What is the differential diagnosis and recommended management for a patient with leukocytosis (white‑blood‑cell count 15.5 ×10⁹/L) and neutrophilia (absolute neutrophil count 12,028/µL)?

Evaluation and Management of Leukocytosis with Neutrophilia

Immediate Assessment

This patient has moderate leukocytosis (WBC 15.5 × 10⁹/L) with marked neutrophilia (ANC 12,028/µL), which most likely represents an acute bacterial infection requiring systematic evaluation for the source and consideration of empiric antibiotics if clinical signs of infection are present. 1

The absolute neutrophil count of 12,028/µL is significantly elevated and warrants urgent clinical assessment, as bacterial infections are the most common cause of this pattern. 1, 2

Differential Diagnosis (Prioritized by Likelihood)

1. Bacterial Infection (Most Common)

• Respiratory tract infections, urinary tract infections, skin/soft tissue infections, and gastrointestinal infections are the most frequent bacterial causes. 1, 2
• An absolute band count ≥1,500 cells/mm³ has the highest likelihood ratio (14.5) for documented bacterial infection. 1, 2
• A left shift (≥16% bands) carries a likelihood ratio of 4.7 for bacterial infection, even with only moderately elevated total WBC. 1, 2
• In patients with cirrhosis and ascites, spontaneous bacterial peritonitis must be excluded immediately via diagnostic paracentesis. 2

2. Severe Clostridium difficile Infection

• Marked leukocytosis (>15 × 10⁹/L) is a marker of severe CDI and associated with high mortality and treatment failure. 3
• This diagnosis requires urgent consideration in patients with diarrhea, recent antibiotic exposure, or healthcare facility exposure. 3

3. Physiologic/Stress-Related Causes

• Emotional stress, acute exercise, surgery, or trauma can cause immediate WBC elevation through catecholamine and cortisol release. 1
• These causes typically resolve within hours and lack other signs of infection or inflammation. 1

4. Medication-Induced

• Corticosteroids, lithium, beta-agonists, and epinephrine commonly cause neutrophilia. 1, 2
• Lithium consistently causes leukocytosis; WBC <4,000/mm³ would be unusual in lithium-treated patients. 1

5. Chronic Inflammatory Conditions

• Adult-onset Still's disease presents with marked leukocytosis: 50% have WBC >15 × 10⁹/L and 37% have >20 × 10⁹/L with neutrophilia. 1
• Inflammatory bowel disease activity correlates with leukocytosis and elevated inflammatory markers. 1

6. Hematologic Malignancy (Less Common but Critical)

• Chronic myeloid leukemia can present with leukocytosis, though typically WBC >100 × 10⁹/L. 3
• Presence of blasts, immature cells, or dysplasia on peripheral smear mandates immediate hematology referral. 4, 5
• Extreme leukocytosis (>100,000/mm³) represents a medical emergency due to cerebral infarction and hemorrhage risk. 1, 4

Diagnostic Algorithm

Step 1: Obtain Manual Differential Within 12-24 Hours

• Manual differential is essential to assess band forms, left shift, toxic granulations, and immature cells that automated analyzers miss. 1, 2
• Calculate absolute band count: if ≥1,500 cells/mm³, likelihood ratio for bacterial infection is 14.5. 1, 2
• Assess for blasts or dysplastic features suggesting malignancy. 4, 5

Step 2: Clinical Evaluation for Infection

• Fever ≥38.3°C (single) or ≥38.0°C sustained for ≥1 hour markedly increases probability of bacterial infection. 2
• Assess for localizing symptoms: respiratory (cough, dyspnea), urinary (dysuria, frequency), abdominal (pain, diarrhea), or skin/soft tissue signs. 1, 2
• Look for signs of sepsis: altered mental status (especially elderly), hypotension, tachycardia, or hemodynamic instability. 2
• In cirrhotic patients with ascites, perform diagnostic paracentesis immediately; ascitic fluid neutrophil count >250 cells/µL indicates spontaneous bacterial peritonitis requiring urgent antibiotics. 2

Step 3: Medication and Exposure Review

• Review current medications: corticosteroids, lithium, beta-agonists. 1
• Assess recent stressors: surgery, trauma, intense exercise within past 24 hours. 1
• Evaluate for recent tick bites if patient has headache, fever, or confusion (rickettsial diseases). 2

Step 4: Laboratory Workup

• C-reactive protein and ESR to assess inflammatory activity. 4
• Comprehensive metabolic panel including liver enzymes, renal function, creatinine. 4
• Blood cultures if systemic infection suspected. 2
• Urinalysis with culture for urinary symptoms. 2
• Stool studies including C. difficile toxin if diarrhea present. 4
• Site-specific cultures as indicated by clinical findings. 2

Step 5: Imaging Studies

• Chest imaging if respiratory symptoms present. 2
• Abdominal imaging if abdominal pain, peritoneal signs, or concern for intra-abdominal infection. 2

Management Approach

If Bacterial Infection Suspected with Clinical Signs

• Initiate empiric broad-spectrum antibiotics without delay if fever, sepsis signs, hemodynamic instability, or high pre-test probability of serious infection (meningitis, spontaneous bacterial peritonitis). 2
• Do not wait for culture results if patient appears clinically ill. 2

If Severe C. difficile Infection Suspected

• Marked leukocytosis (>15 × 10⁹/L) indicates severe CDI requiring aggressive treatment. 3
• Evaluate for toxic megacolon (radiological colonic distension with severe systemic inflammatory response). 3
• Consider colonoscopy/sigmoidoscopy if diagnosis uncertain; pseudomembranous colitis confirms CDI. 3

If Hematologic Malignancy Suspected

• Immediate same-day hematology referral if blasts present on peripheral smear. 4
• If WBC >100,000/µL, this is a medical emergency: initiate aggressive IV hydration (2.5-3 liters/m²/day) to prevent tumor lysis syndrome. 4
• Bone marrow examination with cytogenetics and molecular studies required for definitive diagnosis. 3, 4

If Reactive/Physiologic Cause Identified

• Do not treat asymptomatic patients with antibiotics based solely on elevated neutrophil counts. 1
• Serial measurements more informative than single values for unexplained persistent elevation. 1
• Repeat CBC in 24-48 hours if stress-related cause suspected; should normalize rapidly. 1

Critical Pitfalls to Avoid

• Do not ignore elevated absolute neutrophil count when total WBC is only moderately elevated; left shift can indicate bacterial infection even with WBC <14,000/mm³. 1, 2
• Do not delay treatment while awaiting confirmatory testing if hyperleukocytosis or acute leukemia suspected. 4
• Do not overlook spontaneous bacterial peritonitis in cirrhotic patients; any neutrophilia warrants diagnostic paracentesis. 2
• Do not assume absence of infection based on lack of fever; elderly and immunosuppressed patients may not mount febrile response. 1
• Do not treat based on single mildly elevated value without clinical context; transient elevations occur with exercise, stress, or diurnal variations. 1
• Do not perform leukapheresis if acute promyelocytic leukemia suspected due to fatal hemorrhage risk. 4