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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., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Introduction: It is still unknown whether eosinophilic esophagitis (EoE) patients with localized disease are different from those with extended disease. Methods: We evaluated prospectively included patients in the Swiss EoE cohort. Data on all patients with active disease at baseline, no concomitant gastroesophageal reflux disease, no strictures at baseline, and at least one follow-up visit were analyzed. We compared patients with histologically localized proximal versus distal versus extended (=proximal and distal) disease with regard to patient, disease characteristics, disease presentation, and development of complications. Results: We included 124 patients with a median of 2.5 years of follow-up (73.4% males, median age 35.0 years). Ten patients had proximal (8.1%), 46 patients had distal (37.1%), and 68 patients had extended disease (54.8%). Patients with proximal disease were significantly more often females (80%) compared with patients with distal (26.1%, p = 0.002) or extended disease (19.1%, p < 0.001) and reported less severe symptoms (VAS 0 vs. VAS 1, p = 0.001). Endoscopic and histological disease was less pronounced in the proximal esophagus of proximal EoE compared to extended disease (EREFS 1.0 vs. 3.0, p = 0.001; 27.0 eos/hpf vs. 52.5 eos/hpf, p = 0.008). Patients with proximal disease were less likely to undergo dilation compared to patients with distal disease in the follow-up (3.3% vs. 23.3%, p = 0.010). In a multivariate Cox regression model, proximal eosinophilia was less likely to be associated with treatment failure compared to distal eosinophilia. Conclusion: Although isolated proximal EoE is infrequent, it is associated with less severe disease and better disease outcome. Proximal disease appears to present a unique EoE phenotype. [ABSTRACT FROM AUTHOR]