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Multicenter Study
. 2022 Aug;77(8):2520-2533.
doi: 10.1111/all.15233. Epub 2022 Feb 17.

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

Thomas Greuter  1   2 , Alex Straumann  1 , Yuniel Fernandez-Marrero  3 , Nina Germic  3 , Aref Hosseini  3 , Shida Yousefi  3 , Dagmar Simon  4 , Margaret H Collins  5 , Christian Bussmann  6 , Mirna Chehade  7 , Evan S Dellon  8 , Glenn T Furuta  9 , Nirmala Gonsalves  10 , Ikuo Hirano  10 , Fouad J Moawad  11 , Luc Biedermann  1 , Ekaterina Safroneeva  12 , Alain M Schoepfer  2 , Hans-Uwe Simon  3   13   14   15
Affiliations
Multicenter Study

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

Thomas Greuter et al. Allergy. 2022 Aug.

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/mm2 (<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.

Keywords: dysphagia; eosinophilic esophagitis; esophageal eosinophilia; lymphocytic esophagitis; next generation rna sequencing.

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Conflict of interest statement

TG has consulting contracts with Sanofi‐Regeneron and Falk Pharma GmbH, received travel grants from Falk Pharma GmbH and Vifor, and an unrestricted research grant from Novartis. AS has consulting contracts with Actelion, Celgene‐Receptos, Falk Pharma GmbH, Roche‐Genentech, GSK, Novartis, Nutricia, and Sanofi‐Regeneron. ES is a consultant for Celgene Corp., Regeneron Pharmaceuticals Inc., and Novartis. AMS is a consultant for Falk Pharma GmbH, Adare Pharmaceuticals Inc, Celgene‐Receptos, and Sanofi‐Regeneron. MHC is a consultant for Astra Zeneca, Allakos, Arena, Celgene, Esocap, GlaxoSmithKline, Regeneron and Shire, and has received research funds from Regeneron and Shire. LB has received consulting fees and/or speaker fees from Falk Pharma GmbH, Esocap AG, Sanofi‐Aventis AG, and Calypso Biotech SA. GTF is a consultant for Takeda and Arena and has received research support from Holoclara. MC received research support from hire, Regeneron and Allakos, consulting fees from Shire, Regeneron, Allakos, Adare and Nutricia, and lecture honoraria from Nutricia, Medscape, and the Annenberg Center for Health Sciences at Eisenhower. IH has received consulting fees from Receptos, Regeneron, Shire, and Roche. ESD has received research funding from Adare, Allakos, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos, Regeneron, Shire; consulting fees from Adare, Aimmune, Alivio, Allakos, AstraZeneca, Banner, Biorasi, Calypso, Celgene/Receptos, Enumeral, EsoCap, Gossamer Bio, GSK, Regeneron, Robarts, Salix, Shire; and educational grants from Allakos, Banner, Holoclara. HUS is a consultant for AstraZeneca, GlaxoSmithKline, and Esocap. The other authors have no competing interests to declare. No company representative was involved in conception, writing, or financing of this study.

Figures

FIGURE 1
FIGURE 1
(A) Flow chart of study patients. (B) Proportion of patients classified into the EoE variants EoE‐like esophagitis, lymphocytic esophagitis, and non‐specific esophagitis with representative hematoxylin and eosin pictures. (C) Endoscopic (upper panel) and histological (lower panel) disease activity based on EREFS grading system (EREFS score) and EoE‐HSS grading and staging system. (D) EoE‐HSS grading for EoE variants (all patients) and each EoE variant separately. (E) EoE‐HSS staging for EoE variants (all patients) and each variant separately. Bars indicate mean+/‐SEM
FIGURE 2
FIGURE 2
(A) Immunostaining for CD3 (red), EPX (green), and nuclear counterstaining (DAPI, blue) in healthy controls, classical EoE, EoE variants, and GERD (upper left panel). The three other panels show quantitative analyses. B) EPX deposition scores (ranging from 0 to 3) for classical EoE, EoE variants, GERD, and controls. (C) Number of CRTH2+ T‐cells per mm2 in classical EoE, EoE variants, GERD, and controls. Bars indicate mean+/‐SEM
FIGURE 3
FIGURE 3
(A) Immunostaining for TNF‐a, TSLP, and eotaxin‐3 in healthy controls, classical EoE, EoE variants, and GERD (left panel). Right panels show quantitative analyses. B) Immunostaining for LEKTI (green) in healthy controls, classical EoE, EoE variants, and GERD. Lower panel shows quantitative analyses. Bars indicate mean+/‐SEM
FIGURE 4
FIGURE 4
(A) Venn diagram for significantly up‐ and down‐regulated genes (fold change ≥2) compared with healthy controls in EoE variants, classical EoE, and GERD (upper panel with up‐regulated genes, lower panel with down‐regulated genes). (B) Cluster analysis of genes (in all patients, and with averaged values (z‐scores)) that were significantly up‐ or down‐regulated compared with healthy controls in at least one condition (classical EoE, EoE variants, and GERD). Lower panels show the most upregulated genes in cluster 4 (EoE), cluster 2 (non‐specific esophagitis), and cluster 5 (lymphocytic esophagitis and EoE‐like esophagitis). (C) qPCR for C3 and CCDC80 as possible biomarkers for EoE variants. C3 and CCDC80 have been identified as possible candidate genes in Supplementary Figure S7
FIGURE 5
FIGURE 5
(A) Hierarchical sample clustering of EoE variants (heatmap); (B) Hierarchical sample clustering of EoE variants (averaged values, heatmap); (C) Cluster plot for EoE variant clusters detected by hierarchical sample clustering; (D) Venn diagram showing unique and overlapping genes in EoE variant clusters (significantly changed genes compared with healthy controls); (E) list of the most unique genes in each EoE variant cluster, ranked by false discovery rate (FDR) compared with healthy controls. (F) Immunostaining for CD3, eotaxin‐3, and TSLP in EoE variant clusters (V1‐3). (G) Re‐classification of histologically defined EoE variants into variant clusters (V1‐3). Bars indicate mean+/‐SEM
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References

    1. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128(1):3‐20. - PubMed
    1. Straumann A, Conus S, Grzonka P, et al. Anti‐interleukin‐5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo‐controlled, double‐blind trial. Gut. 2010;59(1):21‐30. - PubMed
    1. Assa'ad AH, Gupta SK, Collins MH, et al. An antibody against IL‐5 reduces numbers of esophageal intraepithelial eosinophils in children with eosinophilic esophagitis. Gastroenterology. 2011;141(5):1593‐1604. - PubMed
    1. Spergel JM, Rothenberg ME, Collins MH, et al. Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double‐blind, randomized, placebo‐controlled trial. J Allergy Clin Immunol. 2012;129(2):pp. 456‐463, 63. - PubMed
    1. Safroneeva E, Straumann A, Coslovsky M, et al. Symptoms have modest accuracy in detecting endoscopic and histologic remission in adults with eosinophilic esophagitis. Gastroenterology. 2016;150(3):581‐590. - PMC - PubMed

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Supplementary concepts