What to do next for a patient with neutrophilia, lymphocytosis, and monocytosis?

Evaluation and Management of Neutrophilia, Lymphocytosis, and Monocytosis

A comprehensive hematologic workup is necessary for a patient presenting with neutrophilia, lymphocytosis, and monocytosis to rule out both reactive causes and hematologic malignancies.

Initial Diagnostic Approach

History and Physical Examination Focus

• Evaluate for infectious causes (bacterial, viral, fungal)
• Check for recent medications that could cause leukocytosis
• Assess for solid tumors or hematologic malignancies
• Look for signs of autoimmune disorders
• Examine for splenomegaly and lymphadenopathy
• Check for cutaneous lesions
• Review for stress-related factors

First-Line Laboratory Workup

• Complete blood count with peripheral blood smear examination
• Bone marrow aspiration and biopsy if peripheral blood findings suggest malignancy
• Conventional cytogenetic analysis
• Molecular assays to exclude bcr/abl fusion gene (to rule out CML)
• Rearrangement of PDGFRA and PDGFRB (to rule out MDS/MPN with eosinophilia)

Differential Diagnosis

Reactive Causes

• Infections (bacterial, viral, fungal)
• Stress response
• Medications (corticosteroids)
• Post-treatment immune response 1
• Allergic reactions (especially with eosinophilia)
• Tissue necrosis or hemolysis (monocytosis)

Malignant Causes

• Chronic Myelomonocytic Leukemia (CMML) 1
• Chronic Lymphocytic Leukemia (CLL) 2
• Chronic Myelogenous Leukemia (CML) 1
• Other myeloproliferative disorders

Specific Diagnostic Tests

For Suspected Hematologic Malignancy

• Flow cytometry to characterize lymphocyte populations
• Molecular testing for specific mutations:
  • SRSF2, TET2, JAK2 or RAS mutations (for CMML) 1
  • BCR-ABL testing (for CML) 1
• HLA typing if bone marrow transplantation might be considered 1

For Suspected Immune-Related Adverse Events

• If patient is on immune checkpoint inhibitors, evaluate for immune-related adverse events 1
• Screen for autoimmune disorders

Management Algorithm

1. Rule out urgent/emergent causes:

   • If fever present: Blood cultures and start empiric antibiotics if neutropenic fever criteria met 1
   • If signs of infection: Appropriate cultures and targeted antimicrobial therapy

2. If malignancy suspected based on peripheral smear or clinical features:

   • Proceed with bone marrow biopsy
   • Initiate appropriate targeted therapy based on diagnosis

3. If reactive cause identified:

   • Treat underlying condition
   • Monitor CBC with differential until resolution

4. If immune checkpoint inhibitor-related:

   • Continue ICI therapy for Grade 1 lymphocytosis
   • For Grade 4 lymphopenia (not your case), consider prophylaxis for opportunistic infections 1

Important Considerations

• Transient post-treatment lymphocytosis, neutrophilia, and monocytosis can occur during initiation of an immune response and may not be clinically significant 1
• Persistent or progressive cytopenias should be evaluated for autoimmune causes with peripheral smear, reticulocyte count, and assessment for hemolysis 1
• Neutrophilia without monocytosis in CLL patients has been associated with better prognosis 2
• In COVID-19 patients, leukocytosis with neutrophilia, lymphopenia, and monocytosis can indicate more severe disease 3

Common Pitfalls to Avoid

• Using outdated reference ranges may lead to misinterpretation of normal neutrophil counts as neutrophilia or under-recognition of neutropenia, eosinophilia, monocytosis, or lymphocytosis 4
• Failing to distinguish between benign/reactive causes and malignant disorders 5
• Not considering medication effects on blood counts
• Missing underlying infections that may be masked by abnormal counts

Remember that while transient elevations in these cell lines can be benign, persistent abnormalities warrant thorough investigation to rule out serious underlying conditions, particularly hematologic malignancies.