Eosinophilic Esophagitis Research Articles

One-food versus 4-food elimination diet for pediatric eosinophilic esophagitis: A multisite randomized trial

BackgroundA 6-food elimination diet in pediatric eosinophilic esophagitis (EoE) is difficult to implement and may negatively impact quality of life (QoL). Less restrictive elimination diets may balance QoL and efficacy. ObjectiveWe performed a multi-site, randomized comparative efficacy trial of a 1-food (milk) elimination diet (1FED) versus 4-food (milk, egg, wheat, soy) elimination diet (4FED) in pediatric EoE. MethodsPatients aged 6 to 17 years with histologically active and symptomatic EoE were randomized 1:1 to 1FED or 4FED for 12 weeks. Primary endpoint was symptom improvement by Pediatric EoE Symptom Score (PEESSv2.0). Secondary endpoints were proportion achieving histologic remission (<15 eosinophils/high-power field [eos/hpf]); change in histologic features (histology scoring system [HSS]), endoscopic severity (endoscopic reference score [EREFS]), transcriptome (EoE diagnostic panel [EDP]), and QoL scores; and predictors of remission. Results63 patients were randomly assigned to 1FED (n=38) and 4FED (n=25). In 4FED versus 1FED, mean PEESSv2.0 improved -25.0 versus -14.5 (p=0.04) but remission rates (41% versus 44%; p=1.00), HSS (-0.25 versus -0.29; p=0.77), EREFS (-1.10 versus -0.58; p=0.47) and QoL scores were similar between groups. The EoE transcriptome normalized in histologic responders to both diets. Baseline peak eosinophil count predicted remission (OR 0.975, 95% CI 0.953–0.999, p=0.04; cut-off ≤42 eos/hpf). The 4FED withdrawal rate (32%) exceeded 1FED (11%) (p=0.0496). ConclusionsAlthough 4FED moderately improved symptoms compared to 1FED, the histologic, endoscopic, QoL, and transcriptomic outcomes were similar in both groups. 1FED is a reasonable first choice therapy for pediatric EoE given its effects, tolerability, and relative simplicity.

579. DUPILUMAB IMPROVES ENDOSCOPIC FEATURES OF EOSINOPHILIC OESOPHAGITIS IN CHILDREN WITH EOSINOPHILIC OESOPHAGITIS: 52-WEEK ANALYSIS OF THE EOE KIDS STUDY

Abstract Introduction Eosinophilic oesophagitis (EoE) is a chronic type 2 inflammatory disease. Dupilumab, a fully human monoclonal antibody that blocks drivers of type 2 inflammation, is approved in the USA for EoE patients aged ≥1 year, weighing ≥15 kg, and in the EU for adult and adolescent EoE patients aged ≥12 years, weighing ≥40 kg. The EoE-Endoscopic Reference Score (EREFS) is a validated tool for assessing oesophageal features of EoE, with subscores for inflammation and remodelling. This study assessed the impact of dupilumab on EREFS in children aged 1–&amp;lt;12 years with active EoE in the phase 3 EoE KIDS trial. Methods In Part A, 102 patients (mean [SD] age: 7.1 [3.05] years) were randomised 2:2:1:1 to receive weight-tiered dupilumab higher-exposure (HE) or lower-exposure, or placebo (two groups) for 16 weeks. In Part B, all patients received dupilumab at their preassigned dupilumab regimen for a further 36 weeks. This analysis focused on the dupilumab HE and placebo groups. EREFS were scored centrally by reviewers blinded to both treatment allocation and time point. Absolute change from baseline in EREFS total score (0−18), and EREFS inflammation (0−10) and remodelling (0−8) subscores were assessed at Weeks 16 and 52. Results A total of 37 and 34 patients received dupilumab HE and placebo, respectively; baseline mean EREFS scores were similar across treatment groups (6.8 vs 7.3) with EREFS inflammation subscores higher than remodelling subscores (6.0 vs 0.9 in the total population). EREFS total score was significantly reduced at Week 16 with dupilumab HE versus placebo (LS mean difference -3.8 [95% CI: -4.9, -2.6], P&amp;lt;0.0001), with improvement sustained through Week 52 in the dupilumab HE group (figure). Similar improvements were observed for EREFS inflammation subscore. Assessment of changes in remodelling was limited by low prevalence of fibrostenotic features in young children. Conclusion Dupilumab HE led to significant improvement in EREFS total score at Week 16 versus placebo, which was sustained through Week 52. Dupilumab HE also improved EREFS inflammation subscore.

265. INITIAL RESULTS FROM RESOLVE, A PHASE 1B DOSE-ESCALATION STUDY OF EP-104GI (EXTENDED-RELEASE FLUTICASONE PROPIONATE INTRA-ESOPHAGEAL INJECTION) FOR EOSINOPHILIC ESOPHAGITIS

Abstract Background Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by inflammation, influx of eosinophils and esophageal remodeling. Therapy for EoE includes swallowed/topical corticosteroids, dupilumab, and dietary elimination; but these are not always effective. EP-104GI is an extended-release fluticasone propionate (FP) intra-esophageal injection being developed as a novel treatment for EoE. EP-104GI consists of coated FP crystals that release locally via diffusion at a pre-defined rate to reduce peak concentrations and prolong therapeutic window. RESOLVE (NCT05608681) is a Phase 1b, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of EP-104GI in patients with EoE. Methods The conservative starting dose of EP-104GI consisted of 1 mg injected at each of 4 sites in 4 quadrants over two ‘rings’ in the esophagus. Dose escalations increase the dose per site and/or number of sites; the second cohort received 1 mg at each of 8 sites. After a single administration of EP-104GI, participants are assessed for up to 24 weeks including adverse events (AEs) and laboratory tests. Efficacy assessments include histological endpoints and patient-reported symptom outcomes including the Straumann Dysphagia Index (SDI). Esophageal biopsies are collected at baseline, Week 4 and Week 12. Results All subjects demonstrated decreased symptom scores compared to baseline, with generally greater responses at the higher EP-104GI dose in Cohort 2 (Fig 1). Histologically, all Cohort 2 patients showed decreases in EoEHSS scores with 2/3 having ≈50% decrease in total grade score and ≈35% decrease in total stage score at Week 4, also, eosinophil counts were reduced by ≈35% at Week 4 and ≈40% at Week 12. Findings from Cohorts 1 and 2 of the ongoing trial include mild-moderate treatment-emergent AEs, the majority occurring on the day of treatment. No AEs were related to EP-104GI. Conclusions The initial results presented here indicate that the novel diffusion-based localized delivery of FP via EP-104GI injection into the esophagus is feasible and safe in patients with EoE and could avoid the side-effects typically associated with swallowed/topical corticosteroids. Efficacy data from the doses studied, although limited at this point, suggest a dose-response relationship with symptom outcomes and also show histologic improvements. These findings support the potential for an interval of at least 6 months between inter-esophageal injections, which may be further extended at the higher doses to be investigated in this study. Recruitment is ongoing.

CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis

Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 (L2-IL5OXA). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5OXA mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.

578. DUPILUMAB EFFICACY IN EOSINOPHILIC OESOPHAGITIS PATIENTS TREATED WITH PRIOR THERAPY AND INADEQUATE RESPONSE, INTOLERANCE, OR CONTRAINDICATION TO SWALLOWED TOPICAL CORTICOSTEROIDS

Abstract Background Improvements in histologic, symptomatic, and endoscopic aspects of eosinophilic oesophagitis (EoE) were observed in patients treated with dupilumab weekly (qw) enrolled in the 3-part, phase 3 LIBERTY EoE TREET study (NCT03633617), regardless of prior inadequate response, intolerance, and/or contraindication to swallowed topical corticosteroids (STC). Here we assess the efficacy of dupilumab qw versus placebo in this STC non-responsive/intolerant subgroup, stratifying further by those with/without history of food elimination diets, proton pump inhibitor (PPI) use at randomisation, or history of oesophageal dilation. Methods This analysis includes patients who received dupilumab 300 mg qw or placebo for 24 weeks in Part B and an additional 28 weeks dupilumab in Part C. Co-primary endpoints (Weeks 24 and 52) include: proportions of patients achieving peak eosinophil count (PEC) ≤6 eosinophils/high-power field (eos/hpf) and absolute change in Dysphagia Symptom Questionnaire (DSQ) score. Secondary endpoints assessed included proportions of patients achieving PEC ≤1 eos/hpf, &amp;lt;15 eos/hpf, % change in PEC, and absolute change in Endoscopic Reference Score, and EoE-Histologic Scoring System grade/stage scores. Results Dupilumab 300 mg qw improved proportions of patients achieving co-primary endpoints, ≤6 eos/hpf and absolute change in DSQ score, and secondary endpoints, ≤1 eos/hpf and &amp;lt;15 eos/hpf at Week 24 versus placebo, regardless of history of food elimination diets, PPI use at randomisation, or history of dilation (Table). Improvements were maintained or continued to improve at Week 52. A similar trend was observed for other secondary endpoints assessed. Placebo-treated patients who switched to dupilumab in Part C demonstrated similar efficacy to patients treated with dupilumab in Part B. Dupilumab safety was consistent with the known dupilumab safety profile. Conclusion Dupilumab qw demonstrated sustained improvements in histologic and symptomatic aspects of EoE up to 52 weeks in adults and adolescents with an inadequate response, intolerance, and/or contraindication to STC, regardless of history of food elimination diets, PPI use, or history of oesophageal dilation. Improvements in endoscopic aspects of EoE up to 52 weeks were also observed.

520. TEMPORARY ESOPHAGEAL EXCLUSION IN THE MANAGEMENT OF DELAYED RECOGNITION OF THORACIC ESOPHAGEAL PERFORATION

Abstract Background Perforation of the esophagus is a rare surgical emergency and timing is crucial for prognosis. Late interventions are likely to result in terminal bipolar esophageal exclusion, requiring a subsequent reconstructive procedure to restore the esophageal transit, associated with high rate of morbidity and mortality. Methods From January 2013 to June 2023, 32 patients with esophageal perforations referred to our center required surgical treatment. We retrospectively analyzed two cases of late middle thoracic perforation treated with temporary esophageal exclusion. Results A 31-year-old male presented in May 2020 after 6 days from perforation due to bolus impaction in eosinophilic esophagitis and a 79-year-old male referred us in November 2022 8 days after Boerhaave syndrome. Direct closure wasn’t feasible due to tissue fibrosis and degeneration. In both cases we performed thoracoscopic toilette with drainage placement and bipolar temporary exclusion of the esophagus. A lateral esophagostomy was performed, and cardias was temporarily excluded. In the first case a PTFE prothesis was used as a loop around the EGJ and fixed on the abdominal esophagus, in the second case TA45 linear stapler loaded with 3.5 staples was used. For nutritional purposes a gastrostomy and a jejunostomy were placed. Post-operatively, pleural empyema was managed conservatively with a thoracic drain and antibiotic therapy, instead mediastinal collection sustained by the perforation was drained through the tangential esophagostomy with a NG tube placed endoscopically across the perforation. The patients were discharged in 27 and 20 POD respectively. The second patient was readmitted in 45 POD due right lobar pneumonia, treated with antibiotics. In the first case the PTFE prothesis was laparoscopically removed after 70 days and the tangential esophagostomy sutured. In the second case esophageal transit was spontaneously restored and esophagostomy was subsequentially sutured. Oral feeding was resumed in both patients, without resulting stenosis or leakage. Conclusion In selected patients with late thoracic esophageal perforations, temporary esophageal exclusion represented an alternative treatment, without mortality and with low morbidity, to terminal esophageal exclusion and a subsequent reconstructive procedure.

639. WHICH FACTORS LEAD PATIENTS WITH BENIGN ESOPHAGEAL STRICTURES FOR SURGICAL TREATMENT BESIDES ENDOSCOPIC TREATMENT?

Abstract Background This work proposes to evaluate patients with benign esophageal strictures, excluding caustic strictures, about their etiologies and poor prognostic factors for the success of endoscopic treatment. Methods It was evaluated in our service 38 patients, from 1992 to 2023, with benign esophageal strictures not related to caustic strictures. We could follow-up 24 patients from 7 months and 384 months (average of 136 months). Four died during the follow- up. We could analyze these following outcomes: clinical symptoms, surgical indications, age, gender, alcohol abuse, smoking, length of stricture, number of endoscopic dilation and stricture etiology. Results Concerning the 24 patients with follow-up, 4 had esophagectomy; 10 underwent endoscopic treatment with fundoplication and 10 were treated with endoscopic and medical treatment. Both groups, endoscopic and medical treatment, and endoscopic treatment with fundoplication had 4 patients that continued symptomatic (40%). The number of endoscopic dilations range from 1 to 101 (average 18) in each patient. The etiology of 38 patients with benign esophageal strictures were: 35 gastroesophageal reflux disease (13 Barrett´s esophagus); one with infectious esophagitis; one eosinophilic esophagitis and another due to esophageal varicose sclerosis. The prognostic factors to surgical treatment will be analyzed by statistical analysis. Conclusion From our data, it is possible to conclude that the endoscopic treatment is effective to manage the majority of benign esophageal strictures, even in association with fundoplication. Moreover, the main etiology was gastroesophageal reflux disease. Only few patients have developed indication to esophagectomy.

Oral viscous budesonide solution for enhanced localized treatment of eosinophilic esophagitis through improved mucoadhesion and permeation

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus that is immune/antigen-mediated and often requires targeted treatment. In clinical practice, an oral viscous budesonide suspension prepared by adding sucralose to a budesonide suspension for inhalation (Pulmicort®) is used to treat adult EoE and enhance retention in the esophageal mucosa. Inspired by this off-label drug use, oral viscous budesonide solutions (OVBSs) were developed in this study, and their capacities for adhesion, permeation, and stability were explored. Given the insolubility of budesonide as a BCS II drug, we first evaluated its equilibrium solubility and found that Transcutol® HP was an excellent choice for creating an OVBS at a concentration of 0.2 mg/g. The rheological properties of the OVBSs were evaluated with a rheometer, and shear-thinning, which aids in swallowing, was observed. The addition of hydroxyethyl cellulose (HEC) increased the adhesion strength of the preparation, which was associated with the hydration and thickening mechanism. This result was confirmed in a dynamic gelation study and in vitro elution experiment conducted with porcine esophagus tissue. Furthermore, the permeabilities of the OVBSs in the porcine esophagus were evaluated with a Franz diffusion cell device. >80 % of the budesonide was released after 24 h, and the release profile was similar to that of the solution. To explore the storage conditions of OVBSs, critical factors such as pH, content, and impurities were determined. It was found that OVBSs exhibited different behaviors at different pH values and temperatures. Notably, the OVBSs containing 1.7 % HEC could be stored for >6 months at a temperature of 5 °C ± 3 °C and a pH of 4.5 without significant degradation. Overall, this study demonstrated that OVBSs have the potential to adhere to the esophageal mucosa, permeate the tissue, and remain stable during storage. Moreover, OVBSs exhibit a distinct advantage over traditional converted inhalation-to-oral budesonide therapies by enabling flexible dose adjustment in clinical applications, thereby potentially minimizing systemic side effects commonly associated with oral glucocorticoid administration.

Abstract ID: 62 Dupilumab Efficacy and Safety up to 52 Weeks in Adult and Adolescent Patients With Eosinophilic Esophagitis: Results From Parts B and C of the Randomized, Placebo-Controlled, Three-Part, Phase 3 LIBERTY EoE TREET Study

Abstract ID: 62 Dupilumab Efficacy and Safety up to 52 Weeks in Adult and Adolescent Patients With Eosinophilic Esophagitis: Results From Parts B and C of the Randomized, Placebo-Controlled, Three-Part, Phase 3 LIBERTY EoE TREET Study

Diagnosis and management of eosinophilic esophagitis and esophageal food impaction in adults : Aposition paper issued by the Austrian Society of Gastroenterology and Hepatology (ÖGGH).

This position paper deals with an expert consensus on diagnosis and management of eosinophilic esophagitis and esophageal food impaction issued by the Austrian Eosinophilic Esophagitis Network, aworking group under the patronage of the Austrian Society of Gastroenterology and Hepatology (ÖGGH). In need of astandardized approach on the management of EoE, recommendations were made based on international guidelines and landmark studies.

Factors Associated With Decision to Treat or Not to Treat Helicobacter pylori Infection in Children: Data From the EuroPedHp Registry.

European and North-American guidelines on management of H. pylori infection in children provide the option not to treat even if the infection is endoscopically confirmed. We used data from the EuroPedHp Registry to identify factors associated with therapy decisions. We included treatment-naïve patients reported between 2017 and 2020 from 30 centers in 17 European countries. Multivariable logistic regression identified factors including comorbidities within and outside the gastrointestinal (GI) tract influencing the decision for or against therapy. Of 1165 patients (52% females, median age 12.8), 28% (321/1165) reported any alarm symptom, 26% (307/1165) comorbidities, and 16% (192/1165) did not receive eradication treatment. Therapy was initiated less often in children having any GI comorbidity (57%, n = 181), particularly in those with eosinophilic esophagitis (60%, n = 35), inflammatory bowel disease (54%, n = 28), and celiac disease (43%, n = 58), compared to those with non-GI (86%, n = 126) or no comorbidity (89%, n = 858), despite similar frequencies of alarm and non-alarm symptoms, ulcers, erosions, and nodular gastritis. Patients with GI and without comorbidities remained more likely untreated in high versus low H. pylori prevalence countries (p < 0.0001). In children without comorbidities, factors favoring therapy included older age, being overweight, having symptoms, erosions, antral nodularity, and available antibiotic susceptibility results. In this cohort, H. pylori-infected children with GI comorbidities compared to no comorbidity showed 75% reduced chance of receiving eradication therapy. We found no evidence supporting different management strategies in infected patients with GI comorbidities compared to all pediatric patients with endoscopically proven H. pylori infection.

IgE- and non-IgE-mediated food allergies - an overview

Food allergies are divided into 2 main categories: IgE-mediated and non-IgE-mediated food allergies. Both forms can have significant health effects but differ in mechanism, symptoms, and management. The manifestation of the 2 forms differs between children and adults. These differences can be observed in the prevalence and the type of most common allergens and clinical presentation. The prevalence of food allergies has increased worldwide in recent decades. IgE-mediated allergies are the best researched and documented. They are particularly common in children, while non-IgE-mediated allergies are less well understood and diagnosed, leading to uncertainty about their prevalence. They often manifest as gastrointestinal symptoms that can occur hours to days after ingestion and are often difficult to distinguish from other food intolerances. The occurrence of food allergies varies significantly geographically. Differences in dietary habits, food composition, and environmental factors can partly explain these differences. There are also indications that genetics may play a role. IgE-mediated and non-IgE-mediated food allergies represent a significant and growing challenge for the global healthcare system. This article provides an in-depth review of both types of food allergy, discussing their potential causes, diagnostic possibilities, and available therapeutic strategies. Some diseases represent a mixed form of IgE and non-IgE-mediated immunological adverse reactions. Eosinophilic oesophagitis is the most common eosinophilic disease, and the diagnosis and treatment options are explained in more detail below.

262. EOSINOPHILIC ESOPHAGITIS: A SEVEN YEAR ANALYSIS OF EPIDEMIOLOGY IN A UNITED KINGDOM COUNTY

Abstract Background Eosinophilic Esophagitis (EoE) is growing in incidence internationally. It is an immune-mediated disease that is characterised by esophageal mucosal eosinophilia and esophageal dysfunction. Awareness of EoE is also crucial for Esophagogastric surgeons as symptoms may mimic reflux disease or neoplasia, key considerations for an accurate differential diagnosis. Presently, there are no incidence estimates of EoE in the adult population in the UK. This study seeks to establish a cohort of EoE patients in Norfolk, a county in the East of England region, and to describe the incidence, characteristics, and diagnostic features of affected patients in both the adult and paediatric populations. Methods A retrospective analysis was performed of a prospectively maintained pathology database servicing a population of 761,000 persons in Norfolk. All newly diagnosed cases of EoE across a seven-year period between January 2017 and December 2023 were identified. Patients included for analysis had a histological diagnosis of EoE with &amp;gt;15 eosinophils/hpf and symptoms of oesophageal dysfunction. Patient electronic health care records were reviewed for histology reports, endoscopic findings, and clinical history. The primary outcome was incidence of EoE within the county. Secondary outcomes assessed included: patient characteristics; allergy and atopy history; endoscopic features, biopsy protocol and referral indication. Results 187 (median age 43 (4-85) years, Male: Female (126:61)) new cases of EoE were identified, of whom eight were in the paediatric age group of ≤16 years. The average annual incidence of EoE was 4.29 [95% CI 2.92, 5.66] and 0.89 [95% CI 0, 1.39] per 100,000 person/years in adult and paediatric groups respectively, with a significantly higher incidence in adults (RR 4.86 (95% CI [2.39 – 9.85] P&amp;lt;0.005) (Figure 1). The most common referral indications for endoscopy were dysphagia (80.7%) and food bolus obstruction episodes (25.1%). The most common endoscopic feature of EoE was circular rings (49.2%). Conclusion This is the first study reporting incidence of EoE in the UK adult population. There was a significantly greater incidence of EoE in adults compared to the paediatric population. However, there was no significant change in incidence of EoE in either group over the study period. Incidence estimates identified are similar to those reported in other European populations. Importantly 18.2% of patients had normal appearance of oesophagus on endoscopy, which reinforces the need to take oesophageal biopsies where there is clinical suspicion. Ideally, prospective registry data is needed for a comprehensive characterisation of incidence and prevalence of EoE.

Abstract ID: 79 Histopathologic Endpoints in Children With Eosinophilic Esophagitis Improved With Dupilumab Treatment: Results From Week 52 of the Phase 3 EOE Kids Trial

Abstract ID: 79 Histopathologic Endpoints in Children With Eosinophilic Esophagitis Improved With Dupilumab Treatment: Results From Week 52 of the Phase 3 EOE Kids Trial

Tissue-specific inducible IL-33 expression elicits features of eosinophilic esophagitis

BackgroundIL-33 is a type 2 inflammatory cytokine that is elevated in the esophageal epithelium of EoE subjects. We previously developed a mouse model of EoE dependent on constitutive overexpression of IL-33 from the esophageal epithelium (EoE33). ObjectiveOur objective was to develop an inducible, IL-33-dependent model of EoE and examine induction of EoE-associated pathology. MethodsWe utilized a tetracycline-inducible system to express IL-33 in the esophagus by generating two transgenic mice. The first (iSophagus) expresses a reverse tetracycline transactivator (rtTA) from the esophageal epithelium. The second (TRE33) features a tetracycline-response element driving expression of IL-33. When crossed, these mice generate an inducible model of EoE (iEoE33). Mice were administered doxycycline-infused chow for up to 2 weeks. Cytokines were assessed by ELISA or bead-based multiplex. T cells were assessed by flow cytometry. Pathology was assessed by histology and immunohistochemistry for IL-33, eosinophil peroxidase, CD4, and Ki-67. iEoE33 was treated with steroids and crossed with IL-13-/- mice. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org. ResultsDoxycycline-treated iEoE33 mice demonstrated expression of IL-33 in the esophageal epithelium, and esophageal pathology including eosinophilia, CD4+ cell infiltrate, basal zone hyperplasia, and dilated intercellular spaces. These findings became pronounced on day 7 of induction, were accompanied by weight loss and esophageal thickening, and were steroid responsive and IL-13 dependent. ConclusionInducible IL-33 expression in the esophageal epithelium elicited features pathognomonic of EoE. iEoE33 enables investigation of EoE disease mechanisms as well as initiation, progression, and resolution.

Sialylated keratan sulfates on MUC5B are Siglec-8 ligands in the human esophagus.

Human sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed on subsets of immune cells. Siglec-8 is an immune inhibitory Siglec on eosinophils and mast cells, which are effectors in allergic disorders including eosinophilic esophagitis. Inhibition occurs when Siglec-8 is crosslinked by multivalent Siglec ligands in target tissues. Previously we discovered a high-affinity Siglec-8 sialoglycan ligand on human airways composed of terminally sialylated keratan sulfate chains carried on a single protein, DMBT1. Here we extend that approach to another allergic inflammatory target tissue, human esophagus. Lectin overlay histochemistry revealed that Siglec-8 ligands are expressed predominantly by esophageal submucosal glands, and are densely packed in submucosal ducts leading to the lumen. Expression is tissue-specific; esophageal glands express Siglec-8 ligand whereas nearby gastric glands do not. Extraction and resolution by gel electrophoresis revealed a single predominant human esophageal Siglec-8 ligand migrating at >2MDa. Purification by size exclusion and affinity chromatography, followed by proteomic mass spectrometry, revealed the protein carrier to be MUC5B. Whereas all human esophageal submucosal cells express MUC5B, only a portion convert it to Siglec-8 ligand by adding terminally sialylated keratan sulfate chains. We refer to this as MUC5B S8L. Material from the esophageal lumen of live subjects revealed MUC5B S8L species ranging from ~1-4MDa. We conclude that MUC5B in the human esophagus is a protein canvas on which Siglec-8 binding sialylated keratan sulfate chains are post-translationally added. These data expand understanding of Siglec-8 ligands and may help us understand their roles in allergic immune regulation.

From Pathogenesis to Treatment: Targeting Type-2 Inflammation in Eosinophilic Esophagitis.

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.

Amniotic fluid modifies esophageal epithelium differentiation and inflammatory responses.

The interplay between genetic and environmental factors during pregnancy can predispose to inflammatory diseases postnatally, including eosinophilic esophagitis (EoE), a chronic allergic disease triggered by food. Herein, we examined the effects of amniotic fluid (AF) on esophageal epithelial differentiation and responsiveness to proallergic stimuli. Multiplex analysis of AF revealed the expression of 66 cytokines, whereas five cytokines including IL-4 and thymic stromal lymphopoietin (TSLP) were not detected. Several proinflammatory cytokines including TNFα and IL-12 were highly expressed in the AF from women who underwent preterm birth, whereas EGF was the highest in term birth samples. Exposure of esophageal epithelial cells to AF resulted in transient phosphorylation of ERK1/2 and the transcription of early response genes, highlighting the direct impact of AF on esophageal epithelial cells. In a three-dimensional spheroid model, AF modified the esophageal epithelial differentiation program and enhanced the transcription of IL-13-target genes, including CCL26 and CAPN14, which encodes for a major genetic susceptibility locus for eosinophilic esophagitis. Notably, CAPN14 exhibited upregulation in spheroids exposed to preterm but not term AF following differentiation. Collectively, our findings call attention to the role of AF as a potential mediator of the intrauterine environment that influences subsequent esophageal disorders.NEW & NOTEWORTHY The interaction between amniotic fluid and the esophageal epithelium during pregnancy modifies esophageal epithelial differentiation and subsequent responsiveness to inflammatory stimuli, including interleukin 13 (IL-13). This interaction may predispose individuals to inflammatory conditions of the esophagus, such as eosinophilic esophagitis (EoE), in later stages of life.

Characterization of a Romanian Pediatric Population with Eosinophilic Esophagitis.

Background/objectives: An increase in the incidence of eosinophilic esophagitis (EoE) in children has been reported worldwide in the last decade. We conducted a study in a tertiary pediatric gastroenterology unit aimed at analyzing the clinical manifestations, biochemical markers, and endoscopic features of children with EoE in comparison to patients with non-eosinophilic esophagitis. Methods: This is a prospective analysis involving children with symptoms related to esophageal dysfunction, who had esophagogastroduodenoscopies with esophageal biopsies between January 2021 and April 2024 at "Dr. Victor Gomoiu" Clinical Children's Hospital, in Bucharest, Romania. For the analysis, patients were considered in either Group 1, classified as EoE, or in Group 2, classified as reflux esophagitis. Results: Among the total of 72 patients diagnosed with esophagitis, 17 patients (Group 1-study group) were classified as EoE and 55 were classified as reflux esophagitis (Group 2-control group). The sex ratio analysis showed a male predominance in the study group (71% vs. 32%, p = 0.002). The main symptoms were regurgitation, eructation, and nausea. Dysphagia was present in two (11.76%) patients from Group 1. Eosinophilia was more prevalent in the EoE group than in the individuals with gastroesophageal reflux disease (GERD) (10 (58.85%) vs. 10 (18.18%, p = 0.001)), as well as the total IgE (11 (64.70%) vs. 6 (10.9%, p = 0.001)). Conclusions: Pediatric gastroenterologists need to be aware of EoE atypical presentation and perform adequate biopsies, mainly in children with refractory GERD-like symptoms, dysphagia, and food bolus impaction. Further analyses in terms of prognosis and treatment response should be addressed in longitudinal studies.

Monitoring for eosinophilic esophagitis in food oral immunotherapy.

Monitoring for eosinophilic esophagitis in food oral immunotherapy.