Hypereosinophilia in 2025: New Classification Systems and Expanding Biologic Therapies

Hypereosinophilia (HE) affects a broad spectrum of patients, ranging from those with incidentally discovered asymptomatic eosinophilia to individuals facing life-threatening multiorgan failure. This 2025 narrative review from the University of Cagliari synthesizes current knowledge on the biology, classification, clinical presentation, and treatment of HE and hypereosinophilic syndrome (HES), incorporating the most recent consensus criteria from the 2021 Working Conference on Eosinophil Disorders and the newly proposed SIAAIC task force framework.

Eosinophils are polymorphonuclear hematopoietic cells whose development, survival, and activation are primarily regulated by IL-3, IL-5, and GM-CSF. In hypereosinophilic states, overactivated eosinophils infiltrate tissues and release cytotoxic granule proteins—including major basic proteins (MBP1/MBP2), eosinophil peroxidase (EPO), eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN)—triggering persistent inflammation, thrombosis, and fibrosis. HES is formally diagnosed when HE (AEC >1.5 × 10⁹/L on two occasions ≥2 weeks apart) is associated with organ damage not explained by another cause. A newer tissue-restricted mono-organ HES category is recognized, where eosinophilic organ damage occurs without peripheral blood HE.

The review details two major contemporary classification systems. Valent (2023) organizes HE into hereditary (HEf), unknown significance (HEus), reactive (HEr), and neoplastic/clonal (HEn) subtypes, while HES variants include familial, idiopathic, primary neoplastic, secondary reactive, and special types including lymphoid variant HES and overlap syndromes (EGPA, Gleich syndrome, IgG4-RD, eosinophilia myalgia syndrome). The SIAAIC task force diverges by explicitly separating HE from HES, excluding overlap syndromes from HES classification, treating lymphocytic HE as a distinct potentially pre-neoplastic entity, and introducing a single-organ HE category. These distinctions carry direct implications for workup and treatment decisions.

Clinically, skin involvement is most prevalent (69% of patients), followed by pulmonary (44%), gastrointestinal (38%), cardiac (~20%), and neurological (~20%) manifestations. Cardiac complications—including restrictive cardiomyopathy, heart failure, and thromboembolism—carry the greatest morbidity and mortality risk. Corticosteroids remain the cornerstone of first-line therapy across subtypes. Imatinib, a tyrosine kinase inhibitor, achieves high response rates specifically in patients harboring the FIP1L1::PDGFRA fusion gene, though resistance and relapse remain challenges. Anti-IL-5 therapies mepolizumab and benralizumab have demonstrated efficacy in reducing eosinophil counts and preventing flares, particularly in idiopathic and lymphocytic HES. Dupilumab (anti-IL-4Rα) and lirentelimab (anti-Siglec-8) are under active investigation.

The review underscores that optimizing outcomes in HE and HES requires precise etiologic classification to guide individualized therapy, vigilant multiorgan monitoring, and participation in ongoing clinical trials to address remaining unmet therapeutic needs.