Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study.

Background: Eosinophilic esophagitis (EoE) and inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are immune-mediated gastrointestinal diseases with overlapped pathogenesis and are sometimes concurrently diagnosed, but their causal relationship remains unclear. We investigated the causal relationship between EoE and IBD and its subtypes via a two-sample bidirectional Mendelian randomization (MR) approach. Methods: MR analyses were performed using summary data of a genome-wide association study (GWAS) on individuals of European ancestry. Independent single-nucleotide polymorphisms correlated with EoE (from a GWAS meta-analysis containing 1,930 cases and 13,634 controls) and IBD (from FinnGen GWASs containing 9,083 IBD, 2,033 CD, and 5,931 UC cases, and GWASs of IBD genetic consortium containing 12,882 IBD, 6,968 UC, and 5,956 CD cases) were selected as instruments. We applied the inverse variance weighted (IVW) method as the primary analysis followed by several sensitivity analyses. For the forward MR study, estimates from IVW methods were subsequently meta-analyzed using a random-effect model. Results: Our results suggested a causal effect of EoE on IBD [pooled odds ratio (OR), 1.07; 95% confidence interval (CI), 1.02-1.13] and EoE on UC (pooled OR, 1.09, 95% CI, 1.04-1.14). No causal link between EoE and CD was observed (pooled OR, 1.05; 95% CI, 0.96-1.16). The reverse MR analyses revealed no causal effect of IBD (and its subtypes) on EoE. Sensitivity analyses confirmed the robustness of primary results. Conclusions: Our findings provided evidence of a suggestive causal effect of EoE on IBD (specifically on UC) in the European population. Increased awareness of concurrent or subsequent IBD in patients with EoE is called for. Still, the present evidence is not adequate enough and ought to be validated by further investigations.

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.

Causality of Helicobacter pylori infection on eosinophilic esophagitis and potential pathogenesis: a Mendelian randomization study.

Background: Observational studies have indicated a possible connection between Helicobacter pylori (H. pylori) infection and eosinophilic esophagitis (EoE), but their causal relationship has yet to be established. To investigate the causal associations between H. pylori infection and EoE, we performed a Mendelian randomization (MR) analysis. Methods: Firstly, we conducted both univariable and multivariable Mendelian randomization (MR) analyses. Furthermore, a two-step MR was carried out to ascertain the potential underlying pathways of these associations, particularly the involvement of inflammatory cytokines. We employed the inverse-variance weighted (IVW) method as the main analysis in our MR study. To enhance the credibility of the results, we also conducted several sensitivity analyses. Results: Our study demonstrated a noteworthy correlation between genetically predicted anti-H. pylori IgG antibody levels and a reduced risk of EoE (OR=0.325, 95% CI=0.165-0.643, P value=0.004, adj p value=0.009). No significant causal associations were detected between other H. pylori antibodies and EoE in our study. When it comes to multivariable MR analysis controlling for education attainment, household income, and deprivation individually, the independent causal impact of anti-H. pylori IgG on EoE persisted. Surprisingly, the two-step MR analysis indicated that inflammatory factors (IL-4, IL-5, IL-13, IL-17, and IFN-γ) did not appear to mediate the protective effect of H. pylori infection against EoE. Conclusion: Findings suggested that among the range of H. pylori-related antibodies, anti-H. pylori IgG antibody is the sole causal factor associated with protection against EoE. Certain inflammatory factors may not be involved in mediating this association. These findings make a significant contribution to advancing our understanding of the pathogenesis of EoE and its evolving etiology.

Helicobacter pylori infection found during upper endoscopy performed for the diagnosis of celiac, inflammatory bowel diseases, and eosinophilic esophagitis: A multicenter pediatric European study.

BACKGROUND: Helicobacter pylori may be found during upper gastrointestinal endoscopy (UGE) performed to diagnose celiac disease (CeD), inflammatory bowel disease (IBD), and eosinophilic esophagitis (EoE). We aimed to describe the frequency of H. pylori in children undergoing UGE for CeD, IBD, and EoE and the number of children receiving eradication treatment. MATERIALS AND METHODS: A retrospective multicenter study from 14 countries included pediatric patients diagnosed with CeD, IBD, and EoE between January 2019 and December 2021. DATA COLLECTED: age, gender, hematologic parameters, endoscopic, histologic, and H. pylori culture results, and information on eradication treatment. RESULTS: H. pylori was identified in 349/3890 (9%) children [167 (48%) male, median 12 years (interquartile range 8.1-14.6)]. H. pylori was present in 10% (173/1733) CeD, 8.5% (110/1292) IBD and 7.6% (66/865) EoE patients (p = NS). The prevalence differed significantly between Europe (Eastern 5.2% (28/536), Southern 3.8% (78/2032), Western 5.6% (28/513)) and the Middle East 26.6% (215/809) [odds ratio (OR) 7.96 95% confidence interval (CI) (6.31-10.1) p < 0.0001]. Eradication treatment was prescribed in 131/349 (37.5%) patients, 34.6% CeD, 35.8% IBD, and 56.1% EoE. Predictors for recommending treatment included erosions/ulcers [OR 6.45 95% CI 3.62-11.47, p < 0.0001] and nodular gastritis [OR 2.25 95% CI 1.33-3.81, p 0.003]. Treatment rates were higher in centers with a low H. pylori prevalence (<20%) [OR 3.36 95% CI 1.47-7.66 p 0.004]. CONCLUSIONS: Identifying H. pylori incidentally during UGE performed for the most common gastrointestinal diseases varies significantly among regions but not among diseases. The indications for recommending treatment are not well defined, and less than 40% of children received treatment.

Eosinophilic Esophagitis: A Review for the Primary Care Practitioner.

This chapter presents an overview of eosinophilic esophagitis (EoE) for the Primary Care Practitioner (PCP). The focus is on helping PCPs keep it in their differential diagnosis by discussing the spectrum of clinical presentations, how to screen for EoE in at-risk populations and subsequently manage the patient with this condition. The authors review epidemiology, risk factors and associated conditions, pathology, clinical presentation, diagnosis, and management options.

Swallowed topical steroid therapy for eosinophilic oesophagitis in children: practical, evidence-based guidance by the BSPGHAN Eosinophilic Oesophagitis Working Group.

OBJECTIVE: To develop evidence-based guidance for topical steroid use in paediatric eosinophilic oesophagitis (pEoE) in the UK for both induction and maintenance treatment. METHODS: A systematic literature review using Cochrane guidance was carried out by the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN) Eosinophilic Oesophagitis (EoE) Working Group (WG) and research leads to determine the evidence base for preparation, dosing and duration of use of swallowed topical steroid (STS) formulations in EoE. Seven themes relating to pEoE were reviewed by the WG, alongside the Cochrane review this formed the evidence base for consensus recommendations for pEoE in the UK. We provide an overview of practical considerations including treatment regimen and dosing. Oral viscous budesonide (OVB) and, if agreed by local regulatory committees, orodispersible budesonide (budesonide 1 mg tablets) were selected for ease of use and with most improvement in histology. A practical 'how to prepare and use' OVB appendix is included. Side effects identified included candidiasis and adrenal gland suppression. The use of oral systemic steroids in strictures is discussed briefly. RESULTS: 2638 citations were identified and 18 randomised controlled trials were included. Evidence exists for the use of STS for induction and maintenance therapy in EoE, especially regarding histological improvement. Using the Appraisal of Guidelines, Research and Evaluation criteria, dosing of steroids by age (0.5 mg two times per day <10 years and 1 mg two times per day ≥10 years) for induction of at least 3 months was suggested based on evidence and practical consideration. Once histological remission is achieved, maintenance dosing of steroids appears to reduce the frequency and severity of relapse, as such a maintenance weaning regimen is proposed. CONCLUSION: A practical, evidence-based flow chart and guidance recommendations with consensus from the EoE WG and education and research representatives of BSPGHAN were developed with detailed practical considerations for use in the UK.

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.

Circulating immunome fingerprint in eosinophilic esophagitis is associated with clinical response to proton pump inhibitor treatment.

Objectives: The aim of the study was to characterize the circulating immunome of patients with EoE before and after proton pump inhibitor (PPI) treatment in order to identify potential non-invasive biomarkers of treatment response. Methods: PBMCs from 19 healthy controls and 24 EoE patients were studied using a 39-plex spectral cytometry panel. The plasmacytoid dendritic cell (pDC) population was differentially characterized by spectral cytometry analysis and immunofluorescence assays in esophageal biopsies from 7 healthy controls and 13 EoE patients. Results: Interestingly, EoE patients at baseline had lower levels of circulating pDC compared with controls. Before treatment, patients with EoE who responded to PPI therapy had higher levels of circulating pDC and classical monocytes, compared with non-responders. Moreover, following PPI therapy pDC levels were increased in all EoE patients, while normal levels were only restored in PPI-responding patients. Finally, circulating pDC levels inversely correlated with peak eosinophil count and pDC count in esophageal biopsies. The number of tissue pDCs significantly increased during active EoE, being even higher in non-responder patients when compared to responder patients pre-PPI. pDC levels decreased after PPI intake, being further restored almost to control levels in responder patients post-PPI. Conclusions: We hereby describe a unique immune fingerprint of EoE patients at diagnosis. Moreover, circulating pDC may be also used as a novel non-invasive biomarker to predict subsequent response to PPI treatment.

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.

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.

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.

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.