In a 56‑year‑old woman with acute fever, vomiting, nausea, known diabetes mellitus, leukocytosis (white blood cell count 10,700/µL), severe thrombocytopenia (platelet count 40,000/µL), anemia (hemoglobin 8.7 g/dL), mild indirect hyperbilirubinemia (total bilirubin 1.9 mg/dL, indirect 1.6 mg/dL), normal transaminases, ferritin >2000 µg/L, and negative PCR for dengue, scrub typhus, malaria, Zika and chikungunya, what are the differential diagnoses and recommended management?

Differential Diagnoses and Management

Most Likely Diagnosis

This patient most likely has hemophagocytic lymphohistiocytosis (HLH) secondary to an undiagnosed infection, and requires immediate bone marrow examination, additional infectious workup, and consideration of immunosuppressive therapy if HLH criteria are met.

The constellation of severe thrombocytopenia (40,000/µL), anemia (Hb 8.7 g/dL), markedly elevated ferritin (>2000 µg/L), indirect hyperbilirubinemia, fever with gastrointestinal symptoms, and negative tropical PCR panel strongly suggests HLH rather than a primary tropical infection 1.

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Key Differential Diagnoses

1. Hemophagocytic Lymphohistiocytosis (HLH) – Primary Consideration

• Ferritin >2000 µg/L is highly suggestive of HLH, particularly when combined with cytopenias affecting multiple cell lines (thrombocytopenia, anemia) 1
• The persistent fever despite negative tropical pathogen testing, combined with hepatic involvement (indirect hyperbilirubinemia) and cytopenias, fulfills several HLH-2004 diagnostic criteria 1
• HLH can be triggered by undiagnosed viral infections, and the negative tropical PCR panel does not exclude other viral triggers 1

2. Rickettsial Disease (Scrub Typhus or Other Rickettsioses)

• Despite negative scrub typhus PCR, rickettsial disease remains in the differential because PCR sensitivity is limited and serology may be negative early in disease 2, 3
• The combination of thrombocytopenia, elevated transaminases (though normal in this case), and fever with gastrointestinal symptoms is characteristic of rickettsial infections 4, 5
• Elevated ferritin >2000 µg/L is unusual for uncomplicated rickettsial disease and suggests either severe rickettsial infection or an alternative diagnosis 4
• Leukocytosis (WBC 10,700) can occur in 30% of scrub typhus cases 5

3. Enteric Fever (Typhoid/Paratyphoid)

• Fever, nausea, vomiting in a diabetic patient with thrombocytopenia and anemia fits the clinical picture of enteric fever 6
• Blood cultures should have been obtained before any antibiotic therapy, as culture sensitivity is 40-80% in the first week 6
• The absence of leukopenia makes typhoid less likely, as leukopenia is characteristic 6

4. Leptospirosis

• Fever with gastrointestinal symptoms, thrombocytopenia, anemia, and indirect hyperbilirubinemia (suggesting hemolysis) are consistent with leptospirosis 6
• Obtain urinalysis immediately to look for proteinuria and hematuria, which are indicative of leptospirosis 6
• Requires specific blood culture techniques (within 5 days of symptom onset, room temperature transport) 6

5. Severe Dengue with Complications

• Although dengue PCR is negative, false-negative PCR can occur depending on timing of sample collection
• Persistent fever beyond the critical phase with ongoing cytopenias and hepatosplenomegaly should raise suspicion for dengue-associated HLH 1, 7

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Immediate Diagnostic Workup

Essential Laboratory Tests to Order NOW

• Bone marrow aspiration and biopsy to evaluate for hemophagocytosis and rule out hematologic malignancy 1
• Repeat ferritin level and obtain triglyceride level (>265 mg/dL supports HLH) 1
• Fibrinogen level (hypofibrinogenemia <150 mg/dL supports HLH) 1
• Peripheral blood smear examination for morulae (present in only 1-20% of ehrlichiosis cases but diagnostic when present) 2
• Comprehensive metabolic panel with liver enzymes (AST/ALT) to assess hepatic involvement 6, 3, 8
• Creatinine and blood urea nitrogen as elevated creatinine predicts mortality in rickettsial disease 4, 5
• Urinalysis for proteinuria and hematuria (leptospirosis) 6
• Coagulation studies (PT/PTT) to assess for DIC 2
• Lactate dehydrogenase (LDH) and indirect bilirubin (already elevated) support hemolysis 1

Infectious Disease Testing

• At least two sets of blood cultures before any antibiotics (for enteric fever, leptospirosis, sepsis) 6, 8
• Paired acute and convalescent serology for rickettsial diseases (IgM/IgG for scrub typhus, spotted fever group), leptospirosis, brucellosis 6, 8
• PCR on EDTA whole blood for rickettsial pathogens if not already done comprehensively 8
• HIV testing as acute HIV can present with fever and cytopenias 6
• EBV and CMV serology as viral triggers for HLH 1
• Hepatitis panel (HAV, HBV, HCV) 6

Imaging

• Abdominal ultrasound to assess for hepatosplenomegaly (supports HLH), ascites (plasma leakage), and gallbladder inflammation 2, 1

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Immediate Management

Empiric Antibiotic Therapy – START NOW

Given the severity of presentation with profound thrombocytopenia, anemia, and markedly elevated ferritin, empiric broad-spectrum therapy covering rickettsial disease and enteric fever is warranted while awaiting diagnostic confirmation.

Recommended Regimen:

• Doxycycline 100 mg IV or PO twice daily – mandatory coverage for rickettsial disease, as delayed treatment increases mortality 2, 6, 3, 8

  • Do NOT delay doxycycline while awaiting serology, as early serologic tests are often negative and treatment within the first 3 days is critical 3, 8
  • Continue for at least 3 days after fever resolves, typically 7-10 days total 2

• Ceftriaxone 2 g IV daily – covers enteric fever (>70% of Salmonella Typhi/Paratyphi are fluoroquinolone-resistant) 6

  • Also provides coverage for leptospirosis and other bacterial causes of sepsis 6

Supportive Care

• Platelet transfusion if platelet count <10,000/µL or if active bleeding occurs 1
• Packed red blood cell transfusion if hemoglobin drops further or patient becomes symptomatic 1
• Aggressive IV fluid resuscitation if hemodynamically unstable 6
• Monitor blood glucose closely given diabetes mellitus 9, 7

HLH-Specific Therapy – If Criteria Met

If bone marrow shows hemophagocytosis and patient meets ≥5 of 8 HLH-2004 criteria, initiate:

• Dexamethasone 10 mg/m² IV daily for the first 2 weeks, followed by tapering regimen over 8 weeks 1
• Consult hematology/oncology immediately for consideration of etoposide if severe or refractory 1

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Critical Pitfalls to Avoid

• Do NOT delay doxycycline therapy while awaiting rickettsial serology, as antibodies are typically absent during the first 7 days when patients present, and delayed treatment significantly increases mortality 3, 8
• Do NOT rule out rickettsial disease based on negative PCR alone, as sensitivity is limited and most patients do not recall tick exposure 3, 8
• Do NOT miss HLH diagnosis by attributing persistent fever and cytopenias solely to infection; ferritin >2000 µg/L demands evaluation for HLH 1
• Do NOT start antibiotics before obtaining blood cultures in stable patients, but this patient's severity warrants immediate empiric therapy after cultures are drawn 6, 8
• Do NOT rely on normal transaminases to exclude rickettsial disease, as 10-40% of cases may have normal liver enzymes early in disease 2

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Monitoring Parameters

• Daily complete blood count to track platelet count, hemoglobin, and white blood cell trends 8, 1
• Daily comprehensive metabolic panel to monitor renal function (creatinine predicts mortality in rickettsial disease) and liver function 4, 5
• Temperature and vital signs every 4-6 hours 6
• Clinical assessment for new symptoms: altered mental status, seizures, bleeding, respiratory distress 2, 1
• Repeat ferritin and triglycerides if HLH is suspected 1

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Disposition

• Admit to hospital with close monitoring given severe thrombocytopenia, anemia, and diagnostic uncertainty 6, 1
• Consider ICU admission if hemodynamic instability, altered mental status, or platelet count continues to drop 2, 5
• Hematology consultation for bone marrow interpretation and HLH management if criteria are met 1
• Infectious disease consultation for complex diagnostic workup and antibiotic stewardship 6, 8