What are the causes of sterile leukocytosis (elevated white blood cell count) in an adult patient with no known medical history?

Causes of Sterile Leukocytosis

Sterile leukocytosis (elevated WBC without infection) occurs most commonly due to physiologic stress responses, medications, chronic inflammatory conditions, and less frequently from primary bone marrow disorders.

Physiologic and Stress-Related Causes

Physical and emotional stress can cause rapid WBC elevation by mobilizing large bone marrow storage pools and intravascularly marginated neutrophils, with counts potentially doubling within hours. 1, 2

• Surgery, trauma, seizures, anesthesia, and vigorous exercise are well-documented triggers of acute leukocytosis through stress-mediated neutrophil demargination 1, 2
• Emotional or psychological stress can similarly elevate WBC counts through catecholamine release 1

Medication-Induced Leukocytosis

Corticosteroids, lithium, and beta-agonists are the most common medications causing leukocytosis, with epinephrine also capable of producing neutrophilia with left shift. 3, 4, 1, 2

• Corticosteroids cause neutrophilia by accelerating release from bone marrow and reducing margination 1
• Lithium stimulates granulocyte production and can cause persistent elevation 1, 2
• Beta-agonists mobilize marginated neutrophil pools 3, 4

Chronic Inflammatory and Metabolic Conditions

Chronic inflammatory conditions, obesity, and smoking represent common non-infectious causes of persistent leukocytosis. 2

• Chronic inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease) maintain elevated WBC through ongoing cytokine stimulation 2
• Obesity is associated with chronic low-grade inflammation and mild leukocytosis 2
• Smoking causes persistent neutrophilia through chronic irritant effects 2

Tissue Damage and PICS

Extensive tissue damage from major trauma, cerebrovascular accidents, or major surgery can drive prolonged leukocytosis through damage-associated molecular patterns (DAMPs) rather than infection, manifesting as persistent inflammation-immunosuppression and catabolism syndrome (PICS). 5

• Patients with major trauma, CVA, or post-surgical states can develop leukocytosis lasting 14.5 ± 10.6 days with peak WBC of 26.4K ± 8.8 5
• This represents a state of continued inflammation with bandemia (18.4 ± 13.8%) and subsequent eosinophilia (>500 in 52% of cases) 5
• These patients often receive unnecessary prolonged antibiotics without benefit, as tissue damage rather than active infection drives the leukocytosis 5

Asplenia

Functional or anatomic asplenia causes persistent mild leukocytosis due to loss of splenic sequestration and filtering of white blood cells. 2

Primary Bone Marrow Disorders (Non-Infectious Malignancies)

Primary bone marrow disorders should be suspected when WBC counts are extremely elevated (>100,000/mm³), when concurrent red blood cell or platelet abnormalities exist, or when constitutional symptoms are present. 1, 6, 2

Chronic Leukemias

• Chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) typically present with gradual onset symptoms and are often diagnosed incidentally on routine blood work 6
• Patients are generally less ill at presentation compared to acute leukemias 6

Myeloproliferative Disorders

• Essential thrombocythemia, polycythemia vera, and primary myelofibrosis can present with leukocytosis 1

Acute Leukemias

• While typically presenting with infection-like symptoms, acute leukemias can occasionally be discovered incidentally 6
• WBC >100,000/mm³ represents a medical emergency due to risk of brain infarction and hemorrhage 1

Key Diagnostic Red Flags for Malignancy

Weight loss, bruising, bleeding, hepatosplenomegaly, lymphadenopathy, or immunosuppression increase suspicion for primary bone marrow disorders requiring hematology referral. 1, 6, 2

• Abnormal peripheral blood smear with immature forms, blasts, or dysplastic features mandates further evaluation 6, 2
• Constitutional symptoms (fever, night sweats, weight loss) without identified infection source suggest malignancy 6, 2

Common Pitfalls to Avoid

• Do not assume all leukocytosis represents infection—physiologic stress, medications, and chronic inflammation are more common causes 1, 2
• Do not overlook medication history, particularly corticosteroids, lithium, and beta-agonists which are frequently missed 1, 2
• Do not prescribe prolonged empiric antibiotics for persistent leukocytosis without documented infection, as this is common in PICS and tissue damage states 5
• Do not delay hematology referral when peripheral smear is abnormal or WBC >100,000/mm³, as these require urgent evaluation 1, 6