I have persistent leukocytosis with white blood cell counts of 16.4, 16.5, 14.3, 10.7, 13.8 and 13.4 ×10³/µL (normal 3.8–10.8 ×10³/µL); what are the possible causes and recommended work‑up?

Persistent Leukocytosis: Diagnostic Workup and Differential Diagnosis

Your persistent leukocytosis (WBC 13.4–16.5 × 10³/µL) requires immediate CBC with manual differential and peripheral blood smear review to identify the elevated cell line and exclude malignant cells, followed by systematic evaluation for infection, inflammatory conditions, medications, and hematologic malignancies. 1, 2

Immediate First-Line Testing

Order these tests now:

• CBC with manual differential to determine which white blood cell line is elevated (neutrophils, lymphocytes, monocytes, eosinophils, or basophils) and calculate absolute counts 1, 2
• Peripheral blood smear review to examine WBC morphology, assess for left shift, and rule out blast cells, immature forms, or dysplastic features 1, 2
• Comprehensive metabolic panel to monitor for tumor lysis syndrome and assess organ function 1, 2

The manual differential is critical because automated counts can miss dysplasia, immature forms, and blast cells that indicate malignancy 1.

Most Likely Causes Based on Your WBC Range

For WBC counts in the 13–17 × 10³/µL range, the differential diagnosis includes:

Benign/Reactive Causes (Most Common)

• Infection (particularly bacterial): A left shift ≥16% band neutrophils increases likelihood ratio to 4.7 for bacterial infection; absolute band count ≥1,500 cells/mm³ increases likelihood ratio to 14.5 1, 2
• Chronic inflammatory conditions: Rheumatologic diseases, inflammatory bowel disease 3, 4
• Medications: Corticosteroids, lithium, beta-agonists 3, 4
• Smoking and obesity 3
• Physical or emotional stress: Surgery, trauma, exercise 3, 4

Hematologic Malignancies (Less Common but Critical to Exclude)

• Chronic myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, chronic myeloid leukemia) 5
• Chronic lymphocytic leukemia (more likely if WBC >50 × 10³/µL) 6
• Chronic myelomonocytic leukemia 5

Red Flags Requiring Urgent Hematology Referral

Refer immediately to hematology/oncology if any of the following are present:

• Blast cells, immature forms, or dysplastic features on peripheral smear 1, 2
• Splenomegaly or lymphadenopathy on examination 1
• Constitutional symptoms: Fever, unintentional weight loss, night sweats, bruising, or fatigue 3, 7
• Concurrent abnormalities in hemoglobin or platelet counts 1, 4
• WBC >100 × 10³/µL (hyperleukocytosis—medical emergency) 5, 4

Systematic Workup Based on Differential Results

If Neutrophil-Predominant Leukocytosis

• Assess for infection systematically: Obtain blood cultures before starting antibiotics if systemic symptoms or sepsis signs present 2
• Check for left shift: Neutrophil percentage >90% has likelihood ratio of 7.5 for bacterial infection 1, 2
• Site-specific evaluation: Urinalysis/culture for urinary symptoms, chest imaging for respiratory symptoms, CT for suspected intra-abdominal infection 2

If Lymphocytosis

• Consider viral infections (especially in younger patients), chronic lymphocytic leukemia (especially if persistent and patient >50 years), or autoimmune conditions 3, 8

If Monocytosis

• If isolated monocytosis with normal total WBC, observation with repeat CBC in 4–6 weeks is appropriate 1
• If persistent with elevated total WBC, consider chronic myelomonocytic leukemia 5

If Eosinophilia

• Evaluate for parasitic infections, allergic conditions, or drug reactions 3, 4

Management Algorithm for Your Specific Case

Since your WBC counts are persistently elevated (13.4–16.5 × 10³/µL):

1. If asymptomatic with no fever, weight loss, or night sweats: Obtain CBC with manual differential and peripheral smear immediately 1, 2

2. If peripheral smear shows normal mature cells without left shift:

   • Review medication list (corticosteroids, lithium, beta-agonists) 3, 4
   • Assess for chronic inflammatory conditions 3
   • Repeat CBC in 2–4 weeks to assess for persistence 1

3. If peripheral smear shows left shift or immature forms: Evaluate for infection with blood cultures, urinalysis, chest imaging as clinically indicated 2

4. If peripheral smear shows any abnormal cells: Urgent hematology referral for bone marrow biopsy 1, 2

Critical Pitfalls to Avoid

• Do not overlook absolute neutrophil count elevation when total WBC is only mildly elevated—left shift can occur with normal WBC and still indicate serious bacterial infection 1, 2
• Do not treat asymptomatic patients with antibiotics based solely on mildly elevated WBC counts without evidence of infection 1, 2
• Do not rely on automated differential alone—manual differential is essential to detect dysplasia or immature forms 1
• Do not ignore leukocytosis without fever, particularly in older adults, as infection can be present without fever 2
• Do not delay hematology referral if constitutional symptoms or abnormal peripheral smear are present 3, 7

When Malignancy Is More Likely

Mortality increases significantly with higher WBC counts: 2.8% for WBC 35–39.9 × 10³/µL versus 33% for WBC 40–50 × 10³/µL 6. While your counts are lower, persistent leukocytosis warrants exclusion of chronic myeloproliferative disorders, especially if accompanied by splenomegaly (WBC count <10 × 10⁹/L is a criterion for complete remission in polycythemia vera and essential thrombocythemia) 5.