What are the key symptoms, diagnostic tests, and treatment options for a patient with suspected visceral leishmaniasis, presenting with prolonged fever, weight loss, and splenomegaly, and a history of travel to endemic regions?

Diagnosis of Visceral Leishmaniasis

In a patient with prolonged fever, weight loss, and splenomegaly with travel to endemic regions, visceral leishmaniasis should be confirmed through parasitological demonstration (bone marrow or splenic aspirate) or rK39 rapid diagnostic testing, with bone marrow examination being the gold standard despite lower sensitivity of peripheral blood PCR. 1, 2

Key Clinical Manifestations

The classic triad consists of:

• Chronic fever (present in 64% of patients), which may be intermittent, remittent with twice-daily spikes, or continuous 2, 3
• Marked splenomegaly (58% of patients), though this may be subtle or absent in HIV-coinfected individuals 1, 2
• Weight loss (21% of patients) with progressive wasting 1, 2

Additional common findings include:

• Hepatomegaly (49% of patients) with variable severity 2, 3
• Weakness/fatigue (57% of patients) 3
• Sweats (37% of patients) 3
• Dry cough (13% of patients) 3
• Hyperpigmentation specifically in patients infected in India and Bangladesh, giving rise to the term "kala-azar" (black fever) 1, 2

The median duration of symptoms before diagnosis is 28 days, though onset is typically subacute or chronic 2, 3

Laboratory Abnormalities

Pancytopenia affecting all cell lines is a defining hematologic feature and should raise immediate suspicion for VL: 1, 2

• Anemia, leukopenia, and thrombocytopenia occur together 2, 4
• Hypoalbuminemia is characteristic 1, 2
• Hypergammaglobulinemia reflecting chronic immune stimulation 1, 2
• Elevated acute inflammatory markers (ESR, CRP) 2, 3
• Elevated liver enzymes (transaminases 2-5 fold elevation) 1, 2, 5

Diagnostic Testing Algorithm

First-Line Diagnostic Approach:

For resource-limited settings or rapid diagnosis:

• rK39 immunochromatographic test (ICT) demonstrates overall sensitivity of 91.9% (95% CI 84.8-96.5) and specificity of 92.4% (95% CI 85.6-96.8) 6
• Critical caveat: Sensitivity is notably lower in East Africa (85.3%) compared to the Indian subcontinent (97.0%), so negative results in East African patients require parasitological confirmation 6
• This test is particularly valuable in patients with febrile splenomegaly and no previous history of VL 6

For definitive parasitological diagnosis:

• Bone marrow aspiration with microscopic examination for Leishmania amastigotes remains the gold standard 1, 5
• Splenic aspirate has higher sensitivity but carries risk of hemorrhage, particularly given the thrombocytopenia 1
• Bone marrow culture in NNN medium can detect promastigote forms within 7 days 5
• PCR testing of peripheral blood (73% positive) or bone marrow specimens (34% positive) provides molecular confirmation 3

Serological Testing:

• Leishmania serology (indirect immunofluorescence antibody test) with titers ≥1/512 supports diagnosis 1, 5
• Serology is positive in 25% of individuals in endemic areas without disease, limiting specificity 1

Critical Epidemiological Context

Travel or residence history in endemic regions is essential: 1, 2

• Mediterranean basin (including Spain, Greece, Turkey) 1, 3, 5
• Indian subcontinent (Bihar, Nepal, Bangladesh) 1, 7
• Horn of Africa (East Africa) 1
• Brazil and other parts of Latin America 1

Latent infection can reactivate years to decades after initial exposure, making VL a consideration even with remote travel history, particularly when immunosuppression develops 1, 2

Special Populations Requiring High Clinical Suspicion

Immunocompromised patients (25% of cases) present with atypical features: 1, 3

• HIV/AIDS patients may lack splenomegaly or have subtle findings 1, 2
• Widespread parasite dissemination to gastrointestinal tract, skin, and other organ systems occurs 1, 2
• VL may be the first opportunistic infection in AIDS patients 1, 2
• Organ transplant recipients, particularly in the first year post-transplant 1
• Patients on TNF-α antagonists (infliximab, adalimumab), corticosteroids, or other immunosuppressive agents 1

Differential Diagnosis to Exclude

Acute presentations (onset <2 weeks): 1, 2

• Malaria (requires three thick blood smears within 72 hours) 1
• Typhoid fever 1
• Acute schistosomiasis 1
• Miliary tuberculosis 1

Subacute/chronic presentations (>2 weeks): 1, 2

• Brucellosis (requires extended blood cultures and serology) 1
• Miliary tuberculosis 1
• Disseminated fungal diseases (histoplasmosis) 1
• Lymphoma or leukemia (though absence of lymphadenopathy argues against this) 1, 8
• Hemophagocytic lymphohistiocytic syndrome (6% of VL patients develop this complication) 2, 3

Critical Diagnostic Pitfalls

Do not dismiss VL based on:

• Remote travel history - reactivation can occur decades after exposure 1, 2
• Absence of splenomegaly - this does not exclude VL in HIV-coinfected or immunocompromised patients 1, 2
• Negative rK39 testing in East African patients - sensitivity is only 85.3% in this region, requiring parasitological confirmation 6
• Positive autoantibodies - polyclonal B cell activation may lead to multiple positive serologic tests mimicking autoimmune disease 8

Untreated VL is potentially fatal, with death resulting from progressive wasting, superinfection, or hemorrhage, making timely diagnosis critical 2

Treatment Considerations

Liposomal amphotericin B (L-AmB) is the treatment of choice: 1, 7, 3

• FDA-approved regimen: 4 mg/kg/day IV on days 1-5,10,17,24,31, and 38 (total dose 40 mg/kg) 1
• In the Greek cohort, 91% of patients received L-AmB with 90% cure rate after first cycle 3
• Treatment with L-AmB is safe and very effective, with 10% requiring a second cycle 3
• In the Indian trial, miltefosine achieved 94% final cure rate at 6 months (50 mg twice daily for patients ≥25 kg) 7

Immunosuppressive medications should be decreased during antileishmanial therapy whenever possible 1