Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross‐sectional multi‐center study

Abstract

Objective: Physicians are increasingly confronted with patients presenting with symptoms of esophageal dysfunction resembling eosinophilic esophagitis (EoE), but absence of significant esophageal eosinophilia. The purpose of this study was to characterize and classify this group of EoE variants.Design: Patients from six EoE-centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <60/mm 2 (<15/hpf) in esophageal biopsies and absence of gastro-esophageal reflux disease (GERD) were included. Clinical, endoscopic, (immuno)-histological, and molecular features were determined and compared with EoE, GERD, and healthy controls. Results:We included 69 patients with EoE variants. Endoscopic abnormalities were found in 53.6%. We identified three histological subtypes: EoE-like esophagitis (36/69, 52.2%), lymphocytic esophagitis (14/69, 20.3%), and non-specific esophagitis (19/69, 27.5%). Immunohistochemistry revealed-in contrast to EoE-no significant increase in inflammatory cell infiltrates compared with GERD and healthy controls, except for lymphocytes in lymphocytic esophagitis. EoE-typical Th2-response was absent in all EoE variants. However, considerable structural changes were detected based on histology and protein expression. Using next generation mRNA sequencing, we found the three EoE variants to have distinct molecular fingerprints partially sharing pronounced traits of EoE. Hierarchical sample clustering of RNA sequencing data confirmed the presence of an EoE-like (characterized by eotaxin-3 expression), non-specific, and lymphocytic variant cluster (characterized by CD3 cells and TSLP expression). Conclusion:All EoE variants are clinically and histologically active conditions despite the absence of esophageal eosinophilia. EoE variants appear to be part of a disease spectrum, where classical EoE represents the most common and apparent phenotype.

Legends of allergology and immunology: Alex Straumann

“…While these patients appear to be a subgroup of EoE patients, a recently published study suggests the existence of non‐eosinophilic variants of esophagitis that all suffer from classical EoE symptoms 7 . Interestingly, all these variants are characterized by distinct gene expression patterns, suggesting different types of inflammatory responses 8 …”

“…7 Interestingly, all these variants are characterized by distinct gene expression patterns, suggesting different types of inflammatory responses. 8 In 2017, Alex closed his doctor's practice in Olten, in which he had worked for about 32 years, after his 70th birthday. He is now a consult physician in the Department of Gastroenterology of the University Hospital Zurich.…”

Eosinophilic Esophagitis beyond Eosinophils – an Emerging Phenomenon Overlapping with Eosinophilic Esophagitis: Collegium Internationale Allergologicum (CIA) Update 2023

“…Lymphocytic esophagitis has been suggested as an EoE variant and characterized in detail in the aforementioned multicenter study [60]. For the first time, mRNA profiles Typical pattern with high number of intraepithelial lymphocytes (≥30 per hpf), gathered mainly in peripapillary fields, peripapillary spongiosis (dilated intercellular spaces) and absence of intraepithelial granulocytes [79] Non-specific esophagitis Histological infiltration of lymphocytes or neutrophils not fulfilling the numerical and distributional criteria of lymphocytic esophagitis [60] Eosinophilic Esophagitis beyond Eosinophils Int Arch Allergy Immunol 2023;184:411-420 DOI: 10.1159/000529910 of lymphocytic esophagitis were compared with EoE, GERD, and esophageal healthy controls. Comparative analyses of mRNA sequencing datasets revealed similar upstream regulators in lymphocytic esophagitis as in the other EoE variants and conventional EoE but not GERD.…”

Models and Tools for Investigating Eosinophilic Esophagitis at the Bench

“…Other transcriptional analyses have suggested that loss of a critical serine protease, SPINK7 , may be an early event in EoE pathogenesis ( 31 ). Most recently bulk RNA sequencing has been applied to study increasingly common EoE variants where eosinophils are reduced or absent, yet inflammation in the esophagus persists ( 32 ). The investigators found that compared to classic EoE and GERD specimens, the three EoE subtypes they identified (EoE-like esophagitis, lymphocytic esophagitis, non-specific esophagitis) all lacked the classic Th2 inflammatory response, despite having endoscopic and histologic structural similarities to classic EoE.…”