efficacy [9]
Combination therapy (HIV-VL coinfection)
Alternatives
- Amphotericin B deoxycholate: 0.5–1.0 mg/kg/day IV (total 1.5–2.0 g) — significant nephrotoxicity [9]
- Pentavalent antimonials (meglumine antimoniate): 20 mg/kg/day IM/IV × 28 days — cardiotoxicity, pancreatitis; resistance in Indian subcontinent [1][9]
- Paromomycin: 15 mg/kg/day IM × 21 days — low toxicity but low barrier to resistance [1]
Medication cautions
- Pentavalent antimonials: require IND application in the US; check β-hCG before use [9]
- Monitor renal function, electrolytes (hypokalemia), and hepatic function with amphotericin B [5]
4. Diet
- Nutritional rehabilitation is critical — malnutrition is both a risk factor and consequence of VL [3][6][15]
- High-calorie, high-protein diet to address cachexia and wasting
- Adequate hydration, especially during amphotericin B infusions (to mitigate nephrotoxicity)
- No specific dietary triggers; a Cochrane review found insufficient evidence for specific nutritional supplements during VL treatment [6]
5. Review of Systems
- Constitutional: Fever pattern, night sweats, weight loss, fatigue, malaise [5]
- GI: Abdominal distension/pain, diarrhea, anorexia, dysphagia (especially HIV-coinfected) [6][9]
- Hematologic: Easy bruising, bleeding (epistaxis, gingival), pallor [6]
- Respiratory: Cough (especially in children; also consider secondary infections) [7]
- Dermatologic: Skin hyperpigmentation (Indian subcontinent), rash, nodules (post-kala-azar dermal leishmaniasis) [3][6]
- Lymphatic: Lymphadenopathy (more common in East Africa) [5]
- Mucosal: Oral/GI lesions in HIV-coinfected patients [9]
6. Collateral History and Family History
- Detailed travel history — even remote travel to endemic areas is relevant; latent reactivation can occur decades later [5]
- Household contacts with similar symptoms (anthroponotic transmission in South Asia/East Africa) [1]
- HIV status of patient and contacts [9]
- Occupational exposure (military, aid workers, agricultural workers in endemic zones)
- History of injection drug use (needle-sharing transmission documented in southern Europe) [9]
- Immunosuppressive medications — TNF-α inhibitors, post-transplant immunosuppression [5]
- No strong hereditary predisposition, but intact cell-mediated immunity (Th1 response) is protective [7]
7. Risk Factors
- Travel to or residence in endemic areas: India, East Africa, Brazil, Mediterranean, South/Central America [1][3]
- HIV/AIDS — most significant immunologic risk factor; atypical presentations, higher relapse rates [5][9]
- Immunosuppression: organ transplant recipients, TNF-α antagonists, chemotherapy, HSCT [5][8]
- Young age (children <5 years in endemic areas) [15]
- Malnutrition — both predisposes to and results from VL [3][15]
- Low socioeconomic status, poor housing (mud walls, thatched roofs attract sandflies) [16]
- Needle sharing among PWID [9]
- Blood transfusion or organ transplant from infected donor [5]
8. Differential Diagnosis
Acute presentation
- Malaria — fever, splenomegaly, anemia; thick/thin smear distinguishes
- Typhoid fever — prolonged fever, hepatosplenomegaly; blood cultures
- Acute Chagas disease (Latin America) — Romana sign, cardiomyopathy
- Miliary tuberculosis — fever, hepatosplenomegaly, pancytopenia
- Viral hepatitis / mononucleosis — transaminitis, atypical lymphocytes
Subacute/chronic presentation
- Brucellosis — undulant fever, hepatosplenomegaly; serology/cultures
- Subacute bacterial endocarditis — fever, splenomegaly, embolic phenomena
- Disseminated histoplasmosis — pancytopenia, hepatosplenomegaly; especially in HIV
- Tropical splenomegaly syndrome (hyperreactive malarial splenomegaly)
- Hepatosplenic schistosomiasis — portal hypertension, splenomegaly
- Hematologic malignancy (lymphoma, leukemia) — pancytopenia, organomegaly
- Hemophagocytic lymphohistiocytosis (HLH) — VL can mimic or trigger HLH [5][10]
- Systemic lupus erythematosus — pancytopenia, hypergammaglobulinemia, positive ANA (VL can produce autoimmune antibodies causing diagnostic confusion) [3][17]
9. Past Medical History
- Prior VL episodes — relapse is common, especially in immunocompromised patients [8][15]
- HIV status and CD4 count — critical for treatment planning and prognosis [9]
- Organ transplant history or use of immunosuppressive agents [5]
- Prior residence in endemic areas, even decades ago [5]
- Post-kala-azar dermal leishmaniasis (PKDL) — 5–10% develop skin manifestations after treatment [4]
- History of splenectomy (alters clinical presentation)
10. Physical Exam
- Vital signs: Fever (often >38.5°C, irregular or remittent pattern), tachycardia, weight loss [5]
- Abdominal: Splenomegaly (can be massive, crossing midline), hepatomegaly [3][5]
- General: Cachexia, pallor, temporal wasting
- Skin: Hyperpigmentation of face, hands, feet, abdomen (Indian subcontinent — "kala-azar" = black fever); petechiae/purpura from thrombocytopenia [3][6]
- Lymph nodes: Lymphadenopathy (especially East Africa) [5]
- Mucosal surfaces: Oral ulcers, GI involvement in HIV-coinfected patients [9]
- Edema: Peripheral edema from hypoalbuminemia in advanced disease [6]
- Signs of secondary infection: Pneumonia, skin infections, oral candidiasis
11. Lab Studies
- CBC: Pancytopenia — anemia (often Hb <10 g/dL), leukopenia (<2,400/µL), thrombocytopenia [5][9]
- Peripheral smear: Eosinopenia is characteristic [5]
- CMP: Elevated liver enzymes, hypoalbuminemia [5]
- Serum protein electrophoresis: Polyclonal hypergammaglobulinemia (reversed A/G ratio) [3][8]
- Inflammatory markers: Elevated CRP, ESR, ferritin [10]
- Triglycerides: May be elevated (HLH overlap) [10]
- HIV testing: Mandatory in all VL cases [9]
- β-hCG: Required before miltefosine or antimonial therapy in patients of childbearing potential [9]
- Renal function and electrolytes: Baseline and monitoring during amphotericin B therapy
Rule-out labs
- Blood cultures (endocarditis, typhoid, brucellosis)
- Malaria smear/RDT
- TB workup (AFB, cultures)
12. Imaging
- Abdominal ultrasound — first-line; confirms and quantifies hepatosplenomegaly; useful for monitoring treatment response
- Chest X-ray — evaluate for secondary infections (pneumonia, TB)
- CT abdomen — not routinely needed; may be obtained if diagnostic uncertainty or concern for lymphoma/other malignancy
- Echocardiography — if pentavalent antimonials are used (cardiotoxicity monitoring)
- Imaging is supportive, not diagnostic — parasitologic confirmation is required [3][5]
13. Special Tests
Serologic
- rK39 rapid diagnostic test (RDT) — primary field diagnostic tool; sensitivity 97% in Indian subcontinent, ~85% in East Africa; lower sensitivity in HIV-coinfected patients [2-3]
- Direct agglutination test (DAT) — alternative serologic test [18]
- Serology cannot distinguish active from past infection and cannot diagnose relapse [3]
Parasitologic (gold standard)
- Bone marrow aspirate — preferred in North America; sensitivity 52–85% [5][19]
- Splenic aspirate — highest sensitivity (93–99%) but risk of hemorrhage; not recommended in North America [5]
- Lymph node aspirate — sensitivity 52–58% [5]
- Giemsa-stained smears for amastigotes (look for kinetoplast and nucleus) [3][5]
Molecular
- PCR (qPCR) — highly sensitive (>95%) on blood and tissue; useful for monitoring treatment response; available through CDC [5][9][18]
- Buffy coat smear — higher yield in HIV-coinfected patients [9]
Contact CDC for diagnostic assistance: parasiteslab@cdc.gov or 404-718-4175 [11]
14. ECG
- Baseline ECG recommended before pentavalent antimonial therapy — risk of QTc prolongation, arrhythmias, and sudden cardiac death [1]
- Monitor ECG during antimonial treatment
- Not routinely required for liposomal amphotericin B or miltefosine therapy
- Consider ECG if concurrent electrolyte abnormalities (hypokalemia from amphotericin B)
15. Assessment
VL should be suspected in any patient with persistent unexplained fever (>2 weeks), splenomegaly, and pancytopenia with a relevant travel or exposure history, even in the distant past. [5][11] The disease has a subacute to chronic course in most cases, with a spectrum from asymptomatic infection to fulminant disease. [3] Atypical presentations are common in HIV-coinfected and other immunocompromised patients, who may lack classic splenomegaly and present with GI, mucosal, or cutaneous involvement. [5][9] VL can mimic hematologic malignancy, autoimmune disease (SLE), and HLH, leading to frequent diagnostic delays. [10][17] Without treatment, VL is uniformly fatal within ~2 years, typically from secondary infections or severe anemia. [3]
Severity stratification
- Mild: ambulatory, moderate organomegaly, mild cytopenias
- Severe: massive splenomegaly, Hb <5 g/dL, severe neutropenia, secondary infections, HLH features, HIV coinfection, malnutrition
16. Treatment Plan
Initial stabilization
- Hemodynamic support, transfusion for severe anemia or active bleeding
- Empiric antibiotics if secondary bacterial infection suspected
- Nutritional support
Definitive therapy (immunocompetent, North America)
- Liposomal amphotericin B (AmBisome) — FDA-approved regimen: 3 mg/kg/day IV on days 1–5, 14, and 21 (total dose ~21 mg/kg) [5][11]
- Alternative (Indian subcontinent): single-dose 10 mg/kg IV — >95% cure rate [4][13]
HIV-coinfected (preferred)
- Combination: Liposomal AmB 30 mg/kg total IV + miltefosine 50 mg BID for 28 days (East Africa) or 14 days (South Asia) [9]
- Alternative: Liposomal AmB monotherapy 20–60 mg/kg total dose [9]
Miltefosine monotherapy (alternative for L. donovani only):
- 2.5 mg/kg/day PO (max 150 mg/day) × 28 days [9][11]
- 30–44 kg: 50 mg BID; ≥45 kg: 50 mg TID [9]
Monitoring during treatment
- Renal function, electrolytes (K⁺, Mg²⁺), CBC, LFTs
- Test of cure: clinical response + parasitologic clearance on bone marrow or PCR negativity [15][18]
Secondary prophylaxis (HIV-coinfected)
17. Disposition
Admission criteria
- All confirmed or strongly suspected VL cases require inpatient treatment initiation (IV liposomal amphotericin B)
- Severe anemia (Hb <7 g/dL), active bleeding, neutropenic fever
- HLH features, multi-organ dysfunction
- HIV coinfection with VL
- Inability to tolerate oral intake
Observation/step-down
Specialist consultation
- Infectious disease — mandatory for all cases; CDC consultation recommended in the US [11]
- Hematology — if HLH suspected or severe pancytopenia
- Tropical medicine — if available
- HIV specialist — for coinfected patients
18. Follow Up / Return Precautions
- Test of cure at end of treatment and at 6 months — clinical assessment ± parasitologic confirmation (bone marrow or PCR) [13][15]
- Relapse monitoring: most relapses occur within 6–12 months; HIV-coinfected patients have the highest relapse rates [9][14]
- Post-kala-azar dermal leishmaniasis (PKDL): 5–10% develop skin lesions months to years after treatment — counsel patients to report new skin changes [4][6]
- Return precautions: instruct patients to seek immediate care for recurrent fever, worsening fatigue, abdominal distension, bleeding, or new skin lesions
- HIV-coinfected patients: ensure ART optimization, monitor CD4 count, and continue secondary prophylaxis until immune reconstitution [9]
- Contraception counseling: if miltefosine used, effective contraception for 5 months post-treatment [9]
- Expected recovery: clinical improvement (defervescence, splenic regression) typically within 1–2 weeks of effective therapy; hematologic recovery over weeks [14]
References
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2. Leishmaniasis. — Pareyn M, Alves F, Burza S, et al. Nature Reviews. Disease Primers. 2025.
3. Leishmaniasis. — Burza S, Croft SL, Boelaert M. Lancet. 2018.
4. Effect of Indoor Residual Spraying on Sandfly Abundance and Incidence of Visceral Leishmaniasis in India, 2016-22: An Interrupted Time-Series Analysis and Modelling Study. — Coffeng LE, de Vlas SJ, Singh RP, et al. The Lancet. Infectious Diseases. 2024.
5. Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). — Aronson N, Herwaldt BL, Libman M, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2016.
6. Nutritional Supplements for Patients Being Treated for Active Visceral Leishmaniasis. — Custodio E, López-Alcalde J, Herrero M, et al. The Cochrane Database of Systematic Reviews. 2018.
7. Rapid Tests for the Diagnosis of Visceral Leishmaniasis in Patients With Suspected Disease. — Boelaert M, Verdonck K, Menten J, et al. The Cochrane Database of Systematic Reviews. 2014.
8. Endemic or Regionally Limited Parasitic and Fungal Infections in Haematopoietic Stem-Cell Transplantation Recipients: A Worldwide Network for Blood and Marrow Transplantation (WBMT) Review. — Muhsen IN, Galeano S, Niederwieser D, et al. The Lancet. Haematology. 2023.
9. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV. — Constance Benson, John Brooks, Shireesha Dhanireddy, et al Infectious Diseases Society of America; Office of AIDS Research Advisory Council (2025). 2025.
10. Visceral Leishmaniasis as a Cause or Mimicker of Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and HLH-04 Criteria Limits. — Renna Bertoli M, Spatuzzo M, Ronci G, et al. The Pediatric Infectious Disease Journal. 2026.
11. Leishmaniasis. — Andrew Abbott, Rebecca J. Chancey, and Sharon L. Roy CDC Yellow Book. 2025.
12. FDA Orange Book. — FDA Orange Book. 2026.
13. Comparison of Short-Course Multidrug Treatment With Standard Therapy for Visceral Leishmaniasis in India: An Open-Label, Non-Inferiority, Randomised Controlled Trial. — Sundar S, Sinha PK, Rai M, et al. Lancet. 2011.
14. AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial. — Burza S, Mahajan R, Kazmi S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2022.
15. Visceral Leishmaniasis: A Forgotten Epidemic. — Zijlstra EE. Archives of Disease in Childhood. 2016.
16. Environmental and Socioeconomic Risk Factors for Visceral and Cutaneous Leishmaniasis in São Paulo, Brazil. — Valero NNH, Prist P, Uriarte M. The Science of the Total Environment. 2021.
17. Case Report: Visceral Leishmaniasis Misdiagnosed as Systemic Lupus Erythematosus in a 36-Year-Old Migrant Worker. — Sheng LP, Lin BZ, Han LN, Wang GQ, Hou FQ. Frontiers in Medicine. 2025.
18. Visceral Leishmaniasis: Recent Advances in Diagnostics and Treatment Regimens. — van Griensven J, Diro E. Infectious Disease Clinics of North America. 2019.
19. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.