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.

A Cricopharyngeal Bar as an Underrecognized Finding in an Adolescent with Eosinophilic Esophagitis.

A 16-year-old Caucasian male with previously diagnosed eosinophilic esophagitis (EoE) 4 years before his initial visit to an allergist-immunologist, scheduled due to severe dysphagia and recurrent food impaction. He had been off EoE therapy for 1 year. After resuming inhaled fluticasone and a proton pump inhibitor (PPI), esophagogastroduodenoscopy (EGD) was immediately scheduled. The dates of the original EGD procedures with the histological summary and EoE therapy are reported in the Table 1. The fourth endoscopy revealed near normal histology, with rare candida staining (Table 1). He was continued on daily PPI and the fluticasone was discontinued. Three weeks of Fluconazole failed to resolve his dysphagia. A repeat barium swallow confirmed a pre-existing cricopharyngeal bar, and he was referred to an otolaryngology for further care. [Table: see text].

Standardizing visual display of gastrointestinal pathology results for improved clinical interpretation.

OBJECTIVES: Pathology is an essential component of disease diagnosis and management in pediatric gastroenterology. Pathology reports have not been standardized in some areas of pediatric gastrointestinal pathology and pathology reporting varies. Development of electronic medical record (EMR) pathology synoptic report templates (PSRT) enables pathology data collection in a specific format and can help standardize pathology reporting. We developed, implemented, and evaluated EMR PSRTs for eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD). METHODS: PSRTs were developed by a multidisciplinary team of pediatric experts of allergy, gastroenterology, and pathology for both EoE and IBD based on available literature and validated scales. Likert surveys (range 1 low acceptance to 5 high acceptance) based on the Technology Acceptance Model assessed user acceptance of the developed PSRTs. The use of PSRTs was monitored via control charts. RESULTS: Overall, evaluation questionnaires achieved >80% response rates. Clinicians and pathologists reported moderate-to-high levels of Perceived Usefulness (median (interquartile range) for EoE PSRT: clinicians 4.0 (4.0, 5.0) and pathologists 3.5 (3.5, 4.0); and IBD PSRT: clinicians 4.0 (3.0, 4.0) and pathologists 4.0 (4.0, 5.0)) and Perceived Ease of Use (EoE PSRT: clinicians 4.5 (4.0, 5.0) and pathologists 4.0 (4.0, 4.0); and IBD PSRT: clinicians 4.0 (4.0, 5.0) and pathologists 4.0 (4.0, 5.0)) of the developed PSRTs. Control charts demonstrated 100% utilization by 2-5 months from launch. CONCLUSIONS: We demonstrate successful implementation of synoptic reporting for both pediatric EoE and IBD pathology. EMR synoptic reporting provides standardization of pathology reporting and improved methods of pathology data presentation, which could potentially optimize provider efficiency, clinician interpretation of pathology results and disease trajectory, patient care, and clinician satisfaction.

Bioinformatics Study on Site-Specific Variations of Eotaxin-3, a Key Chemokine in Eosinophilic Esophagitis (EoE).

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.

Eosinophilic Esophagitis and Inflammatory Bowel Disease: What Are the Differences?

Eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) are chronic inflammatory disorders of the gastrointestinal tract, with EoE predominantly provoked by food and aeroallergens, whereas IBD is driven by a broader spectrum of immunopathological and environmental triggers. This review presents a comprehensive comparison of the pathophysiological and therapeutic strategies for EoE and IBD. We examine the current understanding of their underlying mechanisms, particularly the interplay between environmental factors and genetic susceptibility. A crucial element in both diseases is the integrity of the epithelial barrier, whose disruption plays a central role in their pathogenesis. The involvement of eosinophils, mast cells, B cells, T cells, dendritic cells, macrophages, and their associated cytokines is examined, highlighting the importance of targeting cytokine signaling pathways to modulate immune-epithelial interactions. We propose that advances in computation tools will uncover the significance of G-protein coupled receptors (GPCRs) in connecting immune and epithelial cells, leading to novel therapies for EoE and IBD.

Patients with cardinal symptoms of eosinophilic esophagitis. Prejudice affects clinical practice .

INTRODUCTION: Dysphagia and bolus impaction are the cardinal manifestations of eosinophilic esophagitis (EoE). Esophageal biopsy sampling is mandatory for EoE diagnosis, data though suggest that clinician do not always obtain biopsies from patients with cardinal EoE symptoms during upper gastrointestinal endoscopy even if no other entity than EoE can explain patients symptoms. We aimed to search for the esophageal biopsy procurement rate as also for factors that drive clinicians to obtain esophageal biopsies among patients with cardinal EoE symptoms. METHODS: We retrospectively searched for patients with cardinal EoE symptoms submitted to upper gastrointestinal endoscopy between 1/2018 and 12/2023 in our department. Epidemiologic, clinical, endoscopic, and histological data were analyzed. RESULTS: In total 163 patients with cardinal EoE symptoms (dysphagia: 63 and bolus impaction: 100) were included in the study (M/F: 100/63, mean age: 54 ±â€…22 years). Biopsy sampling was obtained in 77/163 (47.2%) patients and sampling rates did not differ between patients with bolus impaction or dysphagia (47/100, 47% vs 30/63, 47.6%, P  = 0.553). Higher rates of sampling were observed in males ( P  = 0.045), those younger than 65 years old ( P  < 0.001) and patients with endoscopic EoE signs ( P  = 0.004). Age and endoscopic findings compatible to EoE were independently correlated to biopsy sampling. EoE was diagnosed in 35/74 patients (47.3%); the majority of patients were male, with a bolus impaction episode, compatible endoscopic findings and all were younger than 65 years old. CONCLUSION: Clinicians take esophageal biopsies in half of patients with cardinal EoE. Age and supportive endoscopic evidence drive clinicians' decision to obtain esophageal biopsies.

Sustained clinical and histopathological remission in a patient with eosinophilic esophagitis and type-2 comorbidities at 18 months after discontinuation of dupilumab.

Eosinophilic esophagitis (EoE) is a chronic, allergen-mediated, type-2 inflammatory disease with the potential to significantly impact an individual's quality of life. Conventional treatments often result in varied responses, prompting the need for novel therapeutic approaches. We present the case of a 19-year-old male with a medical history marked by eosinophilic esophagitis, severe atopic dermatitis (AD), asthma, and allergic rhinitis. Despite undergoing diverse topical and systemic interventions to address his AD and EoE, the patient's symptoms persisted. However, following the initiation of dupilumab therapy-a dual IL-4 and IL-13 receptor antagonist-the patient experienced a substantial reduction in his Eczema Area and Severity Index score. Notably, a marked improvement was also seen regarding his symptoms of eosinophilic esophagitis. A subsequent esophageal biopsy revealed a significant decrease in eosinophilic inflammation, consistent with established clinical and histologic remission criteria. These findings corroborate the patient's reported relief from symptoms. This case underscores the potential efficacy of dupilumab as a promising therapeutic agent in managing eosinophilic esophagitis. Dupilumab offers a dual benefit of alleviating symptoms and achieving histologic and clinical remission. This novel approach presents a noteworthy advancement in the treatment of EoE.

Real-world efficacy of dupilumab in four cases of paediatric-onset fibrostenotic eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is an increasingly prevalent immune-mediated disease that leads to chronic changes in the oesophagus. These changes can include strictures, narrowing, and stenosis, mediated by an interleukin (IL)-13 pathway, which leads to remodelling and fibrosis through increasing migration of fibroblasts and subepithelial fibrosis via collagen deposition 1. IL-13 downregulates TSPAN12, a gene whose expression regulates fibrosis and causes changes in barrier function and higher rates of fibrostenosis in EoE. Dupilumab, a biologic therapy aimed at blocking IL-13, has been shown to improve EoE-related inflammation and fibrosis in clinical trials. We report here four unique patients with documented oesophageal stenosis with inability to pass a paediatric endoscope due to structuring disease, requiring dilation, who had resolution of their oesophageal narrowing following dupilumab therapy.

Dupilumab for Eosinophilic Esophagitis in Patients 1 to 11 Years of Age.

BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents. METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically. RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).

Development and dysfunction of structural cells in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a disorder characterized by dysfunction and chronic local inflammation of the esophagus. The incidence and prevalence of EoE are increasing worldwide. The mechanisms responsible are poorly understood, and effective treatment options are limited. From the lumen outward, the esophagus comprises stratified squamous epithelium, lamina propria, and muscle. The tissue-specific nature of EoE strongly suggests that structural cells in the esophagus are involved in the EoE diathesis. Epithelial basal cell hyperplasia and dilated intercellular spaces are cardinal features of EoE. Some patients with EoE develop lamina propria fibrosis, strictures, or esophageal muscle dysmotility. Clinical symptoms of EoE are only weakly correlated with peak eosinophil count, implying that other cell types contribute to EoE pathogenesis. Epithelial, endothelial, muscle, and fibroblast cells can each initiate inflammation and repair, regulate tissue resident immune cells, recruit peripheral leukocytes, and tailor adaptive immune cell responses. A better understanding of how structural cells maintain tissue homeostasis, respond to cell-intrinsic and cell-extrinsic stressors, and exacerbate and/or resolve inflammatory responses in the esophagus is needed. This knowledge will facilitate the development of more efficacious treatment strategies for EoE that can restore homeostasis of both hematopoietic and structural elements in the esophagus.

Transnasal Endoscopy Acquires Esophageal Biopsies Adequate for Comprehensive Pathology Evaluation in Patients With Eosinophilic Esophagitis.

BACKGROUND: Transnasal endoscopy (TNE) does not require general anesthesia, an attractive characteristic for monitoring eosinophilic esophagitis (EoE). We evaluated the adequacy of TNE-obtained esophageal biopsies using the EoE Histology Scoring System (EoEHSS). METHODS: The Cincinnati Center for Eosinophilic Disorders database was searched for esophageal biopsies obtained by the same endoscopist, using either TNE or conventional endoscopy (CE). Whole-slide biopsy images were evaluated. The Mann-Whitney test was used for median (interquartile range) values and Fisher exact test for categorical variables. P ≤ .05 was considered significant. RESULTS: Median age (P = .82) or height (P = .83) did not differ between TNE (n = 17) and CE (n = 17) groups. Although median largest piece size (mm2) differed between the groups (TNE: 0.59 (0.45, 0.86), CE: 2.24 (1.09, 2.82), P < .001), all 8 EoEHSS features were evaluated in each group; only 1 feature (lamina propria fibrosis) was missing in both groups (TNE: 19/34, CE: 11/34, P = .09). The median peak eosinophil count/high-power field differed (TNE: 3 (0, 29), CE: 16 (1, 66), P = .03), but overall grade (TNE: 0.17 (0.10, 0.29), CE: 0.22 (0.14, 0.46), P = .12), stage (TNE: 0.14 (0.10, 0.24), CE: 0.20 (0.10, 0.43), P = .15), and non-eosinophil-related individual EoEHSS scores did not differ. CONCLUSIONS: TNE- and CE-obtained esophageal biopsies are similarly sufficient for evaluation of key pathological features in EoE.

Three-Dimensional Cell Culture Models to Investigate the Epithelial Barrier in Eosinophilic Esophagitis.

The squamous epithelium of the esophagus is directly exposed to the environment, continuously facing foreign antigens, including food antigens and microbes. Maintaining the integrity of the epithelial barrier is critical for preventing infections and avoiding inflammation caused by harmless food-derived antigens. This article provides simplified protocols for generating human esophageal organoids and air-liquid interface cultures from patient biopsies to study the epithelial compartment of the esophagus in the context of tissue homeostasis and disease. These protocols have been significant scientific milestones in the last decade, describing three-dimensional organ-like structures from patient-derived primary cells, organoids, and air-liquid interface cultures. They offer the possibility to investigate the function of specific cytokines, growth factors, and signaling pathways in the esophageal epithelium within a three-dimensional framework while maintaining the phenotypic and genetic properties of the donor. Organoids provide information on tissue microarchitecture by assessing the transcriptome and proteome after cytokine stimulation. In contrast, air-liquid interface cultures allow the assessment of the epithelial barrier integrity through transepithelial resistance (TEER) or macromolecule flux measurements. Combining these organoids and air-liquid interface cultures is a powerful tool to advance research in impaired esophageal epithelial barrier conditions.

Comparison of budesonide vehicles in inducing histologic remission in pediatric eosinophilic esophagitis.

OBJECTIVES: Oral viscous budesonide (OVB) is a common medication used to treat eosinophilic esophagitis (EoE). It is typically mixed with Splenda to produce a slurry, but other delivery vehicles have been used in clinical practice. We aimed to evaluate outcomes of pediatric EoE patients treated with OVB using different drug delivery vehicles. METHODS: We performed a retrospective chart review of pediatric EoE patients treated with OVB. The primary aim was to evaluate rates of histologic remission (defined by <15 eosinophils per high power field in both mid and distal esophagus) after 6-12 weeks of OVB treatment for each delivery vehicle. Secondary aims were to evaluate histologic response and endoscopic response and remission of different delivery vehicles, and to compare the efficacy of different treatment regimens. RESULTS: A total of 111 patients were included in the study. Median treatment duration was 3.4 months. Overall rate of histologic remission with OVB was 52.6%. There was no difference in rates of histologic remission (p = 0.313) or response (p = 0.195 and p = 0.681 in mid and distal esophagus, respectively) among the different vehicle types or treatment regimens. Similarly, there was no difference in endoscopic remission and response among the different vehicle types (p = 0.853 and p = 0.727) or treatment regimens (p = 0.244 and p = 0.157). Patients who achieve histologic remission were more likely to be non-Hispanic Caucasian. CONCLUSION: Our findings suggest there is no difference in histologic and endoscopic outcomes with various delivery vehicles or combination therapy with OVB in the treatment of EoE. More palatable and cost-effective vehicles can be used to treat EoE.

Esophageal remodeling in eosinophilic esophagitis.

PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is a Th2 immune/antigen-mediated disorder characterized by esophageal dysfunction and eosinophilic inflammation. Worsening dysphagia and food impactions are significant complications associated with esophageal remodeling and fibrostenotic disease. This review highlights the most recent research findings pertaining to mechanisms of sub-epithelial fibrosis in EoE, current diagnostic tools, and therapeutic approaches. RECENT FINDINGS: Recent studies leveraging publicly available single cell sequencing databases and comparative proteomics have furthered our understanding of the mechanisms mediating fibrosis. Fibroblast crosstalk with the extracellular matrix and with epithelial, endothelial, and T cells have been implicated, with the likely existence of multiple fibroblast sub-types. Accurate diagnosis of remodeling with biopsies remains a challenge due to inadequate depth of sampling. Web-based tools incorporating epithelial findings show promise in predicting subepithelial fibrosis. Impedance planimetry with esophageal distensibility measurements are increasingly utilized tools to assess fibrostenotic severity. Immunostaining and luminal captured proteins associated with remodeling show promise as potential molecular markers of fibrosis. Anti-inflammatory therapy may improve esophageal fibrosis and distensibility, although specific fibrosis-targeted therapy is lacking. SUMMARY: Recent studies highlight novel mechanisms of fibrosis in EoE. Improved understanding of these mechanisms may lead to novel diagnostic strategies and therapies, and thereby inform treatment decisions.