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

Causes of Raised White Blood Cell Count (Leukocytosis)

Leukocytosis is most frequently caused by bacterial infections, followed by physical/emotional stress, medications (especially corticosteroids, lithium, and beta-agonists), and chronic inflammatory conditions, while primary bone marrow malignancies are less common but require urgent exclusion. 1

Infection-Related Causes

Bacterial infections are the leading cause of elevated WBC count and should be systematically evaluated first 1:

• Respiratory tract infections (pneumonia, bronchitis) commonly elevate WBC with neutrophil predominance 1
• Urinary tract infections frequently present with leukocytosis and left shift 1
• Skin and soft tissue infections (cellulitis, abscesses) trigger neutrophilic response 1
• Gastrointestinal infections including spontaneous bacterial peritonitis in cirrhotic patients 1
• Clostridium difficile must be excluded in patients with inflammatory bowel disease presenting with leukocytosis 2
• Cytomegalovirus should be ruled out in IBD flares 2

Critical diagnostic markers for bacterial infection:

• Absolute band count ≥1,500 cells/mm³ has the highest likelihood ratio (14.5) for documented bacterial infection 1, 3
• Percentage of neutrophils >90% has likelihood ratio of 7.5 1
• Left shift (≥16% bands) has likelihood ratio of 4.7, even with normal total WBC 1, 3

Physiological and Stress-Related Causes

Non-infectious physiological triggers frequently cause transient leukocytosis 1:

• Emotional stress triggers release of catecholamines and cortisol 1
• Acute exercise causes immediate WBC elevation, particularly granulocytes and NK cells 1
• Physical stress from surgery, trauma, or seizures doubles peripheral WBC within hours due to demargination from bone marrow storage pools 4, 5
• Pregnancy requires pregnancy-specific reference ranges 4

Medication-Induced Leukocytosis

Several medications consistently elevate WBC count 1:

• Corticosteroids are the most common medication cause 1, 4, 5
• Lithium therapy consistently causes leukocytosis; WBC <4,000/mm³ would be unusual in lithium-treated patients 1
• Beta-agonists trigger neutrophilia 1, 5
• Epinephrine causes neutrophilia through demargination 1

Chronic Inflammatory Conditions

Persistent inflammatory states produce sustained leukocytosis 1:

• Adult-onset Still's disease (AOSD) presents with marked leukocytosis: 50% have WBC >15×10⁹/L and 37% have >20×10⁹/L with marked neutrophilia secondary to bone marrow granulocytic hyperplasia 1
• Inflammatory bowel disease activity correlates with leukocytosis, thrombocytosis, and elevated inflammatory markers 2
• Chronic inflammatory conditions including rheumatologic disorders 4

Hematologic Malignancies (Medical Emergency)

Hyperleukocytosis (WBC >100,000/mm³) represents a medical emergency due to risk of cerebral infarction and hemorrhage. 2, 1, 5

Primary bone marrow disorders require urgent hematology referral 1:

• Acute leukemias present with severe symptoms, constitutional signs, and require immediate cytoreductive therapy 2, 6
• Chronic myeloid leukemia (CML) characterized by basophilia (highly specific finding) and requires BCR-ABL1 testing 3
• Myeloproliferative disorders including polycythemia vera and essential thrombocythemia where leukocytosis independently predicts thrombosis 7
• Acute promyelocytic leukemia requires special attention; leukapheresis is contraindicated due to fatal hemorrhage risk 3

Red flags mandating hematology referral:

• Splenomegaly and lymphadenopathy 1
• Constitutional symptoms (fever, weight loss, bruising, fatigue) 4, 8
• Concurrent abnormalities in red blood cells or platelets 5

Other Causes

Additional etiologies to consider 4, 5:

• Asplenia causes persistent mild leukocytosis 4
• Smoking chronically elevates WBC 4
• Obesity associated with baseline leukocytosis 4
• Allergic reactions and parasitic infections cause eosinophilia-driven leukocytosis 4, 5

Diagnostic Algorithm

Immediate evaluation steps 1, 3:

1. Obtain CBC with manual differential (automated analyzers miss band forms and toxic granulations) within 12-24 hours of symptom onset 2, 3
2. Check vital signs immediately for fever, hypotension, tachycardia, tachypnea indicating sepsis 3
3. Obtain lactate level urgently if sepsis suspected (>3 mmol/L mandates immediate antibiotics) 3
4. Review medication list for corticosteroids, lithium, beta-agonists 1
5. Assess inflammatory markers including CRP and ESR 2, 1
6. Blood cultures before antibiotics if systemic signs present 3

For persistent unexplained leukocytosis:

• Peripheral blood smear review for blast cells, dysplasia, toxic granulations 3, 4
• BCR-ABL1 testing if basophilia present 3
• Bone marrow biopsy with cytogenetics if malignancy suspected 3

Critical Pitfalls to Avoid

• Do not dismiss elevated neutrophil percentage when total WBC is only mildly elevated – left shift with normal WBC still indicates serious bacterial infection 1, 3
• Do not rely on automated differential alone – manual review is essential to identify toxic granulations, vacuolization, and left shift 3
• Do not assume absence of infection based on normal WBC – bacterial infections can present with leukopenia in early or severe disease 9
• Do not delay antibiotics in septic patients awaiting culture results – initiate within 1 hour of sepsis recognition 3
• Do not overlook WBC >100,000/mm³ – this is a medical emergency requiring immediate intervention to prevent cerebral complications 2, 1, 5
• Serial measurements are more informative than single values for unexplained persistent elevation 1