Intraepithelial Eosinophil Counts Research Articles

A213 DUPILUMAB EFFICACY IN EOSINOPHILIC ESOPHAGITIS PERSISTS FOR HISTOLOGIC, SYMPTOMATIC, AND ENDOSCOPIC OUTCOMES REGARDLESS OF CONCOMITANT HIGH-DOSE PROTON PUMP INHIBITOR USE

Abstract Background Proton-pump inhibitor (PPI) therapy is the most commonly used first-line therapy for eosinophilic esophagitis (EoE) but data informing long-term outcomes are limited. Aims This pre-specified analysis of data from the phase 3 LIBERTY EoE TREET (NCT03633617) study assessed the efficacy of weekly dupilumab vs placebo in patients (pts) with and without concomitant PPI use. Methods Pts with peak intraepithelial eosinophil (eos) count ≥15 eos/high-power field (hpf) after ≥8 weeks’ high-dose PPI were randomized to dupilumab or placebo. Pts on high-dose PPIs at screening remained on a high-dose regimen during the treatment period; switching of PPI types was permitted but new initiation of PPIs was prohibited. Endpoints at Week 24 were: proportion of pts achieving ≤6 eos/hpf, absolute change from baseline in Dysphagia Symptom Questionnaire (DSQ) score, % change in peak eos count, absolute change in Endoscopic Reference Score (EREFS) and Histologic Scoring System (HSS) grade/stage scores. Results In Parts A and B, respectively, 61.9% and 71.3% of pts in the dupilumab group and 64.1% and 72.2% in the placebo group were using PPIs at randomization. For pts treated with dupilumab vs placebo in Parts A and B, respectively, ≤6 eos/hpf was achieved by 69.2% (95% confidence interval [CI] 48.2–85.7) vs 8.0% (95% CI 1.0–26.0) and 59.6% (95% CI 45.8–72.4) vs 7.0% (95% CI 2.0–17.0) of pts using PPIs, and by 43.8% (95% CI 19.8–70.1) vs 0% (95% CI 0–23.2) and 56.5% (95% CI 34.5–76.8) vs 4.5% (95% CI 0.1–22.8) of pts not using PPIs. Least squares mean change from baseline in DSQ score for dupilumab vs placebo was –18.5 vs –12.9 and –21.8 vs –14.0 for pts using PPIs in Parts A and B, respectively, and –27.8 vs –3.8 and –28.4 vs –13.3 for those not using PPIs (Figure 1). Dupilumab improved outcomes vs placebo for secondary endpoints, with comparable results in pts with and without concomitant PPI use. Absolute change from baseline in EREFS score is shown in Figure 1. Dupilumab was generally well tolerated. Conclusions Dupilumab improved histologic, symptomatic, and endoscopic aspects of EoE in adults and adolescents, up to 24 weeks, regardless of concomitant high-dose PPI use. Figure 1. Effect of dupilumab 300 mg qw versus placebo on primary endpoints (A) proportion of patients with peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf (B) absolute change from baseline in DSQ total score at Week 24 (C) absolute change from baseline in EREFS total score at Week 24, by concomitant PPI use CI, confidence interval; DSQ, Dysphagia Symptom Questionnaire; EREFS, endoscopic reference score; eos, eosinophils; hpf, high-power field; LS, least squares; PPI, proton pump inhibitor; pt, patient; qw, once weekly; SE, standard error. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

A204 DUPILUMAB IMPROVES HISTOLOGIC, ENDOSCOPIC, AND SYMPTOMATIC ASPECTS OF EOSINOPHILIC ESOPHAGITIS IN PATIENTS AGES 1–ampersand:003C12 YEARS

Abstract Background Dupilumab is approved in Canada for eosinophilic esophagitis (EoE) in patients (pts) aged ≥12 years who weigh ≥40 kg; no treatments are approved for pts aged ampersand:003C12 years. Aims The Phase 3 EoE KIDS trial evaluated dupilumab efficacy and safety vs placebo (PBO) in pts aged 1–ampersand:003C12 years with EoE. Methods Part A was a 16-week (W) PBO-controlled study; pts were randomized 2:2:1:1 to weight-tiered dupilumab on a higher-exposure (HE) or lower-exposure (LE) regimen, or PBO (2 groups) to W16. In Part B, pts continued dupilumab, or switched from PBO to dupilumab (HE/LE), to W52. Results At W16 (Part A), the HE dupilumab group had an improved proportion of pts achieving peak esophageal intraepithelial eosinophil count (PEC) ≤6 eosinophils/high-power field (hpf) vs PBO (67.6% vs 2.9%, Pampersand:003C0.0001; primary endpoint). At W52 (Part B), 62.9% of HE dupilumab/dupilumab pts, and 52.9% of PBO/HE dupilumab pts, achieved PEC ≤6. At W16, the following improved with HE dupilumab vs PBO: EoE-Histologic Scoring System grade and stage scores (–0.88 vs +0.02 and –0.84 vs +0.05, respectively, both Pampersand:003C0.0001); EoE-Endoscopic Reference Score (–3.5 vs +0.3, Pampersand:003C0.0001); overall caregiver assessed EoE status (global impression of change mean [SD], 2.1 [1.2] vs 3.3 [1.4]; lower scores represent more improvement). Improvements were maintained with continuous dupilumab and improved in PBO/dupilumab pts at W52. LE dupilumab maintained similar improvements achieved through W52; however, effects were generally either comparable or numerically lower with LE dupilumab vs HE dupilumab. At W16, COVID-19, rash, headache, and injection-site erythema occurred more frequently in patients receiving dupilumab, with higher incidence than PBO; AEs were similar through W52. Conclusions HE dupilumab met the primary endpoint of PEC ≤6 eos/hpf vs PBO, demonstrated significant changes in histologic and endoscopic aspects of EoE, and improved symptoms with benefits maintained/increased to W52. Funding Agencies Research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

Current smoking reduces small airway eosinophil counts in COPD.

Current smoking reduces small airway intraepithelial eosinophil counts in COPD patients and controls. This provides evidence of an attenuation of type-2 related inflammation in the small airways imposed by current smoking, which may affect ICS response. https://bit.ly/49YSKwG.

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Efficacy and safety of dupilumab up to 52 weeks in adults and adolescents with eosinophilic oesophagitis (LIBERTY EoE TREET study): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

263. DUPILUMAB EFFICACY AND SAFETY TO 52 WEEKS IN ADULT AND ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS: RESULTS FROM LIBERTY EOE TREET

Abstract 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.

Laryngopharyngeal Lesion Appeared in a Patient With Eosinophilic Esophagitis

Question: A 52-year-old woman with eosinophilic esophagitis (EoE) stable on the potassium-competitive acid blocker vonoprazan (VPZ) was presented with a cobblestone-like lesion lying between the hypopharynx and the aryepiglottic fold (Figure A). The lesion was found on esophagogastroduodenoscopy (EGD) performed to examine her newly developed mild hemoptysis. The pharynx and larynx were intact 4 months earlier (Figure B). Chest radiography and sputum test for tuberculosis were negative. Her medical condition included dyslipidemia and urticaria. She did not drink alcohol or smoke cigarettes. For further assessment, she was referred to an otorhinolaryngologist, and subsequently the lesion was biopsied with the use of laryngoscopy under general anesthesia. Histologic evaluation found nuclear enlargement with spongiosis in the epithelium cells (Figure C) and remarkable infiltration of inflammatory cells in the subepithelial layer (Figure D). There was insignificant eosinophilia in the biopsies. p53 immunohistochemical staining showed a few positive epithelial cells (Figure E). In addition, enhanced computed tomography found no lymphadenopathy in the neck. On the basis of the findings, the lesion was diagnosed as possible low-grade dysplasia. From then on, she had been closely monitored, in which both the pharyngo-laryngeal lesion and EoE had not changed for 1 year until both conditions exacerbated with newly developed hoarseness. Esophageal biopsy showed increase in intraepithelial eosinophil counts up to 46 per high-power field (Figure F). For deterioration of EoE, topical corticosteroid (200 μg oral fluticasone twice per day) was added to VPZ. Her symptoms gradually improved, and 2 months later a follow-up EGD found significant improvement in not only EoE but also the pharyngo-laryngeal lesion (Figure G). This unexpected response to the treatment led to histologic reassessment of the lesion.

230. ENDOSCOPIC REFERENCE SCORE REMODELING SUBSCORE AND ESOPHAGEAL EOSINOPHIL COUNT DO NOT CORRELATE IN PLACEBO-TREATED EOSINOPHILIC ESOPHAGITIS PATIENTS FROM DUPILUMAB STUDIES

Abstract Although eosinophils are the hallmark of eosinophilic esophagitis (EoE) with threshold levels required for diagnosis, their exact role in EoE is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses endoscopic inflammatory (edema/exudate/furrows) and remodeling (rings/strictures) features. We assessed the correlations between peak esophageal intraepithelial eosinophil count (eos/high-power field [hpf]) and EREFS in placebo-treated EoE patients from two clinical trials: phase 2 proof-of-concept (POC; NCT02379052; n = 24) and part A of phase 3 TREET (Phase3-PartA; NCT03633617; n = 39). POC was a 12-week trial in adults and Phase3-PartA was a 24-week trial in adults and adolescents. Endoscopic examination of the esophagus was performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory and remodeling subscores and total score using EREFS (higher scores indicate greater severity). Peak eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. Pearson correlations were performed between total/proximal/mid/distal eos/hpf and EREFS total, subscores, and components at BL, EOT, and for change from BL at EOT. Some strong correlations (r > 0.5) were observed between total peak eos/hpf and EREFS at BL in both studies and at EOT in Phase3-Part A (Table). Moderate-to-strong correlations (r > 0.3) were observed between total peak eos/hpf and EREFS inflammation subscore and edema/exudates/furrows individual components (some P > 0.5) in both studies. Correlations of total peak eos/hpf with EREFS remodeling subscore and rings/stricture components were not significant (P = 0.07–0.94). Peak eos/hpf in the proximal, mid, or distal esophagus were more strongly associated with EREFS inflammation subscore (majority moderate-to-strong correlations; P = 0.001–0.66) than EREFS remodeling subscore (weak correlations, P = 0.22–0.99) at BL/EOT for both studies. In these EoE patients, moderate-to-strong correlations were observed between eos/hpf and endoscopic markers of inflammation. No strong correlations were observed between total, proximal, mid, or distal peak eos/hpf and endoscopic parameters of remodeling. These data support a role for intact eosinophils in inflammatory changes in the esophagus in EoE and demonstrate the need for both histology and endoscopic evaluation. Further study, with larger sample sizes, is required to verify these findings in other contexts.

S381 Esophageal Eosinophil Count Does Not Correlate With the Endoscopic Reference Score Remodeling Subscore in Placebo-Treated Eosinophilic Esophagitis Patients in the Phase 2 Proof-of-Concept and Phase 3 TREET Studies

Introduction: Eosinophilic esophagitis (EoE) is a chronic type 2 inflammatory disease of the esophagus. Although eosinophils (eos) are the hallmark of EoE diagnosis, their exact role in disease is unclear. The EoE-Endoscopic Reference Score (EREFS) assesses severity of endoscopically identified inflammatory (edema, exudate, furrows) and remodeling (rings, strictures) aspects of disease activity. To examine the relationship between eosinophilic inflammation and endoscopic disease activity, correlations were assessed between esophageal intraepithelial eos count (eos/high-power field [hpf]) and EREFS in EoE patients (pts) receiving placebo (PBO) in 2 clinical trials: the 12-week phase 2 proof-of-concept study (POC; NCT02379052) in adults and the 24-week Part A of the 3-part, phase 3 TREET study (P3PA; NCT03633617), in adolescents and adults. Methods: Endoscopies of the proximal and distal esophagus were performed at baseline (BL) and end of treatment (EOT) and scored for inflammatory and remodeling subscores, and total score using EREFS (higher scores indicate greater severity). Eos/hpf was measured from pinch biopsies of proximal, mid, and distal esophagus at BL and EOT. Pearson correlations were performed between eos/hpf and EREFS total, subscores, and components at BL, EOT, and change from BL at EOT. Results: Few strong correlations (correlation coefficient > 0.5) were observed at BL between eos/hpf and EREFS in pts receiving PBO of both studies (Table 1). Moderate-to-strong correlations were observed between EREFS total score and eos/hpf in P3PA, but not POC. Moderate-to-strong correlations were observed in both studies between eos/hpf and the EREFS inflammation subscore and inflammatory components of edema, exudates, and furrows (some of which reached statistical significance). All correlations of eosinophil levels to the EREFS remodeling subscore and rings/stricture components were weak-to-moderate and not statistically significant (P values ranged from 0.07 to 0.94). Conclusion: In these EoE pts, no strong correlations were observed between eos/hpf and endoscopic remodeling as assessed by EREFS. Moderate to strong correlations were observed between eos/hpf and endoscopic markers of inflammation. Combined with histology, endoscopic assessment of remodeling aspects of EoE provides a more comprehensive characterization of disease activity. Further study, with larger sample sizes, is required to verify and validate these findings in other populations, duration of observation, and treatment contexts.Table 1.: Correlations between esophageal intraepithelial eosinophil count (eos/hpf) and EREFS total score, inflammation and remodeling subscores, and individual components scores in patients with EoE receiving placebo in the phase 2 POC study and part A of the phase 3 LIBERTY TREET study.

Dupilumab Improves Health-Related Quality of Life (HRQoL) and Reduces Symptom Burden in Patients with Eosinophilic Esophagitis (EoE): Results From Part A of a Randomized, Placebo-Controlled Three-Part Phase 3 Study

Dupilumab, a fully human mAb, blocks the shared receptor component for interleukin-4/interleukin-13. Part A of a 3-part, phase 3 study (NCT03633617) evaluated the efficacy/safety of weekly dupilumab 300mg versus placebo in adolescent/adult EoE patients. Co-primary endpoints, proportion of patients achieving peak esophageal intraepithelial eosinophil count ≤6eos/hpf, and change from baseline in Dysphagia Symptom Questionnaire score at Week 24, were achieved and dupilumab was well tolerated. This analysis assesses dupilumab’s effect versus placebo on HRQoL and symptom burden at Week 24 (secondary/exploratory endpoints).

Eosinophilic Esophagitis in Esophageal Atresia.

Recent studies have reported a higher prevalence of eosinophilic esophagitis in children with esophageal atresia. Under recognition of eosinophilic esophagitis in these patients may lead to excessive use of antireflux therapy and an escalation of interventions, including fundoplication, as symptoms may be attributed to gastroesophageal reflux disease. In addition, long-term untreated eosinophilic esophagitis may lead to recurrent strictures due to transmural esophageal inflammation, necessitating repeated dilatations. Eosinophilic esophagitis should be considered when children with esophageal atresia show persistent symptoms on standard antireflux treatment, increasing dysphagia, and recurrent strictures. Treatment has been found to not only significantly reduce intraepithelial eosinophil count, but also to improve symptoms, and to lower the occurrence of strictures and the need for dilatations. Future prospective studies are warranted in this area.

Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n= 23) or placebo (n= 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P= .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P= .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in thedupilumab group developed injection-site erythema (35%vs 8% in the placebo group) and nasopharyngitis (17%vs 4% in the placebo group). In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.

Eosinophilic Esophagitis

Abstract Eosinophilic esophagitis is an immune-mediated chronic disease of the esophagus. It is clinically characterized by symptoms related to esophageal dysfunction and histologically by eosinophil-rich inflammation with a peak intraepithelial eosinophil count of at least 15 eosinophils per high-power field. Both children and adults can be affected with a strong male predominance. Food appears to be the key trigger, although the exact mechanisms remain unclear. Treatment for eosinophilic esophagitis can be summarized as the 3 D's: dietary, drugs, and dilatation. The differential diagnosis includes gastroesophageal reflux disease, eosinophilic gastroenteritis, drug hypersensitivity, hypereosinophilic syndrome, infection, Crohn disease, connective tissue diseases, and vasculitis.

Eosinophilic Esophagitis and Proton Pump Inhibitor-Responsive Esophageal Eosinophilia; Single Center Experience

Objective: Eosinophilic esophagitis is a chronic inflammatory disease characterized by eosinophilic infiltration and esophagus dysfunction symptoms. Proton pump inhibitor responsive esophageal eosinophilia is similar to eosinophilic esophagitis in terms of clinical, laboratory, genetic expression profile, endoscopic and histopathological features. In this study, we aimed to share demographic features, clinical, laboratory and histopathological findings, and treatment outcomes of patient with eosinophilic esophagitis and proton pump inhibitor responsive esophageal eosinophilia. Materials and Methods: Demographic features, laboratory, endoscopic and histopathological findings, and treatment outcomes of patients followed in our clinic were recorded retrospectively since January 2010. Results: Four thousand six hundred fifty five patients underwent esophagogastroscopy since 2010 in our clinic and 0.4% (n=18) of these patients were diagnosed with eosinophilic esophagitis, and 0.2% (n=8) with proton pump inhibitor-responsive esophageal eosinophilia. The main symptom of patients with eosinophilic esophagitis were food impaction/dysphagia (n=5, 27.8%) and chronic abdominal pain (n=5, 27.8%). Allergen sensitization was found in 14 (77.8%), increased IgE in 12 (66.7%), peripheral eosinophilia in 12 (66.7%), and food allergen sensitization in 10 patients (55.6%) with eosinophilic esophagitis. On histopathological examination, the mean intraepithelial eosinophil count was 48.9 ± 30.9 cells / HPF (400x). When patients with eosinophilic esophagitis (group 1) and proton pump inhibitor-responsive esophageal eosinophilia (group 2) were compared, it was found that chronic abdominal pain was more common in the proton pump inhibitor-responsive esophageal eosinophilia group and food allergen sensitization in the eosinophilic esophagitis group (p<0.05). Total IgE, peripheral eosinophil count and intraepithelial eosinophil count were higher in the eosinophilic esophagitis group, but the differences were not statistically significant. Diet (n=11), medical (n=17) and dilatation (n=1) therapies were used in the eosinophilic esophagitis group. Fibrosis was detected on the histopathological examination in two patients who underwent TED and then SED was started. No side effect was seen any group in long term. Conclusion: Eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia have similar laboratory and histopathological features but eosinophilic esophagitis should be suspected more frequently in the presence of food allergy. Long-term followup is essential in patients with eosinophilic esophagitis.

Diffuse Esophageal Narrowing in Eosinophilic Esophagitis: A Barium Contrast Study.

BackgroundPatients with eosinophilic esophagitis (EoE) present with mechanical type dysphagia. Barium esophagrams occasionally demonstrate focal strictures or multiple concentric rings. Diffuse narrowing has also been reported but may be difficult to recognize because of lack of normative data.AimThe aim of this study is to assess esophageal diameters at multiple sites in healthy controls in comparison with EoE patients.MethodsA standardized barium swallow was performed in 22 healthy male volunteers without esophageal symptoms and compared with 10 untreated EoE patients. A radiopaque ruler attached at the subject’s back was used to measure maximal esophageal diameter at three esophageal sites by a blinded observer. Peak intraepithelial eosinophil counts and Mayo Dysphagia Questionnaire scores were correlated to esophageal diameters in EoE patients.ResultsTwo of 10 EoE patients had areas of focal narrowing on barium Xray. Esophageal diameters were significantly less at all three esophageal sites in EoE patients compared with controls. Using a total esophageal diameter score (i.e., sum of the three diameters) to establish the 95th percentile for minimal diameter in controls, four of 10 EoE patients fell below the normal range. There was no significant correlation between esophageal diameters, peak eosinophil counts and any of the Mayo Dysphagia Questionnaire severity scores.ConclusionPatients with EoE have a diffusely narrow esophagus in comparison to healthy controls, and this abnormality may not be appreciated without using appropriate normative data.

Eosinophilic Esophagitis: Relationship of Subepithelial Eosinophilic Inflammation With Epithelial Histology, Endoscopy, Blood Eosinophils, and Symptoms.

For technical reasons, the histologic characterization of eosinophilic esophagitis (EoE)-specific alterations is almost exclusively based on those found in the esophageal epithelium, whereas little is known about subepithelial abnormalities. In this study, we aimed to systematically assess the nature of subepithelial histologic alterations, and analyze their relationship with epithelial histologic findings, endoscopic features, and symptoms. Adult patients with established EoE diagnosis were prospectively included during a yearly follow-up visit. Patients underwent assessment of clinical, endoscopic, and histologic disease activity using EoE-specific scores. We included 200 EoE patients (mean age 43.5±15.7 years, 74% males) with a median peak count of 36 intraepithelial eosinophils/hpf (IQR 14-84). The following histologic features were identified in the subepithelial layer: eosinophilic infiltration (median peak count of 20 eosinophils/hpf (IQR 10-51)), eosinophil degranulation (43%), fibrosis (82%), and lymphoid follicles (56%). Peak intraepithelial eosinophil counts were higher, identical, and lower when compared to the subepithelial layer in 62.5%, 7%, and 30.5% of patients, respectively. Anti-eosinophilic treatment at inclusion did not influence the relation between subepithelial and epithelial peak eosinophil counts. Subepithelial histologic activity correlated with epithelial histologic activity (rho 0.331, P<0.001), endoscopic severity (rho 0.208, P=0.003), and symptom severity (rho 0.179, P=0.011). Forty percent (21/52) of patients with <15 intraepithelial eosinophils/hpf had subepithelial peak counts of ≥15/hpf. There is a significant but modest correlation between subepithelial histologic activity and epithelial histologic activity, endoscopic severity, and symptom severity. The long-term clinical impact of assessing subepithelial alterations in EoE needs to be further elucidated.

Eosinophilic Esophagitis in Children with Esophageal Atresia.

Recent studies have reported a higher prevalence of eosinophilic esophagitis in children with esophageal atresia. Under recognition of eosinophilic esophagitis in these patients may lead to excessive use of antireflux therapy and an escalation of interventions, including fundoplication, as symptoms may be attributed to gastroesophageal reflux disease. In addition, long-term untreated eosinophilic esophagitis may lead to recurrent strictures due to transmural esophageal inflammation, necessitating repeated dilatations. Eosinophilic esophagitis should be considered when children with esophageal atresia show persistent symptoms on standard antireflux treatment, increasing dysphagia, and recurrent strictures. Treatment has been found to not only significantly reduce intraepithelial eosinophil count, but also to improve symptoms, and to lower the occurrence of strictures and the need for dilatations. Future prospective studies are warranted in this area.

Treatment outcomes for eosinophilic esophagitis in children with esophageal atresia

Eosinophilic esophagitis (EoE) has been reported to be more prevalent in patients with esophageal atresia/tracheoesophageal fistula (EA-TEF). To date, there is limited data on the management of EoE in this group of patients. The aim of this study is to evaluate the treatment outcomes of EoE in children with EA-TEF. A retrospective chart review was performed on all EA-TEF children who were diagnosed with and treated for EoE between January 2000 and September 2013 at the Sydney Children's Hospital. Data collected included details of the patient's treatment, post-treatment endoscopy, symptoms and nutrition. Twenty patients were included in the study. Median age at diagnosis was 26 months (8-103 months), and median time from diagnosis to last follow-up was 23 months (2-132 months). Patients were treated with budesonide slurry, swallowed fluticasone, elimination diet alone or in combination. All patients were on proton pump inhibitors at time of diagnosis of EoE which was continued. Six out of seven patients who had furrowing/exudate in endoscopy at diagnosis had complete resolution at a median follow-up period of 26 months (P = 0.031). Median peak intraepithelial eosinophil count reduced significantly from 30/high-powered field (HPF) (19-80/HPF) to 8/HPF (0-85/HPF) (median time for improvement = 24 months) (P = 0.015). There was a significant reduction in symptoms of dysphagia and reflux post-treatment (P < 0.001). Prevalence of strictures significantly decreased (P = 0.016), as did need for dilatations (P = 0.004). In four out of six patients with gastrostomies at baseline, the feeding improved on treatment of EoE and the gastrostomy could be closed. There was also a nonsignificant trend towards improvement in weight and height 'z scores' of the patients. Treatment of EoE in children with EA-TEF was found to significantly reduce intraepithelial eosinophil count, symptoms, strictures and need for dilatations.

Intravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a chronic allergic disease with limited treatment options. We evaluated QAX576, an mAb against IL-13, in the treatment of patients with EoE. Patients (18-50 years) with proton pump inhibitor-resistant esophageal eosinophilia received intravenous QAX576 (6 mg/kg) or placebo (2:1) at weeks 0, 4, and 8 and were followed for 6 months. The primary end point was the responder rate for a greater than 75% decrease in peak eosinophil counts at week 12. Efficacy was to be declared if the lower 90% confidence limit for the proportion of responders on QAX576 was 35% or greater. Secondary end points included changes in esophageal eosinophil counts, symptoms assessed by questionnaire scores, and quantification of a series of biomarkers. Twenty-three patients completed the study up to week 12, and 18 continued to the end of the study. For the proximal and distal esophageal biopsies combined, the responder rate was 12.5% (90% confidence limit, 1% to 43%) with placebo, compared to 40.0% (90% confidence limit, 22% to 61%) with QAX576. Although the primary end point was not met, the mean esophageal eosinophil count decreased by 60% with QAX576 versus an increase of 23% with placebo (P = .004), and the decrease was sustained up to 6 months. There was a trend for improved symptoms, particularly dysphagia. QAX576 improved expression of EoE-relevant esophageal transcripts, including eotaxin-3, periostin, and markers of mast cells and barrier function, for up to 6 months after treatment. QAX576 was well tolerated. QAX576 significantly improved intraepithelial esophageal eosinophil counts and dysregulated esophageal disease-related transcripts in adults with EoE in a sustained manner.

Non-Celiac Gluten Sensitivity: Literature Review

Background: A significant percentage of the general population report problems caused by wheat and/or gluten ingestion, even though they do not have celiac disease (CD) or wheat allergy (WA), because they test negative both for CD-specific serology and histopathology and for immunoglobulin E (IgE)-mediated assays. Most patients report both gastrointestinal and nongastrointestinal symptoms, and all report improvement of symptoms on a gluten-free diet. This clinical condition has been named non-celiac gluten sensitivity (NCGS). Aim: We attempt to define the current pathogenic, clinical, and diagnostic criteria of this “new” disease, to provide a practical view that might be useful to evaluate, diagnose, and manage NCGS patients. Methods: We reviewed the international literature through PubMed and Medline, using the search terms “wheat (hyper)sensitivity,” “wheat allergy,” “wheat intolerance,” “gluten (hyper)sensitivity,” and “gluten intolerance,” and we discuss current knowledge about NCGS. Results: It has been demonstrated that patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. NCGS diagnosis can be reached only by excluding CD and WA. Recent evidence shows that a personal history of food allergy in infancy, coexistent atopy, positive for immunoglobulin G (IgG) antigliadin antibodies and flow cytometric basophil activation test, with wheat and duodenal and/or ileum–colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. Conclusions: Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroups. Key teaching points: • Most patients report both gastrointestinal and nongastrointestinal symptoms, and all agree that there is an improvement of symptoms on a gluten-free diet. • NCGS diagnosis can be reached only by excluding celiac disease and wheat allergy. • Patients suffering from NCGS are a heterogeneous group, composed of several subgroups, each characterized by different pathogenesis, clinical history, and, probably, clinical course. • A personal history of food allergy in infancy, coexistent atopy, positive IgG antigliadin antibodies (AGA) and flow cytometric basophil activation test, with wheat and duodenal and/or ileum–colon intraepithelial and lamina propria eosinophil counts, could be useful to identify NCGS patients. • Future research should aim to identify reliable biomarkers for NCGS diagnosis and to better define the different NCGS subgroup.

Clinical Features Distinguish Eosinophilic and Reflux‐induced Esophagitis

Diagnosing eosinophilic esophagitis (EoE) depends on intraepithelial eosinophil count of ≥15 eosinophils per high-power field (HPF); however, differentiating EoE from gastroesophageal reflux disease (GERD) continues to be a challenge because no true "criterion standard" criteria exist. Identifying clinical and endoscopic characteristics that distinguish EoE could provide a more comprehensive diagnostic strategy than the present criteria. The aim of the study was to determine symptoms and signs that can be used to distinguish EoE from reflux esophagitis. Adult and pediatric patients with EoE were identified by present diagnostic guidelines including an esophageal biopsy finding of ≥15 eosinophils/HPF. Patients with GERD were age-matched one to one with patients with EoE. Clinical, endoscopic, and histologic information at the time of diagnosis was obtained from the medical record and compared between pairs by McNemar test. A conditional logistic regression model was created using 6 distinguishing disease characteristics. This model was used to create a nomogram to differentiate EoE from reflux-induced esophagitis. Patients with EoE were 75% men and 68% had a history of atopy. Many aspects of EoE were statistically distinct from GERD when controlling for age. Male sex, dysphagia, history of food impaction, absence of pain/heartburn, linear furrowing, and white papules were the distinguishing variables used to create the logistic regression model and scoring system based on odds ratios. The area under the curve of the receiver-operator characteristic curve for this model was 0.858. EoE can be distinguished from GERD using a scoring system of clinical and endoscopic features. Prospective studies will be needed to validate this model.