What is the best course of action for a 22-year-old female patient with pancytopenia, normocytic normochromic anemia, hepatosplenomegaly, normal Complement 3 (C3), slightly elevated Lactate Dehydrogenase (LDH), and high levels of blood uric acid and ferritin?

Urgent Evaluation for Progressive Disseminated Histoplasmosis

This clinical presentation—pancytopenia, hepatosplenomegaly, elevated LDH, hyperuricemia, and markedly elevated ferritin in a young woman—is highly suspicious for progressive disseminated histoplasmosis (PDH) and requires immediate diagnostic workup including blood and urine histoplasma antigen testing, bone marrow examination with fungal cultures, and consideration of empiric antifungal therapy while awaiting results. 1

Key Diagnostic Features

The constellation of findings strongly suggests PDH based on the following characteristic features:

• Hepatosplenomegaly with pancytopenia is a hallmark presentation of progressive disseminated histoplasmosis 1
• Elevated LDH and ferritin are recognized laboratory clues to disseminated fungal infection 1
• Hyperuricemia suggests increased cell turnover from either the infection itself or secondary hemophagocytic syndrome 2
• Normal C3 helps exclude active systemic lupus erythematosus, which could present similarly 1

Critical Differential Diagnosis

While PDH is the primary concern, this presentation requires consideration of:

Hemophagocytic Lymphohistiocytosis (HLH)

• The combination of pancytopenia, hepatosplenomegaly, elevated ferritin, and elevated LDH can indicate HLH, which may be triggered by underlying infection (including histoplasmosis) or lymphoma 2
• Markedly elevated ferritin (often >10,000 ng/mL in HLH) is a key diagnostic feature 2
• Bone marrow examination may reveal hemophagocytosis, though absence does not exclude the diagnosis 2

Hematologic Malignancy

• Hepatosplenic T-cell lymphoma can present with identical features including pancytopenia, organomegaly, elevated LDH and ferritin 2
• This requires bone marrow biopsy with immunohistochemistry and flow cytometry 2

Megaloblastic Anemia

• Although less likely given the severity of presentation, megaloblastic anemia is the most common cause of pancytopenia and should be evaluated 3
• However, the hepatosplenomegaly and markedly elevated ferritin make this diagnosis less probable 3

Immediate Diagnostic Workup

Priority investigations must include:

• Histoplasma antigen testing in blood and urine (most sensitive test for PDH) 1
• Bone marrow aspiration and biopsy with:
  • Fungal stains (GMS, PAS) looking for intracellular yeasts 1
  • Fungal cultures 1
  • Morphologic evaluation for hemophagocytosis 2
  • Flow cytometry and immunohistochemistry to exclude lymphoma 2
• Peripheral blood smear review for circulating abnormal cells or intracellular organisms 3
• Reticulocyte count to assess bone marrow response 1
• Vitamin B12 and folate levels if not already obtained 3
• Ferritin level quantification (absolute value critical for HLH diagnosis) 2
• Triglycerides and fibrinogen (part of HLH diagnostic criteria) 2

Treatment Approach

If Progressive Disseminated Histoplasmosis is Confirmed:

Initiate liposomal amphotericin B (3 mg/kg daily) immediately for moderately severe to severe PDH, followed by itraconazole for maintenance therapy. 1

• PDH is fatal if untreated and requires urgent antifungal therapy 1
• Treatment duration typically extends 12 months or longer 1
• Clinical improvement should be evident within 2 weeks of appropriate therapy 1

If Hemophagocytic Syndrome is Present:

• Consider etoposide-based chemotherapy with corticosteroids and cyclosporine if HLH criteria are met 2
• This may be required even if triggered by histoplasmosis 2

Critical Pitfalls to Avoid

• Do not delay antifungal therapy if clinical suspicion for PDH is high, even while awaiting confirmatory testing—PDH progresses rapidly and is uniformly fatal without treatment 1
• Do not assume iron overload based on elevated ferritin alone; in this context, ferritin is an acute phase reactant reflecting inflammation or hemophagocytosis, not iron stores 1, 2
• Do not perform only bone marrow examination—histoplasma antigen testing has higher sensitivity than bone marrow morphology alone 1
• Do not attribute pancytopenia to nutritional deficiency without excluding life-threatening causes first, despite the normocytic anemia 3
• Recognize that bone marrow may appear hypocellular initially in HLH, with hemophagocytosis becoming apparent only later or in other tissues 2

Geographic and Epidemiologic Considerations

• Obtain detailed travel and residence history, particularly exposure to Ohio and Mississippi River valleys where histoplasmosis is endemic 1
• Assess for immunocompromising conditions (HIV, immunosuppressive medications, hematologic malignancy) that predispose to PDH 1
• Even immunocompetent individuals can develop PDH with heavy exposure 1