What is the diagnosis for a patient presenting with pancytopenia, elevated ESR, fever, significantly elevated liver enzymes (SGOT and SGPT), skin peeling, and blackening of hands?

Diagnostic Approach to Pancytopenia with Fever, Elevated Transaminases, and Skin Changes

This clinical presentation strongly suggests hemophagocytic lymphohistiocytosis (HLH) or a severe systemic inflammatory condition such as Adult-Onset Still's Disease (AOSD), and requires immediate diagnostic workup with serum ferritin, bone marrow examination, and urgent initiation of immunosuppressive therapy if HLH is confirmed. 1, 2, 3

Immediate Life-Threatening Considerations

Pancytopenia in the setting of fever and elevated liver enzymes is a medical emergency that warrants immediate evaluation for hemophagocytic syndrome, which requires prompt immunosuppressive treatment to prevent fatal outcomes. 1

Critical Initial Actions

• Obtain serum ferritin immediately - markedly elevated ferritin (often >10,000 ng/mL) is pathognomonic for hemophagocytic lymphohistiocytosis and is the single most useful test for differential diagnosis 3, 4, 5
• Check thick and thin blood smears urgently to exclude severe malaria, especially with any travel history to endemic areas, as this presentation is characteristic of severe malaria 2
• Initiate broad-spectrum antibiotics within 2 hours using piperacillin-tazobactam 4.5g IV q6h as first-line empiric therapy while awaiting diagnostic workup 2
• Monitor temperature every 4 hours with strict infection control measures 2

Primary Differential Diagnoses

Hemophagocytic Lymphohistiocytosis (Most Likely)

The combination of fever, pancytopenia, elevated liver enzymes (SGOT/SGPT 5x normal), and markedly elevated ESR strongly suggests HLH 3, 4, 5:

• Risk factors associated with death include: age over 30 years, presence of disseminated intravascular coagulation, increased ferritin and beta2-microglobulin, anemia with thrombocytopenia, and jaundice 5
• Diagnostic criteria to assess: fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis on bone marrow examination 2, 3
• Underlying triggers to investigate: viral infections (EBV, CMV, varicella-zoster), disseminated histoplasmosis in HIV/AIDS patients, or hematological malignancies 3, 4, 6

Adult-Onset Still's Disease

The skin peeling and blackening of hands could represent the characteristic salmon-pink evanescent rash of AOSD, though this typically resolves as fever diminishes 1:

• Classic features: quotidian fever spikes, arthralgia/arthritis (64-100% of cases), sore throat (38-92%), and characteristic rash (51-94%) 1
• Laboratory findings: ESR elevated in virtually all patients, leucocytosis with neutrophilia (50% have WBC >15×10⁹/L), anemia of chronic disease, and reactive thrombocytosis 1
• Critical distinction: Pancytopenia in AOSD should alert to hemophagocytic syndrome complication, which necessitates prompt immunosuppressive treatment 1
• Liver involvement: hepatomegaly and abnormal liver biochemistry present in 50-75% of patients, though NSAID use may be a cofactor 1

Disseminated Histoplasmosis

Progressive disseminated histoplasmosis presents with fever, pancytopenia, hepatosplenomegaly, and progressive elevation of hepatic enzymes 1, 6:

• Screen for exposure history to endemic regions (Ohio and Mississippi River valleys) 2
• Diagnostic tests: urine Histoplasma antigen, fungal blood cultures, and buffy coat smears showing intracellular organisms 6
• HIV/AIDS context: common opportunistic infection in advanced AIDS patients with low CD4+ counts, often complicated by hemophagocytosis 6

Essential Diagnostic Workup

Immediate Laboratory Tests

• Peripheral blood smear examination by qualified hematologist to identify schistocytes, dysplastic features, abnormal cells, megaloblastic changes, and atypical lymphocytes 2, 7
• Reticulocyte count to differentiate decreased bone marrow production from peripheral destruction 2, 7
• Serum ferritin - the single most important test for HLH diagnosis 3, 4, 5
• Coagulation studies including fibrinogen, D-dimer, PT/PTT to assess for disseminated intravascular coagulation 5
• Triglycerides - elevated in HLH 2

Infectious Disease Screening

• Viral serologies: EBV DNA, CMV PCR, HIV testing, hepatitis B and C screening 2, 7, 4
• Fungal studies: urine Histoplasma antigen, fungal blood cultures if endemic exposure 1, 6
• Visceral leishmaniasis screening if exposure history to endemic regions exists 2

Bone Marrow Examination (Urgent)

Both bone marrow aspiration and biopsy must be performed simultaneously 7:

• Look for hemophagocytosis - histiocytes engulfing red blood cells, white blood cells, platelets, and their precursors 3, 6
• Fungal stains (GMS stain) to identify Histoplasma capsulatum or other organisms 6
• Flow cytometry and cytogenetics to exclude hematologic malignancy 7

Treatment Algorithm

If HLH Confirmed

Steroid pulse therapy should be initiated immediately - methylprednisolone 1-2 mg/kg IV 3, 4:

• Etoposide-based chemotherapy may be required for refractory cases, though outcomes can be poor 4
• Treat underlying trigger aggressively: antiviral therapy for viral infections, antifungal therapy for histoplasmosis 3, 4, 6

If Disseminated Histoplasmosis Identified

Initiate intravenous amphotericin B immediately for severe disease with parasitemia or severity criteria 2:

• Consider corticosteroid therapy if patients remain febrile and pancytopenic despite amphotericin B, as hemophagocytosis may require additional immunosuppression 6
• Transition to itraconazole for step-down therapy once clinical improvement occurs 1

If AOSD Suspected

High-dose corticosteroids (oral or intravenous) combined with methotrexate is the recommended induction regimen 1:

• Methotrexate dosing: 15-20 mg/m²/week (max 40 mg/week), preferably subcutaneous 1
• If pancytopenia present: this signals hemophagocytic syndrome complication requiring more aggressive immunosuppression 1

Monitoring Strategy

• Complete blood count daily until clear upward trend in all cell lines is established 2
• Temperature monitoring every 4 hours in neutropenic patients 2
• Serial ferritin levels to track response to therapy in HLH 3, 4
• Liver enzymes and coagulation studies every 1-2 days to monitor for worsening 5

Critical Pitfalls to Avoid

• Do not delay bone marrow examination - hemophagocytosis may not be evident on initial peripheral smear and requires marrow evaluation 3, 6
• Do not attribute all findings to drug toxicity - while NSAIDs can cause liver dysfunction, the constellation of pancytopenia, fever, and elevated transaminases suggests systemic disease 1
• Do not miss disseminated histoplasmosis in HIV/AIDS patients - it commonly presents with this exact constellation and requires specific antifungal therapy 6
• Do not wait for all diagnostic results before initiating empiric antibiotics - neutropenic fever requires immediate broad-spectrum coverage 2

Admission Criteria

Hospital admission is mandatory for newly diagnosed pancytopenia with fever, elevated transaminases, and platelet count likely <20×10⁹/L 7