Episodic Angioedema with Eosinophilia (Gleich Syndrome): Clinical Features, Diagnosis, and Management

Episodic angioedema with eosinophilia (EAE), also known as Gleich syndrome, is a rare immune-mediated disorder characterized by recurrent, self-limited episodes of non-urticarial angioedema accompanied by marked peripheral hypereosinophilia and systemic manifestations, including fever, myalgias, transient weight gain, and oliguria. The disease follows a cyclic course with symptom-free intervals and is typically associated with a favorable prognosis, lacking progressive end-organ damage, thereby distinguishing it from classical hypereosinophilic syndromes (HES). This review comprehensively evaluates current evidence regarding the clinical presentation, immunologic characteristics, and pathophysiological mechanisms of EAE. Available data support a central role of Th2-driven immune dysregulation, increased interleukin-5 (IL-5) production, and cyclic eosinophil activation and degranulation. In a subset of patients, aberrant or clonal T-cell populations have been identified, indicating partial pathogenetic overlap with the lymphocytic variant of HES, although EAE maintains a distinct and generally more benign clinical course. EAE remains a diagnosis of exclusion and requires structured evaluation, including assessment of C1 inhibitor and C4 levels to exclude bradykinin-mediated angioedema, and investigation for secondary causes of eosinophilia and myelo- or lymphoproliferative disorders through immunophenotyping, T-cell receptor gene rearrangement analysis, and molecular testing such as FIP1L1–PDGFRA screening. Acute episodes respond rapidly to systemic corticosteroids. In cases of frequent relapse or corticosteroid dependence, steroid-sparing strategies and targeted biologic therapies directed against IL-5 or its receptor represent promising options. Given the rarity of EAE and the absence of standardized algorithms, this review provides a clinically oriented synthesis of diagnostic principles, differential diagnostic considerations, and emerging targeted therapies to improve recognition and evidence-based management of this uncommon yet clinically significant disorder.