What are the differential diagnoses for a patient with recurrent fever, leucopenia, thrombocytopenia, lymphocytosis (lymphocyte count of 78%), elevated erythrocyte sedimentation rate (ESR) of 135, and recent weight loss?

Differential Diagnoses for Prolonged Fever with Cytopenias and Lymphocytosis

The most critical differential diagnoses to consider are hemophagocytic lymphohistiocytosis (HLH), hematologic malignancies (particularly acute lymphocytic leukemia), severe infections (including malaria and severe fever with thrombocytopenia syndrome), and Adult-Onset Still's Disease (AOSD).

Life-Threatening Diagnoses Requiring Immediate Evaluation

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH presents with prolonged fever, cytopenias (leukopenia and thrombocytopenia), markedly elevated ferritin (often >10,000 ng/mL), and elevated ESR 1, 2
• The lymphocytosis pattern (78%) can occur in HLH due to reactive lymphocyte proliferation or underlying viral triggers like EBV 2
• Serum ferritin and soluble IL-2 receptor (sIL2R) levels are critical markers, with ferritin often exceeding 10,000 ng/mL in severe cases 1
• Immediate bone marrow biopsy is essential to identify hemophagocytosis 2

Hematologic Malignancies

• Acute lymphocytic leukemia (ALL) can present with fever, weight loss, leukopenia, thrombocytopenia, and relative lymphocytosis before blast cells appear in peripheral blood 3
• The lupus-like presentation with positive autoantibodies, cytopenias, and constitutional symptoms can mask underlying leukemia for months 3
• Bone marrow biopsy is mandatory even if peripheral smear is initially negative, as repeated smears may miss early leukemic infiltration 3
• Acute myelogenous leukemia can also present similarly with fever, weight loss, and pancytopenia 4

Severe Infections

Severe Fever with Thrombocytopenia Syndrome (SFTS)

• SFTS presents with acute fever, leukopenia, thrombocytopenia, gastrointestinal symptoms, and markedly elevated ferritin and sIL2R 1, 5
• The mortality rate averages 20%, with rapid progression to multiple organ failure 5
• Transmitted by tick bites (Haemaphysalis longicornis, Amblyomma testudinarium) or human-to-human contact 5
• Serum ferritin and sIL2R levels may be better mortality indicators than viral load 1

Severe Malaria

• Consider severe falciparum malaria with fever, thrombocytopenia (often <100,000/μL), and elevated inflammatory markers 6
• Peripheral blood smear for malaria parasites is essential, especially with any travel history 6, 7
• Severe malaria requires immediate IV artesunate 7

Adult-Onset Still's Disease (AOSD)

• AOSD presents with high spiking fevers, markedly elevated ferritin (>1000 ng/mL), elevated ESR (often >100 mm/hr), leukocytosis or leukopenia, and thrombocytopenia 8
• Characteristic features include arthritis (particularly wrists, knees, ankles), salmon-pink rash, and lymphadenopathy 8
• Ferritin >1120 ng/mL has 74.7% sensitivity and 88.9% specificity for AOSD versus sepsis 8
• Glycosylated ferritin ≤20% supports AOSD diagnosis 8

Diagnostic Algorithm

First-Line Laboratory Tests

• Complete blood count with differential, comprehensive metabolic panel, coagulation studies, peripheral blood smear, and blood cultures 6
• Ferritin level, ESR, CRP, LDH, and liver function tests 8, 6
• Direct antiglobulin test (Coombs) if hemolysis suspected 7
• Reticulocyte count to assess bone marrow response 7

Second-Line Tests Based on Initial Results

• Bone marrow biopsy with aspirate for cytology, flow cytometry, and hemophagocytosis evaluation 3, 2
• Soluble IL-2 receptor level (markedly elevated in HLH and lymphoproliferative disorders) 1, 2
• Glycosylated ferritin (≤20% suggests AOSD) 8
• Malaria thick/thin smears and rapid diagnostic test 6, 7
• Viral hepatitis panel, EBV serology, and PCR 2
• Autoimmune markers (ANA, RF, anti-CCP) 3
• SFTS virus PCR if endemic area exposure 1, 5

Imaging Studies

• Chest X-ray or CT to evaluate for lymphadenopathy, infiltrates, or pleural effusions 8
• Abdominal ultrasound or CT for hepatosplenomegaly and lymphadenopathy 2

Critical Management Pitfalls to Avoid

• Do not dismiss the possibility of leukemia based on negative peripheral smears alone; bone marrow biopsy is essential 3
• Do not overlook malaria in patients with fever, anemia, and thrombocytopenia, especially with any travel history 7
• Do not delay bone marrow biopsy when HLH is suspected, as early diagnosis and treatment are critical for survival 2
• Avoid assuming infectious etiology without excluding malignancy, as constitutional symptoms and cytopenias overlap significantly 3, 2
• Monitor for rapid deterioration and multiple organ failure, particularly in SFTS and HLH 1, 5

Additional Considerations

COVID-19

• COVID-19 can present with fever, leukopenia, lymphocytopenia, elevated ESR, and elevated inflammatory markers 8
• However, the lymphocytosis (78%) in this case makes COVID-19 less likely, as COVID-19 typically causes lymphopenia 8

Kawasaki Disease (Less Likely in Adults)

• Kawasaki disease presents with fever, elevated ESR, and thrombocytosis (not thrombocytopenia) in the second week 8
• The thrombocytopenia and lymphocytosis pattern makes this diagnosis unlikely 8