What laboratory tests should be ordered to evaluate a patient with leukopenia (absolute neutrophil count < 1500 cells/µL or low total white‑blood‑cell count)?

Laboratory Evaluation of Leukopenia

Order a complete blood count (CBC) with manual differential, peripheral blood smear, and comprehensive metabolic panel as the initial workup for any patient with leukopenia (ANC < 1500 cells/µL). 1, 2

Initial Essential Laboratory Tests

Immediate First-Line Tests (Within 12–24 Hours)

• CBC with manual differential – Calculate the absolute neutrophil count (ANC = WBC × [% segmented neutrophils + % bands]) to classify neutropenia severity: mild (1.0–1.5 × 10⁹/L), moderate (0.5–1.0 × 10⁹/L), or severe (< 0.5 × 10⁹/L). 1, 2, 3
• Manual peripheral blood smear – Essential to identify dysplasia, immature forms, atypical lymphocytes, or circulating blasts that suggest myelodysplastic syndrome, acute leukemia, or viral infection. 4, 5
• Assess for bi- or pancytopenia – Check hemoglobin and platelet counts; concurrent anemia or thrombocytopenia indicates bone marrow production failure rather than isolated neutrophil destruction. 4, 6
• Left shift assessment – A total band count ≥ 1500 cells/mm³ or band percentage ≥ 6% suggests acute bacterial infection even when total WBC is low. 1

Additional Initial Laboratory Studies

• Comprehensive metabolic panel – Evaluate renal and hepatic function, as these may reveal drug toxicity (e.g., colchicine-induced leukopenia in renal impairment) or systemic illness. 7
• Lactate dehydrogenase (LDH) and uric acid – Elevated levels suggest cell turnover from hematologic malignancy or hemolysis. 1
• Reticulocyte count – Helps distinguish bone marrow failure (low reticulocytes) from peripheral destruction (normal or elevated reticulocytes). 6

Risk-Stratified Additional Testing

For Severe Neutropenia (ANC < 500 cells/µL)

• Blood cultures (two sets from separate sites) – Obtain before antibiotics if fever is present (≥ 38.3°C single reading or ≥ 38.0°C for ≥ 1 hour). 1, 2
• Urinalysis and urine culture – Only if urinary symptoms are present; do not screen asymptomatic patients. 1
• Chest radiograph – If respiratory symptoms, hypoxemia (oxygen saturation < 90%), or respiratory rate ≥ 25 breaths/min are present. 1

For Chronic or Unexplained Neutropenia

• Vitamin B12, folate, and copper levels – Nutritional deficiencies can cause isolated neutropenia or pancytopenia. 8
• Antinuclear antibody (ANA), rheumatoid factor, and anti-neutrophil antibodies – Screen for autoimmune neutropenia, especially in patients with connective tissue disease symptoms. 5, 8
• HIV, hepatitis B, hepatitis C, and EBV/CMV serologies – Viral infections are common causes of transient or chronic neutropenia. 6, 8
• Immunoglobulin levels and lymphocyte subsets (CD3, CD4, CD19, CD20) – Evaluate for immunodeficiency syndromes or chronic lymphocytic leukemia. 1, 6

When Bone Marrow Evaluation Is Indicated

• Bone marrow aspiration and biopsy with cytogenetics – Perform when:
  • Unexplained persistent neutropenia (> 3 months) despite normal initial workup. 6, 8
  • Bi- or pancytopenia suggesting marrow failure. 4, 6
  • Peripheral smear shows dysplasia, blasts, or atypical cells. 1
  • Suspected inherited neutropenia (cyclic neutropenia, severe congenital neutropenia) requiring genetic testing. 6, 8

Critical Pitfalls to Avoid

• Do not delay CBC with manual differential – Automated differentials may miss left shifts, dysplasia, or atypical cells that guide diagnosis. 1, 4
• Do not order blood cultures in afebrile, stable patients – Low yield and rarely influences management in non-febrile leukopenia. 1
• Do not screen for urinary tract infection in asymptomatic patients – Asymptomatic bacteriuria is common and does not require treatment. 1
• Do not assume isolated neutropenia is benign – Always review prior CBCs to assess chronicity and trend; acute drops suggest drug toxicity, infection, or marrow infiltration. 4, 5
• Do not forget to review the medication list – Colchicine, clozapine, chemotherapy, and many other drugs cause dose-dependent or idiosyncratic neutropenia. 8, 7

Monitoring Strategy

• Repeat CBC in 2–4 weeks for asymptomatic mild neutropenia (ANC 1.0–1.5 × 10⁹/L) to distinguish transient from chronic neutropenia. 2, 8
• Daily CBC monitoring for severe neutropenia (ANC < 500 cells/µL) until ANC recovers to > 500 cells/µL. 2
• Weekly CBC for 4–6 weeks in patients starting medications known to cause neutropenia (e.g., chemotherapy, immunosuppressants). 2