What causes an elevated White Blood Cell (WBC) count in the absence of infection?

Causes of Elevated White Blood Cell Count Without Infection

An elevated white blood cell count without signs of infection is most commonly caused by physiologic stress responses, medications, inflammatory conditions, hematologic disorders, or malignancies that require careful evaluation to determine the underlying cause and appropriate management.

Common Non-Infectious Causes of Leukocytosis

Physiologic and Stress-Related Causes

• Acute physical stress: Surgery, trauma, burns, exercise
• Emotional stress: Anxiety, panic attacks
• Pregnancy: Normal physiologic leukocytosis

Medication-Induced Leukocytosis

• Corticosteroids: Cause demargination of neutrophils
• Epinephrine/catecholamines: Increase WBC mobilization
• Lithium: Stimulates granulocyte production
• Growth factors: G-CSF, GM-CSF

Inflammatory Conditions

• Autoimmune disorders: Rheumatoid arthritis, systemic lupus erythematosus
• Vasculitis: Polyarteritis nodosa, giant cell arteritis
• Inflammatory bowel disease: Crohn's disease, ulcerative colitis
• Tissue injury: Burns, myocardial infarction, pulmonary embolism
• Gout: Can cause markedly elevated WBC counts, even >100,000/μL in joint fluid 1

Hematologic Disorders and Malignancies

• Myeloproliferative disorders: Polycythemia vera, essential thrombocythemia
• Leukemia: Acute or chronic forms
• Lymphoma: Hodgkin's and non-Hodgkin's
• Myelodysplastic syndromes: Particularly with disease progression

Other Causes

• Asplenia: Functional or anatomic (post-splenectomy)
• Smoking: Causes chronic leukocytosis
• Obesity: Associated with chronic low-grade inflammation

Diagnostic Approach

Laboratory Evaluation

1. Complete blood count with differential:

   • Evaluate for specific cell line elevations (neutrophils, lymphocytes, eosinophils, etc.)
   • Look for immature forms (bands, metamyelocytes) 2
   • Assess for left shift (≥16% bands or total band count ≥1500/mm³) 2

2. Peripheral blood smear:

   • Evaluate cell morphology for abnormalities
   • Check for toxic granulations, Döhle bodies (suggesting inflammation)
   • Look for blast cells (suggesting malignancy)

3. Additional tests based on clinical suspicion:

   • Inflammatory markers (CRP, ESR)
   • Liver and kidney function tests
   • Specific tests for suspected conditions

Clinical Correlation

• Fever absence doesn't rule out infection: Up to 21.6% of patients with bacteremia may not present with fever 3
• Normal WBC with bandemia: Elevated band counts with normal total WBC can still indicate infection (odds ratio 2.0-2.8 for positive cultures) 4

Important Considerations

When to Suspect Malignancy

• Persistent unexplained leukocytosis
• Accompanying symptoms: weight loss, night sweats, fatigue, bruising
• Abnormal cells on peripheral smear
• Associated cytopenias in other cell lines

When to Suspect Occult Infection

• Presence of bandemia (>10% bands) even with normal total WBC count 4
• Elevated CRP (present in >98% of bacteremic episodes) 3
• Neutrophilia (≥80% neutrophils) 3
• Rapid increase in WBC (>10,000/μL within ≤3 months) 2

Pitfalls to Avoid

1. Assuming normal WBC excludes infection: Bandemia with normal WBC count can indicate infection and carries increased mortality risk 4

2. Overlooking non-infectious causes: Always consider medication effects, stress response, and underlying conditions

3. Missing hematologic malignancies: Persistent unexplained leukocytosis warrants hematology referral 5

4. Focusing only on total WBC count: The differential count provides crucial diagnostic information 2

Management Approach

1. Review medication list for potential causes
2. Assess for physiologic stressors
3. Evaluate for inflammatory conditions
4. Consider hematologic disorders if persistent
5. Monitor trends in WBC count over time
6. Refer to hematology for persistent unexplained leukocytosis

Remember that while an elevated WBC count without obvious infection requires thorough evaluation, the likelihood ratio for bacterial infection increases significantly with leukocytosis >14,000/mm³ (LR 3.7), left shift with >16% bands (LR 4.7), or elevated total band count >1500/mm³ (LR 14.5) 2.