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Oral immunotherapy (OIT) may induce eosinophilic esophagitis (EoE). Proton pump inhibitors (PPIs) are an effective treatment for EoE. However, the effect of PPI treatment is not well established in patients with EoE induced by OIT. Our primary aim was to compare the clinical, endoscopic, and histological response rates to PPIs in children with EoE induced by OIT (EoE+OIT) versus EoE patients without OIT (EoE-OIT). The secondary aims are to describe the clinical and histological features of EoE+OIT. Demographic, clinical, endoscopic, and histological findings of patients with EoE in the gastroenterology clinic at Shamir Medical Center between March 2015 and December 2022 were collected. Comparisons were performed between EoE+OIT and EoE-OIT patients. The study included 42 children (74% male, mean age 11.2), of whom 31 had EoE-OIT and 11 had EoE+OIT. There were no significant differences between groups regarding sex, comorbidities, symptoms, or endoscopic and histological characteristics at diagnosis. All 42 children were treated with PPIs after diagnosis with or without diet changes. The rates of any clinical response were 83.9% and 90.1% in the EoE-OIT group and EoE+OIT group, respectively (p = 1.0). The rate of any endoscopic response was 74.2% for EoE-OIT and 81.8% for EoE+OIT (p = 0.54). Histologically, PPIs were even more effective in the EoE+OIT group, where only 18.2% had no histological response at all compared to 51.6% in the EoE-OIT group (p = 0.1). Conclusion: PPI treatment is as effective in EoE with OIT as it is in EoE due to other etiologies. What is Known: • Proton pump inhibitor (PPI) treatment is effective for achieving clinical response and histologic remission in some patients with eosinophilic esophagitis (EoE). • EoE has also been reported to be triggered by oral immunotherapy (OIT). What is New: • PPI treatment in EoE with OIT is as effective as treatment for EoE due to other etiologies. [ABSTRACT FROM AUTHOR]

This study compared short-term effectiveness of proton pump inhibitors (PPI), swallowed topical corticosteroids (STC), and dietary therapies in reversing clinical and histological features in pediatric patients with eosinophilic esophagitits (EoE). Determinants for treatment choice and PPI therapy effectiveness were also assessed. A cross-sectional study analysis of patients under 18 years old recruited onto the multicenter EoE CONNECT registry was performed. Clinico-histological response was defined as symptomatic improvement plus a peak eosinophil count below 15 per high-power field after treatment. Effectiveness of first-line options used in monotherapy was compared. Overall, 393 patients (64% adolescents) receiving PPI, STC, or dietary monotherapy to induce EoE remission were identified. PPI was the preferred option (71.5%), despite STC providing the highest clinico-histological response rates (66%) compared to PPI (44%) and diet (42%). Logistic regression identified fibrotic features and recruitment at Italian sites independently associated to first-line STC treatment; age under 12 associated to dietary therapy over other options. Analysis of 262 patients in whom PPI effectiveness was evaluated after median (IQR) 96 (70–145) days showed that this effectiveness was significantly associated with management at pediatric facilities and use of high PPI doses. Among PPI responders, decrease in rings and structures in endoscopy from baseline was documented, with EREFS fibrotic subscore for rings also decreasing among responders (0.27 ± 0.63 vs. 0.05 ± 0.22, p < 0.001). Conclusion: Initial therapy choice for EoE depends on endoscopic phenotype, patient's age, and patients' origin. High PPI doses and treatment in pediatric facilities significantly determined effectiveness, and reversed fibrotic endoscopic features among responders. What is Known: • Proton pump inhibitors are widely used to induce and maintain remission in EoE in real practice, despite other first-line alternative therapies possibly providing higher effectiveness. What is New: • Proton pump inhibitors represent up to two-thirds of first-line monotherapies used to induce EoE remission in pediatric and adolescent patients with EoE. The choice of STC as first-line treatment for EoE was significantly associated with fibrotic features at baseline endoscopy and recruitment in Italian centers; age less than 12 years was associated with dietary therapy. • PPI effectiveness was found to be determined by use of high doses, attendance at pediatric facilities, presenting inflammatory instead of fibrotic or mixed phenotypes, and younger age. Among responders, PPI therapy reversed both inflammatory and fibrotic features of EoE after short-term treatment. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is increasing in prevalence but there is a lack of population-based studies. We sought to determine the prevalence, demographics, and associated atopic diseases in the Veterans Affairs (VA) population. Methods: A nationwide analysis of data from the VA patient population was done using a Veterans Health Administration database. EoE was identified using ICD9 (530.13) and ICD10 (K20.0) codes from October 2008 to June 2020. Demographic data, smoking status, BMI, treatment, and ICD codes for atopic diagnoses were collected. Two sample proportion z-tests, Chi-square tests, two-sample t tests, and one-way ANOVA were used to assess associations across demographic categories. Results: We identified a total of 11,775 patients with an EoE diagnosis: 91% male, 83% White, 8.6% Black, and 5% were of Hispanic ethnicity. The prevalence of EoE increased over time. At diagnosis, the mean age was 48.5 years overall, 51.6 years for Black patients, 45.3 years for Hispanic patients, and 48.2 years for Whites. Dysphagia was the most common symptom overall, but a higher percentage of Blacks and females were found to report chest pain (p < 0.0001, h = 0.32). With the exception of urticaria and atopic dermatitis, both Blacks and Hispanics had a higher incidence of atopic conditions compared to other races and ethnicities (p < 0.0001). Conclusion: While EoE is seen primarily in White males, our study shows that a notable percentage of patients were Black or Hispanic, suggesting that EoE should be considered in non-white patients. The later age of diagnosis in this group could represent a lack of awareness about EoE among non-white patients. More research is needed to study these associations. [ABSTRACT FROM AUTHOR]

Eotaxin-3 is a key chemokine with a relevant role in eosinophilic esophagitis, a rare chronic immune/antigen-mediated inflammatory disorder. Eotaxin-3 is a potent activator of eosinophil emergence and migration, which may lead to allergic airway inflammation. We investigated, using bioinformatics tools, the protein structure and the possible effects of the known variations reported in public databases. Following a procedure already established, we created a 3D model of the whole protein and modeled the structure of 105 protein variants due to known point mutations. The effects of the amino acid substitution at the level of impact on protein structure, stability, and possibly function were detected by the bioinformatics procedure and described in detail. A web application was implemented to browse the results of the analysis and visualize the 3D models, with the opportunity of downloading the models and analyzing them using their own software. Among 105 amino acid substitutions investigated, the study evidenced in 44 cases at least one change in any of the investigated structural parameters. Other six variations are also relevant, although a structural effect was not detected by our analysis, because they affected amino acids highly conserved, which suggests a possible function role. All these variations should be the object of particular attention, as they may induce a loss of functionality in the protein. [ABSTRACT FROM AUTHOR]

Background: The Paediatric Eosinophilic Oesophagitis Module (PedsQL-EoE) was developed in English as a valid and reliable questionnaire to assess health-related quality of life (HRQoL) in children with EoE. The aim of this study was to evaluate the validity and reliability of the PedsQL-EoE that was previously adapted to Spanish by our group. Methods: This cross-sectional multicentre study was conducted in 36 paediatric gastroenterology units. Groups with and without dietary restrictions were studied separately. The PedsQL-EoE consists of 33 items divided into seven factors. Age-specific versions of the PedsQL-EoE were sent by e-mail to children and parents. Statistical analysis was used to study the questionnaire structure by means of exploratory factor analysis and interitem correlations. Confirmatory factor analysis (CFA) was applied to verify the proposed model as well as its psychometric properties through SMSR (standardized root mean square), outer loadings and R-square. To study construct validity and reliability, Cronbach´s alpha coefficient, convergent validity (AVE), discriminant validity (HTMT) and intraclass correlation coefficients (ICC) were used. Results: A total of 341 children and 394 parents participated with 307 matched answers. The median age was 12 years, and 75% were male. The questionnaire structure explained 68% and 66% of the total variance for parents and children, respectively. Five items showed negative correlations and were removed from the questionnaire. CFA applied to the new model supported the following construct: SMRS was less than 0.08, outer loadings measured above 0.5, and R2 explained more than 89% of the total variance. Once the modifications were performed, good internal consistency was demonstrated, with Cronbach's alpha values > 0.7, AVE values > 0.5 and HTMT < 0.9 with good child/parent agreement (ICC = 0.80). The most robust model of the PedsQL-EoE module was formed by seven factors: Symptoms I (6 items), Symptoms II (4 items), Treatment (4 items), Worries (3 items), Communication (5 items), Food and Eating (3 items) and Food Feelings (3 items). Conclusions: The final PedsQL-EoE Module version, after the removal of five items, is a valid and reliable tool to be used in children with EoE. The Spanish validated version appears to be a useful instrument for measuring the impact of EoE on Spanish children´s quality of life. [ABSTRACT FROM AUTHOR]

Introduction: High levels of serum food‐specific IgG4 (sIgG4) have been reported in patients with EoE. The objective of this study was to examine whether serum sIgG4 levels to foods and aeroallergens are higher in EoE patients than allergic controls and to investigate the association between sIgG4 and EoE clinical characteristics. Methods: This was a case–control study nested in a prospective EoE Cohort. EoE cases were defined per consensus guidelines, and controls were individuals with symptoms who were confirmed to be EoE‐negative on upper endoscopy. Demographic and clinical information was prospectively collected. Serum IgE and sIgG4 were measured to foods and aeroallergens by ImmunoCAP. Mean levels of sIgG4 were compared between cases and controls, and logistic regression models were used to examine predictors of elevated milk sIgG4 levels. Results: The analysis included 123 individuals (EoE n = 93, control n = 30) with a similar distribution of allergic disease between EoE patients and controls (86% vs. 93%; p =.30). EoE patients had significantly higher sIgG4 levels to all allergens evaluated, with the exception of birch (p =.24). Milk sIgG4 levels were independently associated with milk consumption (OR 4.95; p =.01) and the presence of sIgE to milk (OR 4.23; p =.008). Conclusion: Serum sIgG4 levels to food and aeroallergen proteins were higher in patients with EoE than non‐EoE controls, and higher levels of milk sIgG4 were independently associated with milk consumption and the presence of sIgE to milk proteins. Whether sIgG4 plays a pathogenic role in EoE or could be used as an EoE biomarker remains unknown and warrants further study. [ABSTRACT FROM AUTHOR]

A study published in Digestive Diseases & Sciences explores the relationship between vitamin D levels and eosinophilic esophagitis (EoE), a type of chronic food allergy. The study found that patients with EoE had lower levels of vitamin D compared to controls, although they were not deficient. While there was no direct relationship between vitamin D levels and markers of EoE disease activity, there was a suggestion of lower vitamin D levels in patients with fibrosis. The study suggests that vitamin D supplementation may be beneficial for patients with EoE, but further research is needed to fully understand the relationship between vitamin D and the disease. [Extracted from the article]

Eosinophilic gastrointestinal disease (EGID) is divided into eosinophilic esophagitis (EoE) and non-eosinophilic esophagitis eosinophilic gastrointestinal disease (non-EoE-EGID) based on the involved gastrointestinal segments. Reports regarding non-EoE-EGID are limited, in part because of its rarity. The present study was performed to review non-EoE-EGID, including its pathogenesis, diagnosis, treatment, and prognosis. Additionally, details regarding 28 cases of non-EoE-EGID recently diagnosed at our Japanese tertial medical center are presented and compared with 20 EoE cases diagnosed during the same period at the same medical center. Comparisons of the two groups clarified differences regarding age- and gender-dependent prevalence between the two conditions, and also showed that systemic involvement and disease severity were greater in the non-EoE-EGID patients. Notably, diagnosis of non-EoE-EGID is difficult because of its lack of specific or characteristic symptoms and endoscopic findings. The clinical characteristics of EoE and non-EoE-EGID differ in many ways, while they also share several genetic, clinical, laboratory, and histopathological features. [ABSTRACT FROM AUTHOR]

Toroidal cans have been presented recently to improve the canning process efficiency, and previous studies focused on static and axial rotational processes. End-over-End (EoE) rotation is a significant agitation approach to increase the temperature uniformity of liquid canned products, and it would be important to observe the effect of this process combined with the toroidal cans. Therefore, in this study, this combined effect was considered to improve the process in the view of temperature uniformity. For this purpose, a computational numerical model was developed using - Star CCM+, and this model was validated with experimental data. Then, the rotational rate and headspace amount effects in a toroidal can geometry, including a liquid, were determined using this validated model. The numerical results indicated that these parameters influenced the heat transfer process with a resulting uniform temperature distribution through the EoE processing. • A computational model was developed to determine the EoE agitation on toroidal cans. • Mathematical model validation was carried out with experimentally obtained temperature data. • Effects of headspace amount and EoE rotation rates were evaluated. • A significant temperature uniformity obtained with the EoE rotation effects was demonstrated. [ABSTRACT FROM AUTHOR]

Background and Aims: Data regarding histologic recurrence of EoE on PPI maintenance therapy are lacking.Retrospective review of 101 patients with histologic PPI-responsive EoE.52/101 (51%) patients underwent follow-up EGD with biopsies. Of the 52 patients, 29 (56%) maintained histologic remission and 23 (44%) had histologic recurrence. 21 (40%) patients maintained BID PPI, 20 (39%) tapered to QD, and 11 (21%) had discontinued PPI. Of the 21 patients on BID PPI, 7 (33%) had histologic recurrence, of which 6 (86%) were asymptomatic.Patients on PPI therapy for EoE benefit from serial clinical, endoscopic, and histologic surveillance.Methods: Data regarding histologic recurrence of EoE on PPI maintenance therapy are lacking.Retrospective review of 101 patients with histologic PPI-responsive EoE.52/101 (51%) patients underwent follow-up EGD with biopsies. Of the 52 patients, 29 (56%) maintained histologic remission and 23 (44%) had histologic recurrence. 21 (40%) patients maintained BID PPI, 20 (39%) tapered to QD, and 11 (21%) had discontinued PPI. Of the 21 patients on BID PPI, 7 (33%) had histologic recurrence, of which 6 (86%) were asymptomatic.Patients on PPI therapy for EoE benefit from serial clinical, endoscopic, and histologic surveillance.Results: Data regarding histologic recurrence of EoE on PPI maintenance therapy are lacking.Retrospective review of 101 patients with histologic PPI-responsive EoE.52/101 (51%) patients underwent follow-up EGD with biopsies. Of the 52 patients, 29 (56%) maintained histologic remission and 23 (44%) had histologic recurrence. 21 (40%) patients maintained BID PPI, 20 (39%) tapered to QD, and 11 (21%) had discontinued PPI. Of the 21 patients on BID PPI, 7 (33%) had histologic recurrence, of which 6 (86%) were asymptomatic.Patients on PPI therapy for EoE benefit from serial clinical, endoscopic, and histologic surveillance.Conclusions: Data regarding histologic recurrence of EoE on PPI maintenance therapy are lacking.Retrospective review of 101 patients with histologic PPI-responsive EoE.52/101 (51%) patients underwent follow-up EGD with biopsies. Of the 52 patients, 29 (56%) maintained histologic remission and 23 (44%) had histologic recurrence. 21 (40%) patients maintained BID PPI, 20 (39%) tapered to QD, and 11 (21%) had discontinued PPI. Of the 21 patients on BID PPI, 7 (33%) had histologic recurrence, of which 6 (86%) were asymptomatic.Patients on PPI therapy for EoE benefit from serial clinical, endoscopic, and histologic surveillance. [ABSTRACT FROM AUTHOR]

Summary: Background: Data on the role of the microbiome in adult patients with eosinophilic oesophagitis (EoE) are limited. Aims: To prospectively collect and characterise the salivary, oesophageal and gastric microbiome in patients with EoE, further correlating the findings with disease activity. Methods: Adult patients with symptoms of oesophageal dysfunction undergoing upper endoscopy were consecutively enrolled. Patients were classified as EoE patients, in case of more than 15 eosinophils per high‐power field, or non‐EoE controls, in case of lack of eosinophilic infiltration. Before and during endoscopy, saliva, oesophageal and gastric fundus biopsies were collected. Microbiota assessment was performed by 16 s rRNA analysis. A Sparse Partial Least Squares Discriminant Analysis (sPLS‐DA) was implemented to identify biomarkers. Results: Saliva samples were collected from 29 EoE patients and 20 non‐EoE controls;, biopsies from 25 EoE and 5 non‐EoE controls. In saliva samples, 23 Amplicon Sequence Variants (ASVs) were positively associated with EoE and 27 ASVs with controls, making it possible to discriminate between EoE and non‐EoE patients with a classification error (CE) of 24%. In a validation cohort, the accuracy, sensitivity, specificity, positive predictive value and negative predictive value of this model were 78.6%, 80%, 75%, 80% and 60%, respectively. Moreover, the analysis of oesophageal microbiota samples observed a clear microbial pattern able to discriminate between active and inactive EoE (CE = 8%). Conclusion: Our preliminary data suggest that salivary metabarcoding analysis in combination with machine learning approaches could become a valid, cheap, non‐invasive test to segregate between EoE and non‐EoE patients. [ABSTRACT FROM AUTHOR]

Background: There is likely variation in approach and management of patient with EoE due to lack of standardized care and variation in guidelines. We aimed to identify current practices regarding diagnosis and treatment in children with eosinophillic esophagitis (EoE) in Australia and New Zealand (ANZ). Methods: Information on current diagnostic and management approaches for pediatric EoE was collected via an online survey sent to pediatric gastroenterologists (pGE) in ANZ. We performed a cross-sectional study of pGE using a 49-question instrument regarding evaluation, diagnostic, and therapeutic aspects of EoE between October 2019 and December 2019. Results: Eighty-five percent of the survey responders were from Australia, and 66% were academic. 30% pGE perform > 3 esophageal biopsies for diagnosis of EoE, 40% involve an allergist, 30% use a twice daily PPI trial, and 70% do not exclude other cause of esophageal eosinophilia. For management, only 3% use dietary elimination as an initial therapy, and 24% use less than the recommended doses of swallowed fluticasone. Forty-nine percent were likely to stop treatment in after remission is achieved for 12 months. The EoE endoscopic reference score (EREFS) was not routinely used (49%). Two-thirds of pGE are concerned about long-term effects of recurrent need of general anesthesia. Conclusions: Diagnostic and management strategies for EoE differed widely among pGE in ANZ, including in diagnostic biopsies, assessing competing causes of esophageal eosinophilia, initials selection of treatments, and maintenance strategies. This variability likely reflects continued uncertainty regarding optimal management strategies and stresses the need for pediatric-specific ANZ guidelines to standardize EoE care. [ABSTRACT FROM AUTHOR]

Background: The growing prevalence of eosinophilic esophagitis (EoE) represents a considerable burden to patients and health care systems. Optimizing cost-effective management and identifying mechanisms for disease onset and progression are required. However, the paucity of large patient cohorts and heterogeneity of practice hinder the defining of optimal management of EoE. Methods: EoE CONNECT is an ongoing, prospective registry study initiated in 2016 and currently managed by EUREOS, the European Consortium for Eosinophilic Diseases of the Gastrointestinal Tract. Patients are managed and treated by their responsible specialists independently. Data recorded using a web-based system include demographic and clinical variables; patient allergies; environmental, intrapartum, and early life exposures; and family background. Symptoms are structurally assessed at every visit; endoscopic features and histological findings are recorded for each examination. Prospective treatment data are registered sequentially, with new sequences created each time a different treatment (active principle, formulation, or dose) is administered to a patient. EoE CONNECT database is actively monitored to ensure the highest data accuracy and the highest scientific and ethical standards. Results: EoE CONNECT is currently being conducted at 39 centers in Europe and enrolls patients of all ages with EoE. In its aim to increase knowledge, to date EoE CONNECT has provided evidence on the effectiveness of first- and second-line therapies for EoE in clinical practice, the ability of proton pump inhibitors to induce disease remission, and factors associated with improved response. Drug effects to reverse fibrous remodeling and endoscopic features of fibrosis in EoE have also been assessed. Conclusion: This prospective registry study will provide important information on the epidemiological and clinical aspects of EoE and evidence as to the real-world and long-term effectiveness and safety of therapy. These data will potentially be a vital benchmark for planning future EoE health care services in Europe. [ABSTRACT FROM AUTHOR]

Background In the 3-part, phase 3 LIBERTY EoE TREET study (NCT03633617) dupilumab 300 mg weekly (qw) demonstrated significant improvements in symptoms and eosinophil counts, and clinically meaningful improvement in endoscopic features vs placebo, in adults and adolescents with EoE. The objective of this analysis was to further assess the effect of dupilumab vs placebo on histologic aspects of disease in Parts A and B of LIBERTY EoE TREET. Methods Patients aged ≥12 years were randomized 1:1 to dupilumab 300 mg qw or placebo. Endpoints (at Week 24) were the proportion of patients achieving ≤1, ≤6, and < 15 eosinophils per high-power field (eos/hpf), change from baseline in peak eosinophil count and Histologic Scoring System (HSS) scores, specifically the severity (grade) and extent (stage) of abnormality of the 8 components (basal zone hyperplasia [BZH], eosinophil inflammation [EI], eosinophil abscess [EA], eosinophil surface layering [ESL], dilated intercellular spaces [DIS], surface epithelial alteration [SEA], dyskeratotic epithelial cells [DEC], and lamina propria fibrosis [LPF]). P-values are nominal unless otherwise specified. Results Dupilumab significantly increased the proportion of patients achieving ≤1, ≤6, and < 15 eos/hpf in Part A (P < 0.0001, P < 0.05, and P < 0.0001, respectively) and Part B (all P < 0.0001) vs placebo. Percent change in peak eosinophil count from baseline and HSS grade/stage scores were significantly improved with dupilumab vs placebo for Parts A and B (all P < 0.0001) (Table). Significant improvements were observed for the histologic components BZH, EI, EA, ESL, SEA grade/stage scores (P < 0.0001) in both Parts, DIS grade score in Part A (P < 0.05), and DEC grade/stage scores in Part B (P < 0.05); other components showed numeric improvements. Dupilumab was generally well tolerated. Conclusions Dupilumab 300 mg qw significantly decreased eosinophil counts and improved the severity and extent of histologic aspects of the disease as measured by HSS versus placebo in adults and adolescents with EoE up to 24 weeks, documenting a more global improvement in addition to eosinophil counts. Overall safety was consistent with the known dupilumab safety profile. [ABSTRACT FROM AUTHOR]

Background: Submucosal or lamina propria arteries are not often included in esophageal biopsies. We report an esophageal biopsy with eosinophilic esophagitis (EOE) overlying small arteries with medial hypertrophy to the point of obstruction. Case presentation: A two-year-old boy with a 1-year history of asthma frequently vomited after coughing. Esophageal biopsy showed EOE. Within the lamina propria there were small arteries with markedly thickened media to the point of luminal obstruction next to a hyperplastic lymphoid aggregate. There was no significant inflammatory infiltrate in the arterial walls. Subsequent biopsies did not show these vascular changes. Conclusion: Small artery changes in EOE have not previously been reported, and although the significance is unknown, in this case may be incidental to eosinophilic esophagitis. [ABSTRACT FROM AUTHOR]

Summary: Background: Proton pump inhibitors (PPIs) are the most commonly used first‐line therapy for patients with eosinophilic oesophagitis (EoE). However, many aspects related to PPIs in EoE are still unknown. Aims: To assess the effectiveness of PPI therapy for EoE in real‐world practice. Methods: This cross‐sectional study collected data on PPI efficacy from the multicentre EoE CONNECT database. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom score; histological remission was defined as a peak eosinophil count below 15 eosinophils per high‐power field. Factors associated with effectiveness of PPI therapy were identified by binary logistic regression multivariate analyses. Results: Overall, 630 patients (76 children) received PPI as initial therapy (n = 600) or after failure to respond to other therapies (n = 30). PPI therapy achieved eosinophil density below 15 eosinophils per high‐power field in 48.8% and a decreased symptom score in 71.0% of patients. More EoE patients with an inflammatory rather than stricturing phenotype accomplished clinico‐histological remission after PPI therapy (OR 3.7; 95% CI, 1.4‐9.5); as well as those who prolonged treatment length from 8 to 12 weeks (OR 2.7; 95% CI, 1.3‐5.3). After achieving clinico‐histological remission of EoE, PPI dosage reduction was effectively maintained in 69.9% of patients, but tended to be less effective among those with a stricturing phenotype. Conclusions: Inflammatory EoE phenotype and treatment duration up to 12 weeks correlated with greater chance for inducing remission of EoE. A stricturing phenotype decreased response rates to PPI therapy both initially and in the long term. [ABSTRACT FROM AUTHOR]

Background In Parts A and B of the 3-part, phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab 300 mg weekly (DPL qw) vs placebo (PBO) demonstrated significant efficacy and acceptable safety up to 24 weeks in adults and adolescents with eosinophilic esophagitis (EoE). Patients who completed Parts A and B entered Part C and received DPL qw to 52 weeks. Here we present 52-week results from patients who completed Part B and continued to Part C. Methods Of 80 DPL qw patients in Part B, 74 continued DPL qw in Part C (DPL/DPL). Of 79 PBO pts in Part B, 37 patients received DPL qw in Part C (PBO/DPL). Part B co-primary endpoints were proportion of patients achieving peak esophageal intraepithelial eosinophil (eos) count ≤6 eos/high- power field (hpf) and absolute change from Part B baseline in Dysphagia Symptom Score (DSQ) score at Week 24. Key secondary endpoints are listed in the Table. In Part C, all co-primary and secondary endpoints were assessed at Week 52 as secondary endpoints. Safety was also assessed. Results At Week 52, 84.6% of DPL/DPL and 67.6% of PBO/DPL patients achieved peak eos count ≤6 eos/hpf; mean (SD) absolute change from Part B baseline in DSQ score was −30.26 (15.39) for DPL/DPL and − 27.25 (11.46) for PBO/DPL patients. At Week 52, 100% of DPL/DPL and 78.4% of PBO/DPL patients achieved peak eos count <15 eos/hpf, 30.8% of DPL/DPL and 16.2% of PBO/DPL patients achieved peak eos count ≤1 eos/hpf, and compared to Part B baseline, peak eos count, EREFS, and HSS grade and stage scores were reduced (Table). DPL demonstrated an acceptable safety profile. Conclusion DPL qw demonstrated persistent improvements in clinical, symptomatic, histologic, and endoscopic features of EoE up to 52 weeks and had an acceptable safety profile. PBO patients from Part B who received DPL in Part C showed similar efficacy to dupilumab qw patients of Part B. [ABSTRACT FROM AUTHOR]

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression. [ABSTRACT FROM AUTHOR]

This article provides a summary of a Cochrane review on the medical treatment of eosinophilic esophagitis (EoE). EoE is a chronic inflammatory condition of the esophagus that can affect individuals of all ages, but is more common in males and adults. The review evaluated the efficacy and safety of different medical interventions for EoE, including corticosteroids and biologics. The findings suggest that corticosteroids improve clinical and histological outcomes, while biologics may improve clinical outcomes. However, the cost and availability of biologics should be considered. Further research and cost-effectiveness analyses are needed to fully evaluate and compare these treatments. [Extracted from the article]

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 disease that has been subcategorized into two endoscopic phenotypes: inflammatory and fibrostenotic. Moreover, studies have shown a link between EoE and immunoglobulin G4 (IgG4), a subclass of the immunoglobulin G (IgG) antibody. In this study, we aimed to evaluate the relationship between histologic IgG4 expression and endoscopic phenotypes in patients with EoE. Methods: This case-control study included patients diagnosed with EoE (n = 19) and patients with non-obstructive dysphagia without abnormal findings as controls (NOD; n = 12). The EoE group was further divided into three subgroups based on endoscopic phenotype: inflammatory, fibrostenotic, or combined. Retrospective examination of endoscopic findings and pathological slides was performed to analyze IgG4 staining. Results: Histological analysis revealed a significant difference in IgG4 cell count (15.00 vs. 0.58, p = 0.003) and eosinophil cell count (84.67 vs. 0.08, p < 0.001) between the EoE and NOD groups. Symptom manifestation and blood test results were similar across all three endoscopic EoE phenotypes. However, histological analysis revealed a significant difference in IgG4 cell count between the inflammatory, fibrostenotic, and combined phenotypes (4.13 vs. 17.6 vs. 59.7, p = 0.030). Conclusions: IgG4 expression was higher in EoE patients than in those with NOD, the highest being in the combined phenotype subgroup. These findings emphasize the important role of endoscopic and histological examination in diagnosing EoE and the need for further research in this area. [ABSTRACT FROM AUTHOR]

OBJECTIVE: According to consensus recommendations, the presence of esophageal symptoms, >15 eosinophils/high-power field and unresponsiveness to proton pump inhibitors are required for a diagnosis of eosinophilic esophagitis (EoE). Nevertheless, inconsistency in using these guidelines has been reported in recent publications. The objective of this study was to assess compliance with EoE diagnostic guidelines in published studies on EoE prevalence and to evaluate other clinical and methodological parameters. METHODS: A systematic review was conducted in articles published between 2008 and 2015 on the prevalence of EoE in unselected adults. Studies using EoE diagnostic definitions were judged to be compliant if they included all three components of the definition, partially compliant if they included two and non-compliant if they included one or none. Esophageal biopsy protocol differences and descriptions of patients' characteristics were determined. RESULTS: Among the 20 studies included, eight were performed in a hospital setting and 12 in the general population. Only 40.0% of studies were compliant, 35.0% were partially compliant and 25.0% were noncompliant with the EoE diagnostic definition guidelines. In 60.0% of the studies a proton pump inhibitor trial was not administered. Only 30.0% adhered to the recommendations in the esophageal biopsy protocol. A lack of description of the history of atopia and endoscopic characteristics was observed in many studies. CONCLUSIONS: Partial or non-compliance with the EoE diagnostic definition was observed in most of the published prevalence studies after the publication of the first consensus. The results of these studies might be interpreted taking into account this context. [ABSTRACT FROM AUTHOR]

Background: Although most studies on treatments for eosinophilic esophagitis (EoE) have focused on effects in the epithelium, EoE is a transmural disease. Eosinophils that infiltrate the subepithelial layers of the esophagus lead to fibrosis and the serious complications of EoE, and current therapies have shown minimal effects on this fibrosis. We aimed to elucidate T helper (Th)2 cytokine effects on esophageal fibroblasts and to explore potential fibroblast-targeted therapies for EoE. Methods: We established telomerase-immortalized fibroblasts from human esophageal biopsies. We stimulated these esophageal fibroblasts with Th2 cytokines, and examined effects of omeprazole and inhibitors of the Janus kinase (JAK)—signal transducer and activator of transcription (STAT6) pathway (AS1517499, leflunomide, and ruxolitinib) on STAT6 phosphorylation, STAT6 nuclear translocation, and eotaxin-3 expression. We also measured the effects of these inhibitors in esophageal epithelial cells stimulated with Th2 cytokines. Results: As in esophageal epithelial cells, Th2 cytokines increased STAT6 phosphorylation, STAT6 nuclear translocation, eotaxin-3 transcription and protein secretion in esophageal fibroblasts. Unlike in epithelial cells, however, omeprazole did not inhibit cytokine-stimulated eotaxin-3 expression in fibroblasts. In contrast, JAK-STAT6 pathway inhibitors decreased cytokine-stimulated eotaxin-3 expression in both fibroblasts and epithelial cells. Conclusions: Omeprazole does not inhibit Th2 cytokine-stimulated eotaxin-3 expression by esophageal fibroblasts, suggesting that PPIs will have limited impact on subepithelial EoE processes such as fibrosis. JAK-STAT6 pathway inhibitors block Th2 cytokine-stimulated eotaxin-3 expression both in fibroblasts and in epithelial cells, suggesting a potential role for JAK-STAT inhibitors in treating both epithelial inflammation and subepithelial fibrosis in EoE. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic Th2 and food antigen-mediated disease characterized by esophageal eosinophilic infiltration. Thymic stromal lymphopoetin (TSLP), an epithelial derived cytokine which bridges innate and Th2-type adaptive immune responses in other allergic conditions, is overexpressed in esophageal biopsies of EoE subjects. However, the triggers of TSLP expression in the esophageal epithelium are unknown. The objective of the current study was to characterize TSLP expression in human esophageal epithelium in EoE in vivo and to determine the role of food antigens upon epithelial TSLP expression in vitro. Using immunohistochemistry (IHC), we localized TSLP in esophageal biopsies of active EoE (≥15 eos/hpf), inactive EoE (<15 eos/hpf) and non-EoE control subjects, and found that TSLP expression was restricted to the differentiated suprabasal layer of the epithelium in actively inflamed EoE biopsies. Consistent with these results in vivo, inducible TSLP protein secretion was higher in CaCl2 differentiated telomerase-immortalized esophageal epithelial cells (EPC2-hTERT) compared to undifferentiated cells of the basal phenotype, following stimulation with the TLR3 ligand poly(I:C). To determine whether food antigens could directly induce epithelial TSLP secretion, differentiated and undifferentiated primary esophageal epithelial cells from EoE and non-EoE subjects were challenged with food antigens clinically relevant to EoE: Chicken egg ovalbumin (OVA), wheat, and milk proteins beta-lactoglobulin (blg) and beta-casein. Food antigens failed to induce TSLP secretion by undifferentiated cells; in contrast, only OVA induced TSLP secretion in differentiated epithelial cells from both EoE and control cell lines, an effect abolished by budesonide and NF-κb inhibition. Together, our study shows that specific food antigens can trigger innate immune mediated esophageal TSLP secretion, suggesting that esophageal epithelial cells at the barrier surface may play a significant role in the pathogenesis of EoE by regulating TSLP expression. [ABSTRACT FROM AUTHOR]

Background and Aims: Ultrasonography has shown that eosinophils accumulate in each segment of the esophageal mucosa in human EoE, ultimately promoting esophageal motility dysfunction; however, no mechanistic evidence explains how or why this accumulation occurs. Methods: Quantitative PCR, ELISA, flow cytometry, immunostaining, and immunofluorescence analyses were performed using antibodies specific to the related antigens and receptors. Results: In deep esophageal biopsies of EoE patients, eosinophils and mast cells accumulate adjacent to nerve cell-derived VIP in each esophageal segment. qRT-PCR analysis revealed five- to sixfold increases in expression levels of VIP, CRTH2, and VAPC2 receptors and proteins in human blood- and tissue-accumulated eosinophils and mast cells. We also observed a significant correlation between mRNA CRTH2 levels and eosinophil- and nerve cell-derived VIPs in human EoE (p < 0.05). We provide evidence that eosinophil and mast cell deficiency following CRTH2 antagonist treatment improves motility dysfunction in a chronic DOX-inducible CC10-IL-13 murine model of experimental EoE. Conclusions: CRTH2 antagonist treatment is a novel therapeutic strategy for inflammatory cell-induced esophageal motility dysfunction in IL-13-induced chronic experimental EoE. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation, that develops in a small subset of people with food allergies. Genome-wide association studies (GWASs) have identified 9 independent EoE risk loci reaching genome-wide significance (p < 5 × 10−8) and 27 additional loci of suggestive significance (5 × 10−8 < p < 1 × 10−5). In the current study, we perform linkage disequilibrium (LD) expansion of these loci to nominate a set of 531 variants that are potentially causal. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their genomic sequence context cloned into a GFP reporter library. Analysis of reporter gene expression in TE-7, HaCaT, and Jurkat cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants, representing 6 genome-wide significant EoE loci and 7 suggestive EoE loci, that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in individuals with EoE. Transcription factor enrichment analyses reveal possible roles for cell-type-specific regulators, including GATA3. Our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing functional insights into the effects of genetic variation in this disease. [Display omitted] Shook et al. developed and applied a massively parallel reporter assay for the allergic disease eosinophilic esophagitis (EoE). They identified common polymorphisms associated with EoE risk that also impacted transcriptional regulation. This study is an important step toward understanding how EoE genetic risk variants lead to genotype-dependent biology. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is often misdiagnosed as GERD; therefore, the goal of the current study is to establish a non-invasive diagnostic and monitoring biomarker that differentiated GERD from EoE. Reports indicates that IL-15 responsive iNKT cells and tissue specific IgE have a critical in EoE pathogenesis, not in GERD. Therefore, we tested the hypothesis that the panel of IL-15-responsive T cell and IgE receptors may be novel non-invasive biomarkers for EoE. Accordingly, the receptors of IL-15 responsive T cells (Vα24, Jα18, γδT, αβT) and IgE (FcεRI & FcεRII) were examined. The data indicates that blood mRNA levels of Vα24, Jα18, γδ T, αβ T and FcεRI are significantly reduced in EoE compared to the GERD patients and normal individuals. The ROC curve analysis indicated FcεRII, Jα18 and δ TCR are the positive predictors that discriminate EoE from GERD. Thus, these molecules will be a novel non-invasive diagnostic biomarker for EoE. • Decreased blood IL-15Rα mRNA levels differentiate EoE and GERD patient.. • Decreased blood mRNA levels of IL-15 responsive γδ T cells receptors differentiate EoE and GERD patient. • Decreased blood mRNA levels of IL-15 responsive iNKT cell receptors and IgE receptors differentiate EoE and GERD patient. • The levels of blood T cell receptors mRNA in EoE & GERD with perfect ROC curves establishes non-invasive biomarker for EoE. [ABSTRACT FROM AUTHOR]

Background: The prevalence rate of eosinophilic esophagitis (EoE) between Japan and Western countries is quite different. Although multiple factors, including the genetic background, lifestyle and dietary habits, may account for the difference, the pathogenic mechanism of EoE has not been fully clarified in Japanese. To elucidate whether EoE's pathogenic mechanisms differ between those populations, we performed transcriptome analysis of esophageal biopsy specimens from Japanese EoE patients and compared the identified gene signatures with published microarray data for EoE patients in the US. Methods: We prospectively enrolled adult Japanese EoE patients (n = 4) according to the 2011 consensus guidelines for diagnosis of EoE. Age-matched healthy volunteer subjects (n = 4) were also enrolled as controls. We assessed the gene expression pro les of esophageal biopsies using microarray technology and then compared the identified gene signatures with earlier data generated in the US. Results: Of 42,545 transcripts represented on the microarray, 385 were differentially expressed between the EoE and control samples (≥2 fold change and adjusted p-value of <0.05). Our microarray data showed strong overlapping with the data from US patients with EoE. An EoE-specific-transcript signature is typically composed of IL-13-inducible and eosinophil-related genes, including eotaxin-3/CeC chemokine ligand 26 (CCL26). Conclusions: This transcriptome study suggests that the pathogenetic mechanisms of EoE in Japan and Western countries are similar. Our findings may contribute to a better understanding of the pathogenesis of EoE and to more accurate diagnosis of this disease in Japanese individuals. [ABSTRACT FROM AUTHOR]

Eosinophilic Esophagitis (EoE) is a chronic allergic disorder, whose pathobiology is incompletely understood. Histamine-producing cells including mast cells and basophils have been implicated in EoE. However, very little is currently known about the role of histamine and histamine receptor (HR) expression and signaling in the esophageal epithelium. Herein, we characterized HR (H1R, H2R, H3R, and H4R) expression in human esophageal biopsies and investigate the role of histamine signaling in inducible cytokine expression in human esophageal epithelial cells in vitro. HR expression was quantified in esophageal biopsies from non-EoE control (N = 23), inactive EoE (<15 eos/hpf, N = 26) and active EoE (>15 eos/hpf, N = 22) subjects using qRT-PCR and immunofluorescent localization. HR expression and histamine-mediated cytokine secretion were evaluated in human primary and telomerase-immortalized esophageal epithelial cells. H1R, H2R, and H4R expression were increased in active EoE biopsies compared to inactive EoE and controls. H2R was the most abundantly expressed receptor, and H3R expression was negligible in all 3 cohorts. Infiltrating eosinophils expressed H1R, H2R, and H4R, which contributed to the observed increase in HR in active subjects. H1R and H2R, but not H3R or H4R, were constitutively expressed by primary and immortalized cells, and epithelial histamine stimulation induced GM-CSF, TNFα, and IL-8, but not TSLP or eotaxin-3 secretion. Epithelial priming with the TLR3 ligand poly (I:C) induced H1R and H2R expression, and enhanced histamine-induced GM-CSF, TNFα, and IL-8 secretion. These effects were primarily suppressed by H1R antagonists, but unaffected by H2R antagonism. Histamine directly activates esophageal epithelial cytokine secretion in vitro in an H1R dependent fashion. However, H1R, H2R and H4R are induced in active inflammation in EoE in vivo. While systemic antihistamine (anti-H1R) therapy may not induce clinical remission in EoE, our study suggests that further study of histamine receptor signaling in EoE is warranted and that targeting of additional histamine receptors may lead to novel treatment strategies for this important disease. [ABSTRACT FROM AUTHOR]

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]

OBJECTIVES:Recent consensus guidelines for diagnosis of eosinophilic esophagitis (EoE) have been published. Whether these guidelines have standardized diagnostic criteria for EoE is unknown. We aimed to determine if the EoE guidelines had an impact on the diagnostic criteria reported in the EoE literature, and whether the previously observed variability in diagnostic criteria has become more uniform.METHODS:Two investigators independently conducted a MEDLINE search from 1 January 2007 through 30 June 2010 for all publications reporting EoE in human subjects, and also searched the proceedings of the 2007-2010 American College of Gastroenterology and American Gastroenterological Association meetings, using a predefined search strategy. Data were extracted from all relevant publications.RESULTS:Of the 799 publications identified, 149 original reports, 99 reviews, and 165 abstracts were included. In all, 32 original reports (21%) used diagnostic criteria consistent with each of the three components of the consensus guidelines. There was a significant increase when comparing original articles published after the release of the guidelines with those published earlier (31 vs. 6%, P<0.001). The proportion of original articles using 15 eosinophils per high-power field (eos/hpf) as a histological cut-point increased significantly (P=0.001). There was still substantial variability in biopsy protocols and eosinophil count methodology. The majority of original articles did not report microscope high-power field (HPF) area.CONCLUSIONS:The proportion of original reports with diagnostic criteria consistent with the consensus guidelines has increased significantly. However, the majority of articles still did not conform to all three of the criteria in the guidelines, and biopsy and eosinophil count protocols continue to demonstrate significant variability. Standardization of biopsy and eosinophil count protocols is needed. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Wang et al papers. To view these articles, visit https://doi.org/10.1111/apt.17221 and https://doi.org/10.1111/apt.17312 [ABSTRACT FROM AUTHOR]

R4598 --> 501.1 --> Eosinophilic Esophagitis (EoE) is a chronic condition characterized by esophageal dysfunction including dysphagia, abdominal pain and eosinophilic inflammation (>15/HPF) of the esophagus. At present, the most commonly used treatment for the management of EoE are steroids, both systemic as well as tropical, and dietary elimination. The advantage of the systemic steroids include ease of administration, rapid response, and very high response rate. However, poor solubility and the adverse effect related to prolonged steroid use are well documented. Moreover, there is a high relapse rate of EoE after the treatment is discontinued which limit the use of oral steroids as a maintenance therapy. Similarly, Ranitidine (Zantac), histamin‐2 blocker, used to treat gastrointestinal reflux and heart burns, has been recently withdrawn from the market by FDA due to increased risk of cancer. Digestive Tea has been used at the Traditional Chinese Medicine (TCM) practice to improve gastrointestinal (GI) symptoms such as stomach pain, constipation and abnormal bowel movement. Different versions of Digestion Teas are further developed to address specific clinical GI symptoms. Compound 7, 4 Dihydroxy flavone (DHF) is a flavonoid purified from Glycyrrhiza uralensis from Digestive Tea. Previously our group has shown inhibition of Eotaxin, Th2 cytokines and IgE in‐vitrousing DHF. The objective of this study is to reveal potential mechanisms underlying DHF improving symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein‐protein interaction analyses, and in silico molecular docking. Based on the pathway analyses, the most important targets identified were TNF‐ α, IL‐6, IL1β, MAPK1, MAPK3, AKT1, CASP3 and CCND in AGE‐RAGE pathway. We further validated the targets of our computational modeling in human esophagus biopsy sample by ELISA and qRT‐PCR. We found significant reduction in levels of TNF‐α (p<0.001), IL‐6 (p<0.001), IL‐8 (p<0.001) and IL1‐β (p<0.05) in the supernatant of biopsy sample cultured with DHF. Moreover, gene expression profile showed significant reduction in level of TNF‐ α (p<0.01), IL1‐β (p<0.05), IL‐6 (p<0.01) and CCND (p<0.05) in the biopsy sample cultured with DHF. Furthermore, our molecular docking analysis revealed that DHF can directly bind TNF‐ α with free binding energies of ‐7.7 kcal/mol. Taken together, the current study may lead to development of DHF as an active therapeutic candidate in treatment of EoE. [ABSTRACT FROM AUTHOR]

Summary: Food allergies occur due to a lack of tolerance to the proteins found in foods. While IgE‐ and non‐IgE‐mediated food allergies have different clinical manifestations, epidemiology, pathophysiology, and management, they share dysregulated T cell responses. Recent studies have shed light on the contributions of different T cell subsets to the development and persistence of different food allergic diseases. This review discusses the role of T cells in both IgE‐ and non‐IgE‐mediated food allergies and considers the potential future investigations in this context. [ABSTRACT FROM AUTHOR]

Esophageal eosinophilia and eosinophilic esophagitis (EoE) are increasingly recognized and prevalent conditions, which now represent common clinical problems encountered by gastroenterologists, pathologists, and allergists. The study of EoE has become a dynamic field with an evolving understanding of the pathogenesis, diagnosis, and treatment. Although there are limited data supporting management decisions, clinical parameters are needed to guide the care of patients with eosinophilic-esophageal disorders. In this evidence-based review, recommendations developed by adult and pediatric gastroenterologists are provided for the evaluation and management of these patients. New terminology is emphasized, particularly the concepts of esophageal eosinophilia and proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) as entities distinct from EoE. [ABSTRACT FROM AUTHOR]

Background: The prevalence of Eosinophilic esophagitis (EoE) is increasing, a severe complication of EoE is spontaneous perforation of the oesophagus. It is of great importance to be aware of this risk and handle this severe complication carefully.Case Presentation: A middle-age man with EoE since 2004, had a total esophageal bolus obstruction while eating lunch at the local hospital. Drinking water, in an attempt to release it, led to a total intramural ruptur of the esophageal wall. A CT scan detected the injury and a covered esophageal stent was inserted within 2 h from the injury. Despite the immediate hospital care, he developed mediastinitis, were in need of a laparascopy and intensive care. After 8 weeks the stent was removed and the esophagus was considered healed. Biopsies from the esophagus showed an eosinophilic inflammation (65 eosinophils/HPF). Twelve weeks from the injury he was essentially back in his normal state and was discharged from the hospital. He was placed on a 6 weeks course of topical treatment with budesonide, which needed to be extended due to inadequate remission. Remission was achieved after 12 weeks of treatment.Conclusion: An effective topical steroid treatment in EoE patients is important. EoE patients are in risk of oesophageal perforation, if so, management may be conservative but mediastinal drainage is important if significant extravasation occurs and should be instituted from the start. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is a chronic disease characterized histologically by > 15 eosinophils per high-power field (eos/hpf). Esophageal mucosal mast cells have been implicated in EoE pathogenesis. The association of atopy with EoE has been established but has not been correlated with levels of serum tryptase. The lack of concurrent atopy in some patients suggests the possibility that atopy may either be the related subtype of EoE or may be a sign of comorbidities. No study has looked at whether patients present with different phenotypes/comorbid disease when they have evidence of elevated serum tryptase. We hypothesized that these patients differ with respect to presentation and comorbidities with more refractory GI disease.Aims: To examine whether elevations of serum tryptase associate with different, more severe clinical presentations in EoE patients which may be explained via mast cell activation.Materials and Methods: Retrospective chart review identified 72 patients with EoE with results for serum tryptase between 2015 and 2016. Patients were classified as TryptaseHI (tryptase > 10.9 µg/l) and TryptaseLO (< 10.9 µg/l). Clinical characteristics and treatment response were compared using univariate analysis and multivariate regression between the groups.Results: Out of 72 patients, 12 were tested as TryptaseHI (16.7%, 95% CI 8.1-25.3%). TryptaseHI was associated frequently with asthma (P = 0.0003), urticaria (P = 0.002), arthralgia (P = 0.005), sinusitis (P = 0.03), nausea/vomiting (P = 0.046), and eosinophilic gastrointestinal disease (P = 0.001). Asthma and arthralgia were found to be significantly associated with TryptaseHI (P = 0.0013, P = 0.0098, respectively). Mucosal eosinophil counts and tryptase levels were not correlated (R2 0.095, P = 0.77). Tryptase did not resolve with resolution of esophageal eosinophilia.Conclusions: We found that EoE patients with elevated tryptase levels more commonly presented with asthma, urticaria, arthralgia, nausea/vomiting, sinusitis, and more distal eosinophilia. This indicates that atopy in EoE patients warrants further exploration. The lack of correlation between histologic remission and reduction of serum tryptase levels post-treatment suggests that mast cell activation may be an independent, yet associated disease. More study into this unique association is warranted. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Ravi et al and Ravi & Katzka papers. To view these articles, visit https://doi.org/10.1111/apt.16180 and https://doi.org/10.1111/apt.16223 [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Laserna‐Mendieta et al and Lucendo et al papers. To view these articles, visit https://doi.org/10.1111/apt.15957 and https://doi.org/10.1111/apt.16216 [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Laserna‐Mendieta et al and Miehlke et al papers. To view these articles, visit https://doi.org/10.1111/apt.15957 and https://doi.org/10.1111/apt.16194 [ABSTRACT FROM AUTHOR]

R251 --> Introduction: Reduced esophageal distensibility (ED) in EoE has been attributed largely to fibrosis, but inflammatory cell infiltration and increased tension in esophageal smooth muscle (ESM) also might contribute to reduced ED. EoE is a type 2 immune disease in which type 2 cytokines IL‐4 and IL‐13 signal through the IL‐4 receptor alpha (IL4Rα), activating Janus kinases (JAKs) that in turn activate STAT6. Dupilumab, a monoclonal antibody against IL4Rα, can improve ED in EoE patients, but it is unclear whether this is due to effects on fibrosis, inflammatory cells, or ESM tension. To explore how IL4Rα signaling might affect ESM tension, we treated ESM cells with IL‐13 and selective inhibitors of STAT6 (AS1517499, 600 nM) or JAK1/2 (ruxolitinib, 100 ng/ml). Since ESM tension is induced by phosphorylation of myosin light chains through PKC and ROCK pathways, we also studied effects of selective inhibitors of PKC (calphostin C, 500 nM) and ROCK (Y‐27632, 10 µM) on ESM tension. Methods: Using 1 circular (C) and 1 longitudinal (L) telomerase‐expressing ESM cell lines generated from muscularis propria of a human organ donor, cell contraction was assessed in the attached gel contraction model. Gels containing equal numbers of ESM cells were cultured for 48 hours with and without IL‐13 (50 ng/ml), during which ESM tension developed; contraction was initiated by releasing the gel from the sides of the culture plate. Histamine (100 µM), a contraction mediator, was added immediately prior to release in some studies. Contraction was assessed by measuring gel surface area over 24 hours using Image J. Gel contraction studies were repeated in the presence of pathway inhibitors. Results: In non‐treated cells, gel sizes of CESM were significant smaller at all time points than those of LESM (p<0.001). Compared to non‐treated controls, IL‐13 significantly reduced gel size in both CESM and LESM (Figures 1&2). Also compared to non‐treated controls, IL‐13‐treatment resulted in smaller gel sizes at all time points following histamine stimulation in both CESM and LESM (p<0.05). In LESM, IL‐13‐induced reductions in gel size were significantly inhibited by ruxolitinib, calphostin C, and Y‐27632, but not by AS1517499 (Figure 2). In CESM, these IL‐13‐induced reductions were significantly inhibited by ruxolitinib and calphostin C, but not by Y‐27632 or AS1517499 (Figure 1). Conclusions: CESM generates more baseline tension that LESM. IL‐13 increases tension and enhances the contractile response to histamine in both CESM and LESM. In LESM, both the PKC and ROCK pathways contribute to IL‐13‐mediated increases in tension whereas in CESM, only the PKC pathway contributes to this effect. These findings demonstrate distinct molecular pathways whereby IL‐13 contributes to LESM and CESM tension, and suggest that IL‐13‐induced ESM tension may contribute to the reduced ED of EoE. [ABSTRACT FROM AUTHOR]

Background: First-line treatment of eosinophilic esophagitis (EoE) includes monotherapy with proton-pump inhibitors (PPIs), food elimination diet (FED), or topical corticosteroids. Current guidelines suggest patients with EoE should continue any responsive first-line monotherapies. However, the efficacy of FED monotherapy in patients with EoE responsive to PPI monotherapy has not been well studied. Our study aimed to investigate how attempting FED monotherapy after experiencing remission of EoE after PPI monotherapy influenced long-term EoE management. Methods: We retrospectively identified patients with EoE responsive to PPI monotherapy who trialed FED monotherapy. We then employed a mixed method approach to a prospective cohort. Selected patients were observed long term for quantitative outcomes, while qualitative results were obtained from patient surveys regarding their perspectives on the trial of FED monotherapy. Results: We identified 22 patients who trialed FED monotherapy after experiencing remission of EoE following PPI monotherapy. Of these 22 patients, 13 had remission of EoE with FED monotherapy, while 9 had re-activation of EoE. Out of 22 patients, 15 were enrolled in a cohort for observation. No exacerbations of EoE occurred while on maintenance treatment. Most patients stated that they would recommend this process to others with EoE (93.33%) and that trial of FED monotherapy helped them identify a treatment plan that aligned with their lifestyle (80%). Conclusion: Our work shows that FED monotherapy can be an effective alternative for patients with EoE responsive to PPI monotherapy that may improve patient quality of life, suggesting alternative treatment options should be considered for monotherapy-responsive EoE. [ABSTRACT FROM AUTHOR]

The eosinophilic esophagitis quality of life questionnaire (EoE-QoL) is a validated patient-reported outcome measure used to assess the impact of eosinophilic esophagitis (EoE) on health-related quality of life (HRQoL). Patients completed the PedsQL-EoE (patients <18 years old) or the EoE-QoL-A (patients >=18 years old) at baseline and end of treatment. [Extracted from the article]

Isoliquiritigenin (ILQ) is a natural flavonoid with various pharmacological activities. In this study, we optimized the preparation method of self-nano-emulsion-loaded ILQ to further improve its bioavailability based on our previous study. In addition, its effect on the treatment of eosinophilic esophagitis was also evaluated. Combined surfactants and co-surfactants were screened, and the optimal formulation of ILQ-SNEDDS was determined according to droplet size, droplet dispersity index (DDI), and drug loading. The formulation was composed of ethyl oleate (oil phase), Tween 80 & Cremophor EL (surfactant, 7:3), and PEG 400 & 1,2-propylene glycol (cosurfactant, 1:1), with a mass ratio of 3:6:1. Its physicochemical properties, including drug loading, droplets' size, Zeta potential, appearance, and Fourier transform infrared (FTIR) spectroscopy, were characterized. In vitro release profile, in situ intestinal absorption, and in vivo pharmacokinetics were applied to confirm the improvement of oral ILQ bioavailability by NEDDS. Finally, the efficacy of ILQ-SNEDDS in the treatment of food allergy-induced eosinophilic esophagitis (EOE) was further evaluated. When the ILQ drug loading was 77.9 mg/g, ILQ-SNEDDS could self-assemble into sub-spherical uniform droplets with an average size of about 33.4 ± 2.46 nm (PDI about 0.10 ± 0.05) and a Zeta potential of approximately −10.05 ± 3.23 mV. In situ intestinal absorption showed that optimized SNEDDS significantly increased the apparent permeability coefficient of ILQ by 1.69 times, and the pharmacokinetic parameters also confirmed that SNEDDS sharply increased the max plasma concentration and bioavailability of ILQ by 3.47 and 2.02 times, respectively. ILQ-SNEDDS also significantly improved the apparent signs, allergic index, hypothermia and body weight of EoE model mice. ILQ-SNEDDS treatment significantly reduced the levels of inflammatory cytokines, such as TNF-α, IL-4, and IL-5, and the level of PPE-s-IgE in serum, and significantly inhibited the expression of TGF-β1 in esophageal tissue. SNEDDS significantly improved the solubility and bioavailability of ILQ. Additionally, ILQ-SNEDDS treatment attenuated symptomatology of EoE model mice, which was associated with inhibiting the production of TH2 inflammatory cytokines and PPE-s-IgE and the expression of TGF-β1. The above results shows that ILQ-SNEDDS has great potential as a good candidate for the treatment of eosinophilic esophagitis. [ABSTRACT FROM AUTHOR]

The authors respond to an editorial which highlighted challenges in the investigation of eosinophilic oesophagitis (EoE). They cite two treatment objectives for EoE patients, including a significant reduction in symptoms and prevention of remodeling and stricture formation. They also emphasize the need to further establish the clinical validity of the EoE histological scoring system (EoEHSS).

Introduction: Benzotriazine-1,4-dioxides (BTDOs) such as tirapazamine (TPZ) and its derivatives act as radiosensitizers of hypoxic tissues. The benzotriazine-1-monoxide (BTMO) metabolite (SR 4317, TPZMO) of TPZ also has radiosensitizing properties, and via unknown mechanisms, is a potent enhancer of the radiosensitizing effects of TPZ. Unlike their 2-nitroimidazole radiosensitizer counterparts, radiolabeled benzotriazine oxides have not been used as radiopharmaceuticals for diagnostic imaging or molecular radiotherapy (MRT) of hypoxia. The radioiodination chemistry for preparing model radioiodinated BTDOs and BTMOs is now reported. Hypothesis: Radioiodinated 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ), a novel bioisosteric analogue of TPZ, and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide (I-EOE-TPZMO), its monoxide analogue, are candidates for in vivo and in vitro investigations of biochemical mechanisms in pathologies that develop hypoxic microenvironments. In theory, both radiotracers can be prepared from the same precursors. Methods: Radioiodination procedures were based on classical nucleophilic [131I]iodide substitution on Tos-EOE-TPZ (P1) and by [131I]iodide exchange on I-EOE-TPZ (P2). Reaction parameters, including temperature, reaction time, solvent and the influence of pivalic acid on products' formation and the corresponding radiochemical yields (RCY) were investigated. Results: The [131I]iodide labeling reactions invariably led to the synthesis of both products, but with careful manipulation of conditions the preferred product could be recovered as the major product. Radioiodide exchange on P2 in ACN at 80 ± 5 °C for 30 min afforded the highest RCY, 89%, of [131I]I-EOE-TPZ, which upon solid phase purification on an alumina cartridge gave 60% yield of the product with over 97% of radiochemical purity. Similarly, radioiodide exchange on P2 in ACN at 50 ± 5 °C for 30 min with pivalic acid afforded the highest yield, 92%, of [131I]I-EOE-TPZMO exclusively with no trace of [131I]I-EOE-TPZ. In both cases, extended reaction times and/or elevated temperatures resulted in the formation of at least two additional radioactive reaction products. Conclusions: Radioiodination of P1 and P2 with [131I]iodide leads to the facile formation of [131I]I-EOE-TPZMO. At 80 °C and short reaction times, the facile reduction of the N-4-oxide moiety was minimized to afford acceptable radiochemical yields of [131I]I-EOE-TPZ from either precursor. Regeneration of [131I]I-EOE-TPZ from [131I]I-EOE-TPZMO is impractical after reaction work-up. [ABSTRACT FROM AUTHOR]

Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. EoE shares a common pathogenetic mechanism with other chronic disorders pertaining to the type 2 inflammatory spectrum, such as atopic dermatitis (AD), allergic rhinitis (AR), asthma, and chronic rhinosinusitis with nasal polyps (CRSwNP). The recent advancements in EoE pathogenesis understanding have unveiled new molecular targets implied within the "atopic march" picture as well as specific to EoE. These discoveries have led to the clinical evaluation of several novel drugs (monoclonal antibodies and immune modulators), specifically aimed at the modulation of Th2 inflammation. In this comprehensive review, we have focused on the subtle mechanisms of type 2 inflammatory disorders, highlighting the similarities and differences with EoE, taking a deeper look into the evolving field of biologic therapies, already approved or under current investigation. [ABSTRACT FROM AUTHOR]