Beyond Eosinophils: Redefining the Spectrum of Esophageal Inflammatory Diseases Through an Immune-Centric Paradigm

Traditional classification of esophageal inflammatory diseases (EIDs) relies on predominant cell infiltrates, with eosinophilic esophagitis (EoE) defined by ≥15 eosinophils per high-power field (hpf). However, although cell count thresholds remain clinically useful for defining certain variants, this paradigm alone does not fully capture the spectrum of immune-mediated esophageal inflammation or the complexity of therapeutic responses.

We conducted a comprehensive narrative review of EID literature, emphasizing recent advances in molecular characterization, clinical phenotyping, and therapeutic approaches for classical EoE and its variants.

Four distinct variants exist beyond classical EoE: EoE-like esophagitis (histologic EoE features with <15 eosinophils/hpf), lymphocytic esophagitis (≥30 lymphocytes/hpf), nonspecific esophagitis (mixed inflammatory infiltrates), and mast cell esophagitis (elevated intraepithelial mast cells). Each variant demonstrates unique demographic patterns, molecular signatures, and inflammatory pathways. EoE-like esophagitis shows interleukin-13 pathway overlap with classical EoE and may progress to EoE (62.2% by 6 years), whereas other variants represent distinct T helper type 1-driven or mixed inflammatory entities. Failed clinical trials targeting eosinophil depletion underscore the inadequacy of cell-centric therapeutic approaches, whereas multi-pathway inhibitors like dupilumab demonstrate superior efficacy.

An immune-centric approach recognizing distinct inflammatory pathways across EIDs offers opportunities for precision medicine, earlier intervention, and development of variant-specific biomarkers and targeted therapies. This paradigm shift is essential for advancing the field beyond arbitrary cell count thresholds toward mechanistic understanding of esophageal inflammation.