What is the differential diagnosis and initial management for a 15‑year‑old boy presenting with fever and pancytopenia?

Differential Diagnosis of Pancytopenia with Fever in a 15-Year-Old Male

The differential diagnosis for a 15-year-old male with fever and pancytopenia must prioritize life-threatening hematologic malignancies and bone marrow failure syndromes first, followed by treatable infectious and nutritional causes that can mimic malignancy but respond rapidly to therapy.

Primary Life-Threatening Diagnoses to Rule Out Immediately

Hematologic Malignancies

• Acute leukemia (ALL, AML, or myelodysplastic syndrome) accounts for 13-21% of pancytopenia cases in pediatric patients and requires urgent diagnosis 1, 2
• Peripheral blood smear showing blasts, marked anisocytosis, poikilocytosis, or elevated atypical lymphocytes suggests malignancy 3
• Non-Hodgkin lymphoma, Hodgkin's lymphoma with myelofibrosis, and malignant histiocytosis can present with pancytopenia 4

Bone Marrow Failure Syndromes

• Aplastic anemia represents 18-24% of pancytopenia cases in children and adolescents 5, 1
• High-risk patients with profound neutropenia (ANC <100 cells/µL) and prolonged duration (>7 days) require immediate empiric antibiotics 6
• Hemophagocytic syndrome associated with infection can cause rapidly progressive pancytopenia with fever and multiorgan failure 3, 4

Treatable Infectious Causes (Critical Not to Miss)

Bacterial Infections

• Enteric fever (typhoid) accounts for 10-30% of infectious pancytopenia cases in endemic areas 1, 2
• Bacterial sepsis causes 8.69% of pancytopenia presentations and requires immediate broad-spectrum antibiotics 1
• Brucellosis presents with fever, pancytopenia, hepatosplenomegaly, and mild transaminitis; bone marrow culture has highest sensitivity 6

Parasitic Infections

• Malaria accounts for 8.69% of pancytopenia cases and requires thick/thin blood smears 1
• Kala-azar (visceral leishmaniasis) presents with prolonged fever, splenomegaly, and pancytopenia 2

Tickborne Rickettsial Diseases

• Anaplasmosis causes leukopenia, thrombocytopenia, elevated hepatic transaminases, and mild anemia; blood smear may reveal morulae within granulocytes 6
• Ehrlichiosis presents similarly with fever, headache, myalgia, and characteristic laboratory findings 6

Viral Infections

• Epstein-Barr virus can cause severe pancytopenia with shock and multiorgan failure, particularly in immunocompromised patients; real-time PCR shows high viral load even with negative monospot 3
• HIV seroconversion should be considered with unexplained blood dyscrasia, fever, and lymphadenopathy 6

Nutritional/Metabolic Causes (Rapidly Reversible)

Megaloblastic Anemia

• Most common reversible cause, accounting for 13-28% of pancytopenia cases in pediatric studies 5, 1, 2
• Folate or vitamin B12 deficiency can present with severe thrombocytopenia (platelets ≤20 × 10⁹/L) and bleeding manifestations in 45% of patients 2
• Dimorphic anemia is the predominant blood picture; bone marrow shows hypercellularity with megaloblastic erythropoiesis 5

Critical Initial Evaluation Algorithm

Immediate Laboratory Assessment

• Complete blood count with differential to quantify degree of cytopenias and identify blasts or atypical cells 6
• Peripheral blood smear is mandatory to evaluate for blasts, megaloblastic changes, morulae, or malarial parasites 6, 5, 3
• Reticulocyte count helps distinguish hypoproliferative from consumptive processes 1
• Blood cultures (at least 2 sets) before any antibiotics 6
• Hepatic transaminases and serum sodium level guide differential diagnosis 6

Risk Stratification for Empiric Antibiotics

• High-risk criteria: ANC <100 cells/µL, anticipated prolonged neutropenia (>7 days), or clinical instability 6
• Empiric vancomycin plus antipseudomonal antibiotics (cefepime, carbapenem, or piperacillin-tazobactam) for high-risk patients with fever and neutropenia 6
• Doxycycline should be added immediately if tickborne rickettsial disease is suspected based on epidemiology, as delay increases mortality 6

Bone Marrow Examination

• Bone marrow aspiration/biopsy is conclusive in nearly all cases and differentiates between hypercellular (megaloblastic, leukemia) versus hypocellular (aplastic) etiologies 5, 1
• Obtain before initiating chemotherapy but do not delay antibiotics while awaiting procedure 6
• Bone marrow culture has highest sensitivity for brucellosis 6

Common Clinical Pitfalls to Avoid

Do Not Assume Single Etiology

• Infections and hematologic malignancies can coexist; positive infectious workup does not exclude underlying malignancy 6
• Immunocompromised patients have wider differential including opportunistic infections and atypical presentations 6

Do Not Delay Treatment Based on Appearance

• Clinical appearance is unreliable; neutropenic patients often lack typical signs of inflammation even with severe infection 6
• Skin lesions, no matter how innocuous, require aggressive evaluation with biopsy/aspiration in neutropenic patients 6

Do Not Withhold Antibiotics Pending Cultures

• Treatment decisions should never be delayed while awaiting laboratory confirmation, particularly for rickettsial diseases where delay leads to severe disease and death 6
• Empiric broad-spectrum antibiotics including staphylococcus coverage should be initiated immediately in febrile neutropenic patients 6

Do Not Overlook Treatable Causes

• Megaloblastic anemia and infections "look ominous but respond rapidly to effective therapy" and should be actively sought before assuming malignancy 2
• Severe thrombocytopenia with bleeding in megaloblastic anemia reverses completely with vitamin replacement 2