Th2-High Severe Asthma with Hypereosinophilia in the Spectrum of Type 2 Inflammatory Diseases.

Asthma is among the most common chronic respiratory diseases, affecting approximately 3340 individuals per 100,000 worldwide. It is a heterogeneous condition associated with airway hyperresponsiveness and chronic inflammation. Severe asthma (SA) affects 3-10% of patients, most of whom exhibit Type 2 (T2) inflammation with elevated eosinophil counts or increased fractional exhaled nitric oxide. Although the Global Initiative for Asthma provides detailed guidelines for SA, patients with marked hypereosinophilia (HE; >1500 cells/µL) who do not meet diagnostic criteria for hypereosinophilic syndrome (HES) or eosinophilic granulomatosis with polyangiitis (EGPA) remain insufficiently addressed. In such cases, oral corticosteroids, and T2-targeted monoclonal antibodies (MAbs) inhibiting interleukin-5 or its receptor are the main therapeutic options. For instance, mepolizumab is approved for EGPA, HES, and chronic rhinosinusitis with nasal polyps, but its use in hypereosinophilic SA is limited by eligibility, tolerance, or effectiveness. SA with HE not classified as HES or EGPA is exceptionally rare and may be diagnosed by the exclusion of other potential causes of HE. This review analyzes recent studies and case reports, aiming to expand the understanding of this underrecognized clinical entity, its relation to T2 inflammation and eosinophilic disorders, and to highlight the need for improved diagnostic and therapeutic strategies.