What are the causes of a raised white blood cell (WBC) count, excluding sepsis?

Causes of Raised White Blood Cell Count (WBC) Excluding Sepsis

The most common causes of leukocytosis (raised white blood cell count) excluding sepsis include infections (bacterial, viral, parasitic), inflammatory conditions, medications (especially corticosteroids), physiological stress, hematologic malignancies, and tissue damage. 1

Infectious Causes

Bacterial Infections

• Localized bacterial infections without systemic sepsis:
  • Pneumonia
  • Urinary tract infections
  • Skin/soft tissue infections (cellulitis)
  • Intra-abdominal infections (diverticulitis, appendicitis)
  • Bacterial meningitis 2

Viral Infections

• Viral respiratory infections can cause leukocytosis, though typically with lymphocyte predominance rather than neutrophilia
• Certain viral infections may show WBC counts up to 15.0 x 10^9/L, though bacterial infections typically show higher counts 3

Parasitic Infections

• Parasitic infections with tissue phase involvement often present with eosinophilia
• Increased eosinophil count can contribute to overall leukocytosis 2

Inflammatory Conditions

Autoimmune/Inflammatory Disorders

• Rheumatoid arthritis - 27% of patients show leukocytosis (>10,000/mm³), with higher prevalence (40%) in those on steroid therapy 4
• Inflammatory bowel disease - active disease often shows elevated WBC count 2
• Vasculitis
• Tissue necrosis (pancreatitis, myocardial infarction)

Cardiac Conditions

• Pericarditis - inflammatory pericardial effusions show high WBC counts, particularly with neutrophil predominance in bacterial and rheumatologic origins 2

Medication-Induced Leukocytosis

Corticosteroids

• Cause significant leukocytosis through demargination and delayed apoptosis of neutrophils
• Dose-dependent effect:
  • High-dose steroids: mean increase of 4.84 × 10^9/L WBCs within 48 hours
  • Medium-dose: mean increase of 1.7 × 10^9/L WBCs
  • Low-dose: mean increase of 0.3 × 10^9/L WBCs 5

Other Medications

• Lithium
• Beta-agonists
• Epinephrine
• Granulocyte colony-stimulating factors (G-CSF) 6

Physiological Stress Responses

Physical Stress

• Seizures
• Anesthesia
• Overexertion
• Surgery
• Trauma 6

Emotional/Psychological Stress

• Acute emotional stress can trigger leukocytosis through catecholamine release 6

Hematologic Disorders

Primary Bone Marrow Disorders

• Acute leukemias - often present with extremely elevated WBC counts, sometimes >100,000/mm³ (medical emergency)
• Chronic leukemias - often diagnosed incidentally due to abnormal blood counts
• Myeloproliferative disorders - polycythemia vera, essential thrombocythemia 6

Other Causes

Tissue Damage

• Burns
• Surgery
• Myocardial infarction
• Pulmonary embolism

Metabolic/Endocrine

• Diabetic ketoacidosis
• Thyroid storm
• Cushing's syndrome

Malignancy

• Solid tumors can cause paraneoplastic leukocytosis

Clinical Approach to Leukocytosis

Diagnostic Value of WBC Patterns

• Left shift (increased immature neutrophils/bands) strongly indicates bacterial infection
  • Band counts >1,500 cells/mm³ has likelihood ratio of 14.5 for bacterial infection
  • Neutrophils >90% has likelihood ratio of 7.5 for bacterial infection 1

Red Flags for Serious Causes

• WBC count >100,000/mm³ represents a medical emergency (risk of brain infarction and hemorrhage)
• Concurrent abnormalities in red blood cell or platelet counts suggest bone marrow disorders
• Weight loss, bleeding/bruising, hepatosplenomegaly, or lymphadenopathy suggest malignancy 6

Pitfalls and Caveats

1. Don't assume all leukocytosis is infectious - consider medication effects, especially corticosteroids, which can cause significant increases (up to 4.84 × 10^9/L)

2. Pattern matters - neutrophilia suggests bacterial infection or inflammation, lymphocytosis suggests viral infection, eosinophilia suggests parasitic or allergic conditions

3. Context is crucial - in patients with rheumatoid arthritis on steroids, leukocytosis is common (40%) and doesn't necessarily indicate infection 4

4. Degree matters - extremely high counts (>100,000/mm³) warrant immediate attention for potential leukemia

5. Cardiovascular risk - persistent leukocytosis is associated with increased risk of ischemic stroke in patients with coronary heart disease (HR = 1.39; 95% CI 1.03-1.87) 7

By systematically evaluating the pattern of leukocytosis, associated symptoms, medication history, and other laboratory findings, clinicians can effectively narrow down the differential diagnosis of elevated white blood cell count beyond sepsis.