What is the appropriate workup for a patient with persistent leukocytosis (elevated white blood cell count)?

Workup for Persistent Leukocytosis

Begin with a complete blood count with differential and peripheral blood smear examination to distinguish between benign reactive processes and hematologic malignancies, as this is the critical first step that determines all subsequent management. 1

Initial Laboratory Assessment

Essential First-Line Tests

• Complete blood count with differential is mandatory to quantify the degree of leukocytosis and identify which cell line is elevated 2, 1
• Peripheral blood smear examination is essential and non-negotiable—this allows manual verification of the automated differential and identifies morphologic features that distinguish malignant from reactive processes 1, 3
• Manual differential count must be performed to accurately enumerate blasts, blast equivalents, immature granulocytes (bands), basophils, eosinophils, and to identify dysplastic features 1

The peripheral smear distinguishes between:

• Reactive processes: showing pleomorphic, activated neutrophils with toxic granulation, Döhle bodies, and cytoplasmic vacuolization 1
• Malignant processes: showing monomorphic populations, dysplastic features, increased blasts (≥10-20%), or marked basophilia 1, 3

Critical Threshold Definitions

• Leukemoid reaction: neutrophilic leukocytosis >50,000 cells/μL when the cause is not leukemia 4
• Significant persistent leukocytosis: WBC >13 × 10⁹/L sustained over weeks to months warrants comprehensive evaluation 5
• Blast percentage matters: ≥10% immature myeloid precursors or any lymphoblasts necessitates immediate bone marrow examination 6, 1

Distinguishing Myeloid vs. Lymphoid Leukocytosis

For Myeloid-Predominant Leukocytosis

If the peripheral smear shows neutrophilia with left shift, basophilia, or eosinophilia, immediately exclude chronic myeloid leukemia (CML) and other myeloproliferative neoplasms before attributing to reactive causes. 6, 4

• BCR-ABL1 testing (qualitative RT-PCR or FISH) is mandatory to exclude CML in any unexplained persistent myeloid leukocytosis 6
• JAK2 V617F mutation testing should be performed if polycythemia vera or other myeloproliferative neoplasm is suspected 5
• Bone marrow aspiration and biopsy with cytogenetics are indicated when: 6, 2
  • Dysplastic features are present on peripheral smear
  • Blasts or blast equivalents are ≥5-10%
  • Persistent unexplained leukocytosis with other cytopenias
  • Basophilia >20% or marked eosinophilia
  • Splenomegaly is present

For Lymphoid-Predominant Leukocytosis

• Examine lymphocyte morphology: pleomorphic reactive lymphocytes versus monomorphic population (favoring lymphoproliferative disorder) 1
• Flow cytometry immunophenotyping on peripheral blood is required when lymphoproliferative disorder is suspected, using markers to distinguish B-cell, T-cell, and NK-cell lineages 6, 2, 1
• Bone marrow examination is mandatory if lymphoblasts are identified, as this indicates acute lymphoblastic leukemia 6, 1

Bone Marrow Evaluation (When Indicated)

When bone marrow examination is performed, the following must be included: 6, 2

• Morphologic examination with cytology to assess cellularity and blast percentage
• Cytochemical studies (myeloperoxidase and nonspecific esterase) for AML subclassification 6
• Conventional cytogenetic analysis (karyotyping) to identify chromosomal abnormalities such as t(9;22) for CML, t(15;17) for acute promyelocytic leukemia, or complex karyotypes 6
• Flow cytometry immunophenotyping with comprehensive marker panels 6, 2
• Molecular genetic testing including: 6
  • BCR-ABL1 quantitative PCR if CML is diagnosed
  • FLT3-ITD, NPM1, CEBPA for AML risk stratification
  • JAK2, CALR, MPL mutations for myeloproliferative neoplasms

Evaluation for Reactive Causes

If malignancy is excluded, persistent leukocytosis most commonly results from severe tissue damage, ongoing inflammation, or the persistent inflammation-immunosuppression and catabolism syndrome (PICS) rather than active infection. 7

Clinical Context Assessment

Common causes of reactive leukocytosis include: 7, 4, 3

• Severe infections (though often overdiagnosed as the cause)
• Major trauma (associated with highest bandemia)
• Malignancies (solid tumors causing paraneoplastic leukocytosis)
• Severe hemorrhage or acute hemolysis
• Medications (corticosteroids, G-CSF, lithium)
• Tissue necrosis (myocardial infarction, cerebrovascular accident)

Infectious Workup (If Clinically Indicated)

• Cultures (blood, urine, sputum) should be obtained based on clinical suspicion, not reflexively for all leukocytosis 7
• Viral studies may be considered if infectious etiology is suspected 2
• Imaging (chest CT, abdominal CT/ultrasound) only if specific infectious source is suspected 6

Critical pitfall: Avoid prolonged empiric broad-spectrum antibiotics in patients with persistent leukocytosis without documented infection, as this leads to colonization with resistant organisms (particularly Clostridioides difficile) without improving leukocytosis or outcomes 7

Additional Laboratory Tests

Coagulation Studies

• Prothrombin time, partial thromboplastin time, fibrinogen, and D-dimer should be obtained if acute promyelocytic leukemia is suspected (to assess for disseminated intravascular coagulation) 6, 2

Tumor Lysis Markers (If Malignancy Suspected)

• Lactate dehydrogenase and uric acid levels should be measured when hematologic malignancy is being considered 2

Monitoring and Follow-up

• Serial complete blood counts every 2-4 weeks to assess persistence and trajectory of leukocytosis 6
• Development of eosinophilia (>500 cells/μL) during hospitalization may indicate PICS and suggests tissue damage rather than infection 7
• Repeat peripheral smear if cell counts change significantly or new symptoms develop 1

Key principle: The duration and degree of leukocytosis matter—transient elevations (<2 weeks) with clear precipitant require observation only, while persistent elevations (>2-4 weeks) without obvious cause mandate comprehensive evaluation including consideration of bone marrow examination 7, 5