What is the workup for leukocytosis (elevated white blood cell count) of unknown etiology?

Workup for Leukocytosis of Unknown Etiology

The workup for leukocytosis of unknown etiology should include a complete blood count with differential, peripheral blood smear examination, comprehensive metabolic panel, bone marrow aspiration and biopsy with cytogenetic and molecular studies, and targeted imaging based on clinical suspicion. 1

Initial Laboratory Evaluation

• Complete Blood Count (CBC) with differential

  • Assess absolute counts of different WBC types (neutrophils, lymphocytes, monocytes, eosinophils, basophils)
  • Calculate neutrophil-to-lymphocyte ratio as a marker of inflammation severity
  • Evaluate for presence of immature forms ("left shift") - band counts >1,500 cells/mm³ strongly suggest bacterial infection (likelihood ratio 14.5) 1

• Peripheral Blood Smear

  • Examine for morphological abnormalities in WBCs
  • Look for blast cells, dysplastic changes, or abnormal cell populations
  • Assess for concurrent abnormalities in red blood cells and platelets

• Comprehensive Metabolic Panel

  • Evaluate liver and kidney function
  • Check serum uric acid and lactate dehydrogenase (LDH) which have prognostic relevance 2

• Inflammatory Markers

  • C-reactive protein (CRP) and procalcitonin (PCT) to help distinguish infection from other causes 1
  • PCT rises and clears more quickly than CRP and correlates better with sepsis severity

Bone Marrow Studies

• Bone Marrow Aspiration and Biopsy

  • Indicated when peripheral blood findings suggest a primary hematologic disorder
  • Essential for diagnosis of leukemia and myeloproliferative disorders
  • Should include:
    • Morphologic examination
    • Cytochemistry
    • Immunophenotyping
    • Cytogenetic analysis 2

• Molecular and Genetic Studies

  • Cytogenetic analysis (karyotype with fluorescence in situ hybridization) 2
  • Molecular testing for specific mutations based on suspected diagnosis:
    • For suspected AML: FLT3-ITD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, TP53 2
    • For suspected ALL: BCR-ABL1, KMT2A (MLL) gene translocation 2
    • For suspected CMML: NRAS, KRAS, TET2, CBL, SRSF2 genes 2

Imaging Studies

• Chest Imaging

  • Chest X-ray to screen for infection or malignancy
  • CT scan of chest for patients with suspected T-cell ALL or if thoracic infection/malignancy is suspected 2

• Abdominal Imaging

  • Ultrasound or CT scan of abdomen if hepatosplenomegaly is suspected or to assess for lymphadenopathy
  • Particularly important if fungal infection is suspected 2

• PET/CT

  • Recommended if extramedullary disease is suspected 2

Special Considerations

• Infectious Disease Workup

  • Blood cultures if infection is suspected
  • Specific cultures based on clinical presentation
  • Consider viral studies if lymphocytosis predominates

• Cerebrospinal Fluid Analysis

  • Indicated in patients with neurological symptoms or if acute leukemia is diagnosed
  • Should include cell count, cytology, and flow cytometry 2

• Cardiac Evaluation

  • Echocardiogram recommended for patients with risk factors or history of heart disease 2
  • Particularly important if treatment with anthracyclines is anticipated

Diagnostic Algorithm

1. Determine if leukocytosis is reactive or primary:

   • WBC >100,000/μL strongly suggests a primary bone marrow disorder and represents a medical emergency 3
   • Presence of blast cells, significant dysplasia, or concurrent cytopenias suggests primary disorder
   • History of recent infection, inflammation, stress, or medications suggests reactive cause

2. For suspected reactive leukocytosis:

   • Identify and treat underlying cause (infection, inflammation, medication effect)
   • Monitor WBC count for resolution with treatment of primary condition
   • If leukocytosis persists despite resolution of apparent cause, proceed to bone marrow evaluation

3. For suspected primary hematologic disorder:

   • Urgent hematology consultation
   • Proceed directly to bone marrow studies and molecular testing
   • HLA typing should be performed if allogeneic stem cell transplantation might be considered 2

Common Pitfalls to Avoid

• Assuming normal WBC count excludes infection - other markers like CRP or PCT may be more helpful 1
• Attributing leukocytosis solely to stress without excluding infection - clinical context is crucial 1
• Failure to recognize extreme leukocytosis (>100,000/μL) as a medical emergency requiring immediate intervention 3
• Overlooking medication effects - corticosteroids, lithium, beta-agonists, and epinephrine can cause leukocytosis 1
• Initiating antibiotics before obtaining appropriate cultures - this may obscure the diagnosis 1
• Neglecting to evaluate the peripheral blood smear - this is essential for initial assessment of leukocytosis 4

Remember that persistent unexplained leukocytosis warrants thorough investigation, as it may represent an early sign of a serious underlying condition. The workup should be systematic and comprehensive to avoid missing potentially life-threatening diagnoses.