What is the most common cause of a mildly elevated persistent white blood cell (WBC) count, including neutrophils (neuts) and lymphocytes (lymphs)?

Most Common Cause of Mildly Elevated Persistent WBC, Neutrophils, and Lymphocytes

The most common cause of mildly elevated persistent leukocytosis with both neutrophils and lymphocytes is chronic physiological stress or medication effect (particularly corticosteroids, lithium, or beta-agonists), followed by chronic inflammatory conditions, with bacterial infection being the primary concern requiring immediate exclusion. 1, 2

Initial Diagnostic Priority: Exclude Active Infection

The first step is to systematically exclude bacterial infection, as this represents the most urgent treatable cause:

• Obtain a complete blood count with manual differential to assess absolute neutrophil count and band forms (left shift) within 12-24 hours 1, 3
• An absolute band count ≥1,500 cells/mm³ has the highest likelihood ratio (14.5) for documented bacterial infection 1, 3
• A neutrophil percentage >90% has a likelihood ratio of 7.5 for bacterial infection 1, 3
• A left shift (≥16% bands) has a likelihood ratio of 4.7 for bacterial infection, even with normal total WBC 1, 3

Critical caveat: Do not ignore elevated neutrophil percentages (e.g., 84%) when total WBC is only mildly elevated—left shift can occur with normal WBC and still indicate bacterial infection 3

Systematic Evaluation for Infection

Evaluate for localizing signs of bacterial infection:

• Respiratory tract infections: chest imaging if respiratory symptoms present 3
• Urinary tract infections: urinalysis with culture for urinary symptoms 3
• Skin/soft tissue infections: examine for cellulitis, abscess 1
• Gastrointestinal infections: assess for abdominal pain, diarrhea 1
• Blood cultures if systemic infection suspected 3

In patients with cirrhosis and ascites, perform diagnostic paracentesis to rule out spontaneous bacterial peritonitis (neutrophil count >250 cells/mm³ in ascitic fluid requires immediate antibiotics) 3

Non-Infectious Causes (After Infection Excluded)

Medications (Most Common Non-Infectious Cause)

Review current medications systematically 1, 2:

• Corticosteroids: consistently cause leukocytosis 1, 2, 4
• Lithium: consistently causes leukocytosis; WBC <4,000/mm³ would be unusual in lithium-treated patients 1
• Beta-agonists: cause neutrophilia 1, 2, 4
• Epinephrine: causes neutrophilia 1

Physiological Stress

Emotional and physical stress are extremely common causes of persistent mild leukocytosis 1, 2:

• Emotional stress triggers leukocytosis through catecholamines and cortisol release 1
• Acute exercise causes immediate WBC elevation, particularly granulocytes and NK cells 1
• Physical stressors include surgery, trauma, seizures, anesthesia 2, 4

Chronic Inflammatory Conditions

Consider chronic inflammatory diseases after excluding infection and medication effects 1, 2:

• Adult-onset Still's disease (AOSD): 50% have WBC >15×10⁹/L; 37% have >20×10⁹/L with marked neutrophilia 1
• Other chronic inflammatory conditions (inflammatory bowel disease, rheumatologic conditions) 2

Other Non-Malignant Causes

• Smoking: chronic cause of leukocytosis 2
• Obesity: associated with chronic mild leukocytosis 2
• Asplenia: causes persistent leukocytosis 2

When to Suspect Malignancy

Red flags requiring hematology referral 1:

• Extreme leukocytosis (>100,000/mm³)—represents medical emergency due to risk of cerebral infarction and hemorrhage 1, 4
• Splenomegaly or lymphadenopathy 1
• Concurrent abnormalities in red blood cell or platelet counts 4
• Constitutional symptoms: fever, weight loss, bruising, fatigue 2, 4
• Immature cells on peripheral smear 2

Persistent Inflammation-Immunosuppression and Catabolism Syndrome (PICS)

In hospitalized patients with prolonged unexplained leukocytosis (mean duration 14.5 days), consider PICS 5:

• Associated with major trauma, cerebrovascular accident, major surgery, sepsis 5
• Peak WBC typically 26.4K ± 8.8 on day 9.6 of hospitalization 5
• Development of eosinophilia (>500) is common, median hospital day 12 5
• Represents extensive tissue damage rather than active infection 5

Critical Errors to Avoid

• Do not overinterpret a single mild elevation without clinical context—transient elevations occur with exercise, stress, or diurnal variations 1
• Do not assume absence of infection based on low or normal WBC—bacterial infections can present with leukopenia, particularly in early stages or severe disease 1, 6
• Do not treat asymptomatic patients with antibiotics based solely on mildly elevated neutrophil counts 1
• Serial measurements are more informative than single values for unexplained persistent elevation 1
• A normal WBC does not exclude bacterial infection—sensitivity is low, particularly in elderly or immunosuppressed patients 1