What is the diagnostic workup for an adult patient with no significant past medical history presenting with leukopenia and neutropenia?

Diagnostic Workup for Leukopenia and Neutropenia

For an adult patient with no significant past medical history presenting with leukopenia and neutropenia, begin with a CBC with manual differential and peripheral blood smear review, followed by comprehensive metabolic panel, liver function tests, and targeted testing for medications, infections, autoimmune disorders, and nutritional deficiencies, reserving bone marrow examination for cases with persistent worsening, dysplasia on smear, or bi/pancytopenia. 1

Initial Laboratory Assessment

Essential First-Line Tests

• Obtain a CBC with manual differential to quantify the absolute neutrophil count (ANC) and assess severity—neutropenia is defined as ANC <1,500/mcL 2, 3

• Review a peripheral blood smear manually to evaluate for dysplasia, circulating blasts, or morphologic abnormalities that would mandate immediate bone marrow examination 1, 4

• Obtain comprehensive metabolic panel including lactate dehydrogenase, uric acid, potassium, calcium, and phosphorus to assess systemic conditions 1

• Obtain liver function tests to evaluate hepatic involvement and potential causes 1

• Review all current and recent medications thoroughly, as drugs are the most common cause of acquired neutropenia 1, 5

Targeted Testing for Isolated Leukopenia/Neutropenia

• Test for autoimmune disorders with antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA) 1

• Measure quantitative serum immunoglobulin levels including IgE to assess immune function 1

• Obtain inflammatory markers including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) 1

• Check vitamin B12 and folate levels to assess nutritional deficiencies, particularly important in patients on methotrexate or with dietary restrictions 1

• Consider infectious workup based on clinical context, as infection is a common cause of transient neutropenia 5, 3

Risk Stratification and Decision Points

Immediate Bone Marrow Examination Required If:

• Peripheral blood smear shows dysplasia, circulating blasts, or other morphologic abnormalities—proceed immediately to bone marrow aspiration and biopsy with flow cytometry, cytogenetics (conventional karyotyping), and molecular studies 1, 6

• Pancytopenia or bicytopenia is present—this usually implies insufficient bone marrow production and mandates bone marrow examination 1, 4

• Severe neutropenia with ANC <500/mcL increases susceptibility to life-threatening bacterial or fungal infections and requires urgent evaluation 3

Bone Marrow Examination Indicated If:

• Leukopenia is persistent or worsening on repeat CBC within 2-4 weeks despite removal of potential offending agents 1

• No clear extrinsic cause identified after comprehensive initial workup 7, 3

• Clinical suspicion for underlying hematologic disorder based on duration (chronic neutropenia lasting >3 months) or associated symptoms 3

Special Considerations

Febrile Neutropenia

• If fever develops with neutropenia, this is a medical emergency—immediate hospital admission and broad-spectrum antibiotics are mandatory to reduce mortality 4

• Assess risk of febrile neutropenia systematically in all neutropenic patients 2

Bone Marrow Examination Protocol (When Indicated)

• Obtain fresh bone marrow aspirate for morphologic evaluation with aspirate smears 6

• Obtain adequate bone marrow trephine core biopsy with touch preparations 6

• Perform multicolor comprehensive flow cytometry panel (8-10 colors) sufficient to distinguish myeloid, lymphoid, or mixed lineage abnormalities 6

• Perform conventional cytogenetic analysis (karyotyping) as this is essential for diagnosis and risk stratification 6

• Perform appropriate molecular genetic and/or FISH testing based on initial findings 6

Common Pitfalls to Avoid

• Do not assume benign ethnic neutropenia without excluding other causes—complete the initial workup first 7

• Do not delay bone marrow examination when indicated—dysplasia or cytopenias warrant immediate evaluation 1, 4

• Do not overlook medication history—this is the most common reversible cause of acquired neutropenia 1, 5

• Do not use growth factors empirically—there is no evidence to support continuous use in neutropenic patients without specific indications 6

• Do not perform bone marrow examination for transient, mild neutropenia with clear viral etiology—repeat CBC in 2-4 weeks instead 1, 3