Eosinophilia and Hypereosinophilia: A Practical Approach to Navigating a Broad Differential Diagnosis

Eosinophilia, defined as an absolute eosinophil count (AEC) of ≥ 0.5 × 10⁹/L, is a frequently encountered finding with a vast spectrum of potential underlying etiologies. Hypereosinophilia (HE) is defined as AEC > 1.5 × 10⁹/L and may become life-threatening when eosinophil-induced organ damage occurs, defining the hypereosinophilic syndrome (HES). Among the many causes of HE, rare hematological malignancies, in particular the "myeloid/lymphoid neoplasms (MLN) with eosinophilia and tyrosine kinase (TK) gene fusions," represent phenotypically and prognostically heterogeneous and challenging entities. For this reason, the evaluation of HE constitutes a diagnostic and therapeutic challenge. In this review, we provide a concise overview of eosinophil biology, highlight their physiological role as regulators of immunity, tissue homeostasis, and inflammation, their involvement in diseases affecting nearly all organ systems, and in hematological malignancies in particular. Furthermore, we present a practical, stepwise diagnostic approach to HE, emphasizing early recognition of eosinophil-mediated organ dysfunction to initiate timely treatment, as well as red flags that should raise further hematologic evaluation, including molecular and cytogenetic investigations to identify an underlying clonal disorder. Treatment strategies depend on the underlying etiology and range from supportive care, over corticosteroids to targeted biological therapies and tyrosine kinase inhibitors (TKIs).