What are the causes and management of elevated White Blood Cell (WBC) count?

Elevated White Blood Cell Count: Causes and Management

Primary Causes

Elevated WBC count most commonly results from infection, physiological stress, medications, or chronic inflammatory conditions, with malignant causes being less frequent but requiring systematic exclusion. 1, 2

Infectious Causes

• Bacterial infections are the most important infectious cause, typically producing neutrophil predominance with left shift (≥6% bands or ≥1,500 bands/mm³) and WBC counts ≥14,000 cells/mm³ 1
• Viral infections paradoxically often cause leukopenia rather than leukocytosis, particularly influenza (8-27% show WBC <4 × 10⁹/L) 1
• Absence of fever and localizing symptoms makes bacterial infection unlikely despite elevated WBC 3

Physiological and Medication-Induced Causes

• Corticosteroids cause dose-dependent leukocytosis: low-dose increases WBC by 0.3 × 10⁹/L, medium-dose by 1.7 × 10⁹/L, and high-dose by 4.84 × 10⁹/L, peaking at 48 hours 4
• Lithium therapy consistently elevates WBC; counts below 4,000/mm³ would be unusual in lithium-treated patients 1
• Physical and emotional stress trigger acute leukocytosis through catecholamine and cortisol release, with WBC potentially doubling within hours 1, 2
• Exercise, surgery, trauma, and seizures all produce transient elevations 2, 5

Chronic Inflammatory Conditions

• Smoking, obesity, and inflammatory bowel disease cause persistent mild elevation 1
• Adult-Onset Still's Disease produces striking neutrophilia (50% have WBC >15 × 10⁹/L; 37% have WBC >20 × 10⁹/L) 1

Malignant Causes

• Acute leukemias present with illness, concurrent cytopenias, and often extreme elevations 5
• Chronic leukemias are typically diagnosed incidentally with asymptomatic elevation 5
• Chronic myelomonocytic leukemia (CMML) shows rapidly increasing WBC (>10,000/μL within ≤3 months) in absence of infection as a sign of disease progression 6

Diagnostic Evaluation Algorithm

Initial Assessment

• Obtain CBC with manual differential to assess absolute neutrophil count, band forms, and cell maturity 1
• Check for concurrent cytopenias: anemia or thrombocytopenia suggests bone marrow pathology rather than reactive leukocytosis 3
• Assess systematically for infection: fever, localizing symptoms, or sepsis signs mandate evaluation for bacterial infection 1

Risk Stratification by WBC Level

• WBC >100,000/mm³ represents a medical emergency due to risk of leukostasis (brain infarction, hemorrhage, respiratory failure) 5, 7
• WBC ≥14,000/mm³ with left shift strongly suggests bacterial infection requiring careful assessment 1
• Mild elevations require clinical context—single measurements may reflect transient physiological variation 1

Red Flags for Malignancy

• Fever, weight loss, bruising, or fatigue suggest hematologic malignancy 2
• Hepatosplenomegaly or lymphadenopathy increase suspicion for marrow disorder 5
• Extremely elevated counts or concurrent red blood cell/platelet abnormalities warrant hematology referral 2, 5

Management Strategies

For Reactive Leukocytosis

• Direct all management at the underlying condition: treat infection, remove offending medication, or address inflammatory process 3
• Serial measurements are more informative than single values for persistent unexplained elevation 1
• Do not treat reactive leukocytosis with G-CSF or growth factors—these are reserved for neutropenia, not leukocytosis 3

For Hyperleukocytosis (>100,000/mm³)

• Evaluate immediately for leukostasis symptoms: unexplained hypoxia, neurological changes, renal failure, cardiac ischemia, priapism, or severe retinopathy 3
• Initiate hydroxyurea at 50-60 mg/kg/day until WBC <10-20 × 10⁹/L 6
• Ensure adequate hydration (3 L/m² per day) unless renal insufficiency present 3
• Consider leukapheresis only for symptomatic leukostasis with organ compromise, but this should not delay definitive therapy 6, 3
• Avoid excessive red blood cell transfusions until WBC reduced (increases blood viscosity) 6

For Tissue Destruction-Related Elevation

• Surgical debridement, revascularization, infection control, or supportive care takes priority over leukapheresis 3
• Prompt treatment of underlying condition is more important than addressing the WBC elevation itself 3

For Suspected Malignancy

• Patients with acute leukemia and hyperleukocytosis require immediate referral for induction chemotherapy and leukapheresis 7
• If malignancy cannot be excluded or another likely cause is not identified, refer to hematology/oncology 2

Critical Pitfalls to Avoid

• Normal WBC does not exclude bacterial infection—sensitivity is low, particularly in elderly or immunosuppressed patients 1
• Do not over-interpret single mildly elevated WBC without clinical context—transient elevations occur with exercise, stress, or diurnal variations 1
• Do not routinely perform leukapheresis—it is only indicated for symptomatic leukostasis with organ dysfunction 3
• Leukapheresis is not recommended for APL with high WBC due to different leukemia biology, though may be considered with caution in life-threatening leukostasis unresponsive to other modalities 6
• Increases up to 4.84 × 10⁹/L within 48 hours after high-dose steroids are expected; larger increases suggest other causes 4