Causes of Elevated White Blood Cell Count Without Infection
Elevated white blood cell (WBC) counts without infection can be caused by physiological stress, medications (particularly corticosteroids), exercise, smoking, obesity, chronic inflammatory conditions, hematologic malignancies, and asplenia. 1, 2
Common Non-Infectious Causes of Leukocytosis
Physiological and Stress-Related Causes
- Physical stress: Surgery, trauma, exercise, and emotional stress can cause acute leukocytosis 2
- Physiological variation: The peripheral WBC count can double within hours after certain stimuli due to large bone marrow storage and marginated pools of neutrophils 2
- Pregnancy: Requires use of pregnancy-specific normal ranges for WBC count 2
Medication-Induced Leukocytosis
- Corticosteroids: Can cause significant WBC elevation within 48 hours of administration
- High-dose steroids: Mean increase of 4.84 × 10⁹/L WBCs
- Medium-dose steroids: Mean increase of 1.7 × 10⁹/L WBCs
- Low-dose steroids: Mean increase of 0.3 × 10⁹/L WBCs 3
- Other medications: Various drugs can cause leukocytosis including lithium, beta-agonists, and epinephrine 2
Chronic Medical Conditions
- Smoking: Associated with chronic elevation in WBC count 2
- Obesity: Can lead to persistent leukocytosis 2, 4
- Chronic inflammatory conditions: Rheumatoid arthritis, inflammatory bowel disease, and vasculitis 2
- Asplenia: Absence of spleen function leads to elevated WBC counts 2
- Comorbidities: Diabetes mellitus, chronic kidney disease, and COPD are associated with higher baseline WBC counts 4
Hematologic and Oncologic Causes
- Hematologic malignancies: Leukemia, lymphoma, and myeloproliferative disorders 1, 2
- Solid tumors: Can cause paraneoplastic leukocytosis 2
Exercise-Induced Leukocytosis
- Acute exercise response: WBC counts increase during and after exercise depending on intensity and duration
- Stress hormone mediation: Primarily driven by catecholamines and cortisol
- Differential response: Affects WBC subsets differently (granulocytes, lymphocytes, monocytes) 5
Diagnostic Approach to Leukocytosis Without Infection
Initial Evaluation
- Complete blood count with manual differential: Assess total WBC count, percentage of different cell types, and presence of immature forms 1
- Peripheral blood smear: Evaluate cell morphology, toxic granulations, and cell maturity 2
- Consider age and context-specific normal ranges: Hospital reference ranges (1.6-14.5 × 10⁹/L) differ from outpatient ranges 4
Further Workup Based on Clinical Suspicion
- Medication review: Identify recent corticosteroid use or other medications that can cause leukocytosis 3
- Inflammatory markers: CRP, ESR, and procalcitonin to help distinguish between infectious and non-infectious causes 1
- Specific testing: Based on suspected etiology (e.g., bone marrow evaluation for suspected hematologic malignancy) 1
Clinical Pearls and Pitfalls
Important Considerations
- Serial monitoring: Trends in WBC count are more valuable than single measurements 1
- Context matters: WBC counts between 11-14.5 × 10⁹/L may be normal in hospitalized patients without infection 4
- Demographic factors: Age, race, and BMI influence baseline WBC counts 4
- Corticosteroid effect: WBC response to steroids typically peaks at 48 hours after administration 3
Common Pitfalls
- Overreliance on absolute thresholds: Using outpatient reference ranges for hospitalized patients may lead to unnecessary workups 4
- Failure to consider non-infectious causes: Not recognizing medication effects, particularly steroids 3
- Missing hematologic malignancies: Failing to consider myelodysplastic syndromes in older patients with unexplained cytopenias 1
- Ignoring trends: Focusing on a single WBC measurement rather than monitoring changes over time 1
By systematically evaluating patients with leukocytosis and considering these non-infectious causes, clinicians can avoid unnecessary antibiotic use and pursue appropriate diagnostic workups based on the most likely etiology.