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.

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.

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.

Sublingual immunotherapy for cedar pollinosis possibly triggers eosinophilic esophagitis.

Sublingual immunotherapy (SLIT) is an effective and popular treatment for cedar pollinosis. Although SLIT can cause allergic side effects, eosinophilic esophagitis (EoE) is a lesser-known side effect of SLIT. A 26-year-old male with cedar pollinosis, wheat-dependent exercise-induced anaphylaxis, and food allergies to bananas and avocados presented with persistent throat itching, difficulty swallowing, heartburn, and anterior chest pain 8 days after starting SLIT for cedar pollinosis. Laboratory examination showed remarkably elevated eosinophils, and esophagogastroduodenoscopy revealed linear furrows in the entire esophagus. Histological examination of an esophageal biopsy specimen revealed high eosinophil levels. The patient was strongly suspected with EoE triggered by SLIT. The patient was advised to switch from the swallow to the spit method for SLIT, and the symptoms associated with SLIT-triggered EoE were reduced after switching to the spit method. This case highlights the importance of recognizing SLIT-triggered EoE as a potential side effect of SLIT for cedar pollinosis, especially with the increasing use of SLIT in clinical practice. EoE can occur within a month after initiating SLIT in patients with multiple allergic conditions, as observed in our case. Furthermore, the spit method should be recommended for patients who experience SLIT-triggered EoE before discontinuing SLIT.

Eosinophilic esophagitis as a side-effect of allergen immunotherapy: protocol for a systematic review and meta-analysis.

Summary: Background. Sensitization to food and airborne allergens is common in the majority of patients with eosinophilic esophagitis (EoE). Although there is not a direct cause-effect relationship of IgE-mediated allergy with the pathogenesis of EoE, there is a growing evidence that oral desensitization to food and sublingual immunotherapy (SLIT) may induce the development of EoE as an adverse effect. As part of the 'EoE and Allergen Immunotherapy (AIT)' Task Force funded by the European Academy of Allergy and Clinical Immunology (EAACI), a systematic approach will be followed to review the evidence from the published scientific literature on the development of EoE in children and adults under any type of AIT. Methods. This systematic review will be carried out following the PRISMA statement guidelines. Studies will be assessed for inclusion in the review according to the Population-Interventions-Comparators-Outcomes (PICO) criteria. Results. Expected outcomes will provide evidence on the AIT-EoE development connection. Conclusions. The findings from this review will be used as a reference to provide useful guidelines for physicians treating patients with EoE and/or are practicing AIT.

Barrier Dysfunction in Eosinophilic Esophagitis.

PURPOSE OF REVIEW: Compelling evidence over the past decade supports the central role of epithelial barrier dysfunction in the pathophysiology of eosinophilic esophagitis (EoE). The purpose of this review is to summarize the genetic, environmental, and immunologic factors driving epithelial barrier dysfunction, and how this impaired barrier can further promote the inflammatory response in EoE. RECENT FINDINGS: Common environmental exposures, such as detergents, may have a direct impact on the esophageal epithelial barrier. In addition, the effects of IL-13 on barrier dysfunction may be reduced by 17ß-estradiol, Vitamin D, and the short chain fatty acids butyrate and propionate, suggesting novel therapeutic targets. There are many genetic, environmental, and immunologic factors that contribute to epithelial barrier dysfunction in EoE. This leads to further skewing of the immune response to a "Th2" phenotype, alterations in the esophageal microbiome, and penetration of relevant antigens into the esophageal mucosa, which are central to the pathophysiology of EoE.

Food-induced immediate response of the esophagus in pediatric eosinophilic esophagitis.

BACKGROUND: Food-induced immediate response of the esophagus (FIRE) is a new phenomenon that has been described in eosinophilic esophagitis (EoE) patients. It is suspected when unpleasant symptoms occur suddenly on contact of the triggering food with the esophageal surface and recur with repeated exposures. It can often be mistaken for pollen-food allergy syndrome (PFAS) and solid food dysphagia. Data on FIRE is limited to one survey study and case reports, and there are no screening studies conducted on either adults or children with EoE. In this study, we aimed to screen children aged ≥7 years old with EoE for FIRE. METHODS: Demographic data were collected from medical records. A questionnaire about FIRE was applied to all participants. Skin prick tests were done on suspected patients to identify the triggering foods. FIRE is defined as suitable clinical symptoms with suspected food allergen exposure. RESULTS: A total of 78 patients (74.4% male, median age: 13.5 years) were included. Unpleasant and recurrent symptoms distinct from dysphagia with specific foods were reported in 16.7% of the patients, all of whom had concomitant allergic rhinitis (AR). The symptoms described by almost all patients were oropharyngeal itching and tingling (PFAS: 15.3%) excluding only one patient reporting retrosternal narrowing and pressure after specific food consumption (FIRE: 1.2%). CONCLUSIONS: Although definitive conclusions regarding the true prevalence of FIRE cannot be made, it does not seem to be common as PFAS. However, it deserves questioning particularly in the presence of concurrent AR and/or PFAS in children with EoE.

Ethical Implications of Continuing Oral Immunotherapy After the Development of Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease requiring maintenance therapy. Traditionally, EoE has been a contraindication to oral immunotherapy (OIT) and a rationale for discontinuing treatment because OIT may induce EoE. Most, but not all patients with OIT-induced EoE experience symptom resolution and histologic remission after discontinuing OIT. Recent studies report OIT continuation even after EoE onset, despite the previously accepted standard of care. This creates clinical as well as ethical challenges for allergists treating these patients. Considering the published literature on EoE and OIT and the primary medical ethics principles of beneficence, nonmaleficence, autonomy, and justice, we discuss the ethical implications of pursuing desensitization despite the potential complications associated with EoE. When ethical principles are in opposition, shared decision-making should be employed to determine whether OIT should be continued after an EoE diagnosis. This article highlights the ethical dilemmas allergists face when determining whether patients with a diagnosis of EoE should continue OIT.

Early life exposures as risk factors for non-esophageal eosinophilic gastrointestinal diseases.

OBJECTIVES: Early life exposures increase risk of eosinophilic esophagitis (EoE), but it is unknown whether they contribute to increased risk for non-EoE eosinophilic gastrointestinal diseases (EGIDs). We aimed to assess the association between prenatal, antenatal, and early life factors and non-EoE EGIDs. METHODS: We conducted a case-control study based in EGID Partners, an online patient-centered research network. Adults (≥18 years) with non-EoE EGIDs, caregivers of children <18 years of age with an EGID, and non-EGID adult controls were eligible. Subjects completed our Early Life Exposure Questionnaire, detailing maternal and early childhood exposures. We assessed for associations between non-EoE EGIDs and early life exposures, focusing on exposures previously evaluated in association with EoE. RESULTS: We analyzed 61 non-EoE EGID cases and 20 controls. Of the EGID cases, 14 had eosinophilic gastritis, 19 had eosinophilic enteritis, 6 had eosinophilic colitis, and 22 had multiple areas affected; additionally, 30 had esophageal involvement. Relative to controls, EGID cases were more likely to have had antenatal/perinatal pregnancy-related complications (43% vs 13%; p = 0.02), NICU admission (20% vs 0%; p = 0.03), and antibiotics in infancy (43% vs 10%; p = 0.01). With adjustment for age at diagnosis, we observed increased odds of an EGID for pregnancy complications (aOR 3.83; 95% CI: 0.99-14.9) and antibiotic use in infancy (aOR 7.65; 95% CI: 1.28-45.7). CONCLUSIONS: Early life factors, including pregnancy complications, NICU admission, and antibiotics in infancy, were associated with development of non-EoE EGIDs. The impact of early life exposures on non-EoE EGID pathogenic mechanisms should be investigated.

Description of allergic phenotype in patients with eosinophilic oesophagitis: management protocol proposal.

There is a profile of patient with eosinophilic oesophagitis and atopic background, marked by the existence of IgE-mediated sensitizations. Our aim is to report the observed sensitivities to environmental and food allergens and panallergens in patients with eosinophilic oesophagitis with atopic background as well as characterizing other markers or analytical parameters. We suspect that the prevalence of sensitization to panallergens will be high and this will probably be relevant in terms of the onset and clinical course of the disease. We collated clinical and analytical data from 160 adult patients with a reported diagnosis of eosinophilic oesophagitis. These patients were studied between 1 January 2012 and 31 December 2020. During an initial visit skin tests were performed with full batteries of routine aero-allergens and foodstuffs. Patients were subsequently referred for blood test and determination of specific IgE, blood count and total IgE (in all cases), as well as eosinophilic cation protein and IMMUNOISAC in the centres in which this was available. We were able to detect a broad spectrum of sensitizations to environmental, foodstuffs and panallergens. The most common allergic disease was rhinoconjuntivitis. The sensitizations observed to foodstuffs were atypical for the adult population and were not responsible for manifestations compatible with immediate allergy. An important percentage of patients presented seasonal worsening of choking symptoms. We should be able to identify patients with eosinophilic oesophagitis and atopic background. Identifying this phenomenon would enable giving dietary and environmental recommendations as well as more specific and effective treatments to our patients.

Oral Immunotherapy and Risk of Eosinophilic Esophagitis in Children: 15 Years' Experience.

OBJECTIVES: Oral immunotherapy (OIT) is an effective treatment for children with persistent food allergy, and has concerns about its safety, including eosinophilic esophagitis (EoE). The aim of this study was to evaluate the prevalence of EoE in a large cohort of children who underwent OIT in our center, and to determine if there were any clinical, endoscopic, or histologic differences depending on the food employed for the OIT. METHODS: A retrospective study was performed over a 15-year period (2005-2020). Children who underwent cow's milk (CM), egg, and/or peanut OIT and developed EoE were included. RESULTS: Six hundred and seven OIT were carried out (277 CM-OIT, 322 egg-OIT, and 8 peanut-OIT). Seventeen patients (2.8%) had a confirmed histologic diagnosis of EoE with a higher prevalence for patients who underwent CM-OIT (3.9%) than egg-OIT (2.2%). Symptoms suggestive of EoE and a confirmed diagnosis occurred at median times of 25 and 36 months, respectively, after the build-up phase of the OIT was completed. Choking, abdominal pain, and dysphagia were the most frequent symptoms and lamina propria fibrosis was observed in 41.2% of patients. No significant differences in clinical symptoms, endoscopic, or histologic findings between patients under CM or egg-OIT were found. One-third of patients reported mild symptoms suggestive of EoE before the OIT. CONCLUSIONS: EoE appears to be a rare but important adverse event that can occur even years after OIT. Validated questionnaires to screen EoE before the OIT and in the follow-up of these patients may be the main tool for an early diagnosis.

Psychological Considerations for Food Intolerances: Celiac Sprue, Eosinophilic Esophagitis, and Non-Celiac Gluten Sensitivity.

Several chronic digestive conditions are physiologically based on food intolerance, including celiac disease, nonceliac gluten sensitivity, and eosinophilic esophagitis. Patients are expected to follow medically prescribed diets to eliminate identified food triggers to control symptoms. However, the psychological impacts of these dietary approaches are largely unaddressed in clinical practice. Hypervigilance and anxiety regarding food and symptoms, and disordered eating, may emerge and negatively affect outcomes. Clinicians working with pediatric and adult populations with food intolerances should be aware of these psychological comorbidities, and equally emphasize effective ways to help patients manage the mental and physical aspects of their condition.

Eosinophilic Esophagitis: The Role of Environmental Exposures.

Eosinophilic esophagitis (EoE) is a chronic, non-IgE immune-mediated reaction characterized by eosinophilic infiltration leading to esophageal dysfunction, inflammation, and potential for fibrotic remodeling. Although food allergens are generally considered the leading trigger for EoE, emerging evidence suggests that modifiable environmental factors may also play a role in the pathogenesis of EoE. This article discusses the latest data regarding the role of the exposome, microbiome, and environmental allergens on the development and ongoing inflammation of EoE, focusing on the last 10 years of relevant studies.

Eosinophilic Esophagitis due to Aeroallergens: A Systematic Review and Update.

Eosinophilic esophagitis is a chronic antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by TH2 inflammation (at least 15 eosinophils/high power field) when other secondary systemic and local causes of esophageal eosinophilia are excluded. Although this disease was initially ascribed to a delayed reaction to food allergens, emerging evidence suggests that aeroallergens may also play a role in pathogenesis and disease course. Some studies support seasonal variations in the diagnosis of eosinophilic esophagitis and disease exacerbations owing to the increase in aeroallergens to which patients are sensitized. It is also known that this disease can be caused by extensive, identifiable exposure to aeroallergens and after treatment with specific immunotherapy based on food or aeroallergens. It was recently postulated that treatment of allergic rhinoconjunctivitis can improve the symptoms of eosinophilic esophagitis, although data are limited to case reports and small series. Currently, biomarkers and biologic therapies are not helpful for diagnosis or inducing clinical and histological remission of the disease. Nevertheless, there are high hopes for dupilumab. This review aims to give visibility to the involvement of aeroallergens in the triggering and exacerbation of eosinophilic esophagitis, since many of them, in addition to being airborne and inhalant, can also be ingested as food. Clearly, we must try to identify the cause of the disease to ensure remission.

Models and Tools for Investigating Eosinophilic Esophagitis at the Bench.

Eosinophilic esophagitis (EoE) is an increasingly common food allergy disease of the esophagus that received its medical designation code in 2008. Despite this recency, great strides have been made in the understanding of EoE pathophysiology and type 2 immunity through basic and translational scientific investigations conducted at the bench. These advances have been critical to our understanding of disease mechanisms and generating new hypotheses, however, there currently is only one very recently approved FDA-approved therapy for EoE, leaving a great deal to be uncovered for patients with this disease. Here we review some of the innovative methods, models and tools that have contributed to the advances in EoE discovery and suggest future directions of investigation to expand upon this foundation.

Eosinophilic esophagitis an update in children.

Eosinophilic esophagitis (EoE) is an emerging antigen-mediated, inflammatory disease of unknown etiology. EoE affects about 1/2,000 patients in the United States (US), with a higher prevalence rate in adults (43.4/100,000) than in children (29.5/100,000), prevailing in Caucasians and male sex. EoE is a multifactorial disease typically characterized by type 2 inflammation. Pathogenesis is not entirely understood and is likely non-IgE mediated. Food allergens trigger EoE, stimulating the dysregulated immune cells through an impaired esophageal epithelial barrier. Clinical presentation of EoE depends on age and mainly includes food refusal, vomiting, abdominal or chest pain, dysphagia, and food impaction. Endoscopy is the gold standard to diagnose EoE. The goal of EoE therapy is to achieve clinical and histological remission to prevent esophageal fibrosis and improve patients' quality of life (QoL). Cornerstones of therapy are PPIs, topical steroids, and elimination diets. Over recent decades, research progress has been made in terms of a greater understanding of the EoE pathogenesis and new therapeutic approaches. However, there are still several unmet needs, such as non-invasive tools and biomarkers for monitoring the disease.

The microbiota in eosinophilic esophagitis: A systematic review.

Eosinophilic esophagitis (EoE) is an atopic disease of the esophagus that has shown a significant increase in incidence and prevalence in the last 20 years. The etiology of EoE is unclear, and few studies explore the esophageal microbiota in EoE. The local microbiome has been implicated in the pathogenesis of several allergic and inflammatory diseases, such as asthma and eczema. In this study, we performed a systematic review to evaluate differences in the microbiota profile of patients with EoE compared with controls. MEDLINE, Embase, Cochrane Library, Scopus, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) databases were searched to identify studies investigating the microbiota composition in EoE. Three reviewers screened the articles for eligibility and quality. Seven articles underwent full-text review, and a narrative synthesis was undertaken. The microbiota of the mouth and esophagus are correlated. Patients with active EoE present increased esophageal microbial load and increased abundance in particular species, such as Haemophilus and Aggregatibacter. On the other hand, EoE patients present a decrease in Firmicutes. High microbial load and abundance of Haemophilus are observed in EoE patients, but little evidence exists to demonstrate their influence on inflammation and disease. Understanding microbial signatures in EoE might contribute to the development of novel therapeutic strategies.