Dietary composition of adult eosinophilic esophagitis patients is related to disease severity.

BACKGROUND: In addition to the elimination diet, dietary composition may influence disease severity in patients with eosinophilic esophagitis (EoE) through modulation of the immune response. AIM: To explore the immunomodulatory role of nutrition before and during elimination diet in adult EoE patients. METHODS: Nutritional intake was assessed in 39 Dutch adult EoE patients participating in the Supplemental Elemental Trial (Dutch trial registry NL6014, NTR6778) using 3-day food diaries. In this randomized controlled trial, diagnosed patients received either a four-food elimination diet alone (FFED) or FFED with addition of an amino acid-based formula for 6 weeks. Multiple linear regression analyses were performed to assess associations between the intake of nutrients and food groups per 1000 kCal and peak eosinophil count/high power field (PEC), both at baseline and after 6 weeks. RESULTS: At baseline, we found a statistically significant negative (thus favorable) relationship between the intake of protein, total fat, phosphorus, zinc, vitamin B12, folate, and milk products and PEC (p < .05), while calcium (p = .058) and full-fat cheese/curd (p = .056) were borderline (favorably) significant. In contrast, total carbohydrates, prepacked fruit juice, and white bread were significantly positively (unfavorable) related to PEC (p < .05), while ultra-processed meals (p = .059) were borderline (unfavorably) significant. After dietary intervention, coffee/tea were significantly negatively (favorably) related to PEC, hummus/legumes were significantly positively (unfavorably) related with PEC, while peanuts were borderline significantly positively related (p = .058). CONCLUSION: Dietary composition may be related to inflammation in adult EoE patients. High-quality and anti-inflammatory diets may be a promising adjuvant therapy in the dietary management of EoE.

Extracellular matrix remodeling proteins as biomarkers for clinical assessment and treatment outcomes in eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted. AIMS: To investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients. METHODS: Protein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention. RESULTS: Patients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p < 0.01), whereas low CTX-III levels were observed in patients achieving histological remission (< 15 eos/hpf) (vs. no histological remission (p < 0.05). Progression of endoscopic fibrosis after intervention was associated with increased levels of type-III (PRO-C3) and -VI collagen (PRO-C6) formation (all; p < 0.05). A baseline EREFS inflammatory subscore ≥ 2 correlated with higher neutrophilic activity (Cpa9-HNE) at week 6 (p < 0.05). Moreover, increased degradation of type-III (C3M) and -IV (C4M/PRO-C4) collagens were associated with remission of food impaction after intervention (all; p < 0.05). CONCLUSION: Serum extracellular matrix remodeling proteins demonstrated potential as surrogate biomarkers for assessing histological disease remission, endoscopic fibrosis, and remission of symptoms of food impaction after diet intervention in adult EoE patients.

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).

Responsiveness of a Histologic Scoring System Compared With Peak Eosinophil Count in Eosinophilic Esophagitis.

INTRODUCTION: The optimal instrument for assessing histologic disease activity in patients with eosinophilic esophagitis (EoE) is unclear. We assessed the responsiveness of the EoE Histologic Scoring System (EoE-HSS) when compared with that of the peak eosinophil count (PEC). METHODS: Histopathology slides were obtained from patients with EoE at baseline and after 8 weeks of treatment with swallowed topical budesonide or elimination diet. Two blinded gastrointestinal pathologists scored biopsies on the EoE-HSS, PEC, and 100-mm visual analog scale (VAS) of overall histologic severity. Change was defined as an improvement by ≥0.5 SD in baseline VAS. Responsiveness was quantified using the standardized effect size (SES) and the probability that the index distinguishes a patient with improvement from a patient without improvement, which is the area under the receiver operating characteristic curve (AUC). Longitudinal validity was assessed using Pearson correlations between changes in EoE-HSS and both PEC and VAS. RESULTS: The EoE-HSS grade (SES 2.18 [95% confidence interval, CI: 1.46-2.88]; AUC 0.73 [95% CI: 0.57-0.84]) and stage (SES 2.07 [95% CI: 1.37-2.77]; AUC 0.73 [95% CI: 0.58-0.84]) were highly responsive, similar to PEC (SES 1.44 [95% CI: 0.80-2.07]; AUC 0.73 [95% CI: 0.58-0.84]). The EoE-HSS grade and stage were more highly correlated with changes in VAS (grade 0.92 [95% CI: 0.86-0.95]; stage 0.89 [95% CI: 0.81-0.94]) than with changes in PEC (grade 0.74 [95% CI: 0.58-0.85]; stage 0.66 [95% CI: 0.47-0.80]). DISCUSSION: The EoE-HSS is highly responsive, performs similarly to PEC, and is better correlated with changes in overall histologic activity in patients with EoE.

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.

Mental distress among adult patients with eosinophilic esophagitis.

RATIONALE: Data on the prevalence of mental distress among adult eosinophilic esophagitis (EoE) patients are scarce. Also, a significant gap remains in the understanding of which determinants are related to significant psychological symptoms and whether distressed patients require and receive mental care. METHODS: Adult EoE patients were invited to complete standardized measures on anxiety/depressive symptoms (HADS) and general psychopathology (SCL-90-R). All scores were compared to general population norms. Socio-demographic and clinical factors were assessed. RESULTS: In total, 147 adult EoE patients (61% males, age 43 (IQR 29-52) years were included (response rate 71%). No difference with general population values was found for total anxiety and depressive symptoms (7.8 ± 6.6 vs. 8.4 ± 6.3; p = 0.31). A total of 38/147(26%) patients reported high levels of anxiety and/or depressive symptoms (HADS-A ≥ 8: 35/147(24%) and HADS-D ≥ 8: 14/147(10%)), indicative of a possible psychiatric disorder. In a multivariate analysis, age between 18-35 years was independently associated with high levels of anxiety (HADS-A ≥ 8) (OR 3.0, 95% CI 1.3-6.9; p = 0.01). The SCL-90-R Global Severity Index (GSI) was significantly higher compared to the general population (p < 0.001). Significant signs of general mental distress (GSI ≥ 80th percentile) were observed in 51(36%) EoE patients, of which 29(57%) patients denied having any mental problems and only 8(16%) patients received mental care. CONCLUSION: A considerable proportion of adult EoE patients suffers from mental distress, with a 3-fold risk of significant anxiety in those patients younger than 35 years. Therefore, population-based studies are required and a proactive approach in the screening for and treatment of these psychological symptoms in EoE practice seems essential.

Pharmacotherapies for the Treatment of Eosinophilic Esophagitis: State of the Art Review.

Eosinophilic esophagitis (EoE), a chronic allergic disorder of the esophagus, is characterized by symptoms of esophageal dysfunction and eosinophil-predominant inflammation. The incidence of EoE has increased substantially over the past two decades, coinciding with the so-called allergy epidemic. Current treatment options consist of dietary intervention, endoscopic dilatation, and pharmacotherapy. Given that EoE is a chronic progressive disease that is prone to relapse after cessation of therapy, these treatment options are suboptimal for long-term management. Persistent, uncontrolled esophageal inflammation is associated with esophageal remodeling and stricture formation, thus, the creation and/or discovery of alternative treatments is of paramount importance. The pathogenesis of EoE is currently under intense investigation, and recent insights concerning cellular and molecular etiology have led to the development of therapies that target specific pathophysiological pathways. This article provides an overview of established EoE pharmacotherapies, which include proton pump inhibitors and swallowed topical steroids. Additionally, anti-allergic targets, immunosuppressives, and monoclonal antibodies (such as mepolizumab, reslizumab, QAX576, RPC4046, dupilumab, omalizumab, and infliximab) that have been evaluated as treatments for EoE are summarized. Finally, several promising therapeutic agents (e.g., sialic acid-binding immunoglobulin-like lectin 8 antibodies, the transforming growth factor-ß1 signal blocker losartan, CC chemokine receptor type 3 antagonists, thymic stromal lymphopoietin antibodies, antibodies targeting the α4ß7 integrin, anti-interleukin-9 antibodies, and anti-interleukin-15 antibodies) that target specific molecules or cells implicated in the pathogenesis of EoE are proposed.