Molecular Characterization of Non-Specific Esophagitis Reveals a Distinct Non-Eosinophilic Phenotype With Fibrotic Traits

Abstract

Background

Non-specific esophagitis has been recently described in patients with dysphagia not fulfilling criteria for eosinophilic esophagitis (EoE). Whether it is a distinct entity and how dysphagia can develop in the absence of eosinophilic infiltration remains unknown.

Objective

In this study, we comprehensively characterized non-specific esophagitis aiming to elucidate eosinophil-independent fibrosis mechanisms.

Methods

We cross-sectionally and longitudinally analyzed treatment-naïve patients presenting with non-specific esophagitis defined by esophageal dysfunction and low-grade lymphocytic infiltration (< 30 lymphocytes/hpf) in the absence of tissue eosinophilia and reflux disease (GERD). We compared clinical, endoscopic, (immuno)-histological disease activity to EoE, lymphocytic esophagitis, and GERD. RNA sequencing was performed to investigate disease mechanisms.

Results

We identified 19 patients (6 males, median age 48 years), with a follow-up of 20 months (IQR 10–41). Clinical disease burden was considerable, contrasting mild endoscopic activity (EREFS 0, IQR 0–2). Immunostaining of esophageal biopsies did not reveal increased numbers of eosinophils or mast cells as contributors to the disease. Lymphocytic infiltration (15/hpf, IQR 9–24) was not increased compared to healthy controls (9/hpf, IQR 9–10) or GERD patients (13/hpf, IQR 9–23); 14 (73.6%) patients were treated with topical steroids (symptomatic response in 85.7%) and 6 patients (31.6%) underwent endoscopic dilation. Progression to EoE was observed in 1 patient, while esophageal eosinophilia (< 15 eos/hpf) developed in 3 patients. RNA sequencing (n = 10) revealed a distinct transcriptomic profile, with highly enriched fibrosis-related pathways. Immunostaining for E-Cadherin/Vimentin as a marker for epithelial-mesenchymal transition (EMT, n = 10) confirmed increased EMT compared to controls.

Conclusion

Non-specific esophagitis appears to be a distinct non-eosinophilic phenotype with fibrotic traits. Our data suggest eosinophil-independent development of fibrosis.