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-ß 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.

Effect of amino acid-based formula added to four-food elimination in adult eosinophilic esophagitis patients: A randomized clinical trial.

BACKGROUND: Elimination of key foods restricts dietary options in eosinophilic esophagitis (EoE) patients. Addition of amino acid-based formula (AAF) to an elimination diet might facilitate adherence and, therefore, enhance efficacy of dietary management. AIM: To evaluate whether addition of AAF to a four-food elimination diet (FFED) is more effective than FFED alone in decreasing eosinophilia, endoscopic signs, and clinical outcomes. METHODS: This randomized controlled trial enrolled 41 adult patients with active EoE (≥15 eosinophils (eos) per high power field (hpf)) at baseline biopsy. Subjects were randomized (1:1 ratio) to groups given a FFED or FFED with addition of AAF providing 30% of their daily energy needs (FFED + AAF). Histological disease activity, endoscopic signs, symptoms, and disease-related quality of life (EoEQoL) were measured at baseline and after 6 weeks of intervention. RESULTS: Patients (60% male, age 34.5 (interquartile range (IQR) 29-42.8 years)) were randomized to FFED (n = 20) or FFED + AAF (n = 21); 40 participants completed the diet. Complete histological remission (<15 eos/hpf) was achieved in 48% of FFED + AAF subjects (n = 21) vs. 25% of FFED subjects (n = 20), respectively (p = 0.204). Peak eosinophil counts (PEC) decreased significantly in both groups between baseline and week 6, but the change in PEC between groups was not different (p = 0.130). A significant but similar endoscopic and symptomatic reduction was observed in both groups (all; p<0.05). Total EoEQoL scores significantly improved in the FFED + AAF group between baseline and week 6 (p = 0.007), and not in the FFED group. CONCLUSION: The addition of AAF to a FFED did not lead to a larger decrease in PEC between baseline and 6 weeks, but may result in a significant improvement of QoL in adult EoE patients NL6014 (NTR6778).

Utility of gastric and duodenal biopsy sampling in adult eosinophilic esophagitis patients to rule out other gastrointestinal disorders.

RATIONALE: According to consensus guidelines, if eosinophilic esophagitis (EoE) is suspected, not only esophageal but also gastric and duodenal biopsy specimens should be sampled in order to exclude other generalized or eosinophilic gastrointestinal (GI) disorders, such as eosinophilic gastroenteritis or celiac disease. However, the diagnostic yield for this remains unclear. AIM: To assess the diagnostic yield of biopsy sampling from the stomach and duodenum in adult EoE patients to rule out generalized or eosinophilic GI disorders. METHODS: A retrospective chart-review was conducted in untreated adult EoE patients that underwent upper endoscopy with biopsies sampled from the esophagus, stomach and duodenum. Standardized (electronic) case-report forms were used to extract clinical, endoscopic and histologic data. RESULTS: In total, 93 adults (71% males, age 36.4 (interquartile range 28.4 - 49.1) years) with untreated EoE (≥15 eosinophils/high-power-field) were included. Symptoms of dysphagia and food impaction were reported in 93% and 58%, respectively of the patients. Typical endoscopic EoE-features were present in 77 (85%) patients. The yield of routinely sampled gastric and duodenal biopsy specimens in our cohort was 3.6% (95% confidence interval: 2.6-4.8%) (n/N = 1/93) for a relevant other generalized or eosinophilic GI diagnosis and 30% for other histological diagnosis such as non-specific or H. Pylori gastritis. In total, 62 (67%) patients presented with other GI symptoms and/or endoscopic abnormalities of the stomach and/or duodenum - which both may be suggestive for other relevant GI conditions. The diagnostic yield for a relevant generalized or eosinophilic GI disorder in this subgroup was, 4.8% (95%CI 3.4 - 6.7%) (n/N = 1/62). CONCLUSION: Gastric and duodenal biopsy specimens seem to have limited diagnostic value for the exclusion of generalized or eosinophilic GI disorders in adults with EoE.KEY POINTSEvidence is lacking on the diagnostic value of additional biopsies sampled form the stomach and duodenum to rule out other relevant generalized or eosinophilic gastrointestinal (GI) disorders.The yield of gastric and duodenal biopsies routinely sampled in our cohort was 3.6% for a relevant other generalized or eosinophilic GI diagnosis and 30% for other histological diagnosis such as non-specific or H. Pylori gastritis.The diagnostic yield for a relevant generalized or eosinophilic GI disorder in the subgroup of patients (67%) presenting with other GI symptoms and/or endoscopic abnormalities of the stomach and/or duodenum - which both may be suggestive for other relevant GI conditions was, 4.8%.Gastric and duodenal biopsy specimens seem to have limited diagnostic value for the exclusion of generalized or eosinophilic GI disorders in adults with EoE.

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 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.

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%.

Abnormal Responses to Local Esophageal Food Allergen Injections in Adult Patients With Eosinophilic Esophagitis.

Skin tests and measurement of serum levels of immunoglobulin E do not accurately identify foods for elimination from the diets of patients with eosinophilic esophagitis (EoE). We investigated whether an esophageal prick test, in which the esophageal mucosa is challenged by local injection of allergen extracts, could identify individuals with esophageal sensitization. During endoscopy, 6 allergens were injected in the esophagus of 8 patients with EoE and 3 patients without EoE (controls). A second endoscopy was performed after 24 hours to evaluate delayed responses. Five of the 8 patients with EoE had evidence for an acute response (luminal obstruction and mucosal blanching); 2 other patients had a delayed wheal or flare reaction. No responses were observed in controls. We conclude that esophageal mucosal food allergen injections induce acute and/or delayed responses in patients with EoE but not controls. The esophageal prick test deserves further exploration because it may guide elimination diets.

Systematic Review: Disease Activity Indices in Eosinophilic Esophagitis.

OBJECTIVES: There is no clear consensus regarding the most appropriate measure(s) of eosinophilic esophagitis (EoE) disease activity. We aimed to identify all scoring indices used for the measurement of disease activity in EoE, appraise their operating properties, and discuss their value as outcome measures. METHODS: MEDLINE, EMBASE, and CENTRAL (The Cochrane library) were searched from inception to 11 May 2016. Randomized controlled trials (RCTs), cohort, case-control, and cross-sectional studies that reported outcomes to measure EoE disease activity or response to treatment were eligible. Operating properties of histologic, endoscopic, and patient reported/symptomatic and health-related quality of life measures were critically appraised according to guidelines proposed by the United States Food and Drug Administration. RESULTS: Of 4,373 citations, 130 studies were eligible, of which 20 were RCTs. Although no index met all evaluative criteria, we found that: (1) the EoE histologic scoring system (EoEHSS) is the most valid histologic measure; (2) the Endoscopic Reference Score (EREFS) is the most reliable and responsive endoscopy measure; and (3) the Eosinophilic Esophagitis Activity Index (EEsAI) or the Dysphagia Symptoms Questionnaire (DSQ) had superior construct validity and responsiveness in adults. The Pediatric Quality of Life Inventory EoE was the most valid pediatric symptomatic measure. CONCLUSIONS: Current evidence supports the use of the EoEHSS and EREFS as measures of histologic and endoscopic EoE disease activity, respectively, and the EEsAI, DSQ, or Pediatric Quality of Life Inventory EoE as measures of adult and pediatric symptoms. Additional research is needed to optimize endpoint configuration to facilitate development of new therapies.

Disease activity in eosinophilic esophagitis is associated with impaired esophageal barrier integrity.

In eosinophilic esophagitis (EoE), the esophageal barrier integrity is impaired. Integrity can be assessed with different techniques. To assess the correlations between esophageal eosinophilia and various measures of mucosal integrity and to evaluate whether endoscopic impedance measurements can predict disease activity, endoscopies and mucosal integrity measurements were performed in adult EoE patients with active disease (≥15 eosinophils/high-power field) at baseline (n = 32) and after fluticasone (n = 15) and elemental dietary treatment (n = 14) and in controls (n = 19). Mucosal integrity was evaluated during endoscopy using electrical tissue spectroscopy (ETIS) measuring mucosal impedance and transepithelial electrical resistance (TER) and transepithelial molecule-flux through biopsy specimens in Ussing chambers. We included 61 measurements; 32 of patients at baseline and 29 after treatment, 3 patients dropped out. After treatment, 20 patients were in remission (≤15 eosinophils/high-power field) and these measurements were compared with 41 measurements of patients with active disease (at baseline or after failed treatment). All four mucosal integrity measures showed significant impairment in active EoE compared with remission. Eosinophilia was negatively correlated with ETIS and TER and positively with transepithelial molecule flux (P ≤ 0.001). The optimal ETIS cutoff to predict disease activity was 6,000 Ω·m with a sensitivity of 79% [95% confidence interval (CI) 54-94%], specificity of 84% (95% CI 69-94%), positive predictive values of 89% (95% CI 77-95%) and negative predictive values of 71% (95% CI 54-84%). In EoE patients, markers of mucosal integrity correlate with esophageal eosinophilia. Additionally, endoscopic mucosal impedance measurements can predict disease activity.NEW & NOTEWORTHY In adult patients with eosinophilic esophagitis (EoE), the mucosal integrity, measured by making use of four different parameters, correlates strongly with esophageal eosinophilia. The accuracy of endoscopically measured mucosal impedance to distinguish active disease from remission was acceptable with moderate specificity and sensitivity. Mucosal impedance measurements can predict disease activity in adult EoE patients.

Esophageal and Small Intestinal Mucosal Integrity in Eosinophilic Esophagitis and Response to an Elemental Diet.

OBJECTIVES: The esophageal mucosal integrity is impaired in eosinophilic esophagitis (EoE) and it has been suggested that the duodenal permeability is increased. The absence of food allergens may restore the integrity. The aims of this study were to assess duodenal permeability in EoE and to evaluate the effect of an elemental diet on the esophageal and duodenal integrity. METHODS: In this prospective study 17 adult EoE patients and 8 healthy controls (HC) were included. Esophageal biopsy specimens were sampled before and after 4 weeks of elemental diet to measure eosinophil counts and gene expression of tight junction and barrier integrity proteins. Esophageal and duodenal impedance were measured by electrical tissue impedance spectroscopy and Ussing chambers were used to measure transepithelial resistance (TER) and transepithelial molecule flux. Small intestinal permeability was measured using a test, measuring lactulose/mannitol (L/M) ratios. RESULTS: In EoE patients, the esophageal but not the duodenal integrity was impaired, compared with HC. We observed no significant difference between L/M ratios of HC and EoE patients. After diet, eosinophil counts decreased significantly, which was paralleled by normalization of esophageal impedance and transepithelial molecule flux. The esophageal TER improved significantly, but did not reach values seen in HC. Esophageal expression of genes encoding for barrier integrity proteins filaggrin and desmoglein-1 was impaired at baseline and restored after diet. CONCLUSIONS: An elemental diet restores esophageal integrity, suggesting that it is at least partly secondary to allergen exposure. Duodenal integrity seems not to be affected in EoE, and possibly plays a minor role in its pathophysiology.

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

BACKGROUND: 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. OBJECTIVE: To determine whether endoscopic signs can distinguish PPI-REE from EoE. METHODS: 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. RESULTS: 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)]. CONCLUSION: 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 EoE.

Evaluating the endoscopic reference score for eosinophilic esophagitis: moderate to substantial intra- and interobserver reliability.

BACKGROUND AND STUDY AIMS: Recently the Endoscopic Reference Score (EREFS) for endoscopic assessment of eosinophilic esophagitis was introduced, with good interobserver agreement for most signs. The EREFS has not yet been evaluated by other investigators and intraobserver agreement has not been assessed. The aim of this study was to further validate the EREFS by assessing interobserver and intraobserver agreement of endoscopic signs in patients with eosinophilic esophagitis. PATIENTS AND METHODS: High-quality endoscopic images were made of the esophagus of 30 patients with eosinophilic esophagitis (age 36 years, range 23 - 46 years; 5 female), 6 of whom were in remission. At least three depersonalized images per patient were incorporated into a slideshow. Images were scored by four expert and four trainee endoscopists who were blinded to the patients' conditions. Interobserver agreement was assessed. After 4 weeks, the images were rescored in a different order to assess intraobserver agreement. RESULTS: Interobserver agreement was substantial for rings (κ 0.70), white exudates (κ 0.63), and crepe paper esophagus (κ 0.62), moderate for furrows (κ 0.49) and strictures (κ 0.54), and slight for edema (κ 0.12). Intraobserver agreement was substantial for rings (median κ 0.64, IQR 0.46 - 0.70), furrows (median κ 0.69, IQR 0.50 - 0.89), and crepe paper esophagus (median κ 0.69, IQR 0.62 - 0.83), moderate for white exudates (median κ 0.58, IQR 0.54 - 0.71) and strictures (median κ 0.54, IQR 0.33 - 0.70), and less than chance for edema (median κ 0.00, IQR 0.00 - 0.29). Inter- and intraobserver agreement was not substantially different between expert and trainee endoscopists. CONCLUSIONS: Using the EREFS, endoscopic signs of eosinophilic esophagitis were scored consistently by expert and trainee endoscopists.