What is the cause of leukopenia, thrombocytopenia, and fever in a young female?

Differential Diagnosis of Leukopenia, Thrombocytopenia, and Fever in a Young Female

The combination of leukopenia, thrombocytopenia, and fever in a young female requires urgent evaluation for serious bacterial infection, viral illness (particularly dengue, CMV, or severe fever with thrombocytopenia syndrome), hematologic malignancy, or autoimmune conditions including immune thrombocytopenia (ITP) with concurrent infection. 1, 2, 3

Immediate Diagnostic Approach

Initial laboratory evaluation must include:

• Complete blood count with differential to assess severity of cytopenias and identify abnormal cells 1, 3
• Peripheral blood smear reviewed by a hematologist or pathologist to exclude pseudothrombocytopenia, identify blast cells, schistocytes, or atypical lymphocytes 3
• Comprehensive metabolic panel including liver function tests 1, 2
• Inflammatory markers (CRP, ESR, procalcitonin) to distinguish infectious from non-infectious causes 2
• Blood cultures (before antibiotics) 2
• Urinalysis and urine culture (catheterized specimen) 2

Critical Infectious Etiologies

Severe bacterial infections including bacteremia, meningitis, and urosepsis can present with fever and pancytopenia, particularly in the context of sepsis with disseminated intravascular coagulation or hemophagocytic lymphohistiocytosis 4. Young females aged 2 months to 2 years with fever without source have a 3-7% prevalence of urinary tract infection, increasing to 8.1% in girls aged 1-2 years 5, 2.

Viral infections are critical considerations:

• Dengue, severe fever with thrombocytopenia syndrome (SFTS), and other viral hemorrhagic fevers characteristically present with concurrent leukopenia, thrombocytopenia, and normal or low CRP 6, 7
• Cytomegalovirus (CMV) infection can cause leukopenia and thrombocytopenia 8
• The presence of one viral infection does not exclude concurrent bacterial infection 2

SFTS prediction score (leukopenia + thrombocytopenia + normal CRP) has sensitivity 0.85 and specificity 0.98 for differentiating SFTS from other febrile illnesses in endemic areas 6. In SFTS patients, serum ferritin and soluble IL-2 receptor levels may be better mortality indicators than viral load 7.

Hematologic Malignancy Considerations

Acute leukemia or myelodysplastic syndrome must be excluded when fever accompanies pancytopenia 3. The peripheral smear is critical—abnormalities such as blasts, abnormal white cell morphology, or findings inconsistent with isolated thrombocytopenia mandate bone marrow examination 5, 3.

Bone marrow examination is indicated when:

• Systemic symptoms or abnormal physical findings are present 3
• Peripheral smear shows abnormalities inconsistent with ITP 3
• Patient is older than 60 years (less relevant for young females) 3
• Pancytopenia rather than isolated thrombocytopenia is present 3

Immune Thrombocytopenia with Infection

Primary ITP is characterized by isolated thrombocytopenia without leukopenia 5. However, secondary ITP can be associated with viral infections (HIV, hepatitis C, CMV), autoimmune disorders, or recent vaccinations 3. The concurrent presence of leukopenia makes isolated ITP less likely and suggests either:

• Bone marrow suppression from infection or drug effect 8, 9
• Hemophagocytic lymphohistiocytosis 7, 4
• Hematologic malignancy 3

Testing for HIV and hepatitis C is recommended in adults with suspected immune thrombocytopenia 3.

Drug-Induced Cytopenias

Medication history is essential, as drugs can cause leukopenia through bone marrow suppression or immune mechanisms 8, 9. Colchicine, for example, can cause leukopenia particularly in the presence of concurrent viral infection like CMV 8. Drug-induced fever occurs with mean lag time of 21 days (median 8 days) after drug initiation 2.

Risk Stratification for Serious Bacterial Infection

Age-specific risk assessment:

• Neonates (0-28 days) have 13% incidence of serious bacterial infection and require comprehensive evaluation including lumbar puncture 2
• Young infants (29-90 days) have 9% incidence and may be risk-stratified using validated criteria 2
• Fever with leukopenia and thrombocytopenia increases risk regardless of age 5

Management Priorities

Empiric antibiotics should be initiated immediately after blood cultures if serious bacterial infection is suspected, particularly in patients with:

• Fever with neutropenia (absolute neutrophil count <500/μL or <1000/μL with expected decline) 5
• Signs of sepsis or hemodynamic instability 4
• High-risk features including hypotension, altered mental status, or severe mucositis 5

Supportive care includes monitoring for complications:

• Bleeding risk from thrombocytopenia 5
• Infection risk from neutropenia 5
• Organ dysfunction from sepsis or hemophagocytic lymphohistiocytosis 7, 4

Common Pitfalls

Do not assume isolated ITP when leukopenia is present—this combination requires broader differential diagnosis including infection, malignancy, and bone marrow disorders 3.

Do not delay antibiotics while awaiting diagnostic workup in patients with fever and neutropenia, as mortality increases with delayed treatment 5.

Do not overlook geographic and exposure history for endemic infections like SFTS, dengue, malaria, scrub typhus, or leptospirosis 6, 4.

Do not dismiss normal CRP in the setting of fever with cytopenias—certain viral infections characteristically present with normal inflammatory markers 6.