Fibrostenotic eosinophilic esophagitis phenotype is defined by a proliferative gene signature.
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ABSTRACT:
SUBMITTER: Menard-Katcher C
PROVIDER: S-EPMC9892276 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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Fibrostenotic eosinophilic esophagitis phenotype is defined by a proliferative gene signature.
Menard-Katcher Calies C Liu Cuining C Galbraith Matthew D MD Benson Taylor T Burger Cassandra C Dobias Devin D Larsen Leigha L O'Brien Carol C Spencer Lisa A LA Furuta Glenn T GT Masterson Joanne C JC
Allergy 20221105 2
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Project description:ObjectivesEosinophilic esophagitis (EoE) is a chronic inflammatory condition that causes esophageal remodeling and stricture formation. We compared the clinical course of symptoms, endoscopic findings, histology, and changes in phenotype over time in EoE patients with inflammatory and fibrostenotic phenotypes.MethodsData were obtained from EoE patients from three medical centers and followed prospectively. Endoscopic features and histology from index and follow-up endoscopies were recorded. Behavior was classified as inflammatory if endoscopic findings demonstrated furrows or white plaques and as fibrostenotic if endoscopic findings included fixed rings or strictures.ResultsTwo hundred and fifty-six EoE patients were included in the analysis. The mean age was 32±18 years, 25% of patients were <18 years, 89% of patients were Caucasians, and 74% of patients were male. The mean duration of symptoms before diagnosis was 6.8±7.2 years with a follow-up of 1.7±1.9 years (maximum follow-up of 12 years). Fifty-four percent of patients presented with fibrostenotic EoE, whereas 46% presented with inflammatory EoE. Patients with inflammatory disease were younger than those with fibrostenotic disease (24±19 vs. 39±15 years, P<0.001). Patients with fibrostenotic disease had a longer duration of symptoms than those with inflammatory disease (8.1±7.7 vs. 5.3±6.3 years, P=0.002). Over the study period, 47 (18%) had remission of inflammatory EoE, 68 (27%) continued to have inflammatory disease, 74 (29%) continued to have fibrostenotic disease, 65 (25%) fibrostenotic patients had regression of fibrosis, and 2 patients (1%) progressed from inflammatory disease to fibrostenotic disease. Patients who had regression from their fibrostenosis were more likely than patients who continued to demonstrate fibrostenosis to have a decrease in proximal (54% vs. 32%, P<0.001) and distal (70% vs. 38%, P<0.001) eosinophilia.ConclusionsMost EoE patients maintained their phenotype or had an improvement with <1% progressing from inflammatory to fibrostenosis. This suggests that early therapeutic strategies aimed at controlling inflammation may interrupt, decrease, or prevent the remodeling fibrosis in EoE.
| S-EPMC4816096 | biostudies-literature
Project description:ObjectivesEsophageal dilation is commonly performed in eosinophilic esophagitis (EoE), but there are few long-term data. The aims of this study were to assess the safety and long-term efficacy of esophageal dilation in a large cohort of EoE cases, and to determine the frequency and predictors of requiring multiple dilations.MethodsWe conducted a retrospective cohort study in the University of North Carolina EoE Clinicopathological Database from 2002 to 2014. Included subjects met consensus diagnostic criteria for EoE. Clinical, endoscopic, and histologic features were extracted, as were dilation characteristics (dilator type, change in esophageal caliber, and total number of dilations) and complications. Patients with EoE who had undergone dilation were compared with those who did not and also stratified by whether they required single or multiple dilations.ResultsOf 509 EoE patients, 164 were dilated a total of 486 times. Those who underwent dilation had a longer duration of symptoms before diagnosis (11.1 vs. 5.4 years, P<0.001). Ninety-five patients (58%) required >1 dilation (417 dilations total, mean of 4.4±4.3 per patient). The only predictor of requiring multiple dilations was a smaller baseline esophageal diameter. Dilation was tolerated well, with no major bleeds, perforations, or deaths. The overall complication rate was 5%, primarily due to post-procedural pain. Of 164 individuals dilated, a majority (58% or 95/164) required a second dilation. Of these individuals, 75% required repeat dilation within 1 year.ConclusionsDilation in EoE is well-tolerated, with a very low risk of serious complications. Patients with long-standing symptoms before diagnosis are likely to require dilation. More than half of those dilated will require multiple dilations, often needing a second procedure within 1 year. These findings can be used to counsel patients with fibrostenotic complications of EoE.
| S-EPMC4758887 | biostudies-literature
Project description:BackgroundPhenotypes of eosinophilic esophagitis (EoE) are not well-characterized.ObjectiveTo describe clinical features of patients with EoE with predefined phenotypes, determine predictors of these phenotypes, and make inferences about the natural history of EoE.DesignRetrospective study.SettingTertiary-care center.PatientsIncident EoE cases from 2001 to 2011 that met consensus diagnostic guidelines.InterventionReview of records.Main outcome measurementsEndoscopic phenotypes, including fibrostenotic, inflammatory, or mixed. Other groups of clinical characteristics examined included atopy, level of esophageal eosinophilia, and age of symptom onset. Multinomial logistic regression assessed predictors of phenotype status.ResultsOf 379 cases of EoE identified, there were no significant phenotypic differences by atopic status or level of eosinophilia. Those with the inflammatory phenotype were more likely to be younger than those with mixed or fibrostenotic (13 vs 29 vs 39 years, respectively; P < .001) and less likely to have dysphagia, food impaction, and esophageal dilation (P < .001 for all). The mean symptom length before diagnosis was shorter for inflammatory (5 vs 8 vs 8 years; P = .02). After multivariate analysis, age and dysphagia independently predicted phenotype. The odds ratio (OR) for fibrostenosis for each 10-year increase in age was 2.1 (95% CI, 1.7-2.7). The OR for dysphagia was 7.0 (95% CI, 2.6-18.6).LimitationsRetrospective, single-center study.ConclusionIn this large EoE cohort, the likelihood of fibrostenotic disease increased markedly with age. For every 10-year increase in age, the odds of having a fibrostenotic EoE phenotype more than doubled. This association suggests that the natural history of EoE is a progression from an inflammatory to a fibrostenotic disease.
| S-EPMC4599711 | biostudies-literature
Project description:Background & aimsEosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences.MethodsEsophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro.ResultsTSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling.ConclusionsPatients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.
| S-EPMC8792211 | biostudies-literature
Project description:BackgroundFibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE.ObjectiveWe investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE.MethodsLOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting.ResultsGene ontology and pathway analyses linked TNF-α and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-α-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-α stimulates epithelial LOX expression through activation of nuclear factor κB and TGF-β-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE.ConclusionsThere is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-α secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.
| S-EPMC6586527 | biostudies-literature
Project description:BackgroundIndirect consequences of COVID-19 in eosinophilic esophagitis (EoE) are not known.AimTo determine the impact of COVID-19-related endoscopy cancellations on outcomes in EoE patients.MethodsIn this retrospective cohort study, we assessed whether adult EoE patients who had routine endoscopy scheduled from mid-March 2020 to May 2020 (pandemic start) were canceled or proceeded, and if canceled, ultimately returned. We extracted clinical, endoscopic, and histologic data for their pre-COVID procedure as well as the next procedure performed, if a patient returned. Outcomes included histologic response (< 15 eos/hpf) and endoscopic severity. Those with delayed care were compared to those who returned as scheduled.ResultsOf 102 patients identified, 75 had procedures canceled, and 20 (27%) never returned. For the 55 who were canceled but returned, mean time between procedures was 1.1 ± 0.7 years with a delay of 0.5 ± 0.3 years. While treatment rates were similar between the pre- and delayed post-COVID EGD, more patients required a dilation after their return (71% vs 58%; p = 0.05) and their esophageal diameter had significantly decreased (16.8 mm to 15.0 mm; p < 0.001). Of 17 individuals who did not have stricture, narrowing, or dilation pre-pandemic, during their next endoscopy 5 (29%) had a stricture, 1 (6%) had a narrowing, and 7 (41%) required dilation.ConclusionOf EoE patients with canceled endoscopies during the beginning of the COVID-19 pandemic, > 25% never returned for care, which is a previously unmeasured impact of the pandemic. Those who returned had > 1 year between procedures with progression of fibrotic features and need for esophageal dilation.
| S-EPMC9255524 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue from pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA sequencing of paired human esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease. Unbiased analysis of differentially expressed genes in tissue revealed a strong IFN signature that was significantly enriched in EoE patients as compared with patients with gastroesophageal reflux disease. Both type I and type II IFN-responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of IFN gene sets was observed in pediatric EoE biopsies as compared with non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that human peripheral CD4+ T cells from children with EoE produce IFN-γ upon activation with EoE-causal allergens. Together, this work identifies a conserved IFN signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process in humans.
| S-EPMC7946729 | biostudies-literature
Project description:ObjectiveTo review the understanding of the pathogenesis of eosinophilic esophagitis (EoE) and the role of the immune system in the disease process.Data sourcesPeer-reviewed articles on EoE from PubMed searching for "Eosinophilic Esophagitis and fibrosis" in the period of 1995 to 2013.Study selectionsStudies on the clinical and immunologic features, pathogenesis, and management of EoE.ResultsRecent work has revealed that thymic stromal lymphopoietin and basophil have an increased role in the pathogenesis of disease. Additional understanding on the role of fibrosis in EoE is emerging.ConclusionThe incidence of EoE is increasing like most atopic disease. Similar to other allergic diseases, EoE is treated with topical steroids and/or allergen avoidance.
| S-EPMC4332835 | biostudies-literature
Project description:Eosinophilic esophagitis (EoE) is an allergic inflammatory disease of the esophagus that occurs in both children and adults. Previous studies of affected tissue in pediatric cohorts have identified prominent signatures of eosinophilia and type 2 inflammation. However, the details of the immune response in adults with EoE are still being elucidated. To determine whether EoE in adults shares inflammatory profiles with those observed in children, we performed RNA-sequencing of paired esophageal biopsies and blood samples from adults with EoE or gastroesophageal reflux disease (GERD). Unbiased analysis of differentially expressed genes in tissue revealed a strong interferon signature that was significantly enriched in EoE patients as compared to patients with GERD. Both type I and type II interferon responsive genes were upregulated in adult biopsies, but not in blood. A similar increase in expression of interferon gene sets was observed in pediatric EoE biopsies as compared to non-EoE samples, and in public pediatric and adult RNA-sequencing data. Finally, we found that peripheral CD4+ T cells from children with EoE produce IFNG upon activation with EoE-causal allergens. Together, this work identifies a conserved interferon signature in pediatric and adult EoE, highlighting a role for non-type 2 inflammatory networks in the disease process.
2020-08-22 | GSE156651 | GEO