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Background: Eosinophilic esophagitis (EoE) involves a chronic immune‐mediated response to dietary antigens. Recent work identifies T‐cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food‐specific T‐cell repertoire. We sought to confirm T‐cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers. Methods: Bulk TCR sequencing was performed on mRNA isolated from esophageal biopsies obtained from adults and children with EoE (n = 15) who had food triggers confirmed by endoscopic evaluation. Non‐EoE adult and pediatric controls (n = 10) were included. Differences in TCR clonality by disease and treatment status were assessed. Shared and similar V‐J‐CDR3s were assessed based on specific food triggers. Results: Active EoE biopsies from children but not adults displayed decreased unique TCRα/β clonotypes and increased relative abundance of TCRs comprising >1% of the total compared to non‐EoE controls and paired inactive EoE samples. Among patients in which baseline, post diet elimination, and food trigger reintroduction samples (n = 6) were obtained, we observed ~1% of TCRs were shared only between pre‐diet elimination and trigger reintroduction. Patients with a shared EoE trigger (milk) had a greater degree of shared and similar TCRs compared to patients with differing triggers (seafood, wheat, egg, soy). Conclusion: We confirmed relative clonality in children but not adults with active EoE and identified potential food‐specific TCRs, particularly for milk‐triggered EoE. Further studies are needed to better identify the broad TCR repertoire relevant to food triggers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

As seen, expression of non-fs EoE is intermediate between FS-EoE and controls in these examples regardless if statistically different between FS-EoE and non-fs EoE or not. Approximately 90% of the DEGs identified between FS-EoE versus control follow a pattern in which non-fs EoE has expression intermediate between controls and FS EoE. Eosinophilic Esophagitis (EoE) is a chronic inflammatory esophageal disease in which a subset of patients undergo pathologic tissue remodeling. [Extracted from the article]

Background: Eosinophilic esophagitis (EoE) is a chronic non‐IgE‐mediated allergic disease of the esophagus. An unbiased proteomics approach was performed to investigate pathophysiological changes in esophageal epithelium. Additionally, an RNAseq‐based transcriptomic analysis in paired samples was also carried out. Methods: Total proteins were purified from esophageal endoscopic biopsies in a cohort of adult EoE patients (n = 25) and healthy esophagus controls (n = 10). Differentially accumulated (DA) proteins in EoE patients compared to control tissues were characterized to identify altered biological processes and signaling pathways. Results were also compared with a quantitative proteome dataset of the human esophageal mucosa. Next, results were contrasted with those obtained after RNAseq analysis in paired samples. Finally, we matched up protein expression with two EoE‐specific mRNA panels (EDP and Eso‐EoE panel). Results: A total of 1667 proteins were identified, of which 363 were DA in EoE. RNA sequencing in paired samples identified 1993 differentially expressed (DE) genes. Total RNA and protein levels positively correlated, especially in DE mRNA‐proteins pairs. Pathway analysis of these proteins in EoE showed alterations in immune and inflammatory responses for the upregulated proteins, and in epithelial differentiation, cornification and keratinization in those downregulated. Interestingly, a set of DA proteins, including eosinophil‐related and secreted proteins, were not detected at the mRNA level. Protein expression positively correlated with EDP and Eso‐EoE, and corresponded with the most abundant proteins of the human esophageal proteome. Conclusions: We unraveled for the first time key proteomic features involved in EoE pathogenesis. An integrative analysis of transcriptomic and proteomic datasets provides a deeper insight than transcriptomic alone into understanding complex disease mechanisms. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis (EoE) is a rapidly emerging, chronic inflammatory, genetically impacted disease of the esophagus, defined clinically by symptoms of esophageal dysfunction and, pathologically, by an eosinophil-predominant tissue infiltration. However, in four EoE families, we have identified patients presenting with EoE-typical and corticosteroid-responsive symptoms, but without tissue eosinophilia. The aim of this study was to clinically and immunologically characterize these patients with EoE-like disease. Methods Five patients suffering from an EoE-like disease were evaluated with endoscopic, histologic, functional, and quantitative immunohistological examinations, and mRNA expression determination. Results The frequency of first-generation offspring of patients affected by EoE or EoE-like disease was 40%. Immunofluorescence analysis confirmed an almost complete absence of eosinophils in the esophageal tissues of patients with EoE-like disease, but revealed a considerable T-cell infiltration, comparable to EoE. In contrast to EoE, eotaxin-3 mRNA and protein were markedly reduced in EoE-like disease ( P < 0.05). The mRNA expression levels of three selected EoE genes ( eotaxin-3, MUC4, and CDH26) allowed to discriminate between EoE-like disease, EoE, and normal epithelium. Conclusions Patients suffering from 'EoE without eosinophilia' do not fulfill formally the diagnostic criteria for EoE. However, their clinical manifestation, immunohistology, and gene expression pattern, plus the fact that they bequeath EoE to their offspring, suggest a uniform underlying pathogenesis. Conventional EoE, with its prominent eosinophilia, therefore appears to be only one phenotype of a broader 'inflammatory dysphagia syndrome' spectrum. In this light, the role of the eosinophils, the definition of EoE, and its diagnostic criteria must likely be reconsidered. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is a T‐cell‐mediated disease that is caused by specific foods and results in esophageal dysfunction. Existing allergy testing modalities are not helpful when attempting to identify EoE‐causal foods necessitating empiric food elimination and recurrent endoscopy. The goal of this study was to identify and compare allergen‐specific immune features that can be assayed in a minimally invasive manner to predict clinical food allergy in EoE. Methods: We obtained blood samples from control subjects (n = 17), subjects with clinical EoE milk allergy (n = 17), and subjects with immunoglobulin E‐mediated milk allergy (n = 9). We measured total and milk‐specific plasma immunoglobulin G (IgG)4 levels and peripheral memory CD4+ T helper (TH) cell proliferation and cytokine production after stimulation with endotoxin‐depleted milk proteins. Sensitivity and specificity for predicting clinical EoE milk allergy were calculated and compared between approaches. Results: Total and milk‐specific IgG4 levels were not significantly different between control subjects and subjects with clinical EoE milk allergy. Stimulation with milk proteins caused TH lymphocytes from subjects with clinical EoE milk allergy to proliferate more (%P1 of 38.3 ± 4.6 vs. 12.7 ± 2.8, p < 0.0001), and produce more type 2 cytokines (%IL‐4+ of 33.7 ± 2.8 vs. 6.9 ± 1.6, p < 0.0001) than cells from control subjects. Milk‐dependent memory TH‐cell proliferation (sensitivity and specificity of 88% and 82%, respectively) and interleukin 4 (IL‐4) production (sensitivity and specificity of 100%) most strongly predicted clinical EoE milk allergy. Conclusions: Peripheral markers of allergen‐specific immune activation may be useful in identifying EoE‐causal foods. Assaying milk‐dependent IL‐4 production by circulating memory TH lymphocytes most accurately predicts clinical EoE milk allergy. [ABSTRACT FROM AUTHOR]

Given the limited clinical effect of eosinophil-directed therapies in EoE to date, our data support exploring the clinical benefit of anti-MC agents in EoE. Pearson correlations performed with MC-specific protease carboxypeptidase A3 ( I CPA3 i ) demonstrated a strong correlation with eosinophil transcriptional signatures, including the eotaxin receptor I CCR3 i , the eosinophil granule lysophospholipase ( I CLC i ), and the eosinophil chemokines eotaxin-3 ( I CCL26 i ) and I IL5 i (Figures 1 and 2A). Abbreviations EoE eosinophilic esophagitis EDP eosinophilic esophagitis diagnostic panel MC mast cell PEC peak eosinophil count Eosinophilic esophagitis (EoE) is a type 2 inflammatory disorder characterized by esophageal inflammation, eosinophil infiltration, tissue remodeling, and stricture.[1] Currently, diagnosis of EoE is based on clinical assessments and a peak tissue eosinophil count (PEC) of >=15 eosinophils per high powered field, although PEC does not correlate well with symptom severity, and eosinophil reduction to normal levels does not correlate with symptomatic improvement in some studies.[1] Numerous studies have demonstrated that mast cells (MCs) are also present in significantly greater numbers in EoE than in normal esophageal biopsies. [Extracted from the article]

Background: Eosinophilic esophagitis (EoE) is a chronic, food‐driven allergic disease, characterized by eosinophil‐rich inflammation in the esophagus. The histopathological and clinical features of EoE have been attributed to overproduction of the type 2 cytokines IL‐4 and IL‐13, which mediate profound alterations in the esophageal epithelium and neutralizing of their shared receptor component (IL‐4Rα) with a human antibody drug (dupilumab) demonstrates clinical efficacy. Yet, the relative contribution of IL‐4 and IL‐13 and whether the type II IL‐4 receptor (comprised of the IL‐4Rα chain in association with IL‐13Rα1) mediates this effect has not been determined. Methods: Experimental EoE was induced in WT, Il13ra1−/−, and Krt14Cre/Il13ra1fl/fl mice by skin‐sensitized using 4‐ethoxymethylene‐2‐phenyl‐2‐oxazolin (OXA) followed by intraesophageal challenges. Esophageal histopathology was determined histologically. RNA was extracted and sequenced for transcriptome analysis and compared with human EoE RNAseq data. Results: Induction of experimental EoE in mice lacking Il13ra1 and in vivo IL‐13 antibody‐based neutralization experiments blocked antigen‐induced esophageal epithelial and lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo targeted deletion of Il13ra1 in esophageal epithelial cells rendered mice protected from experimental EoE. Single‐cell RNA sequencing analysis of human EoE biopsies revealed predominant expression of IL‐13Rα1 in epithelial cells and that EoE signature genes correlated with IL‐13 expression compared with IL‐4. Conclusions: We demonstrate a definitive role for IL‐13 signaling via IL‐13Rα1 in EoE. These data provide mechanistic insights into the mode of action of current therapies in EoE and highlight the type II IL‐4R as a future therapeutic target. [ABSTRACT FROM AUTHOR]

Characterization of the esophageal microbiota in EoE subjects relative to non-EoE controls was performed by comparison of steroid-naïve subjects with active or inactive EoE to non-EoE controls. We aimed to characterize the bacterial and fungal communities in the esophageal mucosa of children with EoE and non-EoE controls and examine the effects of TSS on the microbiota in children with EoE. Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by an eosinophil-predominant inflammation of the esophageal mucosa.1 We have previously characterized bacterial communities of the human esophagus in healthy children and adults.2 Our data and work from others suggest that the normal esophageal bacterial microbiota is dominated by I Firmicutes i species.2-4 Active inflammation in EoE is associated with bacterial dysbiosis, specifically with an increase in members of the I Proteobacteria i .2,3 However, while some have described the role of bacteria in atopic gastrointestinal diseases,5 little is known about the role of fungi in allergic esophageal inflammation or the role of topical swallowed steroids (TSS) in disease-associated dysbiosis. [Extracted from the article]

Abbreviations CCHMC Cincinnati Children's Hospital Medical Center CEGIR Consortium of Eosinophilic Gastrointestinal Disease Researchers EDP eosinophilic esophagitis diagnostic panel EoE eosinophilic esophagitis HPF high-power field MC Mast cells; PRO, Patient-reported outcome EEsAI eosinophilic esophagitis activity index PEESS Pediatric Eosinophilic Esophagitis Symptom Scores HSS EoE Histology Scoring System EREFS EoE endoscopic reference score CONFLICT OF INTEREST M.E.R. is a consultant for Pulm One, Spoon Guru, Allakos, ClostraBio, Serpin Pharm, Celgene, Shire, AstraZeneca, GlaxoSmithKline, Allakos, Adare, Regeneron, and Novartis and has an equity interest in the first five, as well as royalties from reslizumab (Teva Pharmaceuticals) and UpToDate. Mast cells (MCs) are involved in allergy, including EoE,2 and neuromodulation.3 MCs reside in peripheral tissue and communicate with nearby structures, including nerve endings. We divided active EoE into four quartiles by using I CPA3 i + I HPGDS i sum as a MC count surrogate marker; the highest and lowest quartiles represented MC-high and MC-low, respectively. [Extracted from the article]

Background: Esophageal histology is critical for diagnosis and surveillance of disease activity in eosinophilic esophagitis (EoE). A validated noninvasive biomarker has not been identified. We aimed to determine the utility of blood and urine eosinophil‐associated proteins to diagnose EoE and predict esophageal eosinophilia. Methods: Blood and urine were collected from children undergoing endoscopy with biopsy. Absolute eosinophil count (AEC), plasma eosinophil‐derived neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein‐1 (MBP‐1), galectin‐10 (CLC/GAL‐10), Eotaxin‐2 and Eotaxin‐3, and urine osteopontin (OPN) and matrix metalloproteinase‐9 (MMP‐9) were determined. Differences were assessed between EoE and control, and with treatment response. The capacity to predict EoE diagnosis and esophageal eosinophil counts was assessed. Results: Of 183 specimens were collected from 56 EoE patients and 15 non‐EoE controls with symptoms of esophageal dysfunction; 33 EoE patients had paired pre‐ and post‐treatment specimens. Plasma (CLC/GAL‐10, ECP, EDN, Eotaxin‐3, MBP‐1) and urine (OPN) biomarkers were increased in EoE compared to control. A panel comprising CLC/GAL‐10, Eotaxin‐3, ECP, EDN, MBP‐1, and AEC was superior to AEC alone in distinguishing EoE from control. AEC, CLC/GAL‐10, ECP, and MBP‐1 were significantly decreased in patients with esophageal eosinophil counts <15/hpf in response to treatment. AEC, CLC/GAL‐10, ECP, EDN, OPN, and MBP‐1 each predicted esophageal eosinophil counts utilizing mixed models controlled for age, gender, treatment, and atopy; AEC combined with MBP‐1 best predicted the counts. Conclusions: We identified novel panels of eosinophil‐associated proteins that along with AEC are superior to AEC alone in distinguishing EoE from controls and predicting esophageal eosinophil counts. [ABSTRACT FROM AUTHOR]

Background: Dysphagia is the main symptom of adult eosinophilic esophagitis (EoE). We describe a novel syndrome, referred to as "food‐induced immediate response of the esophagus" (FIRE), observed in EoE patients. Methods: Food‐induced immediate response of the esophagus is an unpleasant/painful sensation, unrelated to dysphagia, occurring immediately after esophageal contact with specific foods. Eosinophilic esophagitis experts were surveyed to estimate the prevalence of FIRE, characterize symptoms, and identify food triggers. We also surveyed a large group of EoE patients enrolled in the Swiss EoE Cohort Study for FIRE. Results: Response rates were 82% (47/57) for the expert and 65% (239/368) for the patient survey, respectively. Almost, 90% of EoE experts had observed the FIRE symptom complex in their patients. Forty percent of EoE patients reported experiencing FIRE, more commonly in patients who developed EoE symptoms at a younger age (mean age of 46.4 years vs 54.1 years without FIRE; P <.01) and in those with high allergic comorbidity. Food‐induced immediate response of the esophagus symptoms included narrowing, burning, choking, and pressure in the esophagus appearing within 5 minutes of ingesting a provoking food that lasted less than 2 hours. Symptom severity rated a median 7 points on a visual analogue scale from 1 to 10. Fresh fruits/vegetables and wine were the most frequent triggers. Endoscopic food removal was significantly more commonly reported in male patients with vs without FIRE (44.3% vs 27.6%; P =.03). Conclusions: Food‐induced immediate response of the esophagus is a novel syndrome frequently reported in EoE patients, characterized by an intense, unpleasant/painful sensation occurring rapidly and reproducibly in 40% of surveyed EoE patients after esophageal contact with specific foods. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated disease characterized by symptoms related to esophageal dysfunction and an eosinophil-predominant inflammation. This study has aimed to investigate whether the recently observed sensitization to Candida albicans in patients with EoE is owing to pre-existing disease and its underlying abnormal epithelial barrier or, alternatively, is linked to corticosteroid ( CS) therapy. Methods Medical histories, as well as serum and tissue samples of 60 patients with EoE (15 CS naive, 45 with current or previous CS therapy) and 20 controls, stored in the Swiss Eosinophilic Esophagitis Database ( SEED) and Biobank, were analyzed. We applied Immuno CAP to measure IgE levels and immunofluorescence techniques to examine epithelial barrier components. Results Patients with EoE had higher total IgE levels and were more frequently sensitized to C. albicans than controls. In EoE tissue specimens, increased numbers of eosinophils and mast cells, a higher expression levels of thymic stromal lymphopoietin ( TSLP), cathelicidin, proteases, that is, the kallikreins ( KLK)-5 and KLK-7, were observed as compared with controls, while reduced expression of lympho-epithelial Kazal-type-related inhibitor ( LEKTI), filaggrin, E-cadherin, claudin, occludin, desmoglein-1 was found, independent of CS therapy. In CS-treated EoE, significantly lower numbers of CD1a+ cells and cathelicidin expression were noted as compared to CS-naive EoE. Conclusion This study provides further evidence that EoE is associated with an abnormal epithelial barrier and postulates that CS therapy, by reducing innate immune mechanisms, may promote C. albicans colonization and likely subsequent sensitization. [ABSTRACT FROM AUTHOR]

Wilcoxon matched-pairs signed rank test: *p < .05, **p < .01. gl In contrast, a less invasive biopsy-based ex vivo food challenge test may be considered a promising tool for the identification of causative foods in EoE patients. Of the in total 17 foods that induced acute responses following local injections, 9 foods (53%) corresponded with patient's clinical history, 6 (35%) with SPT results and 6 (35%) with serum IgE results. Elimination diets without the causative foods induce histological and clinical remission in patients with eosinophilic esophagitis (EoE), an allergen-driven type 2 inflammatory disease of the esophagus.[1] However, current tests using skin or serum are poorly predictive of the causative foods,[2] likely because the allergic inflammation may be restricted to the esophagus. [Extracted from the article]

Background: Food‐induced immediate response of the esophagus (FIRE) is a new phenomenon that has been described in eosinophilic esophagitis (EoE) patients. It is suspected when unpleasant symptoms occur suddenly on contact of the triggering food with the esophageal surface and recur with repeated exposures. It can often be mistaken for pollen‐food allergy syndrome (PFAS) and solid food dysphagia. Data on FIRE is limited to one survey study and case reports, and there are no screening studies conducted on either adults or children with EoE. In this study, we aimed to screen children aged ≥7 years old with EoE for FIRE. Methods: Demographic data were collected from medical records. A questionnaire about FIRE was applied to all participants. Skin prick tests were done on suspected patients to identify the triggering foods. FIRE is defined as suitable clinical symptoms with suspected food allergen exposure. Results: A total of 78 patients (74.4% male, median age: 13.5 years) were included. Unpleasant and recurrent symptoms distinct from dysphagia with specific foods were reported in 16.7% of the patients, all of whom had concomitant allergic rhinitis (AR). The symptoms described by almost all patients were oropharyngeal itching and tingling (PFAS: 15.3%) excluding only one patient reporting retrosternal narrowing and pressure after specific food consumption (FIRE: 1.2%). Conclusions: Although definitive conclusions regarding the true prevalence of FIRE cannot be made, it does not seem to be common as PFAS. However, it deserves questioning particularly in the presence of concurrent AR and/or PFAS in children with EoE. [ABSTRACT FROM AUTHOR]

Abstract: Background: Recent data associate eosinophilic esophagitis (EoE) with IgG4 rather than IgE, but its significance and function have not been determined. Our aims were to measure esophageal IgG4 levels and to determine functional correlations as assessed by histologic and transcriptome analyses. Methods: This case‐control study included pediatric subjects with EoE (≥15 eosinophils/HPF) and non‐EoE controls. Protein lysates were analyzed for IgA, IgM, and IgG1‐IgG4 using the Luminex 100 system; IgE was quantified by ELISA. Esophageal biopsies were scored using the EoE histology scoring system. Transcripts were probed by the EoE diagnostic panel, designed to examine the expression of 96 esophageal transcripts. Results: Esophageal IgG subclasses, IgA, and IgM, but not IgE, were increased in subjects with EoE relative to controls. The greatest change between groups was seen in IgG4 (4.2 mg/g protein [interquartile range: 1.0‐13.1 mg/g protein] vs 0.2 mg/g protein [0.1‐0.9]; P < .0001). Tissue IgG4 levels correlated with esophageal eosinophil counts (P = .0006); histologic grade (P = .0011) and stage (P = .0112) scores; and IL4, IL10, IL13, but not TGFB1, expression and had strong associations with a subset of the EoE transcriptome. Esophageal IgG4 transcript expression was increased and correlated with IgG4 protein levels and IL10 expression. Conclusion: These findings extend prior studies on IgG4 in adult EoE to the pediatric population and provide deeper understanding of the potential significance and regulation of IgG4, demonstrating that IgG4 is a relevant feature of the disease; is closely related to esophageal eosinophil levels, type 2 immunity and T regulatory cytokines; and is likely produced locally. [ABSTRACT FROM AUTHOR]

Keywords: epidemiology; food allergy; food protein-induced enterocolitis syndrome; FPIES; prevalence EN epidemiology food allergy food protein-induced enterocolitis syndrome FPIES prevalence 1466 1469 4 06/01/20 20200601 NES 200601 Abbreviations FA food allergy FPIES food protein-induced enterocolitis syndrome Eosinophilic esophagitis (EoE) is an atopic disease characterized by eosinophilic inflammation in the esophagus,[1] with the highest disease burden in Western industrialized countries.[2] However, prevalence estimates differ substantially between studies, ranging from as low as 2.3/100 000 in Denmark to as high as 90.7/100 000 in part of the United States.[2] The aforementioned prevalence studies are based on electronic medical records or pathology reports, health insurance claims, patients referred to third level healthcare systems, or subspecialty physician-administered questionnaires;[3] therefore, they tend to reflect specific population prevalence, with consequent potential for socioeconomic and comorbidity selection biases.[2] To the best of our knowledge, no US population-based EoE prevalence estimates have been previously reported. However, the fact that incidence of EoE and its comorbidity is similar to what reported before suggest that this survey-based approach may have captured a population carrying a real EoE diagnosis. Epidemiology, food allergy, food protein-induced enterocolitis syndrome, FPIES, prevalence. [Extracted from the article]

Tissue eosinophils express the IL-33 receptor ST2 and type 2 cytokines in patients with eosinophilic esophagitis Keywords: clinical immunology; eosinophils; flow cytometry; interleukins; mucosal immunity EN clinical immunology eosinophils flow cytometry interleukins mucosal immunity 656 660 5 02/01/22 20220201 NES 220201 ACKNOWLEDGMENTS We would like to acknowledge the contributions from the Harvard Stem Cell Institute-Center for Regenerative Medicine Flow Cytometry Core and the Program for Membrane Biology Microscopy Core at Simches Research Center, Massachusetts General Hospital. ST2 was robustly detected on tissue eosinophils from patients with active EoE (Figure 1C, 1E), whereas blood eosinophils from healthy control, remission, and active EoE were uniformly low for ST2 (Figure 1D, 1F-G; Figure S1). [Extracted from the article]

Background: Eosinophilic esophagitis (EoE) is a chronic, inflammatory disease of the esophagus with a rapidly increasing incidence. However, population-based epidemiologic data on EoE are rare and limited to regions with less than 200 000 inhabitants. We evaluated the incidence and prevalence of EoE over time in Canton of Vaud, Switzerland. Materials and methods: Canton of Vaud lies in the French-speaking, Western part of Switzerland. As of December 2013, it had a population of 743 317 inhabitants. We contacted all pathology institutes (n = 6) in this canton to identify patients that have been diagnosed with esophageal eosinophilia between 1993 and 2013. We then performed a chart review in all adult and pediatric gastroenterology practices to identify patients with EoE. Results: Of 263 patients with esophageal eosinophilia, a total of 179 fulfilled the diagnostic criteria for EoE. Median diagnostic delay was 4 (IQR 1-9) years. No patient was diagnosed with EoE prior to 2003. Incidence of EoE increased from 0.16/100 000 inhabitants in 2004 to 6.3/100 000 inhabitants in 2013 (P < 0.001). The cumulative EoE prevalence in 2013 was 24.1/100 000. The incidence in males was 2.8 times higher (95% CI 2.01-3.88, P < 0.001) when compared to that in females. The annual EoE incidence was 10.6 times higher (95%-CI 7.61-14.87, P < 0.001) in the period from 2010 to 2013 when compared to that in the period from 1993 to 2009. Conclusions: The incidence and cumulative prevalence of EoE in Canton of Vaud, Switzerland, has rapidly increased in the past 10 years. [ABSTRACT FROM AUTHOR]

Background: Eosinophils are specialized granulocytic effector cells that store and release highly active mediators used in immune defense. Eosinophils are also implicated in the pathogenesis of allergic disorders, including eosinophilic esophagitis (EoE), a chronic disorder characterized by infiltration of eosinophils into the esophagus and release of mediators that damage tissue, resulting in gastrointestinal morbidity, food impaction, and dysphagia. Treatment with elimination diets and/or topical corticosteroid therapy slow disease progression, but are complicated by adverse effects, limited compliance, and loss of response to therapy. We hypothesized that a single administration of an adeno‐associated virus (AAV) coding for an anti‐eosinophil monoclonal antibody that induces eosinophil clearance (anti‐Siglec‐F) would treat on a persistent basis a murine model of EoE. Methods: A mouse model of peanut‐induced EoE that mimics the human disease was established by sensitization and challenge with peanut extract. After challenge, these mice exhibited an EoE phenotype demonstrated by elevated levels of blood eosinophils, infiltration of eosinophils in the esophagus with associated esophageal remodeling and food impaction. Results: The mice were treated with a single intravenous administration (1011 genome copies) of AAVrh.10mAnti‐Eos, a serotype rh.10 AAV vector coding for an anti‐Siglec‐F monoclonal antibody. Vector administration resulted in persistent, high levels of anti‐Siglec‐F antibody expression. Administration of AAVrh.10mAnti‐Eos to the mouse model of EoE reduced blood (P < 0.02) and esophageal eosinophil numbers (P < 0.002) protected from esophageal tissue remodeling and minimized food impaction. Conclusion: These results suggest that a single treatment with AAVrh.10mAnti‐Eos has the potential to provide persistent therapeutic benefit to patients with EoE. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. EoE is frequently associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross-reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE-mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, defined I clinically i by the presence of symptoms of esophageal dysfunction and I histologically i by an eosinophil predominant infiltration in the esophageal mucosa.[1] Due to its chronicity, EoE requires both short-term and long-term treatments.[2] Therapeutic goals are (a) to control clinical activity (resolution of symptoms); and (b) to control biological activity to avoid stricture formation and bolus impaction, a potentially life-threatening event. Treatment of EoE consists of the 3 D's: Drugs, Diet, and Dilation.[2] Dilation should be seen as an add-on treatment since it does not affect underlying inflammation (Figure). Most importantly, any therapy should be maintained as cessation of treatment results in an EoE relapse within only few months.[11] If histological response is not achieved, we recommend switching from PPI ("PPI non-response") or elimination diet to STC. [Extracted from the article]

Background Eosinophilic esophagitis (EoE) afflicts both children and adults. It has been debated whether pediatric EoE and adult EoE represent different disease entities. The objectives of this study were to determine whether the blood eosinophil molecular pattern of children with EoE is (i) distinct from that of healthy children; and (ii) different from that of adults with EoE. Methods Blood eosinophils from children and adults with EoE, and healthy controls, were analyzed with flow cytometry regarding levels of CD23, CD44, CD54, CRTH2, FOXP3, and galectin-10. Eosinophil FOXP3 and galectin-10 m RNA levels were determined by qPCR. The data were analyzed using a multivariate method of pattern recognition. Results An eosinophil molecular pattern capable of distinguishing children with EoE from control children was identified. A smaller fraction of eosinophils from children with EoE expressed CD44 and a larger fraction expressed CRTH2 than the controls. Eosinophils from children with EoE also had higher levels of galectin-10 m RNA and lower levels of FOXP3 m RNA. The eosinophils from children with EoE had lower levels of surface CD54 and of FOXP3 m RNA compared with the eosinophils from the adult patients. A key finding was the detection in healthy individuals of age-related differences in the levels of several eosinophil markers. Conclusions Children with EoE can be distinguished from healthy children based on the molecular patterns of their blood eosinophils. Age-related physiologic differences in eosinophil molecular patterns may partly explain the different blood eosinophil phenotypes in children vs adults with EoE. [ABSTRACT FROM AUTHOR]

Protein expression positively correlated with EDP and Eso-EoE, and corresponded with the most abundant proteins of the human esophageal proteome. Duygu Yazici, Eren Cagan, Ge Tan, Manru Li, Evan Do, Ozan C. Kucukkase, Abdurrahman Simsek, Muhammed Ali Kizmaz, Tugce Bozkurt, Tamer Aydin, Anja Heider, Beate Rückert, Marie-Charlotte Brüggen, Raja Dhir, Liam O'Mahony, Mubeccel Akdis, Kari C. Nadeau, Ferah Budak, Cezmi A. Akdis, Ismail Ogulur This study provides evidence that epithelial barrier function is compromised in severe COVID-19, which is also in line with the epithelial barrier theory. We demonstrated certain protein biomarkers with disease progression from moderate to severe COVID-19 and death. [Extracted from the article]

Background: Eosinophilic esophagitis (EoE) exhibits esophageal dysfunction owing to an eosinophil-predominant inflammation. Activated eosinophils generate eosinophil extracellular traps (EETs) able to kill bacteria. There is evidence of an impaired barrier function in EoE that might allow pathogens to invade the esophagus. This study aimed to investigate the presence and distribution of EETs in esophageal tissues from EoE patients and their association with possible epithelial barrier defects. Methods: Anonymized tissue samples from 18 patients with active EoE were analyzed. The presence of DNA nets associated with eosinophil granule proteins forming EETs and the expression of filaggrin, the protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI), antimicrobial peptides, and cytokines were evaluated by confocal microscopy following immune fluorescence staining techniques. Results: Eosinophil extracellular trap formation occurred frequently and was detected in all EoE samples correlating with the numbers of infiltrating eosinophils. While the expression of both filaggrin and LEKTI was reduced, epithelial antimicrobial peptides (human beta-defensin-2, human beta-defensin-3, cathelicidin LL-37, psoriasin) and cytokines (TSLP, IL-25, IL-32, IL-33) were elevated in EoE as compared to normal esophageal tissues. There was a significant correlation between EET formation and TSLP expression (P = 0.02) as well as psoriasin expression (P = 0.016). On the other hand, a significant negative correlation was found between EET formation and LEKTI expression (P = 0.016). Conclusion: Active EoE exhibits the presence of EETs. Indications of epithelial barrier defects in association with epithelial cytokines are also present which may have contributed to the activation of eosinophils. The formation of EETs could serve as a firewall against the invasion of pathogens. [ABSTRACT FROM AUTHOR]

Early in the 1990s, several case series described adults suffering from dysphagia and children with refractory reflux symptoms, both accompanied by an eosinophil-predominant infiltration, thereby conclusively distinguishing it from gastroesophageal reflux disease. Eosinophilic esophagitis ( Eo E) was recognized as its own entity in the adult and in the pediatric literature. In the last decade, evidence has accumulated that Eo E represents a T-helper ( Th)2-type inflammatory disease. Remodeling of the esophagus is a hallmark of Eo E, leading to esophageal dysfunction and bolus impaction. Familial occurrence and disease association with single-nucleotide polymorphisms underscore the influence of genetics in this disease. Eosinophilic esophagitis may affect individuals at any age, although the clinical presentation is highly age dependent. There is a significant allergic bias in the Eo E population, with the majority of patients having concurrent allergic rhinitis, asthma, eczema, and/or a history of atopy. One noteworthy difference is that in children, Eo E seems to be primarily a food antigen-driven disease, whereas in adults, mainly aeroallergen sensitization has been observed. Treatment modalities for Eo E include the 3 Ds: drugs, diet, and dilation. The crucial question of whether adult and pediatric Eo E are different phenotypes of one single entity or whether we are confronted with two different diseases is still open. Here, we review similarities and differences between Eo E in adults and children. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with type 2 inflammation and epithelial barrier dysfunction. The etiology is unknown, however, genetic heritability studies suggest environmental factors play a key role in pathogenesis. Detergents, such as sodium dodecyl sulfate (SDS), are common ingredients in household products such as dish soap and toothpaste. We hypothesized detergent exposure decreases epithelial barrier function and induces esophageal inflammation. Methods: Immortalized esophageal epithelial cells (EPC2) were cultured in air‐liquid interface (ALI) and exposed to SDS. Barrier function/activity was assessed by transepithelial electrical resistance (TEER), FITC‐dextran flux, and RT‐PCR. Additionally, SDS‐treated mouse esophageal organoids were evaluated for morphology. To investigate the effects of SDS in vivo, mice were treated with 0.5% SDS in drinking water for 14 days. Esophagi were assessed by gross morphology, histopathology, protein expression, and bulk RNA sequencing. Results: When EPC2 cells were exposed to SDS (5 μg/ml) for 96 h, TEER decreased (p = 0.03), and FITC‐dextran flux increased (p = 0.0002). mRNA expression of IL‐33 increased 4.5‐fold (p = 0.02) at 6 h and DSG1 decreased (p < 0.0001) by 72 h. Disrupted epithelial integrity was noted in SDS‐treated esophageal organoids. When mice were exposed to SDS, they showed increased esophageal width, chemokine, and metalloprotease levels. Mice treated with SDS also showed increased IL‐33 protein expression, basal zone hyperplasia, CD4+ cell infiltration, and esophageal eosinophilia. RNA sequencing revealed upregulation of immune response pathway genes. Conclusion: Exposure to SDS decreases esophageal barrier integrity, stimulates IL‐33 production, and promotes epithelial hyperplasia and tissue eosinophilia. Detergents may be a key environmental trigger in EoE pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The association between seasonality and diagnosis and/or recrudescence of eosinophilic esophagitis (EoE) remains unclear, with some studies demonstrating a higher diagnostic rate in those months with a higher aeroallergen load while others rule out this association. Methods: We performed a systematic search of the MEDLINE, EMBASE, and SCOPUS databases for studies on the seasonality of the initial diagnosis or recrudescence (i.e., food bolus impaction) of EoE. Summary estimates, including 95% confidence intervals, were calculated for seasonal variation in diagnosis or incidence of food bolus impaction. A random-effects meta-regression model was made using aggregate-level data to compare seasonality in EoE diagnosis and recrudescence. Publication bias risks were assessed by means of funnel plot analysis. Results: Of 1078 references found, data were finally collected from 18 studies which included a total of 16 846 EoE patients. Of all new cases of EoE diagnosed per year, 27.1% were diagnosed in spring and 21.5% in winter. No overall statistical differences in the annual seasonal distribution of newly diagnosed EoE cases were observed in the random-effects meta-regression model (P = 0.132). Similarly, a homogenous distribution of episodes of EoE recrudescence throughout the year was noted, with no significant differences between seasons (P = 0.699). No significant publication bias was found. Conclusions: This systematic review found no significant variations in the seasonal distribution of either the diagnosis or clinical recrudescence of EoE throughout the year. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis (EoE) is a chronic antigen-mediated clinicopathologic disease of the esophagus characterized by an eosinophil-predominant inflammatory infiltrate. A clinical hallmark is extensive tissue remodeling including basal zone hyperplasia, fibrosis, and angiogenesis. However, the cellular mechanisms responsible for these processes are not fully defined. We hypothesized that targeting granulocyte-macrophage colony-stimulating factor ( GM- CSF; an agonist cytokine linked with eosinophil survival and activation) would be protective in a preclinical model of EoE. Methods Eosinophilic esophagitis-like esophageal inflammation was induced in the L2- IL5OXA EoE mouse model, and GM- CSF production was assessed by m RNA and protein analyses. Granulocyte-macrophage colony-stimulating factor-receptor-alpha expression patterns were examined by flow cytometric and immunofluorescence analysis. L2- IL5OXA EoE mice were treated with anti- GM- CSF neutralizing antibody or isotype control and assessed for histopathological indices of eosinophilia, epithelial hyperplasia, and angiogenesis by immunohistochemistry and RT- PCR. Results Significantly increased levels of esophageal GM- CSF expression was detected in the L2- IL5OXA mouse EoE model during active inflammation. Granulocyte-macrophage colony-stimulating factor-receptor-alpha was predominantly expressed on esophageal eosinophils during EoE, in addition to select cells within the lamina propria. Anti- GM- CSF neutralization in L2- IL5OXA EoE mice resulted in a significant diminution of epithelial eosinophilia in addition to basal cell hyperplasia and vascular remodeling. This treatment response was independent of effects on esophageal eosinophil maturation or activation. Conclusion Granulocyte-macrophage colony-stimulating factor is a potential therapeutic target to reduce esophageal eosinophilia and remodeling. [ABSTRACT FROM AUTHOR]

Background: A combination of proton‐pump inhibitors (PPI) and topical steroids (TS) is used to treat children with eosinophilic esophagitis (EoE). However, a subset of children do not respond to this combination therapy. We aimed to identify the esophageal transcriptional, cell composition, and microbial differences between the non‐responders (EoE‐PPI‐TSnr; n = 7) and responders (EoE‐PPI‐TSr; n = 7) to the combination therapy for EoE and controls (n = 9) using metatranscriptomics. Methods: Differential gene expression analysis was used to identify transcriptional differences, validated using the EoE diagnostic panel (EDP). Deconvolution analysis was performed to identify differences in their cell type composition. Microbiome analysis was conducted from esophageal biopsies RNAseq data, and microbial abundance was correlated with esophageal gene expression. Results: In all, 3164 upregulated and 3154 downregulated genes distinguished EoE‐PPI‐TSnr from EoE‐PPI‐TSr. Eosinophilic inflammatory response, cytokine signaling, and collagen formation pathways were significantly upregulated in EoE‐PPI‐TSnr. There was a 56% overlap in dysregulated genes between EoE‐PPI‐TSnr and EDP, with a perfect agreement in the directionality of modulation. Eosinophils, dendritic cells (DCs), immature DCs, megakaryocytic‐erythroid progenitors, and T helper type 1 cells were significantly higher in EoE‐PPI‐TSnr. There was no significant difference in microbiome diversity. The relative abundance of Fusobacterium sp. and Acinetobacter sp. notably differed in EoE‐PPI‐TSnr and correlated with the key pathways. Conclusion: Our results provide critical insights into the molecular, cellular, and microbial factors associated with the lack of response to PPI and TS combination therapy in children with EoE. This study advances our understanding of the pathobiology of EoE while guiding personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disorder, almost always related to food antigens, in which isolated mucosal esophageal infiltration of eosinophils, mast cells, and basophils leads to esophageal dysfunction.[[1]] The goal of this brief review is to discuss a potential diagnosis and treatment options in pediatrics. GLO:1X5/01jun20:all14188-fig-0001.jpg PHOTO (COLOR): Diagnostic algorithm for diagnosis of eosinophilic esophagitis* gl Once the diagnosis of EoE is established, there are two main therapeutic approaches: dietary therapy or swallowed topical steroids (biologic therapy may be available in the future; Figure). Because EoE is not only a chronic disease but also a disease where clinical symptoms do not always correlate with histologic findings, whenever a therapy is started or changed, an endoscopy with biopsy must be performed approximately 3-4 months later. [Extracted from the article]

Background: Eosinophilic esophagitis (EoE) is a food allergen driven disease that is accompanied by interleukin (IL) 13 overexpression and esophageal barrier dysfunction allowing transepithelial food allergen permeation. Nutraceuticals, such as short‐chain fatty acids (SCFAs) that restore barrier function and increase immune fitness may be a promising tool in the management of EoE. Here, we investigated the effects of the SCFAs acetate, propionate, and butyrate on an IL‐13‐compromised human esophageal epithelial barrier, including the mechanisms involved. Methods: An air‐liquid interface culture model of differentiated human EPC2‐hTERT (EPC2) was used to study whether SCFAs could restore barrier function after IL‐13‐induced impairment. Esophageal epithelial barrier function was monitored by transepithelial electrical resistance (TEER) and FITC‐dextran paracellular flux, and was further examined by qPCR and immunohistochemical analysis. G protein‐coupled receptor (GPR) GPR41, GPR43, GPR109a, or histone deacetylase (HDAC) (ant)agonists were used to assess mechanisms of action of SCFAs. Results: IL‐13 stimulation decreased TEER and increased FITC flux, which was counteracted by butyrate and propionate, but not acetate treatment. Barrier proteins FLG and DSG1 mRNA expression was upregulated following butyrate and propionate treatment, whereas expression of eosinophil chemoattractant CCL26 and protease CAPN14 was downregulated. Similarly, butyrate and propionate restored FLG and DSG1 protein expression. Similar effects were observed with an HDAC antagonist but not with GPR agonists. Conclusion: Nutraceuticals butyrate and propionate restore the barrier function of esophageal epithelial cells after an inflammatory insult and may be of therapeutic benefit in the management of EoE. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Noninvasive biomarkers for diagnosing and monitoring eosinophilic esophagitis (EoE) are currently lacking. This study evaluates 20 biomarkers in serum and saliva, aiming to assess their diagnostic potential in pediatric EoE patients and healthy individuals.Blood and saliva from children undergoing upper endoscopy were analyzed for biomarkers, including absolute eosinophil count (AEC), eosinophil‐derived neurotoxin (EDN), total and specific IgG4‐antibodies (sIgG4), specific IgE‐antibodies (sIgE) and 15‐hydroxyeicosatetraenoic acid (15(S)‐HETE). Some patients participated twice, forming a longitudinal cohort. The ability to use the biomarkers to predict the EoE diagnosis was evaluated.Analysis from 105 children divided into active EoE, remission, and healthy, revealed elevated levels of serum biomarkers (AEC, EDN, 15(S)‐HETE, sIgG4, and sIgE) in active EoE compared to healthy individuals. A combination of biomarkers (AEC, EDN, sIgE to egg white and wheat) and symptoms showed an AUC of 0.92 in distinguishing between the three groups. We further showed that optimal cutoff values for these biomarkers could discriminate between active EoE and healthy with a sensitivity of 88% and a specificity of 100% in distinguishing EoE (active and in remission) from healthy. Longitudinally, levels of EDN, sIgG4 to Bos d 4, Bos d 5, Bos d 8, gliadin, and birch, and sIgE to milk decreased in patients progressing from active EoE to remission (p <.05).This study identified novel biomarkers associated with EoE and proposes a panel, together with symptoms, for effective discrimination between active EoE, EoE in remission, and healthy individuals. The findings may contribute to a less invasive diagnostic method and may be a potential surveillance tool for pediatric EoE patients. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Recently, we have identified a dysregulated protein signature in the esophageal epithelium of eosinophilic esophagitis (EoE) patients including proteins associated with inflammation and epithelial barrier function; however, the effect of proton pump inhibitor (PPI) treatment on this signature is unknown. Herein, we used a proteomic approach to investigate: (1) whether PPI treatment alters the esophageal epithelium protein profile observed in EoE patients and (2) whether the protein signature at baseline predicts PPI response.We evaluated the protein signature of esophageal biopsies using a cohort of adult EoE (n = 25) patients and healthy controls (C) (n = 10). In EoE patients, esophageal biopsies were taken before (pre) and after (post) an 8‐week PPI treatment, determining the histologic response. Eosinophil count PostPPI was used to classify the patients: ≥15 eosinophils/hpf as non‐responders (non‐responder) and < 15 eosinophils/hpf as responders (R). Protein signature was determined and differentially accumulated proteins were characterized to identify altered biological processes and signaling pathways.Comparative analysis of differentially accumulated proteins between groups revealed common signatures between three groups of patients with inflammation (responder‐PrePPI, non‐responder‐PrePPI, and non‐responder‐PostPPI) and without inflammation (controls and responder‐PostPPI). PPI therapy almost reversed the EoE specific esophageal protein signature, which is enriched in pathways associated with inflammation and epithelial barrier function, in responder‐PostPPI. Furthermore, we identified a set of candidate proteins to differentiate responder‐PrePPI and non‐responder‐PrePPI EoE patients before treatment.These findings provide evidence that PPI therapy reverses the alterations in esophageal inflammatory and epithelial proteins characterizing EoE, thereby providing new insights into the mechanism of PPI clinical response. Interestingly, our results also suggest that PPI response could be predicted at baseline in EoE. [ABSTRACT FROM AUTHOR]

Background Eosinophilic esophagitis ( Eo E) is often associated with atopic airway and skin diseases. More than 80% of Eo E patients are sensitized to aero- and/or food allergens. Immunoglobulin ( Ig) E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases. Aim The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult Eo E patients. Methods Ig E in sera of 35 patients with active Eo E were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray. Results Ig E sensitization to Candida albicans was found in 43% of Eo E patients. More than 80% of Eo E patients were sensitized to aeroallergens and 22% to food-specific allergen components, whereas 69% of the patients exhibited specific Ig E to cross-reactive allergens. Among the latter, profilins were identified as most frequent Ig E cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult Eo E patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related ( PR) 10 and lipid transfer proteins ( LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens. Conclusion Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult Eo E patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of Eo E. [ABSTRACT FROM AUTHOR]

242/4381 patients with a diagnosis of EoE had an ED visit with at least one ICD-9/CPT codes for esophageal symptoms as stated above. Table shows the results of the case-crossover analysis of PM SB 2.5 sb exposure and ED visits. The odds ratios increased in size as the outcomes increased in EoE specificity (OR = 2.85 for any ED visit to OR = 5.52 for impaction), although not statistically different. [Extracted from the article]

Keywords: eosinophils; esophagitis; food allergy; milk food allergy; epicutaneous immunotherapy EN eosinophils esophagitis food allergy milk food allergy epicutaneous immunotherapy 1573 1576 4 05/17/21 20210501 NES 210501 Eosinophilic esophagitis (EoE) is an allergic disease of the esophagus without any curative therapy. After CM-induced EoE was confirmed, EPIT was applied daily for 9 months during a CM-free period, followed by CM-containing diet for 2 months. Eosinophils, esophagitis, food allergy, milk food allergy, epicutaneous immunotherapy. [Extracted from the article]

Keywords: eosinophilic enteritis; eosinophilic gastritis; eosinophilic gastrointestinal disease; GATA-3; pediatric subjects; T-bet EN eosinophilic enteritis eosinophilic gastritis eosinophilic gastrointestinal disease GATA-3 pediatric subjects T-bet 1042 1044 3 03/02/22 20220301 NES 220301 ACKNOWLEDGEMENTS The study was funded by Mayo Clinic, Phoenix Children's Hospital Foundation, and the Donald R. Levin Family Foundation. We recently examined T-bet and GATA-3 expression in biopsies from pediatric subjects with EoE, proton pump inhibitor-responsive EoE, and controls and found that both T-bet and GATA-3 expression were increased in EoE subjects.3 This study expands on our initial findings by examining these nuclear transcription factors in subjects with eosinophilic gastritis and/or duodenitis. Slides were digitized and analyzed as previously described.3 Percentages of T-bet+and GATA-3+ nuclei were correlated to tissue eosinophil counts and compared between EG/EoD cases and controls. [Extracted from the article]

A study published in the journal Allergy suggests that salivary immunoinflammatory proteins could be used as a less invasive method for identifying children with eosinophilic esophagitis (EoE). Currently, EoE is diagnosed through invasive procedures. The study collected saliva samples from children with EoE and controls and used proximity extension analysis to analyze the proteins. The findings indicate that a panel of proteins could accurately distinguish children with EoE from controls and differentiate between different subtypes of EoE. This research suggests that salivary proteins have diagnostic potential and could serve as non-invasive biomarkers for EoE, but further research is needed to validate these findings. [Extracted from the article]

Background Eosinophilic esophagitis (EoE) is a severe inflammatory disease of the esophagus which is characterized histologically by an eosinophilic infiltration into the esophageal tissue. The efficacy of probiotics in the context of atopic diseases has been well investigated but, to date, there has been no study which has evaluated probiotic effects on EoE inflammation. This study sought to identify a probiotic which improves esophageal inflammation in experimental EoE. Methods Two candidate probiotics, Lactococcus lactis NCC 2287 and Bifidobacterium lactis NCC 2818, were tested in a murine model of EoE elicited by epicutaneous sensitization with Aspergillus fumigatus protein extract. Administration of bacterial strains in drinking water was used, respectively, as a preventive or treatment measure, or continuously throughout the study. Inflammatory parameters were assessed in the esophagus, skin, and lungs after allergen challenge. Results In this EoE model, supplementation with L. lactis NCC 2287 significantly decreased esophageal and bronchoalveolar eosinophilia but only when given as a therapeutic treatment. No significant effect on eosinophilia was observed when NCC 2287 was given as a preventive or a continuous intervention. NCC 2287 supplementation had no significant effect on immunoglobulin levels, skin symptom scores, or on transepidermal water loss. Supplementation with another probiotic, B. lactis NCC 2818, had no significant effect on esophageal eosinophilia. Conclusion We identified a L. lactis strain, able to attenuate esophageal eosinophilic inflammation in a preclinical model of EoE. This effect is strain specific and depends on the timing and duration of bacterial supplementation. Confirmation of these observations in human clinical trials is warranted. [ABSTRACT FROM AUTHOR]

Background Cow's milk protein, a major food trigger for Eo E in both children and adults, should be continuously avoided once identified as such. This study evaluates tolerance of a cow's milk-based extensively hydrolyzed formula (e HF) with regard to disease remission maintenance in adult patients with milk-triggered Eo E. Methods Seventeen adult patients in whom cow's milk was consecutively demonstrated to trigger EoE after an empiric six-food elimination diet-based study protocol and who subsequently maintained disease remission were prospectively recruited. They were given 400 ml of a cow's milk-based e HF daily for 8 weeks. Intraepithelial peak eosinophil and blood eosinophil counts, esophageal-related symptoms, serum total and specific IgE to major milk proteins, and eosinophil cationic protein were monitored before and after e HF intake. Results Thirteen male and four female patients aged 17-56 completed the study protocol. 15 patients (88.24%) achieved and maintained EoE remission, while an infiltration of ≥15 eosinophils/hpf reappeared in the remaining two patients. No differences in age, gender, symptoms, and endoscopic appearance at baseline conditions or personal/family allergic background were observed between those patients who tolerated the e HF and those who did not. Symptom scores did not significantly change after e HF intake and were significantly lower than those documented at baseline conditions or after cow's milk challenge. No differences were documented in blood eosinophil counts or serum markers after e HF intake. Conclusion Most adult patients with EoE triggered by cow's milk tolerate a cow's milk-based e HF, thus providing them with a safe, economical alternative to cow's milk. [ABSTRACT FROM AUTHOR]

Background: Germline‐encoded innate immune pattern recognition receptors (PRR) are expressed at epithelial surfaces and modulate epithelial defenses. Evidence suggests that stimulation of the Toll‐like receptor (TLR) family of PRR may regulate epithelial barrier integrity by upregulating tight junction (TJ) complex protein expression, but it is not known whether this mechanism is utilized in esophageal epithelial cells. TJ complex proteins maintain intact barrier function and are dysregulated in atopic disorders including eosinophilic esophagitis. Methods: Pattern recognition receptors expression was assessed in EoE and control primary esophageal epithelial cells, demonstrating robust expression of TLR2 and TLR3. The three‐dimensional air‐liquid interface culture (ALI) model was used to test whether TLR2 or TLR3 stimulation alters epithelial barrier function using an in vitro model of human epithelium. Transepithelial electrical resistance (TEER) and FITC‐Dextran permeability were evaluated to assess membrane permeability. ALI cultures were evaluated by histology, immunohistochemistry, Western blotting, and chromatin immunoprecipitation (ChIP). Results: TLR3 stimulation did not change TEER in the ALI model. TLR2 stimulation increased TEER (1.28‐ to 1.31‐fold) and decreased paracellular permeability to FITC‐Dextran, and this effect was abolished by treatment with anti‐TLR2 blocking antibody. TJ complex proteins claudin‐1 and zonula occludens‐1 were upregulated following TLR2 stimulation, and ChIP assay demonstrated altered histone 4 acetyl binding at the TJP1 enhancer and CLDN1 enhancer and promoter following zymosan treatment, implying the occurrence of durable chromatin changes. Conclusions: Our findings implicate the TLR2 pathway as a potential regulator of esophageal epithelial barrier function and suggest that downstream chromatin modifications are associated with this effect. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co‐localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits. Methods: This study included adult subjects with EoE (n = 13) and non‐EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co‐localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4‐food protein interactions were confirmed with co‐immunoprecipitation and mass spectrometry. Results: IgG4‐CMP co‐localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p =.02; Bos d 5, p =.002; Bos d 8, p =.002). Co‐localization was also significantly higher in the active EoE group compared to non‐EoE controls (Bos d 4, p =.0013; Bos d 5, p =.0007; Bos d 8, p =.0013). AutoSTOMP identified eosinophil‐derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain‐14 in IgG4‐enriched areas. Co‐immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens. Conclusion: These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression. [ABSTRACT FROM AUTHOR]

The increased incidence of allergic diseases and food-induced anaphylaxis overtime demands an urgent development of disease-modifying therapies that reverse the synthesis of IgE and the induction of IgE-mediated allergic reactions. Keywords: allergic sensitization; food allergens; germinal center; IgE synthesis EN allergic sensitization food allergens germinal center IgE synthesis 1545 1549 5 05/17/21 20210501 NES 210501 Understanding the biology of IgE in humans has become a matter of interest that remains incompletely understood due to the rarity of peripheral IgE SP + sp cells. Biology of IgE production: IgE cell differentiation and the memory of IgE responses. [Extracted from the article]

Trait profiles in difficult-to-treat asthma: clinical impact and response to systematic assessment - P.2418 Tiffany Lin, Jonathan Pham, Eve Denton, Joy Lee, Fiona Hore-Lacy, Asger Sverrild, Stephanie Stojanovic, Tunn Ren Tay, Kavitha Garuna Murthee, Naghmeh Radhakrishna, Monique Dols, Janet Bondarenko, Janine Mahoney, Robyn E. O'Hehir, Eli Dabscheck, Mark Hew We performed latent class analysis on 241 difficult-to-treat asthma patients undergoing systematic assessment at Alfred Health in Melbourne, Australia. Month 12 peanut-specific IgG4/IgE ratio as well as month 12 peanut-specific Ara h 2 levels had moderate predictability for an eliciting dose >=300 mg peanut protein. Abbreviations: CRD, component-resolved diagnostic; IgE, immunoglobulin E; kUA/L, kilounits of allergen-specific IgE per liter; LTP, lipid transfer protein. [Extracted from the article]

Background Long-lasting food impactions requiring endoscopic bolus removal occur frequently in patients with eosinophilic esophagitis ( Eo E) and harbor a risk for severe esophageal injuries. We evaluated whether treatment with swallowed topical corticosteroids is able to reduce the risk of occurrence of this complication. Methods We analyzed data from the Swiss Eo E Cohort Study. Patients with yearly clinic visits, during which standardized assessment of symptoms, endoscopic, histologic, and laboratory findings was carried out, were included. Results A total of 206 patients (157 males) were analyzed. The median follow-up time was 5 years with a total of 703 visits (mean 3.41 visits/patient). During the follow-up period, 33 patients (16 % of the cohort) experienced 42 impactions requiring endoscopic bolus removal. We evaluated the following factors regarding the outcome 'bolus impaction' by univariate logistic regression modeling: swallowed topical corticosteroid therapy ( OR 0.503, 95%- CI 0.255-0.993, P = 0.048), presence of EoE symptoms ( OR 1.150, 95%- CI 0.4668-2.835, P = 0.761), esophageal stricture ( OR 2.832, 95%- CI 1.508-5.321, P = 0.001), peak eosinophil count >10 eosinophils/ HPF ( OR 0.724, 95%- CI 0.324-1.621, P = 0.433), blood eosinophilia ( OR 1.532, 95%- CI 0.569-4.118, P = 0.398), and esophageal dilation ( OR 1.852, 95%- CI 1.034-3.755, P = 0.017). In the multivariate model, the following factors were significantly associated with bolus impaction: swallowed topical corticosteroid therapy ( OR 0.411, 95%- CI 0.203-0.835, P = 0.014) and esophageal stricture ( OR 2.666, 95%- CI 1.259-5.645, P = 0.01). Increasing frequency of use of swallowed topical steroids was associated with a lower risk for bolus impactions. Conclusions Treatment of Eo E with swallowed topical corticosteroids significantly reduces the risk for long-lasting bolus impactions. [ABSTRACT FROM AUTHOR]

The article discusses the identification of salivary immunoinflammatory proteins that can help diagnose children with eosinophilic esophagitis (EoE). The study found that inflammatory cytokines, including interleukin-17, correlated with the severity of esophageal mucosal involvement, but not with peak eosinophil count. The research suggests that EoE pathophysiology involves more than just eosinophils, highlighting the need for a multidimensional assessment in disease monitoring and management. Additionally, IL-17 may play a role in EoE pathogenesis, but further studies are needed to confirm its utility as a noninvasive biomarker. [Extracted from the article]