What are the differential diagnoses and recommended work‑up for a febrile traveler with eosinophilia, splenomegaly, elevated lactate dehydrogenase, modestly raised erythrocyte sedimentation rate, and mildly increased ferritin?

Differential Diagnosis and Work-Up for Febrile Traveler with Eosinophilia, Splenomegaly, and Elevated LDH

This patient's constellation of findings—eosinophilia with splenomegaly, elevated LDH, and modestly elevated inflammatory markers—most strongly suggests acute schistosomiasis (Katayama syndrome) if there is freshwater exposure in Africa 2-9 weeks prior, or malaria if returning from sub-Saharan Africa, both of which require immediate diagnostic testing and empirical treatment to prevent life-threatening complications. 1, 2

Immediate Priority: Rule Out Life-Threatening Tropical Infections

Malaria Assessment

• Obtain three thick and thin malaria films plus rapid diagnostic test (RDT) immediately, as malaria is the most common diagnosis in febrile returning travelers (28-47% from Africa) and can rapidly progress to fatal disease. 1
• Splenomegaly increases the probability of malaria 5-14 times (LR+ 5.1-13.6), making this finding highly significant in your patient. 1
• Raised LDH slightly increases the probability of malaria, though it is less specific than thrombocytopenia or hyperbilirubinemia. 1
• If malaria films are negative, repeat testing at 24 and 48 hours (three films over 72 hours total) to exclude malaria with confidence. 1

Schistosomiasis (Katayama Syndrome) Assessment

• Eosinophilia very strongly increases the probability of schistosomiasis (LR+ 22-32), making this the most likely helminth infection in your patient. 1
• Document any freshwater swimming or bathing in African lakes/rivers 2-9 weeks prior to symptom onset, as this timing is classic for acute schistosomiasis. 1, 2
• If freshwater exposure occurred 2-9 weeks ago with eosinophilia >5000/μL, initiate empirical praziquantel 40 mg/kg as a single dose immediately without waiting for confirmatory serology, as recommended by the CDC. 2, 3
• Add prednisone 20 mg daily for 5 days to reduce symptom duration in Katayama syndrome. 2, 3
• Schistosomiasis serology should be sent but will be negative if tested within 4-12 weeks of exposure (during the pre-patent period when eosinophilia is highest). 1

Secondary Differential Diagnoses Based on Travel Region

If Returning from Asia

• Dengue fever is the most common tropical diagnosis (13-18% of febrile cases from Asia), with leucopenia and thrombocytopenia increasing probability (LR+ 6 and 5 respectively). 1
• Enteric fever accounts for 3-17% of febrile cases from Asia, with splenomegaly increasing probability (LR+ 6-10)—this must be distinguished from malaria. 1
• Send two sets of blood cultures prior to any antibiotics, as sensitivity reaches 80% in typhoid. 1

If Returning from Latin America

• Dengue represents 8-13% of febrile cases. 1
• Leptospirosis is fairly common (10% in one study) and should be considered. 1

Comprehensive Helminth Work-Up

First-Line Parasitic Testing

• Obtain three separate concentrated stool specimens for ova and parasites on different days, as this has high diagnostic yield for intestinal helminths. 1, 2, 3, 4
• Send Strongyloides stercoralis serology immediately, as this parasite can persist lifelong and cause fatal hyperinfection syndrome if the patient becomes immunocompromised in the future. 1, 3, 4
• Send schistosomiasis serology based on freshwater exposure history, though it may be negative in acute infection. 1, 3

Critical Timing Considerations

• Eosinophilia may be transient during the tissue migration phase (pre-patent period) when stool microscopy is still negative. 1
• Eosinophilia often resolves when the parasite reaches the gut lumen, at which point stool microscopy becomes positive. 1
• Serological tests do not become positive until 4-12 weeks after infection, so negative serology does not exclude acute helminth infection. 1

Essential Laboratory Work-Up

Complete Blood Count with Differential

• Calculate absolute eosinophil count (AEC) to determine severity: mild (500-1500/μL), moderate (1500-5000/μL), or severe (>5000/μL). 2, 4
• Check for thrombocytopenia, which strongly increases probability of malaria (LR+ 2.9-11) and dengue (LR+ 5). 1
• Check for leucopenia, which increases probability of dengue (LR+ 6). 1

Biochemical Markers

• Obtain comprehensive metabolic panel with liver function tests, LDH, and uric acid to assess for organ damage. 2
• Check for hyperbilirubinemia, which increases probability of malaria (LR+ 5.3-7.3). 1
• Your patient's ESR of 36 mm/hr and ferritin of 209 ng/mL are modestly elevated but not in the range typically seen in hemophagocytic lymphohistiocytosis (ferritin >10,000 ng/mL has 90% sensitivity and 96% specificity for HLH). 5, 6

Additional Testing

• Send two sets of blood cultures prior to any antibiotic therapy. 1
• Perform urinalysis to check for proteinuria and hematuria (seen in leptospirosis) or hemoglobinuria (rare in malaria). 1
• Obtain chest X-ray to evaluate for pulmonary infiltrates if respiratory symptoms are present. 1, 2

Empirical Treatment Strategy

When Investigations Are Negative

• Initiate empirical albendazole 400 mg twice daily for 3 days when stool microscopy and serology are negative, as this covers Ascaris, hookworm, and Strongyloides. 2, 3
• Consider adding ivermectin 200 μg/kg as a single dose for broader helminth coverage, particularly for Strongyloides. 3

Geographic-Specific Empirical Treatment

• If freshwater exposure in Africa 2-9 weeks prior: Praziquantel 40 mg/kg single dose, repeated at 6-8 weeks, plus prednisone 20 mg daily for 5 days. 2, 3
• If travel to endemic areas without specific exposure history: Albendazole 400 mg twice daily for 3 days plus ivermectin 200 μg/kg single dose. 3

Critical Pitfalls to Avoid

Do Not Miss Strongyloides

• Never start corticosteroids before excluding Strongyloides, as steroids can precipitate fatal hyperinfection syndrome in undiagnosed strongyloidiasis. 3, 4
• Strongyloides can present over 50 years after exposure and is diagnosed in 10-73% of returning travelers with eosinophilia. 1

Do Not Assume Normal Tests Exclude Disease

• Normal eosinophil counts do not exclude helminth infection, as many infected patients have normal counts. 4
• Normal imaging does not exclude helminth infection, as many parasitic infections cause eosinophilia without radiographic abnormalities, especially in early stages. 3
• Negative serology in the first 4-12 weeks does not exclude acute helminth infection. 1

Do Not Delay Malaria Testing

• Three negative malaria films over 72 hours are required to exclude malaria with confidence—a single negative test is insufficient. 1
• Absence of thrombocytopenia strongly reduces probability of malaria (LR- 0.2), but does not exclude it. 1

Follow-Up and Monitoring

Short-Term Follow-Up

• Repeat complete blood count 2-4 weeks post-treatment to assess decrease in eosinophil count. 3
• Repeat praziquantel at 6-8 weeks if schistosomiasis was treated, to ensure eradication of immature forms. 2, 3

Long-Term Considerations

• Refer to hematology if moderate-to-severe eosinophilia (≥1.5 × 10⁹/L) persists for more than 3 months after infectious causes have been excluded or treated. 4
• Screen for end-organ damage if hypereosinophilia persists, including cardiac (troponin, NT-proBNP, echocardiography), pulmonary (chest X-ray, pulmonary function tests), and neurologic assessment. 4