What is the significance of a high red‑cell distribution width with neutrophilia, monocytosis, and eosinophilia, and what initial evaluation should be performed?

High RDW-SD with Neutrophilia, Monocytosis, and Eosinophilia

Primary Recommendation

This constellation of findings—elevated red cell distribution width with concurrent neutrophilia, monocytosis, and eosinophilia—requires immediate evaluation to exclude myeloid/lymphoid neoplasms with eosinophilia, particularly those with tyrosine kinase (TK) fusion genes, while simultaneously investigating for secondary causes including iron deficiency, inflammatory conditions, parasitic infections, and solid malignancies. 1, 2

Clinical Significance

The combination of elevated RDW with multiple elevated white cell lineages is particularly concerning because:

• Myeloid/lymphoid neoplasms with eosinophilia and TK fusion genes characteristically present with neutrophilia, basophilia, thrombocytosis, monocytosis, myeloid immaturity, and both mature and immature eosinophils with varying degrees of dysplasia. 1

• Elevated RDW reflects abnormal erythropoiesis and may indicate iron deficiency (even with normal MCV), vitamin deficiencies, hemolysis, or inflammatory conditions. 2, 3

• The presence of monocytosis and eosinophilia together raises concern for hematologic malignancy, as secondary (reactive) eosinophilia is frequently observed in lymphoid malignancies including Hodgkin lymphoma and T-cell lymphomas. 1

Immediate Diagnostic Workup

Essential Laboratory Studies

Order the following tests immediately:

• Complete blood count with manual differential to confirm neutrophilia, monocytosis, eosinophilia, and assess for dysplasia, immature cells, or blasts. 1, 2

• Peripheral blood smear review by hematopathologist to evaluate for myeloid immaturity, dysplastic features, and abnormal eosinophil morphology. 1

• Serum ferritin (<30 μg/L confirms iron deficiency without inflammation; <100 μg/L with inflammation), transferrin saturation (<16-20%), and C-reactive protein to distinguish iron deficiency from inflammatory causes. 2, 3

• Reticulocyte count to assess bone marrow response and distinguish hemolysis from production defects. 2, 3

• Vitamin B12 and folate levels, as combined deficiencies with iron can produce elevated RDW with normal MCV. 2, 3

Hematologic Malignancy Evaluation

If peripheral smear shows any concerning features (dysplasia, immature cells, abnormal eosinophils):

• Bone marrow aspiration and biopsy with cytogenetics and molecular testing for TK fusion genes (including FIP1L1-PDGFRA, which is associated with endomyocardial thrombosis and fibrosis). 1

• Flow cytometry to evaluate for clonal populations and aberrant immunophenotypes. 1

• Imaging studies (echocardiogram, CT chest/abdomen/pelvis) to assess for target organ involvement, lymphadenopathy, splenomegaly, or solid tumors. 1

Secondary Causes to Exclude

Rule out the most common secondary causes systematically:

• Parasitic infections (particularly Strongyloides stercoralis): Stool ova and parasites × 3, Strongyloides serology, especially if exposure history exists. 1

• Allergic disorders: Detailed medication history, IgE levels, specific allergen testing if indicated. 1

• Solid malignancies: Age-appropriate cancer screening, particularly lung, gastrointestinal, and genitourinary malignancies, as eosinophilia in solid tumors typically indicates advanced disease. 1

• Autoimmune/inflammatory conditions: ANA, RF, ANCA, complement levels if clinical features suggest systemic lupus erythematosus or vasculitis. 4

Interpretation Algorithm

If RDW Elevated with Low MCV:

• Strongly suggests iron deficiency anemia; confirm with ferritin and initiate iron supplementation while investigating gastrointestinal blood loss. 2, 3

If RDW Elevated with Normal MCV:

• May indicate early iron deficiency, combined iron and vitamin B12/folate deficiency (where microcytosis and macrocytosis cancel out), hemolysis, or inflammatory anemia. 2, 3
• Check ferritin, B12, folate, reticulocyte count, and inflammatory markers simultaneously. 2, 3

If RDW Elevated with High MCV:

• Suggests vitamin B12 or folate deficiency; however, 31% of pernicious anemia patients may have normal RDW, so do not exclude deficiency based on RDW alone. 5

Critical Pitfalls to Avoid

• Do not attribute eosinophilia solely to allergies or parasites when accompanied by neutrophilia and monocytosis—this combination warrants hematologic malignancy evaluation. 1

• Do not assume iron deficiency based on elevated RDW alone without checking ferritin, as inflammation elevates RDW independently (32% of anemia of chronic disease patients have elevated RDW). 6

• Do not overlook combined deficiencies: iron deficiency with B12/folate deficiency produces elevated RDW with normal MCV, masking both conditions. 3

• Do not delay bone marrow evaluation if peripheral smear shows dysplasia, immature cells, or abnormal eosinophil morphology, as myeloid/lymphoid neoplasms require prompt diagnosis for appropriate therapy. 1

• Do not miss FIP1L1-PDGFRA fusion gene testing, as this specific mutation is associated with life-threatening endomyocardial complications and responds to targeted therapy. 1

Urgent Consultation Triggers

Consult hematology immediately if:

• Peripheral smear shows dysplasia, blasts, or immature myeloid cells 1
• Absolute eosinophil count >1,500/μL with organ involvement (cardiac, pulmonary, neurologic, dermatologic) 1
• Splenomegaly, lymphadenopathy, or constitutional symptoms (fever, weight loss, night sweats) 1
• Thrombocytopenia or anemia with elevated RDW and multiple elevated white cell lineages 1

Consult infectious disease if:

• Travel or exposure history suggests parasitic infection, particularly in immunocompromised patients where Strongyloides hyperinfection can be fatal 1