Pediatric Severe Eosinophilia: Etiological Spectrum, Diagnostic Algorithm, and Case‐Based Insights From a Tertiary Care Center

Purpose Pediatric hypereosinophilia (HE) is rare, and its evaluation is challenging due to diverse etiologies and limited access to advanced laboratory testing in low‐ and middle‐income countries (LMICs). Methods We retrospectively analyzed five children with HE (absolute eosinophil count > 5.0 × 10 9 /L) evaluated at a tertiary center. Clinical, hematologic, and molecular findings were reviewed, and diagnostic timelines were compared between clonal and non‐clonal cases. Based on these observations, a tiered, laboratory‐driven diagnostic pathway adapted for LMICs was developed. Results Five patients (median age: 6 years; range: 1.5–10 years) were included. The median absolute eosinophil count (AEC) at presentation was 12.8 × 10 9 /L (range: 6.5–21.5 × 10 9 /L). Three cases (60%) were clonal eosinophilia—one PDGFRB‐rearranged myeloid/lymphoid neoplasm and two acute myeloid leukemia subtypes [AML with CBFB::MYH11, AML with RUNX1::RUNX1T1]—and two cases (40%) were non‐clonal [one Hyper‐IgE syndrome with secondary hemophagocytic lymphohistiocytosis (HLH), one secondary eosinophilia (drug‐induced, phenytoin/phenobarbitone)]. Clonal cases demonstrated higher leukocyte counts, earlier bone marrow and molecular testing, and shorter median time to diagnosis (6 vs. 14 days), enabling prompt initiation of imatinib or AML‐directed therapy with remission in all. In contrast, non‐clonal HE required sequential exclusion of clonal disease, delaying immunosuppressive or drug‐withdrawal strategies. Conclusion A structured, laboratory‐driven algorithm beginning with blood counts, smear, and parasitic testing, and escalating to early bone marrow with cytogenetic/molecular studies for high‐risk phenotypes, enabled timely identification of clonal HE while conserving resources in reactive cases. This LMIC‐adapted pathway highlights laboratory turnaround time as a critical determinant of outcomes and provides a practical framework for pediatric HE evaluation.