Omineca Herald, December, 28, 1977

EoE is an increasingly recognized disorder, characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophagus. The incidence increased from 0.01 in 1996 to 2.07 per 100,000 inhabitants in 2015, these rates outpaces the expanding endoscopy rates. The natural course of EoE is characterized by a progression from atypical symptoms and the inflammatory endoscopic phenotype in childhood, towards symptoms of dysphagia and food impaction accompanied with the fibrostenotic phenotype in adults. If EoE is left untreated, the risk for stricture formation increased significantly. We have demonstrated that the mucosal integrity in EoE patients with active disease is impaired compared with patients in remission and controls and that it is a promising predictor of disease activity which can be used to follow up EoE patients after treatment. In contrary to other atopic diseases the duodenal mucosal integrity is not affected in EoE. Treatments include topical corticosteroids and dietary elimination of food allergens. In this thesis we have demonstrated that an elemental diet can induce quick histologic and clinical disease remission with improved patients’ adherence. Furthermore complete absence of food allergens restored the impaired mucosal integrity. However, diets remain cumbersome since standard allergy tests perform poorly as tools to guide elimination diets. We have demonstrated that an esophageal prick test (EPT), in which the esophageal mucosa was challenged by local allergen injections could identify sensitization patterns in EoE patients and not in controls. The EPT deserves further exploration because it may guide elimination diets. In conclusion, the studies described in this thesis have provided interesting new observations on the epidemiology, pathophysiology, diagnostics and treatment of EoE

The Habitual Diet of Dutch Adult Patients with Eosinophilic Esophagitis Has Pro-Inflammatory Properties and Low Diet Quality Scores

We determined the nutritional adequacy and overall quality of the diets of adult patients with eosinophilic esophagitis (EoE). Dietary intakes stratified by sex and age were compared to Dietary Reference Values (DRV). Overall diet quality was assessed by two independent Diet-Quality-Indices scores, the PANDiet and DHD-index, and compared to age- and gender-matched subjects from the general population. Lastly, food and nutrient intakes of EoE patients were compared to intakes of the general population. Saturated fat intake was significantly higher and dietary fiber intake significantly lower than the DRV in both males and females. In males, the DRV were not reached for potassium, magnesium, selenium, and vitamins A and D. In females, the DRV were not reached for iron, sodium, potassium, selenium, and vitamins A, B2, C and D. EoE patients had a significantly lower PANDiet and DHD-index compared to the general population, although the relative intake (per 1000 kcal) of vegetables/fruits/olives was significantly higher (yet still up to 65% below the recommended daily amounts) and alcohol intake was significantly lower compared to the general Dutch population. In conclusion, the composition of the habitual diet of adult EoE patients has several pro-inflammatory and thus unfavorable immunomodulatory properties, just as the general Dutch population, and EoE patients had lower overall diet quality scores than the general population. Due to the observational character of this study, further research is needed to explore whether this contributes to the development and progression of EoE

Food‐induced immediate response of the esophagus—A newly identified syndrome in patients with eosinophilic esophagitis

Background Dysphagia is the main symptom of adult eosinophilic esophagitis (EoE). We describe a novel syndrome, referred to as “food-induced immediate response of the esophagus” (FIRE), observed in EoE patients. Methods Food-induced immediate response of the esophagus is an unpleasant/painful sensation, unrelated to dysphagia, occurring immediately after esophageal contact with specific foods. Eosinophilic esophagitis experts were surveyed to estimate the prevalence of FIRE, characterize symptoms, and identify food triggers. We also surveyed a large group of EoE patients enrolled in the Swiss EoE Cohort Study for FIRE. Results Response rates were 82% (47/57) for the expert and 65% (239/368) for the patient survey, respectively. Almost, 90% of EoE experts had observed the FIRE symptom complex in their patients. Forty percent of EoE patients reported experiencing FIRE, more commonly in patients who developed EoE symptoms at a younger age (mean age of 46.4 years vs 54.1 years without FIRE; P < .01) and in those with high allergic comorbidity. Food-induced immediate response of the esophagus symptoms included narrowing, burning, choking, and pressure in the esophagus appearing within 5 minutes of ingesting a provoking food that lasted less than 2 hours. Symptom severity rated a median 7 points on a visual analogue scale from 1 to 10. Fresh fruits/vegetables and wine were the most frequent triggers. Endoscopic food removal was significantly more commonly reported in male patients with vs without FIRE (44.3% vs 27.6%; P = .03). Conclusions Food-induced immediate response of the esophagus is a novel syndrome frequently reported in EoE patients, characterized by an intense, unpleasant/painful sensation occurring rapidly and reproducibly in 40% of surveyed EoE patients after esophageal contact with specific foods

Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029

PPI-responsive esophageal eosinophilia cannot be distinguished from eosinophilic esophagitis by endoscopic signs

Eosinophilic esophagitis (EoE) is a chronic antigen-mediated disease histologically characterized by eosinophil-predominant inflammation. One-third of patients respond to proton pump inhibitor (PPI) treatment; this group is identified as having PPI-responsive esophageal eosinophilia (PPI-REE). If we could predict the response to PPIs on the basis of endoscopic signs, futile treatment efforts and additional endoscopies to assess treatment response can be prevented. To determine whether endoscopic signs can distinguish PPI-REE from EoE. Endoscopic images of 30 EoE and 30 PPI-REE patients were included. Baseline characteristics were compared between groups. Complete clinical remission after a PPI trial for at least 8 weeks was classified as PPI-REE. Per patient, at least three depersonalized images were incorporated into a slideshow. These images were scored by two experienced endoscopists according to a validated classification system. Characteristics were highly comparable between EoE and PPI-REE patients. Endoscopic signs were similar and did not enable differentiation between EoE and PPI-REE [presence of: rings (P=0.893), white exudates (P=0.209), furrows (P=0.371), edema (P=0.554), crepe paper esophagus (P=1.000), and strictures (P=0.071)]. Endoscopic signs at baseline endoscopy cannot distinguish EoE from PPI-REE before a PPI trial; the demographic and clinical characteristics in both groups are similar. Endoscopic features do not enable differentiation between PPI-REE and Eo

Emerging incidence trends of eosinophilic esophagitis over 25 years: Results of a nationwide register-based pathology cohort

Rationale: Eosinophilic esophagitis (EoE) has emerged from a case-reportable illness in the early 1990s to a distinct clinicopathological entity. Increasing worldwide incidences have been observed, although due to various study designs estimates are inconsistent. Aim: To determine population-based annual incidence rates over a time period of 25 years. Methods: A nationwide register-based pathology (PALGA) search was performed to identify reports describing esophageal eosinophilia between 1995 and 2019. EoE was identified if the diagnosis was confirmed by the pathologist. Crude incidence rates were estimated by the number of new EoE cases per year and matched with population data. Results: Between 1995 and 2019, 7361 unique patients’ reports mentioned esophageal eosinophilia, of these 4061 were classified as EoE (71% male, mean age 37.9 ± 18.4 years). In total, 639 (16%) children (<18 years) were diagnosed. The EoE incidence increased from 0.01 in 1995 (95% CI: 0.0 – 0.04) to 3.16 (95% CI: 2.90 – 3.44) per 100.000 inhabitants in 2019. EoE was significantly more prevalent in males (OR 2.48 | 95% CI: 2.32 – 2.65; vs. females p < 0.001) and adults (OR 1.42 | 95% CI: 1.31 – 1.55; vs. children p < 0.001). Highest incidences were observed in 2019, being 4.37 (95% CI: 3.94 – 4.84) vs. 1.97 (95% CI: 1.68 – 2.29) per 100.000 males and females, respectively (p < 0.001). No seasonal variation was observed. Conclusion: Over the past quarter century, the annual rates of newly diagnosed EoE patients raised dramatically and this increase has not reached a deceleration yet

The natural course of eosinophilic esophagitis and long-term consequences of undiagnosed disease in a large cohort

Background: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammation that may lead to stricture formation. This narrowing can cause major complications including food impactions. Despite increasing interest in EoE accurate data on its natural course is scarce. Therefore, we aimed to investigate the natural course of EoE and to evaluate the association between undiagnosed disease and the occurrence of complications over two decades in a large cohort. Methods: We retrospectively analyzed charts of patients diagnosed with EoE between 1996 and 2015, collected from 15 hospitals throughout the Netherlands. Histologic, clinical, and endoscopic characteristics were identified and stratified by age and diagnostic delay. Results: We included 721 patients (524 males, 117 children (≤18 years)). Dysphagia and food impactions were more common in adults whereas children more often presented with vomiting and abdominal pain (all p < 0.001). The prevalence of fibrotic endoscopic features was higher in adults (76%) than in children (39%) (p < 0.001). As time with undiagnosed disease progressed the percentage of patients with strictures and food impactions increased from 19% and 24% (diagnostic delay ≤ 2 years) to 52% and 57% (diagnostic delay ≥ 21 years) (p < 0.001), respectively. In a multivariate logistic regression model, diagnostic delay (odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.05-1.13) and male gender (OR = 2.69, 95% CI = 1.61-4.50) were the major risk factors for stricture presence. Conclusion: During the natural course of EoE, progression from an inflammatory to a fibrostenotic phenotype occurs. With each additional year of undiagnosed EoE the risk of stricture presence increases with 9%

Elemental diet decreases inflammation and improves symptoms in adult eosinophilic oesophagitis patients.

BACKGROUND: Eosinophilic oesophagitis (EoE) is a chronic disease, driven by food allergens. Elemental diets are effective for the management of children with EoE, but studies on the effect of elemental diets in adults are scarce and poor palatability challenges dietary adherence. AIMS: To assess the effect of an elemental diet (Neocate, Nutricia, Utrecht, the Netherlands) on the inflammation, symptoms and endoscopic signs in adult EoE patients. METHODS: In this prospective study, 21 patients with active EoE, confirmed by biopsies showing ≥15 eosinophils per microscopic high power field (HPF) and symptoms of oesophageal dysfunction were included. Patients underwent endoscopy before and 4 weeks after diet. Histological disease activity (peak eosinophil count/HPF), and endoscopic signs were scored by physicians. Symptoms and adherence to the diet were evaluated by questionnaires. Serum total IgE levels and total eosinophil counts were determined and the expression of inflammatory cytokines was analysed by qPCR. RESULTS: In total, 17 (81%) of the patients completed the diet, of whom 12 (71%) showed complete histological response (≤15 eosinophils/HPF) and 4 (24%) showed partial histological response (≥50% reduction of baseline eosinophil count). Peak eosinophil counts decreased significantly after the diet from 40 to 9 per HPF (P ≤ 0.001). A marked improvement in endoscopic signs was observed. Symptoms decreased significantly in all subjects, and 15 patients (88%) became completely asymptomatic (P ≤ 0.001). In 14 patients (82%), blood eosinophil count and serum IgE decreased (P ≤ 0.05). CONCLUSION: Elemental diet reduces eosinophilic inflammation and induces clinical remission in adult patients with eosinophilic oesophagitis

Gene expression and clinical outcomes after dietary treatment for eosinophilic esophagitis: A prospective study

Background: Eosinophilic esophagitis (EoE) is an allergen-mediated disease and elimination diets have proven to be effective to obtain clinical and histological remission. However, the effect of elimination diets on specific EoE transcripts and their clinical correlates is relatively unknown. The main aim of the study was to evaluate the effect of dietary treatment (four-food elimination diet [FFED]) with or without addition of amino acid-based formula (AAF) on a variety of pro-/anti-inflammatory, epithelial/barrier function and remodeling/fibrosis-related markers of disease activity and clinical correlates (eosinophils, symptoms, and endoscopic signs) in adult EoE patients. Methods: We conducted an analysis of biopsy samples and data collected during a randomized controlled trial with an elimination diet in adult patients with active EoE (≥15 eosinophils [eos] per high-power field [hpf]). Demographics, symptoms (SDI-score), endoscopic signs (EREFS) and peak eosinophil counts/hpf were recorded at baseline and after 6 weeks of treatment. Transcripts of 10 indicated genes were measured (qPCR) and compared to clinical correlates at baseline and after treatment. Key Results: Forty patients (pooled FFED + FFED + AAF) (60% male, age 34.5 (interquartile range [IQR] 29–42.8 years) completed the diet. Peak eosinophil counts/hpf, symptoms and endoscopic signs were significantly decreased after 6 weeks dietary treatment. DSG-1 levels were significantly upregulated from baseline to week 6, whereas IL-13, CAPN-14, IL-5, IL-10, CCL-26, POSTN, TSLP, CPA-3, and TGF-β were significantly downregulated after 6 weeks of diet (all; <0.01). Prior to treatment, upregulation of CAPN-14 and lower levels of DSG-1 were associated with clinical fibrotic phenotypes, whereas upregulation of IL-10 was linked to food impaction phenotypes. Conclusion: These findings strongly suggest that elimination diets, besides a clinical and histological response, are associated with a broad transcriptional response at the level of the esophageal epithelium