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.

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.

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.

Embracing Diversity, Equity, Inclusion, and Accessibility in Eosinophilic Gastrointestinal Diseases.

Eosinophilic gastrointestinal diseases (EGIDs) including eosinophilic esophagitis (EoE) are rare diseases in which eosinophils abnormally infiltrate the gastrointestinal tract. Because these are rare diseases, there is limited information regarding race and ethnicity in EGIDs and even less is known about the impact of socioeconomic factors. There is some evidence that access to care in rural settings may be affecting epidemiologic understanding of EGIDs in the pediatric populations. Future work should try to evaluate bias in research and strive for representation in clinical trials and medicine.

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.

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).

Prevalence of eosinophilic gastrointestinal diseases in children with short bowel syndrome: A single center study.

Patients with short bowel syndrome (SBS) have multiple risk factors for eosinophilic gastrointestinal diseases (EGIDs) including increased risk for intestinal dysbiosis and food allergy compared to their counterparts with normal anatomy. However, there is limited data on the prevalence of EGIDs in children with SBS. We aimed to define the prevalence of EGIDs in an SBS cohort and its association with different risk factors via a retrospective chart review of patients with SBS at Children's National Hospital. The prevalence of eosinophilic esophagitis in our SBS cohort was 10%, eosinophilic gastritis was 4.9%, and eosinophilic enteritis was 4.9%. SBS patients with history of allergy or atopy were more likely to have esophageal and intestinal eosinophilia on biopsy than patients without allergy. The prevalence of EGIDs in our SBS cohort is significantly higher than in the general population and may be associated with allergic polarization.

La infección por Helicobacter pylori se asocia con disminución del riesgo de esofagitis eosinofílica en pacientes mexicanos / Helicobacter pylori infection is associated with decreased odds for eosinophilic esophagitis in Mexican patients

Objetivos La incidencia de la esofagitis eosinofílica (EEo) está aumentando en algunas regiones del mundo. Estudios retrospectivos han encontrado asociación inversa con la infección por Helicobacter pylori (H. pylori). Un estudio prospectivo reciente ha cuestionado esta relación. Por lo que buscamos evaluar esta relación en pacientes mexicanos. Pacientes y métodos Evaluamos pacientes adultos sin erradicación previa de la infección por H. pylori. Los casos se definieron por la presencia de síntomas esofágicos y > 15 eosinófilos/campo de alto poder (CAP) en biopsias de esófago. Los controles, por la presencia de < 15 eosinófilos/CAP. La infección por H. pylori se estableció por histología. Los pacientes fueron pareados por edad y género, asignando cuatro controles por caso. Resultados Se incluyeron 190 pacientes: 38 casos y 152 controles. Los casos tuvieron mayor frecuencia de atopia, disfagia, impactación alimentaria, eosinofilia periférica y anormalidades endoscópicas de EEo. La prevalencia de la infección por H. pylori fue de 63,6%. Los casos tuvieron prevalencia significativamente menor que los controles (36,8 vs. 70,4%, odds ratio (OR) 0,21, intervalo de confianza (IC) 95% 0,08-0,69, p = 0,001). Los pacientes atópicos tuvieron menor prevalencia en comparación con aquellos sin atopia: 13,1 vs. 50,5% (OR 0,20, IC 95% 0,06-0,69, p < 0,001), particularmente con rinitis alérgica y alergia alimentaria. Conclusiones Observamos una relación inversa entre la infección por H. pylori y EEo así como con atopia. Se necesitan estudios en modelos experimentales de EEo que clarifiquen el papel del H. pylori en esta interacción, así como estudios robustos que incluyan otros factores que puedan influir en esta relación (socioeconómicos, culturales, microbiota, etc.) (AU)

Background The incidence of eosinophilic esophagitis (EoE) is increasing in some regions of the world. Retrospective studies have found an inverse association with Helicobacter pylori infection (H. pylori). A recent prospective study has questioned this relationship. We aimed to evaluate this relationship in Mexican patients. Patients and methods We evaluated adult patients without prior eradication of H. pylori. Cases were defined by the presence of esophageal symptoms and >15 eosinophils/high power field (HPF) in the esophageal biopsy. Controls were defined by the presence of <15 eosinophils/HPF in esophageal biopsy. H. pylori infection was defined by histology. Patients were matched by age and gender assigning four controls per case. Results We included 190 patients: 38 cases and 152 controls. Cases had higher frequency of atopy, dysphagia, food impaction, peripheral eosinophilia, and endoscopic EoE abnormalities. The overall prevalence of H. pylori was 63.6%. Cases had significantly lower prevalence of H. pylori than controls (36.8% vs. 70.4%, OR 0.21 95% CI 0.08–0.69, p = 0.001). Atopic patients had lower prevalence of H. pylori than non-atopic: 13.1% vs. 50.5% (OR 0.20, 95% CI 0.06–0.69, p < 0.001), particularly allergic rhinitis and food allergy. Conclusions We observed an inverse relationship between H. pylori and EoE as well as atopy. Studies in experimental models of EoE that clarify the role of H. pylori in this interaction are required, as well as robust studies that include other factors (socioeconomic, cultural, microbiota, etc.) in order to clarify this relationship (AU)

Sleep, Anxiety, Somatization, Quality of Life, and Resilience in Pediatric Patients With Eosinophilic Esophagitis.

INTRODUCTION: Emerging evidence suggests a high burden of psychosocial comorbidities in patients with eosinophilic esophagitis (EoE), although factors associated with this burden have not been explored. We aimed to increase understanding of the psychosocial burden of EoE and assess factors that are associated with disease burden. METHODS: We conducted a cross-sectional study of patients with EoE (n = 87) recruited from a single-center, multidisciplinary pediatric eosinophilic gastrointestinal disorders clinic (2019-2021). Participants (aged 8-18 years) completed validated assessments during routine clinic visit to assess EoE symptoms (Pediatric Eosinophilic Esophagitis Symptom Score version 2.0), quality of life (Pediatric Quality of LIfe- Eosinophilic Esophagitis), anxiety state and trait (State-Trait Anxiety Score for Children), somatization (Child Somatic Symptoms Inventory 24), sleep disordered breathing (Pediatric Sleep Questionnaire) and, in a subset (n = 35), resilience (Connor Davidson Resilience Scale). Clinical and demographic data were collected. RESULTS: Participants were at a mean (SD) age of 12.8 (3.1) years, and 26% (n = 23) were female. Shorter disease duration (6-12 months) was associated with higher symptom burden ( P = 0.03), somatization ( P < 0.01), and anxiety (State-Trait Anxiety Score for Children Trait P < 0.01) scores. Participants with neurodevelopmental comorbidities had higher anxiety trait, somatization, sleep disordered breathing, and lower quality of life ( P < 0.01 for all). Symptom burden was significantly associated with increased somatic symptoms (adjusted ß [aß] = 0.34; 95% confidence interval 0.23-0.45) and decreased quality of life (aß = -0.42; 95% confidence interval -0.59 to -0.25) but not state anxiety, trait anxiety, or disordered sleep breathing. DISCUSSION: Pediatric patients with a recent diagnosis of EoE can experience higher EoE symptoms, somatization, and anxiety when compared with those with a longer-standing diagnosis. Patients earlier in their diagnosis and with neurodevelopmental disorders may experience increased somatization and anxiety that may warrant additional support services.

A retrospective cohort study on oesophageal food bolus obstruction in the North Denmark region in 2021-two thirds were never diagnosed with a cause.

BACKGROUND: Food bolus obstruction (FBO) leading to hospital treatment is often associated with eosinophilic oesophagitis (EoE), stenosis, or oesophageal cancer (1). Danish national guidelines recommend that patients with FBO undergo a diagnostic upper endoscopy within two weeks of presentation to exclude possible malignancy, and histological evaluation of eight biopsies (2, 3). AIMS: The aims of this study were to (1) report the incidence and describe the causes and treatment of FBO in the North Denmark Region (NDR), (2) determine the proportion of patients who underwent upper endoscopy and biopsy according to regional and national guidelines, and (3) identify International Classification of Diseases 10th Revision (ICD-10) diagnosis and procedure codes applied to the hospital visits due to FBO in the NDR. METHODS: Among all acute hospital visits in the NDR in 2021, all visits with ICD-10 codes possibly reflecting FBO, as well as a random sample of 14,400 visits with unspecific ICD-10 codes (R and Z codes), were screened manually for possible FBO. Diagnosis, follow-up, and treatment of all patients with FBO were recorded. RESULTS: The median patient age was 66.0 (Q1-Q3: 49.8-81.0) years, and half of the patients had experienced FBO before. Two thirds of patients (66.0%) were never diagnosed with a cause of FBO, followed by 17.3% with EoE. 30% of patients did not undergo upper endoscopy within two weeks of the hospital visit, and 50.7% were never biopsied in the oesophagus. Of 1886 hospital visits with registry ICD-10 codes that possibly reflected FBO, 8.4% were due to FBO, while FBO was present in 0.028% of the random sample of unspecific ICD-10 codes. CONCLUSIONS: Most hospitalized FBO patients in the NDR in 2021 were never diagnosed with a cause. In these patients there is a high risk of overlooked EoE or upper gastrointestinal cancers. The area needs immediate focus and changed routines to improve treatment and prevent new FBO.

Prevalence of Esophageal Eosinophilia, Eosinophilic Esophagitis, and Lymphocytic Gastritis in Children with Celiac Disease: A Saudi Tertiary Center Experience.

Background: Celiac disease (CD) is an immune-mediated enteropathy that has been associated with other immune-related gastrointestinal disorders, such as eosinophilic esophagitis (EoE) and lymphocytic gastritis (LG). To our knowledge, this is the first study in Saudi Arabia that has described such an association. Aim: To evaluate the prevalence of EoE and LG in children and adolescents with CD. Methods: This was a retrospective cross-sectional study of all pediatric patients (aged 0-18 years) with CD following up at King Abdulaziz University Hospital, between January, 2014, and December, 2021. The study examined clinical, demographic, endoscopic, and histopathological data. Results: Seventy-five patients with CD were included in the analysis. The median age was 12 years (range, 2-18 years). Male constituted 54.7% of the overall cohort (n = 41). The most common clinical symptoms were short stature (54.7%), weight loss (34.7%), abdominal pain (33.3%), abdominal distension (29.3%), anorexia (29.3%), diarrhea (24%), and vomiting (21.3%). The esophageal biopsy results reported were basal cell hyperplasia in 24 patients (32.9%), esophageal eosinophilia in 23 patients (31.5%), and EoE in 3 patients (4.1%). The gastric biopsy results were normal in 40 patients (53.3%). The most common abnormality was chronic inactive gastritis with no Helicobacter pylori (HP) infection (16%). LG was found in 3 patients (4%). Conclusions: The prevalence of EoE in this cohort of patients with CD was lower than the prevalence recorded in a number of other studies. Further studies are needed to determine the effects of a gluten-free diet (GFD) on EOE and LG.

A Comprehensive Global Population-Based Analysis on the Coexistence of Eosinophilic Esophagitis and Inflammatory Bowel Disease.

BACKGROUND: We explored inflammatory bowel disease (IBD) and eosinophilic esophagitis (EoE) coexistence using a global dataset. Investigating their epidemiology, risks, and impact, we aimed to enhance the understanding of concurrent diagnoses and patient outcomes. METHODS: A retrospective population-based cohort study was conducted using deidentified patient data from the TriNetX database (2011-2022). We estimated the incidence and prevalence of EoE in patients with IBD, including both Crohn's disease (CD) and ulcerative colitis (UC), and vice versa. Risks of select immune-mediated conditions and disease complications were compared among patients with EoE, IBD, or concurrent diagnoses. RESULTS: Our results included 174,755 patients with CD; 150,774 patients with UC; and 44,714 patients with EoE. The risk of EoE was significantly higher among patients with CD (prevalence ratio [PR] 11.2) or UC (PR 8.7) compared with individuals without IBD. The risk of IBD was higher in patients with EoE (CD: PR 11.6; UC: PR 9.1) versus those without EoE. A propensity-matched analysis of IBD patients revealed that, when comparing patients with and without EoE, the relative risk of immune-mediated comorbidities was significantly greater for celiac disease, IBD-related inflammatory conditions, eczema and asthma (CD: n = 1896; UC: n = 1231; p < 0.001). Patients with a concurrent diagnosis of EoE and IBD had a higher composite risk of IBD-related complications (CD: adjusted HR (aHR) 1.14, p < 0.005; UC: aHR 1.17, p < 0.01) and lower risk of food bolus impaction (aHR 0.445, p = 0.0011). CONCLUSION: Simultaneous EoE and IBD increased IBD-related complications risk, needing more treatment (glucocorticoids, biologic therapy, abdominal surgery), while reducing EoE-related issues like food bolus impaction.

Helicobacter pylori infection is associated with decreased odds for eosinophilic esophagitis in Mexican patients. / La infección por Helicobacter pylori se asocia con disminución del riesgo de esofagitis eosinofílica en pacientes mexicanos.

BACKGROUND: The incidence of eosinophilic esophagitis (EoE) is increasing in some regions of the world. Retrospective studies have found an inverse association with Helicobacter pylori infection (H. pylori). A recent prospective study has questioned this relationship. We aimed to evaluate this relationship in Mexican patients. PATIENTS AND METHODS: We evaluated adult patients without prior eradication of H. pylori. Cases were defined by the presence of esophageal symptoms and >15 eosinophils/high power field (HPF) in the esophageal biopsy. Controls were defined by the presence of <15 eosinophils/HPF in esophageal biopsy. H. pylori infection was defined by histology. Patients were matched by age and gender assigning four controls per case. RESULTS: We included 190 patients: 38 cases and 152 controls. Cases had higher frequency of atopy, dysphagia, food impaction, peripheral eosinophilia, and endoscopic EoE abnormalities. The overall prevalence of H. pylori was 63.6%. Cases had significantly lower prevalence of H. pylori than controls (36.8% vs. 70.4%, OR 0.21 95% CI 0.08-0.69, p = 0.001). Atopic patients had lower prevalence of H. pylori than non-atopic: 13.1% vs. 50.5% (OR 0.20, 95% CI 0.06-0.69, p < 0.001), particularly allergic rhinitis and food allergy. CONCLUSIONS: We observed an inverse relationship between H. pylori and EoE as well as atopy. Studies in experimental models of EoE that clarify the role of H. pylori in this interaction are required, as well as robust studies that include other factors (socioeconomic, cultural, microbiota, etc.) in order to clarify this relationship.

Eosinophilic esophagitis is associated with increased risk of later inflammatory bowel disease in a nationwide Swedish population cohort.

BACKGROUND: Earlier studies on the possible association between eosinophilic esophagitis (EoE) and inflammatory bowel disease (IBD) have been contradictory. METHODS: Patients with biopsy-verified EoE diagnosed between 1990 and 2017 in Sweden (n = 1587) were age- and sex-matched with up to five general population reference individuals (n = 7808). EoE was defined using pathology reports from all 28 pathology centers in Sweden (the ESPRESSO study). Multivariate Cox regression then estimated hazard ratios for future IBD. IBD was defined based on the international classification of disease codes and histopathology codes. In secondary analyses, sibling comparators were used to further reduce potential familial confounding. Additionally, we performed logistic regression examining earlier IBD in EoE. RESULTS: During follow-up until 2020, 16 (0.01%) EoE patients and 21 (0.003%) general population reference individuals diagnosed with IBD, corresponding to a 3.5-fold increased risk of future IBD (aHR = 3.56; 95% CI 1.79-7.11). EoE was linked to Crohn's disease (aHR = 3.39 [95% CI 1.02-9.60]) but not to ulcerative colitis (aHR = 1.37; 95% CI 0.38-4.86). Compared to their siblings, patients with EoE were at a 2.48-fold increased risk of IBD (aHR = 2.48; 95% CI 0.92-6.70). Earlier IBD was 15 times more likely in EoE patients than in matched reference individuals (odds ratio, 15.39; 95% CI 7.68-33.59). CONCLUSION: In this nationwide cohort study, EoE was associated with a 3.5-fold increased risk of later IBD diagnosis. This risk increase may be due to shared genetic or early environmental risk factors, but also surveillance bias could play a role.

Achalasia is Strongly Associated With Eosinophilic Esophagitis and Other Allergic Disorders.

BACKGROUND & AIMS: Achalasia has been assumed to be an autoimmune disease targeting esophageal myenteric neurons. Recently, we proposed an alternative hypothesis that achalasia sometimes might be allergy-driven, caused by a form of eosinophilic esophagitis (EoE) in which activated eosinophils and/or mast cells infiltrating esophageal muscle release products that disrupt motility and damage myenteric neurons. To seek epidemiologic support for this hypothesis, we identified patients with achalasia in the Utah Population Database, and explored their frequency of having EoE and other allergic disorders. METHODS: We used International Classification of Diseases codes to identify patients with achalasia and allergic disorders including EoE, asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, hives/urticaria, and anaphylaxis. We calculated relative risk (RR) for each allergic disorder by comparing the number observed in patients with achalasia with the expected number in individuals matched for birthyear and sex, and we performed subanalyses for patients age ≤40 versus age >40 years. RESULTS: Among 844 patients with achalasia identified (55% female; median age at diagnosis, 58 years), 402 (47.6%) had ≥1 allergic disorder. Fifty-five patients with achalasia (6.5%) had EoE (1.67 EoE cases expected), for a RR of 32.9 (95% confidence interval, 24.8-42.8; P < .001). In 208 patients with achalasia age ≤40 years, the RR for EoE was 69.6 (95% confidence interval, 46.6-100.0; P < .001). RR also was increased significantly for all other allergic disorders evaluated (all greater than 3-fold higher than population rates). CONCLUSIONS: Achalasia is strongly associated with EoE and other allergic disorders. These data support the hypothesis that achalasia sometimes might have an allergic etiology.

Histological Phenotyping in Eosinophilic Esophagitis: Localized Proximal Disease Is Infrequent but Associated with Less Severe Disease and Better Disease Outcome.

INTRODUCTION: It is still unknown whether eosinophilic esophagitis (EoE) patients with localized disease are different from those with extended disease. METHODS: We evaluated prospectively included patients in the Swiss EoE cohort. Data on all patients with active disease at baseline, no concomitant gastroesophageal reflux disease, no strictures at baseline, and at least one follow-up visit were analyzed. We compared patients with histologically localized proximal versus distal versus extended (=proximal and distal) disease with regard to patient, disease characteristics, disease presentation, and development of complications. RESULTS: We included 124 patients with a median of 2.5 years of follow-up (73.4% males, median age 35.0 years). Ten patients had proximal (8.1%), 46 patients had distal (37.1%), and 68 patients had extended disease (54.8%). Patients with proximal disease were significantly more often females (80%) compared with patients with distal (26.1%, p = 0.002) or extended disease (19.1%, p < 0.001) and reported less severe symptoms (VAS 0 vs. VAS 1, p = 0.001). Endoscopic and histological disease was less pronounced in the proximal esophagus of proximal EoE compared to extended disease (EREFS 1.0 vs. 3.0, p = 0.001; 27.0 eos/hpf vs. 52.5 eos/hpf, p = 0.008). Patients with proximal disease were less likely to undergo dilation compared to patients with distal disease in the follow-up (3.3% vs. 23.3%, p = 0.010). In a multivariate Cox regression model, proximal eosinophilia was less likely to be associated with treatment failure compared to distal eosinophilia. CONCLUSION: Although isolated proximal EoE is infrequent, it is associated with less severe disease and better disease outcome. Proximal disease appears to present a unique EoE phenotype.