Professionals

Authors
Marc Pfefferle et al.

Journal
Allergy. 2026 May 1.  doi: 10.1111/all.70364.

Paper of the Month – Selected and discussed by Helen Larsson

🎯 Study Aim

This study explored whether non-specific esophagitis is a true disease entity rather than an inconclusive biopsy finding, and whether esophageal fibrosis can develop without the eosinophilic inflammation typically associated with eosinophilic esophagitis (EoE).

🔬 Methods

Nineteen patients with dysphagia, low-grade lymphocytic inflammation, no eosinophilia, and no GERD were followed in a multicenter longitudinal study. They were compared with patients with EoE, lymphocytic esophagitis, GERD, and healthy controls using clinical assessment, endoscopy (EREFS), histology (EoE-Hss and peak eosinophilic counts, immunostaining, and RNA sequencing).

📊 Key Findings

Patients with non-specific esophagitis had significant swallowing symptoms despite often normal endoscopy and only mild or absent conventional histologic abnormalities. Unlike EoE, they showed minimal eosinophil or mast cell infiltration, but molecular analyses revealed a distinct pro-fibrotic signature with tissue remodeling, epithelial barrier dysfunction, and increased epithelial-mesenchymal transition (EMT). These findings suggest that fibrosis can occur even without classic eosinophilic inflammation. Most patients improved with topical steroids, though some required dilation and a small number later developed eosinophilic features.

🧠 Interpretation

For clinicians, this study is highly relevant because it reflects a common real-world challenge: patients with typical EoE-like symptoms but biopsies that do not meet diagnostic criteria. Non-specific esophagitis may represent a separate fibrotic esophageal disorder rather than a mild or missed form of EoE. This broadens our understanding of dysphagia and suggests that relying only on eosinophils may overlook clinically meaningful disease.

⚠️ Critical Appraisal

The study’s strengths include detailed molecular profiling, appropriate control groups, and longitudinal follow-up. However, the cohort was small, GERD was not excluded with pH monitoring, and fibrosis was inferred mainly through molecular and EMT markers rather than direct functional tools such as EndoFLIP. These limitations mean the findings are hypothesis-generating rather than definitive.

📝 Take-Home Message

As treating physicians, we should recognize that patients with severe dysphagia but no eosinophilia may still have a biologically active esophageal disease. Non-specific esophagitis may represent an underrecognized fibrotic phenotype where barrier dysfunction and tissue remodeling drive symptoms, reminding us to think beyond eosinophils when evaluating unexplained esophageal dysfunction.