Paul Menard-Katcher

Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

Anatomic abnormalities are common potential explanations of manometric esophagogastric junction outflow obstruction.

Esophagogastric junction outflow obstruction (EGJOO) is an esophageal motility diagnosis associated with a myriad of conditions. The frequency of EGJOO attributed to anatomic causes compared to idiopathic causes is uncertain. Our study aims to identify the frequency of EGJOO and to compare these two groups.

Lack of Knowledge and Low Readiness for Healthcare Transition in Eosinophilic Esophagitis and Eosinophilic Gastroenteritis.

Objectives: A growing population of adolescents/young adults with eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE) will need to transition from pediatric to adult health providers. Measuring health care transition (HCT) readiness is critical, but no studies have evaluated this process in EoE/EGE. We determined the scope and predictors of HCT knowledge in patients and parents with EoE/EGE and measured HCT readiness in adolescents/young adults. Methods: We conducted an online survey of patients 13 years or older and parents of patients with EoE/EGE who were diagnosed when 25 years or younger. Parents answered questions regarding their children and their own knowledge of HCT. HCT readiness was assessed in adolescents/young adults aged 13 to 25 years with the Self-Management and Transition to Adulthood with Rx Questionnaire (a 6-domain self-report tool) with a score range of 0 to 90. Results: Four hundred fifty participants completed the survey: 205 patients and 245 parents. Included in the analysis (those diagnosed with EoE/EGE at age 25 years or younger) were 75 of 205 patients and children of 245 parent respondents. Overall, 78% (n = 52) of the patients and 76% (n = 187) of parents had no HCT knowledge. Mean HCT readiness score in adolescents/young adults (n = 50) was 30.4 ± 11.3 with higher scores in domains of provider communication and engagement during appointments. Mean parent-reported (n = 123) score was 35.6 ± 9.7 with higher scores in medication management and disease knowledge. Conclusions: There was a significant deficit in HCT knowledge, and HCT readiness scores were lower than other chronic health conditions. HCT preparation and readiness assessments should become a priority for adolescents/young adults with EoE/EGE and their parents.

Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study

BACKGROUND Eosinophilic oesophagitis is understood in terms of quantifiable histological, endoscopic, and molecular features. Data are scant for inter-relations of these features and their potential to identify distinct disease endotypes. We aimed to identify clinical-pathological correlations between endoscopic and histological disease variables by transcription profiling of the oesophagus of patients with eosinophilic oesophagitis of varying severity and disease activity states. METHODS We did a cross-sectional study across ten hospital sites in the USA associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. We analysed oesophageal biopsy specimens taken from paediatric and adult patients with eosinophilic oesophagitis (discovery cohort), using the eosinophilic oesophagitis diagnostic panel (EDP), a set of 96 informative transcripts. Histological and endoscopic features were assessed by quantification of oesophageal eosinophils and use of the eosinophilic oesophagitis histology scoring system (HSS) and the eosinophilic oesophagitis endoscopic reference score (EREFS). Associations among the various histological, endoscopic, and molecular features were analysed by Spearman correlation. Results were replicated in a biologically independent, single-centre, validation cohort of patients with active eosinophilic oesophagitis. FINDINGS The discovery cohort contained 185 samples and the validation cohort comprised 100 specimens. In the discovery cohort, EDP showed intersite consistency, significant correlation with oesophageal eosinophils (p<0·0001), and similar findings between paediatric and adult patients. Of eight HSS domains, basal zone hyperplasia correlated with the EDP (median Spearman ρ 0·47 [IQR 0·36-0·60]). Of five EREFS features, distal furrows correlated with the EDP (median Spearman ρ 0·42 [0·32-0·50]). By analysing active eosinophilic oesophagitis in the discovery cohort, the EDP identified three clusters associated with distinct endotypes (termed EoEe1-3) despite similar eosinophil levels. EoEe1 was associated with a normal-appearing oesophagus (risk ratio [RR] 3·27, 95% CI 1·04-10·27; p=0·0443), an inverse association with a history of oesophageal dilation (0·27, 0·09-0·82; p=0·0105) and showed relatively mild histological, endoscopic, and molecular changes. EoEe2 showed an inflammatory and steroid-refractory phenotype (RR 2·77, 95% CI 1·11-6·95; p=0·0376) and had the highest expression of inflammatory cytokines and steroid-responding genes. EoEe3 was associated with a narrow-calibre oesophagus (RR 7·98, 95% CI 1·84-34·64; p=0·0013) and adult onset (2·22, 1·19-4·12; p=0·0155), and showed the highest degree of endoscopic and histological severity and the lowest expression of epithelial differentiation genes. These endotypes were replicated in the validation cohort by clustering and with an eosinophilic oesophagitis endotype-prediction algorithm. INTERPRETATION Our new disease classification stratifies patients with eosinophilic oesophagitis into subgroups with potential clinical and therapeutic significance and provides a framework for a precision medicine approach to eosinophilic oesophagitis. FUNDING National Institutes of Health.

Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites

Background: Patient‐reported outcome metrics for eosinophilic esophagitis (EoE) have been developed and validated but not used in a multicenter pediatric population or systematically aligned with histology. Objective: We sought to understand (1) the potential of caregiver report to predict patient self‐reported symptoms and (2) the correlation of patient‐reported outcome domains with histology. Methods: Patients with EoE (n = 310) and their parents participating in the Consortium of Gastrointestinal Eosinophilic Disease Researchers (CEGIR) observational clinical trial were queried for baseline patient symptoms and quality of life (QOL) by using the Pediatric Eosinophilic Esophagitis Symptom Score, version 2 (PEESSv2.0), and the Pediatric QOL EoE module (PedsQL‐EoE), and biopsy specimens were analyzed by using the EoE Histology Scoring System. Results: PEESSv2.0 parental and child reports aligned across all domains (r = 0.68‐0.73, P < .001). PedsQL‐EoE reports correlated between parents and children across ages and multiple domains (r = 0.48‐0.79, P < .001). There was a tight correlation between symptoms on PEESSv2.0 and their effects on QOL both on self‐report and parental report (P < .001). Self‐reported symptoms on PEESSv2.0 (positively) and PedsQL‐EoE (inversely) showed a weak correlation with proximal, but not distal, peak eosinophil counts and features and architectural tissue changes on the EoE Histology Scoring System (P < .05). Conclusions: Parents of children with EoE aged 3 to 18 years accurately reflected their childrens disease symptoms and QOL. Self‐ and parent‐reported symptoms correlate with proximal esophageal histology. Our data suggest that parental report in young children can function as an adequate marker for self‐reported symptoms and that self‐reported symptoms can reflect changes in tissue histology in the proximal esophagus. These findings should be considered during clinical trials for drug development.

Tu1122 Factors Associated With Underutilization of Esophageal Biopsies in Patients Undergoing Upper Endoscopy for Acute Food Impaction

How Do Gastroenterologists Assess Overall Activity of Eosinophilic Esophagitis? Alain Schoepfer, Radoslaw Panczak, Marcel Zwahlen, Claudia Kuehni, Michael Coslovsky, Elisabeth Maurer, Nadine Haas, Jeffrey A. Alexander, Evan S. Dellon, Nirmala Gonsalves, Ikuo Hirano, John Leung, Christian Bussmann, Margaret H. Collins, Robert Newbury, Giovanni DePetris, Thomas C. Smyrk, John T. Woosley, Pu Yan, Guang-Yu Yang, Yvonne Romero, David A. Katzka, Glenn Furuta, Sandeep K. Gupta, Seema Aceves, Mirna Chehade, Carine Blanchard, Alex Straumann, Ekaterina Safroneeva