What is the initial workup for leukocytosis (elevated white blood cell count)?

Initial Workup for Leukocytosis

Order a complete blood count (CBC) with manual differential immediately to characterize which white blood cell line is elevated, followed by peripheral blood smear review to assess cell morphology and identify malignant cells. 1

First-Line Laboratory Tests

Essential Initial Tests

• CBC with manual differential (not automated) is the cornerstone test to identify which cell line is elevated and calculate absolute counts 2, 1
• Peripheral blood smear review to examine WBC morphology, assess for left shift (increased band neutrophils), and rule out blast cells or other malignant cells 1, 3
• Comprehensive metabolic panel to monitor for tumor lysis syndrome and assess organ function, particularly if malignancy is suspected 1

Critical Morphologic Features to Identify

• Blast cells indicate acute leukemia requiring urgent hematology referral 3, 4
• Lymphoma cells suggest lymphoproliferative disorder 4
• Myeloid precursors may indicate myeloproliferative disorder or severe infection 4
• Left shift (≥16% band neutrophils) has a likelihood ratio of 4.7 for bacterial infection even with normal total WBC 2

Differential Diagnosis Based on Cell Type

Neutrophilic Leukocytosis (Most Common)

The diagnostic power of neutrophilic markers for bacterial infection, in descending order: 2

• Absolute band count ≥1,500 cells/mm³ (likelihood ratio 14.5 for bacterial infection) 2, 1
• Neutrophil percentage >90% (likelihood ratio 7.5) 2, 1
• Left shift ≥16% bands (likelihood ratio 4.7) 2, 1
• Total WBC ≥14,000 cells/mm³ (likelihood ratio 3.7) 2, 1

Lymphocytic Leukocytosis

• Flow cytometry should be ordered if lymphoproliferative disorder is suspected based on morphology to identify clonal T or B lymphocyte populations 1, 4
• Monomorphic lymphocyte appearance suggests malignancy, while pleomorphic lymphocytosis suggests viral infection or drug reaction 4

Site-Specific Evaluation Based on Clinical Context

If Infection is Suspected

• Blood cultures before starting antibiotics if systemic symptoms or sepsis signs are present 1, 5
• Urinalysis and urine culture if urinary symptoms present or source unclear 1
• Chest imaging if respiratory symptoms present 2, 1
• CT imaging for suspected intra-abdominal infections 1
• Diagnostic paracentesis in cirrhotic patients with ascites (neutrophil count >250 cells/mm³ in ascitic fluid indicates spontaneous bacterial peritonitis) 2

If Malignancy is Suspected

Constitutional symptoms (fever, night sweats, weight loss) combined with abnormal peripheral smear mandate urgent hematology referral 3. Bone marrow aspiration and biopsy are required for definitive diagnosis of hematologic malignancies, not only for morphologic review but also to detect chromosomal abnormalities not detectable on peripheral blood FISH 6.

Special Considerations for Severe Leukocytosis

Hyperleukocytosis (>100,000/μL)

This represents a medical emergency requiring: 5

• Aggressive IV hydration (2.5-3 liters/m²/day) titrated to fluid balance
• Allopurinol or rasburicase to prevent tumor lysis syndrome in high-risk patients
• Hydroxyurea (50-60 mg/kg/day) for rapid WBC reduction
• Leukapheresis consideration for organ-threatening leukostasis (cerebral or pulmonary), except in acute promyelocytic leukemia where it is contraindicated due to fatal hemorrhage risk

Common Pitfalls to Avoid

• Do not overlook absolute neutrophil count elevation when total WBC is only mildly elevated - left shift can occur with normal WBC and still indicate serious bacterial infection 2, 1
• Do not treat asymptomatic patients with antibiotics based solely on mildly elevated WBC counts - this leads to unnecessary antibiotic use and potential complications 1
• Do not ignore leukocytosis without fever - particularly in older adults, infection can be present without fever 1
• Do not delay hematology referral if blast cells are present - acute leukemias require urgent subspecialist evaluation due to life-threatening complications 3
• Recognize persistent inflammation-immunosuppression and catabolism syndrome (PICS) in hospitalized patients with prolonged unexplained leukocytosis, often associated with extensive tissue damage rather than active infection, where empiric antibiotics are unlikely to be beneficial 7