Prospective study of an amino acid-based elemental diet in an eosinophilic gastritis and gastroenteritis nutrition trial.

BACKGROUND: Eosinophilic gastritis/gastroenteritis (EoG/EoGE) are rare disorders with pathologic gastric and/or small intestinal eosinophilia lacking an approved therapy. An allergic mechanism is postulated but underexplored mechanistically and therapeutically. OBJECTIVE: We evaluated the effectiveness of a food allergen-free diet (elemental formula) in controlling gastrointestinal eosinophilia in adult EoG/EoGE. METHODS: Adults aged 18 to 65 years with histologically active EoG/EoGE (≥30 eosinophils per high-power field) in the stomach and/or duodenum and gastrointestinal symptoms within the month preceding enrollment were prospectively enrolled onto a single-arm clinical trial to receive elemental formula for 6 consecutive weeks. The primary end point was percentage of participants with complete histologic remission (<30 eosinophils per high-power field in both stomach and duodenum). Exploratory outcomes were improvement in symptoms, endoscopy results, blood eosinophilia, quality of life, Physician Global Assessment score, and EoG-relevant gastric transcriptome and microbiome. RESULTS: Fifteen adults (47% male, average age 37.7 years, average symptom duration 8.8 years) completed the trial. Multi-gastrointestinal segment involvement affected 87%. All subjects had complete histologic remission in the stomach (P = .002) and duodenum (P = .001). Scores improved in overall PhGA (P = .002); EGREFS (P = .003); EGDP (P = .002); SODA pain intensity (P = .044), non-pain (P = .039), and satisfaction (P = .0024); and PROMIS depression (P = .0078) and fatigue (P = .04). Food reintroduction reversed these improvements. The intervention was well tolerated in 14 subjects, with 1 serious adverse event reported in 1 subject. CONCLUSION: An amino acid-based elemental diet improves histologic, endoscopic, symptomatic, quality-of-life, and molecular parameters of EoG/EoGE; these findings and disease recurrence with food trigger reintroduction support a dominant role for food allergens in disease pathogenesis. CLINICALTRIALS: gov Identifier: NCT03320369.

Bulk T-cell receptor sequencing confirms clonality in pediatric eosinophilic esophagitis and identifies a food-specific repertoire.

BACKGROUND: Eosinophilic esophagitis (EoE) involves a chronic immune-mediated response to dietary antigens. Recent work identifies T-cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food-specific T-cell repertoire. We sought to confirm T-cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers. METHODS: Bulk TCR sequencing was performed on mRNA isolated from esophageal biopsies obtained from adults and children with EoE (n = 15) who had food triggers confirmed by endoscopic evaluation. Non-EoE adult and pediatric controls (n = 10) were included. Differences in TCR clonality by disease and treatment status were assessed. Shared and similar V-J-CDR3s were assessed based on specific food triggers. RESULTS: Active EoE biopsies from children but not adults displayed decreased unique TCRα/ß clonotypes and increased relative abundance of TCRs comprising >1% of the total compared to non-EoE controls and paired inactive EoE samples. Among patients in which baseline, post diet elimination, and food trigger reintroduction samples (n = 6) were obtained, we observed ~1% of TCRs were shared only between pre-diet elimination and trigger reintroduction. Patients with a shared EoE trigger (milk) had a greater degree of shared and similar TCRs compared to patients with differing triggers (seafood, wheat, egg, soy). CONCLUSION: We confirmed relative clonality in children but not adults with active EoE and identified potential food-specific TCRs, particularly for milk-triggered EoE. Further studies are needed to better identify the broad TCR repertoire relevant to food triggers.

Long-Term Outcomes of the Six-Food Elimination Diet and Food Reintroduction in a Large Cohort of Adults With Eosinophilic Esophagitis.

INTRODUCTION: Eosinophilic esophagitis (EoE) is an immune-mediated inflammatory condition with tissue eosinophilia resulting in esophageal dysfunction. The six-food elimination diet (SFED) is an EoE treatment approach that removes milk, wheat, soy, eggs, tree nuts/peanuts, and fish/shellfish. After histologic remission, food reintroduction occurs to identify a food trigger. Outcomes from large series of adults undergoing SFED and food reintroduction as clinical care are not known. METHODS: A retrospective review (2006-2021) of adult patients with EoE from an academic center was completed. Patients were classified as full responders (<15 eos/hpf) after SFED. If reintroduction was pursued, food triggers identified were recorded. RESULTS: Two hundred thirteen patients completed SFED. One hundred fifteen patients (54%) had response <15 eos/hpf after SFED. Seventy-seven percent of responders had symptom improvement. Thirty-two percent of initial nonresponders underwent repeat dietary elimination. Fifty-eight percent of patients (n = 123) achieved <15 eos/hpf after either initial or extended SFED. Seventy-eight percent of responders underwent food reintroduction. Sixty-nine percent had 1 food trigger identified, 24% had 2 allergens identified, and 4% had 3 allergens identified. The most common food triggers identified were milk, wheat, and soy. DISCUSSION: This study describes the largest cohort reported of adult patients with EoE completing SFED with food reintroduction. The overall SFED histologic response was 54%, which increased to 58% with 1 additional round of dietary therapy, suggesting that 31% may respond in a second attempt. Most patients who completed food reintroduction had a single food trigger identified. Dietary elimination with specific food trigger identification is a feasible alternative to medical therapy for adults with EoE.

Low Prevalence of Extraesophageal Gastrointestinal Pathology in Patients with Eosinophilic Esophagitis.

BACKGROUND: Limited data are available to support current guidelines recommendations on obtaining gastric and duodenal biopsies of patients with clinical and histologic manifestations consistent with eosinophilic esophagitis (EoE) to rule out eosinophilic gastritis (EG) or duodenitis (EoD). Our study examined the prevalence of concomitant extraesophageal, gastrointestinal pathology to better characterize the diagnostic yield of additional biopsies. METHODS: This was a single-center, retrospective study which utilized ICD 9 codes (530.13) and search queries of pathology reports ("Eosinophilic esophagitis," "EoE") to identify EoE patients. Patient endoscopy reports, pathology reports, and office notes were manually reviewed to characterize cases. RESULTS: The electronic health record search yielded 1,688 EoE adults. In those who had extra-esophageal biopsies obtained, EG was identified in 34 (3.4%), H. pylori in 45 (4.6%), EoD in 27 (3.3%), and histology consistent with celiac disease in 20 (2.5%). Endoscopic abnormalities were found in the stomach of 92% of patients with EoE and EG and in the duodenum of 50% of patients with EoE and EoD. Symptoms of dyspepsia and/or abdominal pain occurred in a significantly greater proportion of patients with extraesophageal disease (64% vs. 19% in EoE group, p < 0.001). Overall, extraesophageal pathology would have been missed in 1.4% of patients lacking either symptoms or endoscopic signs suggestive of extraesophageal disease. CONCLUSIONS: The yield of gastric and duodenal biopsies in adults with EoE is low, with 6.5% of patients demonstrating histologic features of celiac disease, Helicobacter pylori, EG, and/or EoD. Biopsies of extraesophageal, gastrointestinal sites in patients with suspected or previously diagnosed EoE should consider symptom and endoscopy manifestations as well as the potential impact of histopathologic findings on clinical management.

One-Hour Esophageal String Test: A Nonendoscopic Minimally Invasive Test That Accurately Detects Disease Activity in Eosinophilic Esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus. METHODS: In a prospective, multisite study, children and adults (ages 7-55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation. RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n = 62), inactive EoE (n = 37), and patient controls with a normal esophagus (n = 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eighty-seven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information. DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.

Assessing Adherence and Barriers to Long-Term Elimination Diet Therapy in Adults with Eosinophilic Esophagitis.

BACKGROUND: The six-food elimination diet (SFED) is an effective treatment approach for eosinophilic esophagitis (EoE), but it can be challenging and affect patients' quality of life. AIM: Assess patients' long-term adherence to SFED and potential factors influencing adherence. METHODS: EoE patients were recruited online via multiple platforms. Patients were classified as reaching the maintenance stage if they responded to SFED and identified specific trigger foods by reintroduction. Maintenance stage patients were categorized into those actively following the elimination diet (ACTIVE) and those no longer on their prescribed diet (FORMER). Participants completed a study-specific questionnaire assessing patient experiences related to SFED use. RESULTS: Forty-two participants were identified as having reached the SFED's maintenance stage. 57% (24/42) of the maintenance stage patients were ACTIVE users. FORMER users rated the SFED's effectiveness at treating symptoms (5.45 ± 3.96, 10 max.) lower than ACTIVE users (8.29 ± 2.76, p = .02). A greater percentage of FORMER users (100%) agreed social situations create challenges in following the diet compared to ACTIVE users (67%, p < .05). Anxiety related to SFED was also higher among FORMER users (64%) compared to ACTIVE users (21%, p < .01). Both ACTIVE (95.8%) and FORMER (81.8%, NSS) users would recommend the elimination diet to other EoE patients. CONCLUSIONS: Understanding SFED adherence is multifactorial and complex. Factors influencing SFED adherence during long-term maintenance with diet therapy include diet effectiveness, social situations, and diet-related anxiety. Despite a lower than expected long-term adherence to maintenance of an elimination diet, the majority would recommend diet therapy as a treatment to other EoE patients.

Comparison of endoscopy and radiographic imaging for detection of esophageal inflammation and remodeling in adults with eosinophilic esophagitis.

BACKGROUND AND AIMS: Eosinophil predominant mucosal inflammation is central to the diagnosis and activity assessment of eosinophilic esophagitis (EoE). Esophageal mural remodeling is an important consequence of EoE that is responsible for adverse events of dysphagia, food impaction, and esophageal stenosis. The aim of this study was to compare upper endoscopy (EGD) with barium upper GI study (UGI) for the detection of esophageal inflammation and remodeling in adults with EoE. METHODS: A retrospective review on a single-center database of adults with confirmed EoE identified those with EGD and UGI performed within 6 months of each another. Studies were reviewed for mucosal inflammatory and remodeling abnormalities. RESULTS: Seventy patients were included. Initial UGI results were consistent with EoE in 10% and suggestive of EoE in 39%. Review of UGI by a senior GI radiologist increased detection of changes consistent with EoE (34%). EGD identified characteristic abnormalities in 93%, which was significantly greater than UGI (67%). Inflammatory features were more frequently appreciated on EGD (74%) compared with UGI (21%). There was no significant difference in fibrostenotic changes observed on EGD (84%) versus UGI (73%). CONCLUSIONS: EGD and UGI have similar sensitivity for identifying the remodeling consequences of EoE; however, inflammatory features are better assessed on EGD. Inadequate sensitivity of UGI for composite features of EoE limits its capabilities as a diagnostic test, although radiologists' awareness significantly increases the diagnostic yield of UGI. UGI and EGD may identify fibrostenotic changes unappreciated by its counterpart and thus provide complementary information in select patients.

Improvement in Esophageal Distensibility in Response to Medical and Diet Therapy in Eosinophilic Esophagitis.

OBJECTIVES: We aimed to evaluate the effect of medical and diet therapies on esophageal distensibility assessed using the functional lumen imaging probe (FLIP) and the association of changes in esophageal distensibility with clinical outcomes in eosinophilic esophagitis (EoE). METHODS: Patients with EoE were evaluated with FLIP during endoscopy at baseline and following therapy without interval dilatation. Evaluation also included a validated patient-reported outcome (PRO; a positive PRO was considered at a 30% score improvement), mucosal biopsies, and scoring of endoscopic features of EoE. FLIP data were analyzed to calculate the distensibility plateau (DP). RESULTS: In all, 18 patients (ages 19-54 years; 4 female) treated with topical steroid (8), elimination diet (6), and/or proton-pump inhibitor (4 only treated with proton-pump inhibitor) were included. Follow-up testing occurred at a mean (range) of 14.6 (8-28) weeks. Improvement was observed in DP (13.9 (12.2-19.2) to 16.8 mm (15.8-19.2), P=0.007) and peak eosinophil count (45 (29-65) to 23 per high-power field (h.p.f.) (5-53), P=0.042). Nine patients had a positive symptomatic outcome. Six of 8 (75%) patients with a DP increase ≥2 mm had a positive PRO (P=0.077), while 2 of 7 (29%) patients that achieved an eosinophil count <15/h.p.f. had a positive PRO (P=0.167). CONCLUSIONS: Improvement in esophageal body distensibility can be achieved with medical and diet therapies without dilation in EoE. Improved DP appeared to be better indicator of symptomatic improvement than eosinophil count, supporting FLIP as a valuable outcome measure in EoE.

Esophageal microbiome in eosinophilic esophagitis.

OBJECTIVE: The microbiome has been implicated in the pathogenesis of a number of allergic and inflammatory diseases. The mucosa affected by eosinophilic esophagitis (EoE) is composed of a stratified squamous epithelia and contains intraepithelial eosinophils. To date, no studies have identified the esophageal microbiome in patients with EoE or the impact of treatment on these organisms. The aim of this study was to identify the esophageal microbiome in EoE and determine whether treatments change this profile. We hypothesized that clinically relevant alterations in bacterial populations are present in different forms of esophagitis. DESIGN: In this prospective study, secretions from the esophageal mucosa were collected from children and adults with EoE, Gastroesophageal Reflux Disease (GERD) and normal mucosa using the Esophageal String Test (EST). Bacterial load was determined using quantitative PCR. Bacterial communities, determined by 16S rRNA gene amplification and 454 pyrosequencing, were compared between health and disease. RESULTS: Samples from a total of 70 children and adult subjects were examined. Bacterial load was increased in both EoE and GERD relative to normal subjects. In subjects with EoE, load was increased regardless of treatment status or degree of mucosal eosinophilia compared with normal. Haemophilus was significantly increased in untreated EoE subjects as compared with normal subjects. Streptococcus was decreased in GERD subjects on proton pump inhibition as compared with normal subjects. CONCLUSIONS: Diseases associated with mucosal eosinophilia are characterized by a different microbiome from that found in the normal mucosa. Microbiota may contribute to esophageal inflammation in EoE and GERD.

Expression of cytosolic peroxiredoxins in Plasmodium berghei ookinetes is regulated by environmental factors in the mosquito bloodmeal.

The Plasmodium ookinete develops over several hours in the bloodmeal of its mosquito vector where it is exposed to exogenous stresses, including cytotoxic reactive oxygen species (ROS). How the parasite adapts to these challenging conditions is not well understood. We have systematically investigated the expression of three cytosolic antioxidant proteins, thioredoxin-1 (Trx-1), peroxiredoxin-1 (TPx-1), and 1-Cys peroxiredoxin (1-Cys Prx), in developing ookinetes of the rodent parasite Plasmodium berghei under various growth conditions. Transcriptional profiling showed that tpx-1 and 1-cys prx but not trx-1 are more strongly upregulated in ookinetes developing in the mosquito bloodmeal when compared to ookinetes growing under culture conditions. Confocal immunofluorescence imaging revealed comparable expression patterns on the corresponding proteins. 1-Cys Prx in particular exhibited strong expression in mosquito-derived ookinetes but was not detectable in cultured ookinetes. Furthermore, ookinetes growing in culture upregulated tpx-1 and 1-cys prx when challenged with exogenous ROS in a dose-dependent fashion. This suggests that environmental factors in the mosquito bloodmeal induce upregulation of cytosolic antioxidant proteins in Plasmodium ookinetes. We found that in a parasite line lacking TPx-1 (TPx-1KO), expression of 1-Cys Prx occurred significantly earlier in mosquito-derived TPx-1KO ookinetes when compared to wild type (WT) ookinetes. The protein was also readily detectable in cultured TPx-1KO ookinetes, indicating that 1-Cys Prx at least in part compensates for the loss of TPx-1 in vivo. We hypothesize that this dynamic expression of the cytosolic peroxiredoxins reflects the capacity of the developing Plasmodium ookinete to rapidly adapt to the changing conditions in the mosquito bloodmeal. This would significantly increase its chances of survival, maturation and subsequent escape. Our results also emphasize that environmental conditions must be taken into account when investigating Plasmodium-mosquito interactions.