Evaluation of Leukocytosis
Obtain a complete blood count with manual differential immediately, examining for left shift (≥16% bands or ≥1500 bands/mm³), which has the highest predictive value (likelihood ratio 14.5) for bacterial infection, and initiate empiric antibiotics promptly if infection is suspected, even in the absence of fever. 1, 2
Immediate Laboratory Assessment
- Order CBC with manual differential (not automated) to assess absolute neutrophil count, band forms, and immature cells within 12-24 hours of symptom onset 3, 1
- Examine peripheral blood smear personally for:
- Left shift: ≥16% band neutrophils or absolute band count ≥1500 cells/mm³ (likelihood ratio 14.5 for bacterial infection) 1, 2
- Neutrophil percentage >90% (likelihood ratio 7.5 for infection) 2
- Blast cells, dysplasia, or immature forms suggesting malignancy 4
- Toxic granulations indicating active infection 5
Critical threshold interpretation:
- WBC >14,000 cells/mm³ has likelihood ratio 3.7 for bacterial infection 1, 6
- WBC >100,000/mm³ (hyperleukocytosis) represents a medical emergency requiring immediate intervention 7, 1
Clinical Evaluation for Infection Source
Search systematically for infection even without fever - leukocytosis alone indicates high probability of bacterial infection 1, 2:
- Respiratory: pneumonia, empyema (most common cause) 2
- Urinary: obtain urinalysis only if dysuria, hematuria, new incontinence, or suspected urosepsis present 3
- Skin/soft tissue: cellulitis, abscess 2
- Abdominal: peritonitis, cholecystitis, appendicitis 2
- Bloodstream: obtain blood cultures before antibiotics if fever, hypotension, or sepsis suspected 1, 6
Common pitfall: Do not dismiss leukocytosis in afebrile patients - bacterial infection frequently presents with elevated WBC without fever 1, 2
Non-Infectious Causes to Exclude
Medication-induced (review current medications):
- Corticosteroids (most common) 2
- Lithium (WBC <4,000 would be unusual on lithium) 2
- Beta-agonists 2
- Epinephrine 2
Physiologic stress responses:
- Emotional/physical stress, surgery, trauma 2, 5
- Acute exercise (immediate elevation, catecholamine-mediated) 2
Inflammatory conditions:
- Adult-onset Still's disease: 50% have WBC >15×10⁹/L, 37% >20×10⁹/L with marked neutrophilia 3, 2
- Chronic inflammatory disorders 2
Management Algorithm
If Infection Suspected (WBC >14,000 or left shift present):
Obtain cultures before antibiotics:
Initiate empiric broad-spectrum antibiotics immediately based on suspected source 1, 6
Monitor for clinical response over 24-48 hours 6
If Hyperleukocytosis (WBC >100,000):
This is a medical emergency due to risk of cerebral infarction, hemorrhage, and tumor lysis syndrome 7, 1:
- Aggressive hydration to prevent tumor lysis syndrome 1
- Cytoreductive chemotherapy without delay if acute leukemia suspected 3, 1
- Avoid leukapheresis in acute promyelocytic leukemia - can precipitate fatal hemorrhage 3, 1
- Transfuse platelets if <10×10⁹/L 6
If Malignancy Suspected:
Red flags requiring hematology referral:
- Blasts on peripheral smear 4
- Persistent unexplained leukocytosis >20,000 5
- Constitutional symptoms: fever, weight loss, bruising, fatigue 5
- Splenomegaly, lymphadenopathy 3
- Dysplastic cells or immature forms 4
Obtain bone marrow aspiration and biopsy for definitive diagnosis 8, 4
Critical Pitfalls to Avoid
- Never ignore elevated neutrophil percentage (>90%) even with normal total WBC - left shift can occur with normal counts and still indicates bacterial infection 2
- Do not perform leukapheresis in suspected acute promyelocytic leukemia - risk of fatal hemorrhage 3, 1
- Do not delay antibiotics waiting for culture results if bacterial infection suspected 1, 6
- Do not overlook leukocytosis in elderly patients - associated with increased mortality in nursing home-acquired pneumonia and bloodstream infections 3, 1
- Serial measurements are more informative than single values for unexplained persistent elevation 2