What are the etiologies and recommended workup for a mild neutrophil‑predominant leukocytosis?

Etiology and Workup of Mild Neutrophil-Predominant Leukocytosis

For mild neutrophil-predominant leukocytosis (WBC 10-13 × 10⁹/L with neutrophil predominance), the most common etiologies are benign reactive processes including infection, inflammation, medications (corticosteroids, lithium, beta-agonists), physical or emotional stress, smoking, and obesity, which collectively account for the vast majority of cases. 1, 2

Etiologic Categories

Benign Reactive Causes (Most Common)

• Infection: Bacterial infections are the most frequent trigger, causing rapid doubling of peripheral WBC within hours due to mobilization from bone marrow storage pools 1, 2
• Medications: Corticosteroids, lithium, and beta-agonists are the most commonly implicated drugs 2
• Physiologic stress: Surgery, exercise, trauma, emotional stress, and seizures can all elevate neutrophil counts acutely 1, 2
• Chronic conditions: Smoking, obesity, asplenia, and chronic inflammatory disorders produce persistent mild elevations 1

Malignant Causes (Less Common but Critical)

• Chronic myeloid neoplasms: Chronic neutrophilic leukemia (CNL) requires WBC ≥13 × 10⁹/L with CSF3R mutation, while atypical CML requires similar thresholds with dysplasia 3
• Myeloproliferative neoplasms: Polycythemia vera can develop neutrophilic leukocytosis during progression to post-polycythemic myelofibrosis, associated with worse prognosis 4
• Acute leukemia: Presence of ≥20% blasts in blood or bone marrow defines acute leukemia and fundamentally changes management 5

Diagnostic Workup Algorithm

Initial Assessment

Step 1: Repeat CBC with differential and peripheral blood smear review 1, 6

• Confirm the elevation is persistent (not transient)
• Assess white blood cell maturity, uniformity, and presence of toxic granulations 1
• Count blast cells meticulously—≥20% blasts defines acute leukemia 5
• Look for immature myeloid precursors (≥10% suggests chronic myeloid neoplasm) 3

Step 2: Obtain historical neutrophil counts 6

• Timing of the change is crucial for distinguishing acute reactive processes from chronic conditions 6
• Baseline counts help determine if this represents new pathology versus chronic stable elevation

Step 3: Targeted history for red flags 1, 2

• Constitutional symptoms: Fever, unintentional weight loss, night sweats suggest malignancy 1
• Bleeding/bruising: Suggests concurrent platelet dysfunction or thrombocytopenia from bone marrow disorder 2
• Fatigue: May indicate anemia from marrow infiltration 1
• Medication review: Specifically ask about corticosteroids, lithium, beta-agonists 2
• Infection symptoms: Localizing signs of bacterial infection 1, 2
• Splenomegaly/hepatomegaly: Palpable organomegaly increases suspicion for myeloproliferative disorder 2, 4

Risk Stratification for Malignancy

Low suspicion for malignancy if:

• WBC <13 × 10⁹/L with identifiable benign cause (infection, recent stress, medications) 1, 2
• No constitutional symptoms, bleeding, or organomegaly 2
• Peripheral smear shows mature neutrophils without dysplasia or immature forms 1
• No concurrent cytopenias (anemia or thrombocytopenia) 2

High suspicion for malignancy if:

• WBC ≥13 × 10⁹/L without clear reactive cause 3
• Constitutional symptoms present (fever, weight loss, fatigue) 1
• Concurrent cytopenias or abnormal red cell/platelet counts 2
• Peripheral smear shows dysplasia, immature myeloid precursors ≥10%, or blasts 5, 3
• Hepatosplenomegaly or lymphadenopathy on examination 2, 4

Further Testing Based on Risk

For low-risk patients:

• Repeat CBC in 2-4 weeks to establish if transient or persistent 7
• Address identifiable causes (treat infection, discontinue offending medications if possible) 1
• If persistent without explanation, proceed to high-risk workup 1

For high-risk patients (immediate workup):

1. Comprehensive metabolic panel: Monitor for tumor lysis syndrome risk 8
2. Peripheral blood smear expert review: Confirm blast count, assess for dysplasia 8
3. Bone marrow aspiration and biopsy within 24-48 hours if blasts ≥20% or unexplained persistent leukocytosis with concerning features 5
   • Morphologic examination of aspirate smears, touch imprints, and core biopsy 8
   • Multicolor flow cytometry panel to distinguish AML, ALL, or myeloproliferative neoplasm 8
   • Conventional cytogenetics (karyotype) mandatory 8
   • Molecular testing: CSF3R for CNL, ASXL1/SETBP1 for atypical CML, BCR-ABL1 exclusion 3
4. Imaging: Chest X-ray or CT if mediastinal mass suspected; abdominal ultrasound or CT for hepatosplenomegaly assessment 8

Common Pitfalls to Avoid

• Do not dismiss mild leukocytosis without peripheral smear review—blast cells or dysplasia can be present even with modest WBC elevations 1, 6
• Do not attribute leukocytosis to infection without documenting infection resolution and WBC normalization—persistent elevation after infection treatment suggests alternative diagnosis 1
• Do not delay bone marrow biopsy if blasts are present or malignancy suspected—acute leukemia requires urgent diagnosis and treatment initiation 5
• Do not overlook medication history—corticosteroids are frequently missed as a cause of leukocytosis 2
• Do not ignore concurrent cytopenias—the combination of leukocytosis with anemia or thrombocytopenia strongly suggests primary bone marrow disorder 2

When to Refer to Hematology/Oncology

Immediate referral (within 24-48 hours): 1

• Any blast cells identified on peripheral smear 5
• WBC >100 × 10⁹/L (medical emergency due to hyperviscosity risk) 2
• Unexplained persistent leukocytosis with constitutional symptoms, organomegaly, or concurrent cytopenias 1, 2

Routine referral (within 1-2 weeks): 1

• Persistent unexplained leukocytosis after excluding common benign causes
• Dysplastic features on peripheral smear without blasts 3