What are the common causes of leukocytosis?

Causes of Leukocytosis

Leukocytosis is most frequently caused by bacterial infections, followed by physiological stress (exercise, emotional stress, surgery), medications (corticosteroids, lithium, beta-agonists), chronic inflammatory conditions, and less commonly by primary hematologic malignancies. 1

Infectious Causes

Bacterial infections are the leading cause of leukocytosis and should be systematically excluded first. 1

• A left shift (≥16% band neutrophils or absolute band count ≥1,500 cells/µL) has a likelihood ratio of 4.7 to 14.5 for bacterial infection, making it the most predictive laboratory finding. 2, 1
• Neutrophil percentage >90% has a likelihood ratio of 7.5 for bacterial infection. 2
• Common bacterial infections include respiratory tract infections, urinary tract infections, skin/soft tissue infections, gastrointestinal infections, and spontaneous bacterial peritonitis in cirrhotic patients. 1
• In inflammatory bowel disease patients, exclude Clostridium difficile and Cytomegalovirus as triggers. 1

Critical pitfall: A normal total WBC count does not exclude bacterial infection—left shift can occur with normal WBC counts, particularly in elderly or immunosuppressed patients. 1

Physiological and Stress-Related Causes

The peripheral WBC count can double within hours due to demargination from large bone marrow storage pools. 3

• Emotional stress triggers leukocytosis through catecholamine and cortisol release. 1
• Acute exercise causes immediate WBC elevation, particularly granulocytes and NK cells. 1
• Surgery, trauma, and seizures provoke acute leukocytosis through stress responses. 3, 4

Medication-Induced Leukocytosis

• Corticosteroids are the most common medication cause. 1, 4
• Lithium therapy consistently causes leukocytosis; WBC <4,000/mm³ would be unusual in lithium-treated patients. 1
• Beta-agonists and epinephrine cause neutrophilia through adrenergic stimulation. 1, 4

Chronic Inflammatory and Autoimmune Conditions

• Adult-Onset Still's Disease (AOSD) presents with marked neutrophilic leukocytosis: 50% of patients have WBC >15×10⁹/L and 37% have WBC >20×10⁹/L, resulting from bone marrow granulocyte hyperplasia. 5, 6, 1
• Kawasaki disease demonstrates leukocytosis with granulocyte predominance during acute illness; leukopenia or lymphocyte predominance suggests an alternative diagnosis. 5
• Chronic inflammatory conditions cause persistent leukocytosis through ongoing bone marrow stimulation. 6

Hematologic Malignancies (Urgent Recognition Required)

Acute Leukemia

• Detection of blast cells in peripheral blood signals acute leukemia and warrants urgent hematology consultation. 2
• Acute leukemias present with severe constitutional symptoms and require immediate cytoreductive therapy. 1

Chronic Myeloid Leukemia (CML)

• Marked leukocytosis with basophilia, eosinophilia, and left-shifted myeloid maturation (myelocytes, promyelocytes) is characteristic of CML. 2
• Splenomegaly occurs in >50% of CML patients at diagnosis. 2

Chronic Lymphocytic Leukemia (CLL)

• Progressive lymphocytosis with >50% increase over 2 months or lymphocyte doubling time <6 months. 6

Medical Emergency: Hyperleukocytosis

• WBC counts >100,000/µL constitute a medical emergency due to risks of leukostasis, cerebral infarction, hemorrhage, disseminated intravascular coagulation, and tumor lysis syndrome. 2, 6, 1
• Immediate management: aggressive IV hydration (2.5-3 liters/m²/day), uric acid-lowering therapy (allopurinol or rasburicase), cytoreduction with hydroxyurea (50-60 mg/kg/day), and consideration of leukapheresis. 2, 6

Other Causes

• Asplenia, smoking, and obesity are associated with chronic leukocytosis. 3
• Neuroleptic Malignant Syndrome presents with leukocytosis (typically 15,000-30,000 cells/mm³) alongside hyperthermia, rigidity, and altered mental status. 5
• Allergic reactions and parasitic infections cause eosinophilia-driven leukocytosis. 3, 4

Diagnostic Approach Algorithm

1. Obtain CBC with manual differential within 12-24 hours—automated analyzers miss band forms, toxic granulations, and immature cells. 2, 1
2. Assess for infection: fever, localizing symptoms, or sepsis signs require immediate evaluation. 1
3. Review medications: corticosteroids, lithium, beta-agonists. 1
4. Examine peripheral smear manually for blast cells, left shift, basophilia/eosinophilia, dysplasia, or monomorphic lymphocytes. 2, 7
5. Check inflammatory markers (CRP, ESR) if available. 1
6. Red flags requiring hematology referral: blast cells, extreme leukocytosis (>100,000/µL), splenomegaly, lymphadenopathy, constitutional symptoms (fever, weight loss, bruising, fatigue), or concurrent cytopenias. 2, 1, 3

Critical Pitfalls to Avoid

• Do not ignore high neutrophil percentage (>90%) when total WBC is normal—left shift indicates bacterial infection even with normal counts. 1
• Do not rely solely on automated analyzer flags—manual smear review is mandatory. 2
• Do not assume absence of infection based on normal WBC—sensitivity is low in elderly and immunosuppressed patients. 1
• Do not treat asymptomatic patients with antibiotics based solely on mild leukocytosis—transient elevations occur with exercise, stress, or diurnal variation. 1
• Serial measurements are more informative than single values for unexplained persistent elevation. 1