Impact of STAT6 Variants on the Response to Proton Pump Inhibitors and Comorbidities in Patients with Eosinophilic Esophagitis.

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 (STAT6), CYP2C19, CYP3A4, CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. -75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants.

Eosinophilic Esophagitis: Clinical Pearls for Primary Care Providers and Gastroenterologists.

Eosinophilic esophagitis (EoE) is a chronic and progressive immune-mediated esophageal disorder. Given its increasing incidence, it is now a leading cause of dysphagia and food impaction in the United States. Eosinophilic esophagitis is most common in adult White men and has a high concurrence rate with other atopic conditions like allergic rhinitis, bronchial asthma, and eczema. The initial presentation includes symptoms of esophageal dysfunction, classically solid-food dysphagia. Without treatment, inflammation can progress to fibrosis with the formation of strictures, leading to complications such as food impaction. It is a clinicopathologic disease requiring compatible clinical symptoms and histologic evidence of eosinophil-predominant inflammation of the esophageal epithelium with more than 15 eosinophils per high-power field. The mainstay of management includes the 3 d's (diet, drugs, dilation): dietary modifications to eliminate trigger food groups; medications including proton pump inhibitors, swallowed topical glucocorticoids, and dupilumab; and esophageal dilation to manage strictures. Various elimination diets have been found to be effective, including 1-food, 2-food, 4-food, and 6-food elimination diets. Dupilumab, a humanized monoclonal antibody that regulates interleukin 4 and 13 signaling pathways, has shown promising results in clinical trials and was approved by the Food and Drug Administration in 2022 for use in EoE. Symptom alleviation, although important, is not the sole end point of treatment in EoE as persistent inflammation, even in the absence of symptoms, can lead to esophageal fibrosis and stricture formation over time. The chronic nature and high recurrence rates of EoE warrant maintenance therapy in patients with EoE after initial remission is achieved.

Endoscopic findings in children born with oesophageal atresia in an academic unit in South Africa.

BACKGROUND: Oesophageal atresia (OA) is one of the most common congenital gastrointestinal (GI) abnormalities. Due to advances in multidisciplinary care, early prognosis has improved with emphasis shifting to the long-term impact of this disease. Literature suggests a higher incidence of Barrett's and eosinophilic oesophagitis in these children, with an increased risk of oesophageal carcinoma. Guidelines for adults born with OA include routine endoscopy and lifelong screening of the upper gastrointestinal tract (GIT). Despite this, uncertainty remains regarding the necessity and frequency of endoscopic surveillance for children born with OA. We describe our endoscopic findings in children born with OA. METHODS: A prospective analytic cohort study was undertaken, which included all children born with OA, that were followed-up in our unit between 2020 and 2022. History regarding feeding and GI symptoms were documented after which an endoscopy was performed. RESULTS: During the study period, 37 endoscopies were performed in patients born with OA at a median age of 25 months. The most common clinical appearance on endoscopy was anastomotic strictures followed by oesophagitis. Twelve patients had biopsies taken, with abnormal histology in all but one patient. The most common histological finding was oesophagitis with lymphocytes and chronic gastritis. Two patients had Helicobacter Pylori infection, and one had findings suggestive of eosinophilic oesophagitis. CONCLUSION: All patients with a clinical indication for an endoscopy had abnormal clinical or histological findings, thus concurring with the literature in highlighting the need for regular endoscopy. We recommend regular clinical follow-up and endoscopic surveillance if clinically indicated for children born with OA.

Monitoring pediatric eosinophilic esophagitis disease activity using an unsedated blind esophageal brushing model: A pilot study.

BACKGROUND: Recurrent upper endoscopies are essential for monitoring therapy response and disease activity in patients with eosinophilic esophagitis (EoE), leading to increased costs, procedural complications, and anesthesia exposure. The aim of this study was to examine an office-based model using serial sedation-free blind esophageal epithelial brushing (BEEB) to monitor therapy response through eosinophil-derived neurotoxin (EDN) levels and guide therapy plans in pediatric EoE patients. METHODS: EoE patients (≤21 years of age) were enrolled in this prospective study. Subjects were placed on dietary, pharmacologic, or combination therapy with the goal of inducing or maintaining remission. To assess response to sequential interventions, subjects underwent sequential sedation-free BEEBs through nasogastric tubes to measure EDN levels. Based on serial brushings, an individual plan of diet, medications, or a combination of both was created for each subject, and a final endoscopy was then performed to validate the accuracy of the individual plans. RESULTS: Twenty-four subjects completed the study. The average peak eosinophil count in patients with active EoE was 58.1 ± 30.8 eosinophils per high-power field and mean EDN level was 165.2 ± 191.3 µg/mL. A total of 42 BEEBs were completed. Individual therapy plans based on sequential BEEB were accurate in 19 out of the 24 patients (79%) and specifically nine out of 10 patients (90%) treated with elimination diets. CONCLUSION: This study suggests that office-based sedation-free BEEBs can be used to monitor therapy response and disease activity in pediatric EoE patients.

The Relationship Between Eosinophilic Esophagitis and Immunotherapy.

Immunotherapy is a treatment approach based on the principle of incremental allergen exposure to achieve desensitization. Recently, oral immunotherapy has been introduced as a treatment of IgE-mediated food allergy. Some patients receiving oral immunotherapy for food allergy may develop eosinophilic esophagitis. Here, we summarize the literature examining this association, its treatment, and outcomes and discuss possible explanations for this clinical phenomenon. We further identify potential associations with aeroallergen sensitivity and other forms of immunotherapy including subcutaneous immunotherapy and sublingual immunotherapy. Finally, we discuss management of immunotherapy-induced eosinophilic esophagitis. Epicutaneous immunotherapy is highlighted as an area of therapeutic investigation.

An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission.

Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15+ macrophages, PRDM16+ dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of TH17 cells. Ligand-receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9+IL-4+IL-13+ TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4+ TRM cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.

Epidemiologic and Clinical Clues to the Etiology of Eosinophilic Esophagitis.

Despite the rising prevalence and incidence of eosinophilic esophagitis (EoE), the etiology and pathophysiology remain unknown. Studies to date suggest that complex interactions between genetic and environmental risk factors result in the development and presentation of disease. Examining environmental factors both in the early life and later life exposures offers potential clues for the development of EoE, although challenges exist in making causal inferences due to diagnostic delay and access, ascertainment biases, and misclassification of cases. The authors review studies supporting early life factors as etiologic factors in the development of EoE.

Pathophysiology and Clinical Impact of Esophageal Remodeling and Fibrosis in Eosinophilic Esophagitis.

Most of the major clinical signs and consequences of eosinophilic esophagitis seem to be related to tissue remodeling. Important data on remodeling activity in patients with eosinophilic esophagitis are provided by a range of current and new biologic markers and diagnostics. To completely clarify the possible advantages and restrictions of therapeutic approaches, clinical studies should take into consideration the existence and reversibility of esophageal remodeling. The degree of mucosal or submucosal disease activity may not be reflected by epithelial eosinophilic inflammation, which is used to define one criterion of disease activity".

Clinical Evaluation of the Child with Eosinophilic Esophagitis.

The diagnosis of eosinophilic esophagitis (EoE) is based on clinical symptoms of esophageal dysfunction and eosinophil predominant esophageal inflammation. Clinical symptoms in children with EoE vary based on age and may be nonspecific. EoE has a male predominance with the majority having comorbid atopic disorders. At present, treatment options include medications (proton pump inhibition, swallowed topical steroids), dietary therapy or biologic therapy (dupilumab, approved for those ≥12 years of age). Outside of EoE in the context of oral immunotherapy, EoE is typically chronic requiring lifelong therapy. Long-term complications including feeding difficulties, malnutrition, and fibrostenotic disease.

Pathophysiology of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, progressive immune-mediated disease associated with antigen-driven type 2 inflammation and symptoms of esophageal dysfunction. Research over the last 2 decades has dramatically furthered our understanding of the complex interplay between genetics, environmental exposures, and cellular and molecular interactions involved in EoE. This review provides an overview of our current understanding of EoE pathogenesis.

Clinical Evaluation of the Adult with Eosinophilic Esophagitis.

Adult patients with eosinophilic esophagitis (EoE) typically present with a history of dysphagia for solids, sometimes with additional reflux-like pain and a history of prior food impactions. In contrast to these alarming symptoms, the general appearance and physical examination of adult patients with EoE is in line with apparently healthy individuals. Therefore, the diagnosis is based on a history of solid-food dysphagia and eosinophilic tissue infiltration. Importantly, the increasing prevalence of EoE variants, that is, typical EoE symptoms in the absence of a relevant eosinophilia, and several studies with eosinophil-targeting drugs, call the pathogenic role of eosinophils into question.

Endoscopic Features of Eosinophilic Esophagitis.

Edema, rings, exudates, furrows, and strictures (EREFS) represent the major endoscopic features of eosinophilic esophagitis (EoE). The Endoscopic Reference System (EREFS) grading system is easy to learn and apply during daily clinical practice in the diagnosis and follow-up of EoE patients. When endoscopy is performed by an EoE-experienced physician, the EREFS criteria will identify the majority of EoE patients. The EREFS score from the area of greatest involvement of the esophagus should be reported. The EREFS grading system was formally validated as an endoscopy score and several randomized placebo-controlled trials have shown responsiveness of the EREFS score to therapeutic interventions.

Histopathology of Eosinophilic Esophagitis.

Microscopic examination of esophageal biopsies is essential to diagnose eosinophilic esophagitis (EoE). Eosinophil inflammation is the basis for the diagnosis, but additional abnormalities may contribute to persistent symptoms and epithelial barrier dysfunction. Both peak eosinophil count and assessments of additional features should be included in pre-therapy and post-therapy pathology reports. Pathologic abnormalities identified in esophageal biopsies of EoE are reversible in contrast to esophageal strictures.

Dietary Management of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated food allergy-driven disease characterized by eosinophilic inflammation of the esophagus leading to symptoms of esophageal dysfunction. Prior studies have supported the key role of food allergen exposure as the main driver behind the etiopathogenesis showing that removal of food antigens can result in disease remission in both children and adults. These landmark studies serve as the basis for the rising interest and evolution of dietary therapy in EoE. This article will focus on the rationale for dietary therapy in EoE and provide helpful tools for the implementation of dietary therapy in practice.

Recognition and Management of Feeding Dysfunction in the Pediatric Patient with Eosinophilic Esophagitis.

Feeding is a complex skill requiring coordination of multiple body systems. Multiple factors are considered in feeding dysfunction in pediatric patients with eosinophilic gastrointestinal disorders, including overall development, nutritional status, mealtime behaviors, and medical comorbidities. Symptoms of feeding dysfunction vary by age, with maladaptive learned feeding behaviors spanning all age ranges. Knowledge of the normal acquisition of feeding skills is critical to interpret the impact of the disease and plan appropriate intervention. Assessment and treatment from a feeding and swallowing disorders specialist can dramatically impact successful outcomes in nutrition, growth, mealtime dynamics and ultimatly quality of life for children and their caregivers in home and social settings.

Pathophysiology of Non-Esophageal Eosinophilic Gastrointestinal Disorders.

Eosinophilic gastrointestinal disorder (EGID) is an umbrella term encompassing a group of chronic, immune-mediated disorders characterized by eosinophil-rich inflammation affecting one or more segments of the gastrointestinal tract. A recent consensus in nomenclature and emerging data made possible through multi-center consortia are beginning to unravel the molecular and cellular underpinnings of EGIDs below the esophagus. These emerging findings are revealing both overarching commonalities related to a food allergen-driven, chronic, Th2-mediated immune response as well as location-specific nuances in the pathophysiology of the collective EGIDs. Altogether, these advances offer promise for improved diagnoses and more efficacious interventional strategies.

Role of Mast Cells in Eosinophilic Gastrointestinal Diseases.

Mast cells play a central role in the pathogenesis of eosinophilic gastrointestinal disorders (EGIDs), including eosinophilic esophagitis. Their interactions with immune and structural cells, involvement in tissue remodeling, and contribution to symptoms make them attractive targets for therapeutic intervention. More is being discovered regarding the intricate interplay of mast cells and eosinophils. Recent studies demonstrating that depletion of eosinophils is insufficient to improve symptoms of EGIDs have raised the question of whether other cells may play a role in symptomatology and pathogenesis of EGIDs.

Pharmacologic Management of Eosinophilic Esophagitis.

Proton pump inhibitors (PPIs), swallowed topical corticosteroids (STSs), and dupilumab are highly effective therapies for the treatment of eosinophilic esophagitis. Shared decision-making informs the choice of therapy and factors such as ease of use, safety, cost, and efficacy should be addressed. PPIs are the most common medication utilized early in the disease course; however, for nonresponders, STSs are an excellent alternative. Dupilumab is unlikely to replace PPIs or STSs as first-line therapy, except in highly specific circumstances. Identification of novel biologic pathways and the development of small molecules may lead to a wider range of treatment options in the future.

Associations of Eosinophilic Gastrointestinal Disorders with Other Gastrointestinal and Allergic Diseases.

Eosinophilic gastrointestinal disorders (EGIDs) are becoming more common causing significant suffering and reduced quality of life. These conditions can affect different parts of the digestive system, either individually or in combination. Recognition of their link to allergic disorders or other gastrointestinal (GI) diseases has raised questions about their shared underlying mechanisms, which has had implications for diagnosis and management. The authors critically examine the current understanding of the connection between EGIDs and allergic conditions (ie, atopic dermatitis, allergic rhinitis, asthma, and food allergy) and GI diseases (ie, inflammatory bowel disease, celiac disease, gastroesophageal reflux disease, and motility disorders).

Health-Related Quality of Life in Patients with Eosinophilic Esophagitis.

Measuring health-related quality of life (HRQOL) gained relevance in research and clinical practice in patients with eosinophilic esophagitis. The physical discomfort and social and psychological consequences of this food-related disease substantially affect HRQOL. Determinant of an impaired HRQOL include symptom severity, disease duration, biological disease activity, and psychological factors. Patients prioritize symptom relief and improved HRQOL as treatment objectives. Available treatment options can address these goals; however, there is a suboptimal adherence to treatment. There is a need for enhanced patient guidance and education. The assessment of HRQOL will help to prioritize patient's needs in management.