What is the initial workup and treatment for a patient presenting with leukopenia (low white blood cell count)?

Workup for Leukopenia

Begin with a complete blood count with manual differential to determine the absolute neutrophil count (ANC) and assess for blasts, dysplastic changes, or other lineage abnormalities, as this single test determines both severity and guides all subsequent management decisions 1.

Initial Laboratory Assessment

The cornerstone of evaluation requires specific laboratory tests performed immediately:

• Complete blood count with manual differential examining for leukemic blasts, dysplastic changes, and calculation of ANC 1
• Comprehensive metabolic panel including BUN, creatinine, electrolytes, calcium, albumin, and LDH 2, 1
• Peripheral blood smear with manual count to evaluate cell morphology, maturity, and rule out acute leukemia or primary bone marrow disorders 1, 3
• Coagulation screening (PT, PTT, fibrinogen) if any invasive procedures are anticipated 2

Review all previous blood counts to assess the dynamic development and chronicity of the leukopenia, as this distinguishes transient from chronic causes 3, 4.

Severity Classification and Risk Stratification

Classify severity based on ANC to determine urgency of management 1:

• Mild leukopenia: WBC 3.0-4.0 × 10⁹/L requires monitoring only 1
• Moderate neutropenia: ANC 1.0-1.5 × 10⁹/L requires closer surveillance 1
• Severe neutropenia: ANC <1.0 × 10⁹/L demands aggressive management 1
• Profound neutropenia: ANC ≤0.1 × 10⁹/L represents highest risk for life-threatening infection 1

When to Proceed to Bone Marrow Evaluation

Bone marrow aspirate and biopsy are indicated when 1:

• Persistent unexplained leukopenia on repeat testing
• Any cytopenia accompanied by other lineage abnormalities (bicytopenia or pancytopenia)
• Presence of blasts or dysplastic cells on peripheral smear
• Concern for hematologic malignancy based on clinical presentation

The bone marrow evaluation must include morphologic assessment with cytochemistry, conventional cytogenetic analysis (karyotyping), flow cytometry immunophenotyping, molecular genetic testing, and FISH analysis if specific abnormalities are suspected 2, 1.

Additional Workup Based on Clinical Context

For Suspected Infectious or Immune Causes

• Viral studies (HIV, EBV, CMV, hepatitis panel) 1
• Antinuclear antibodies and rheumatologic workup 1
• Blood cultures before initiating antibiotics if febrile 1

For Suspected Malignancy

• Serum LDH and uric acid levels 1
• Beta-2 microglobulin 1
• Serum protein electrophoresis 1
• PET/CT scan if extramedullary disease or lymphadenopathy suspected 2
• Lumbar puncture if CNS involvement possible (particularly in blastic plasmacytoid dendritic cell neoplasm) 2

For Suspected Drug-Induced Leukopenia

Review all medications, particularly recent additions within 2-3 weeks, as beta-lactam-induced leukopenia typically occurs after 2 weeks of cumulative therapy 5, 6. Colchicine can cause leukopenia even at low doses with chronic administration 5.

Immediate Management Based on Severity

Mild Leukopenia (WBC 3.0-4.0 × 10⁹/L)

• Close observation without immediate intervention 1
• Avoid unnecessary antimicrobial prophylaxis to prevent antibiotic resistance 1
• Repeat CBC in 1-2 weeks to assess trajectory 4

Severe Neutropenia with Fever (ANC <1.0 × 10⁹/L + Temperature >38.2°C)

This constitutes a medical emergency requiring immediate action 3, 4:

• Obtain blood cultures and other appropriate cultures before initiating antibiotics 1
• Initiate broad-spectrum antibiotics immediately without waiting for culture results 1
• Admit to hospital for close monitoring 3
• Consider filgrastim (G-CSF) 5 mcg/kg/day subcutaneously only for high-risk patients with profound neutropenia (≤0.1 × 10⁹/L), expected prolonged neutropenia (≥10 days), age >65 years, uncontrolled primary disease, or signs of systemic infection 1, 7

Severe Neutropenia Without Fever

• Avoid invasive procedures due to infection risk 1
• Educate patient on neutropenic precautions (hand hygiene, avoiding crowds, monitoring temperature) 4
• Daily monitoring if ANC <0.5 × 10⁹/L 4

Disease-Specific Management Considerations

For Myelodysplastic Syndromes

• Supportive therapy with erythropoietic stimulating agents for severe anemia (Hb ≤10 g/dL with serum erythropoietin ≤500 mU/dL) 1
• Myeloid growth factors only for febrile severe neutropenia, not for prophylaxis 1
• Hypomethylating agents (azacitidine or decitabine) for high blast counts 1

For Drug-Induced Leukopenia

• Discontinue offending agent immediately 1, 5
• For clozapine-induced leukopenia: stop if WBC 2.0-3.0 × 10⁹/L or ANC 1.0-1.5 × 10⁹/L, monitor daily, resume only when WBC >3.0 × 10⁹/L and ANC >1.5 × 10⁹/L 1
• For clozapine with WBC <2.0 × 10⁹/L or ANC <1.0 × 10⁹/L: permanent discontinuation required 1

Critical Pitfalls to Avoid

• Do not assume all leukopenia requires treatment; mild cases often need observation only 1
• Do not use prophylactic antibiotics or G-CSF in mild leukopenia as this promotes resistance without benefit 1
• Do not perform invasive procedures in severely neutropenic patients without compelling indication due to infection risk 1
• Do not delay antibiotics in febrile neutropenia while awaiting culture results, as mortality increases significantly with each hour of delay 3, 4
• Do not overlook medication review, as drug-induced leukopenia is common and reversible 8, 5, 6

When to Escalate Care

Immediate medical attention is required for 1:

• Development of fever with severe neutropenia (ANC <1.0 × 10⁹/L)
• Signs of infection (hypotension, tachycardia, altered mental status)
• Progressive worsening of leukopenia on serial measurements
• New symptoms suggesting underlying malignancy (night sweats, weight loss, lymphadenopathy)