What are the causes of leukocytosis?

Causes of Leukocytosis

Leukocytosis arises from infectious, inflammatory, physiologic stress, medication-related, and hematologic malignant causes, with bacterial infection being the most common etiology requiring immediate clinical assessment. 1, 2

Infectious Causes

Bacterial infections are the predominant infectious cause of leukocytosis, typically producing neutrophilic leukocytosis with left shift (increased immature neutrophils). 1, 2

• Pneumonia accounts for 47% of infection-related leukocytosis in hospitalized patients with WBC ≥15,000 cells/mm³. 3
• Urinary tract infections represent 29% of infection-related cases in the same population. 3
• Soft tissue infections cause 16% of infection-related leukocytosis. 3
• Clostridium difficile infection is present in 16% of all patients with leukocytosis ≥15,000 cells/mm³, and rises to 25% in those with WBC >30,000 cells/mm³ without hematologic malignancy—even without diarrheal symptoms. 3
• Parasitic infections and allergic conditions produce eosinophilia-predominant leukocytosis. 1
• Childhood viral illnesses typically cause lymphocytosis rather than neutrophilic leukocytosis. 1

Physiologic and Stress-Related Causes

Physical and emotional stress can double the peripheral WBC count within hours by mobilizing the large bone marrow storage pool and intravascularly marginated neutrophils. 1, 2

• Surgery, exercise, trauma, and emotional stress are acute stressors capable of producing immediate leukocytosis. 1
• Seizures, anesthesia, and overexertion represent specific physical stressors that elevate WBC counts. 2
• Physiologic stress accounts for 38% of leukocytosis cases in hospitalized patients. 3

Medication-Induced Leukocytosis

Corticosteroids, lithium, and beta-agonists are the medications most commonly associated with leukocytosis. 1, 2

• Medications or drugs account for 11% of leukocytosis in tertiary care settings. 3

Chronic Inflammatory and Other Nonmalignant Conditions

• Chronic inflammatory conditions produce sustained leukocytosis through ongoing immune activation. 1
• Asplenia removes the splenic filtering mechanism, leading to persistent elevation in circulating leukocytes. 1
• Smoking and obesity are associated with chronic low-grade leukocytosis. 1
• Necrosis or inflammation accounts for 6% of cases in hospitalized patients. 3

Hematologic Malignancies

Primary bone marrow disorders should be suspected when WBC counts are extremely elevated or when concurrent abnormalities in red blood cells or platelets are present. 2, 4

Chronic Myeloid Leukemia (CML)

• CML typically presents with marked leukocytosis, basophilia, eosinophilia, and left-shifted myeloid maturation (increased myelocytes, promyelocytes). 5
• Leukocytosis with immature granulocytes and increased basophils or eosinophils points toward CML rather than reactive leukocytosis. 5
• The hallmark is leukocytosis with basophilia and immature granulocytes (metamyelocytes, myelocytes, promyelocytes, occasional blasts). 5
• Splenomegaly is present in slightly >50% of CML patients at diagnosis. 5
• Leukostatic symptoms are uncommon in chronic-phase CML despite WBC often exceeding 100,000/μL, but become more frequent with disease transformation. 6

Acute Leukemias

• Patients with acute leukemia are more likely to be acutely ill at presentation with fever, weight loss, bruising, or fatigue. 2, 4
• Blast cells in peripheral blood indicate acute leukemia and require immediate hematology referral. 6

Chronic Leukemias and Myeloproliferative Disorders

• Chronic leukemias are often diagnosed incidentally because of abnormal blood counts in asymptomatic patients. 2
• Hematologic disease accounts for 6% of leukocytosis in hospitalized patients. 3

Critical Thresholds and Red Flags

WBC counts >100,000/μL represent a medical emergency due to risk of brain infarction, hemorrhage, leukostasis, disseminated intravascular coagulation, and tumor lysis syndrome, requiring immediate interventions including aggressive IV hydration, allopurinol or rasburicase, hydroxyurea, and consideration of leukapheresis. 6, 2

Features Suggesting Malignancy

• Weight loss, bleeding, bruising, or fatigue suggest hematologic malignancy. 1, 2
• Liver, spleen, or lymph node enlargement increases suspicion for marrow disorders. 2
• Splenomegaly or lymphadenopathy on examination requires immediate hematology referral. 6
• Peripheral smear showing blast cells, immature forms, or dysplastic features regardless of WBC count requires immediate hematology referral. 6
• Concurrent abnormalities in red blood cell or platelet counts suggest primary bone marrow pathology. 2

Diagnostic Approach

A manual differential count is essential to assess for left shift (≥16% bands or absolute band count ≥1,500 cells/mm³), immature forms, or dysplastic features. 6, 7

• Left shift ≥16% band neutrophils increases likelihood ratio to 4.7 for bacterial infection, even with normal total WBC. 6, 7
• Absolute band count ≥1,500 cells/mm³ increases likelihood ratio to 14.5 for bacterial infection. 6, 7
• Neutrophil percentage >90% increases likelihood ratio to 7.5 for bacterial infection. 7
• Total WBC ≥14,000 cells/mm³ has likelihood ratio of 3.7 for bacterial infection. 6

Common Pitfalls

• Do not ignore leukocytosis in the absence of fever—serious bacterial infections can present without fever, particularly in elderly patients. 7
• Do not rely on automated analyzer flags alone—manual differential is mandatory for accurate assessment of band forms and immature cells. 7
• Do not dismiss isolated leukocytosis as benign without assessing the differential count—the pattern of elevation (neutrophilic vs. lymphocytic vs. eosinophilic) guides diagnosis. 1, 4
• Consider C. difficile infection even without diarrhea when WBC ≥15,000 cells/mm³, especially if >30,000 cells/mm³. 3