What is the appropriate evaluation and management approach for a patient with chronically elevated White Blood Cell (WBC) count, neutrophils, and lymphocytes, considering their overall medical history, demographic information, and potential underlying causes such as infections, autoimmune disorders, or hematological malignancies?

Evaluation and Management of Chronic Leukocytosis with Elevated Neutrophils and Lymphocytes

A chronically elevated WBC count with concurrent neutrophilia and lymphocytosis requires systematic exclusion of reactive causes through targeted history, peripheral smear review, and laboratory evaluation before pursuing bone marrow biopsy for hematologic malignancy. 1

Initial Diagnostic Approach

Critical History Elements

• Medication review: Corticosteroids, lithium, and beta-agonists commonly cause leukocytosis 2. Glucocorticoid excess (including exogenous steroids) causes leukocytosis in approximately 40% of cases, with mean WBC counts around 10,500 cells/μL 3

• Infection exposure: Travel to tuberculosis-endemic areas, parasitic infections, or tick-borne illnesses can cause persistent leukocytosis 1. Recurrent infections suggesting HIV, hepatitis C, or endocarditis must be excluded 1

• Constitutional symptoms: Fever, night sweats, weight loss, or arthralgias suggest Adult-onset Still's disease (which demonstrates leukocytosis with fever spikes in 51-87% of cases) or hematologic malignancy 1

• Autoimmune symptoms: Photosensitivity, oral ulcers, or joint pain can cause chronic leukocytosis in systemic lupus erythematosus and rheumatoid arthritis 1

• Smoking status and obesity: Both are nonmalignant causes of chronic leukocytosis 4

Physical Examination Priorities

• Splenomegaly: Present in 14-65% of chronic myelomonocytic leukemia (CMML) cases and suggests clonal disorder 1

• Lymphadenopathy: Present in 32-74% of CMML cases 1

• Cutaneous lesions: Vasculitic purpuric rash or salmon-colored evanescent rash suggests Adult-onset Still's disease 1

Mandatory Laboratory Evaluation

Peripheral Blood Smear Analysis

Manual differential analysis is mandatory, as automated analyzers miss critical morphologic features 1:

• Dysgranulopoiesis: Pseudo-Pelger-Huët anomaly and hypogranulation suggest myelodysplastic syndrome or CMML 1

• Immature cells: Promonocytes and blasts (>1%) raise concern for CMML 1. Neutrophil precursors (left shift) can indicate reactive process or chronic neutrophilic leukemia 1, 5

• Morulae in monocytes: Diagnostic of ehrlichiosis 1

• Rouleaux formation: Suggests plasma cell dyscrasia 1

Essential Laboratory Tests

• Absolute cell counts: Calculate absolute neutrophil count, absolute lymphocyte count, and absolute monocyte count to distinguish relative from absolute elevations 1

• Comprehensive metabolic panel: Including calcium, albumin, creatinine, and liver function tests 1

• Inflammatory markers: ESR and CRP are virtually always elevated in Adult-onset Still's disease and CMML 1

• Infectious workup: HIV testing is essential in all adults with unexplained lymphocytosis 6. CMV, EBV, and other viral studies should be performed as needed 6

• Flow cytometry: Characterize lymphocyte subsets if primary immunodeficiency suspected 6

When to Pursue Bone Marrow Evaluation

Bone marrow aspiration and biopsy are indicated when 1:

• Absolute monocyte count ≥1 × 10⁹/L persists for >3 months without identified reactive cause
• Concurrent cytopenias or dysplastic features are present
• Constitutional symptoms accompany persistent leukocytosis
• WBC count >100,000/mm³ (medical emergency due to risk of brain infarction and hemorrhage) 2

Do not delay bone marrow evaluation beyond 3 months in unexplained leukocytosis, as CMML has poor prognosis and early identification allows consideration of allogeneic stem cell transplantation 1

Bone Marrow Studies Should Include

• Morphological examination with blast percentage 1
• Conventional cytogenetic analysis 1
• Molecular assays 1
• Gomori's silver impregnation for bone marrow fibrosis 1

Management Based on Etiology

If Reactive Cause Identified

• Treat underlying condition: Infection, inflammation, or medication-induced leukocytosis typically resolves with treatment of the primary cause 4

• Monitor lymphocyte counts regularly if lymphocytosis persists 6

If Severe Lymphocytopenia Develops (Grade 3-4: <500/mm³)

• Prophylaxis against opportunistic infections: Pneumocystis jirovecii pneumonia and Mycobacterium avium complex 6

• Hold immunosuppressive medications if applicable 6

• CMV screening and HIV/hepatitis testing 6

Critical Clinical Pitfalls to Avoid

• Do not confuse relative and absolute cell counts: Always calculate absolute values from total WBC and differential percentage to avoid unnecessary workup or missed diagnoses 1

• Do not attribute persistent leukocytosis to inflammation without excluding infection: Tuberculosis, endocarditis, and parasitic infections require specific treatment and can mimic inflammatory conditions 1

• Do not overlook chronic neutrophilic leukemia: This rare disorder presents with persistent neutrophilia in the leukemoid range (WBC >40-50 × 10⁹/L), elevated leukocyte alkaline phosphatase, hepatosplenomegaly, elevated vitamin B12, and is Philadelphia chromosome-negative 5

• Recognize stress-induced leukocytosis: Physical stress (seizures, anesthesia, overexertion) and emotional stress can double peripheral WBC count within hours due to demargination from bone marrow storage pools 2. The neutrophil-to-lymphocyte ratio increases with severity of stress, with marked neutrophilia and lymphocytopenia correlating with clinical severity 7