Research gaps in eosinophilic esophagitis: unanswered questions and future directions.

Eosinophilic esophagitis (EoE) has emerged as a leading cause of dysphagia worldwide, yet significant knowledge gaps persist across fundamental aspects of disease management. This comprehensive narrative review examines critical research opportunities spanning five interconnected domains that collectively hamper optimal patient care. Despite advances in understanding type 2 inflammation, EoE pathogenesis remains incompletely characterized, particularly regarding gene-environment interactions, epithelial barrier dysfunction mechanisms, and tissue remodeling pathways. The diagnosis currently relies on endoscopy with biopsies with an arbitrary eosinophil threshold of 15 eosinophils/high-power field, while molecular endotypes and non-invasive biomarkers lack validation. Treatment strategies remain largely empirical without strong evidence-based therapeutic hierarchies, comparative effectiveness data, or reliable response predictors. The lack of head-to-head comparison trials of different interventions limits evidence-based treatment selection, while combination therapy approaches remain mostly underexplored. Challenges in defining optimal treatment targets persist, as recent eosinophil-depleting biologics achieved histologic responses without symptomatic improvement, highlighting the limitations of eosinophil-centric disease models. Disease trajectory prediction and long-term outcome monitoring lack systematic approaches, while primary prevention strategies remain undefined despite escalating global incidence. Addressing these research gaps through coordinated multidisciplinary efforts has the potential to transform EoE management from empirical to personalized, evidence-based approaches, ultimately improving patient outcomes and potentially enabling disease prevention.