Initial Workup for Leukocytosis

First-Line Laboratory Tests

The American College of Physicians recommends ordering 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
A CBC with manual differential is the cornerstone test to identify which cell line is elevated and calculate absolute counts, according to the American Society of Hematology 2, 1
Peripheral blood smear review is essential to examine WBC morphology, assess for left shift, and rule out blast cells or other malignant cells, as recommended by the American Society of Clinical Pathology 1
A comprehensive metabolic panel should be ordered to monitor for tumor lysis syndrome and assess organ function, particularly if malignancy is suspected, as suggested by the National Comprehensive Cancer Network 1

The presence of left shift (≥16% band neutrophils) has a likelihood ratio of 4.7 for bacterial infection even with normal total WBC, according to the Infectious Diseases Society of America 2
An absolute band count ≥1,500 cells/mm³ has a likelihood ratio of 14.5 for bacterial infection, as reported by the American College of Emergency Physicians 2, 1
A neutrophil percentage >90% has a likelihood ratio of 7.5 for bacterial infection, according to the American Thoracic Society 2, 1
A total WBC ≥14,000 cells/mm³ has a likelihood ratio of 3.7 for bacterial infection, as suggested by the Society of Critical Care Medicine 2, 1

If infection is suspected, blood cultures should be ordered before starting antibiotics if systemic symptoms or sepsis signs are present, as recommended by the American Society of Microbiology 1, 3
Urinalysis and urine culture should be ordered if urinary symptoms are present or the source is unclear, according to the American Urological Association 1
Chest imaging should be ordered if respiratory symptoms are present, as suggested by the American College of Radiology 2, 1
CT imaging is recommended for suspected intra-abdominal infections, according to the American College of Surgeons 1
Diagnostic paracentesis is indicated in cirrhotic patients with ascites, with a neutrophil count >250 cells/mm³ in ascitic fluid indicating spontaneous bacterial peritonitis, as reported by the American Association for the Study of Liver Diseases 2

Hyperleukocytosis (>100,000/μL) represents a medical emergency requiring aggressive IV hydration, allopurinol or rasburicase, hydroxyurea, and consideration of leukapheresis, according to the American Society of Hematology 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, as recommended by the National Comprehensive Cancer Network 4

Absolute neutrophil count elevation should not be overlooked when total WBC is only mildly elevated, as left shift can occur with normal WBC and still indicate serious bacterial infection, according to the American College of Physicians 2, 1
Asymptomatic patients should not be treated with antibiotics based solely on mildly elevated WBC counts, as this leads to unnecessary antibiotic use and potential complications, as suggested by the American Society of Infectious Diseases 1
Leukocytosis without fever should not be ignored, particularly in older adults, as infection can be present without fever, according to the American Geriatrics Society 1