A patient with long‑term exposure to malaria presents with massive painless splenomegaly, mild anemia, thrombocytopenia, polyclonal immunoglobulin M elevation, and recurrent febrile episodes; what is the most likely diagnosis, how should it be evaluated, and what is the recommended management?

Tropical Splenomegaly Syndrome (Hyperreactive Malarial Splenomegaly)

Most Likely Diagnosis

This clinical presentation is diagnostic of hyperreactive malarial splenomegaly (HMS), formerly called tropical splenomegaly syndrome, which results from an aberrant immunological response to chronic malaria exposure rather than active parasitemia. 1, 2

Pathophysiology and Clinical Features

HMS represents a disturbance in T-lymphocyte control of the humoral immune response to recurrent malaria, possibly linked to specific HLA Class II antigens. 3 The syndrome is characterized by:

• Massive painless splenomegaly (the defining feature) 1, 2
• Polyclonal IgM hypergammaglobulinemia with markedly elevated anti-malarial antibody titers 1, 2, 3
• Mild anemia (recurrent episodes can be profound) 3
• Thrombocytopenia (common hematologic finding) 1
• Recurrent febrile episodes despite the absence of detectable parasitemia on routine smears 1
• Hepatomegaly frequently accompanies the splenomegaly 4

The gross overproduction of IgM antibodies leads to high molecular weight immune complex formation, persistent splenomegaly, and increased susceptibility to infections. 3

Diagnostic Evaluation

Essential Diagnostic Criteria

The diagnosis requires meeting all of the following criteria 2:

• Long-term residence in a malaria-endemic area (often years of exposure) 1, 2
• Massive splenomegaly (typically extending well below the costal margin) 2, 4
• Markedly elevated serum IgM levels 1, 2, 4
• High anti-plasmodial antibody titers 2, 5
• Regression of splenomegaly by at least 40% within six months after curative antimalarial treatment 2

Laboratory Testing

Parasitemia detection requires specialized techniques because routine thick and thin blood films are often negative. 1 The workup should include:

• PCR-based testing to demonstrate low-grade malarial parasitemia that may be missed on microscopy 1
• Rapid antigen-detecting dipstick tests can be useful adjuncts 1
• Complete blood count showing anemia and thrombocytopenia 1, 3
• Serum protein electrophoresis demonstrating polyclonal IgM elevation 1, 2
• Anti-malarial antibody titers (markedly elevated) 2, 5

Critical Differential Diagnoses to Exclude

B-cell lymphoma and splenic lymphoma are the primary differential diagnoses in tropical settings and must be ruled out. 2 Additional conditions to exclude include:

• Chronic visceral leishmaniasis (Kala-azar) 5
• Chronic myeloid leukemia 5
• Lymphoproliferative disorders 5
• Congenital hemolytic anemias 5

Clonality analysis distinguishes HMS from lymphoproliferative disorders, as HMS shows polyclonal rather than monoclonal B-cell expansion. 2

Recommended Management

Antimalarial Treatment

Long-term antimalarial prophylaxis is the cornerstone of treatment for patients remaining in endemic areas. 5 However, recent evidence supports short-term curative antimalarial therapy for patients who have permanently left endemic regions. 2

The treatment approach includes:

• Curative antimalarial therapy (specific regimen based on local resistance patterns) 2
• Monthly follow-up to monitor splenomegaly regression 5
• Long-term prophylaxis if the patient returns to or remains in an endemic area 5

Monitoring and Follow-up

Splenomegaly should regress by at least 40% within six months of initiating treatment, which confirms the diagnosis retrospectively. 2 Follow-up should include:

• Monthly clinical assessments with spleen size measurement 5
• Serial complete blood counts to monitor anemia and thrombocytopenia 3
• Repeat IgM levels to document normalization 2

Prognosis and Complications

Patients with gross disease experience high mortality, constituting a major public health problem in endemic communities where HMS affects a majority of adults. 3 Complications include:

• Profound recurrent anemia requiring transfusion 3
• Increased susceptibility to bacterial and other infections 3
• Splenic rupture (rare but catastrophic) 4

Common Pitfalls

Do not mistake HMS for acute malaria—the absence of parasites on routine blood films does not exclude the diagnosis, as HMS represents chronic immune dysregulation rather than active infection. 1 Do not overlook lymphoproliferative malignancy, which can present identically and requires clonality testing to differentiate. 2