Classification of patients with esophageal eosinophilia by patterns of sensitization revealed by a diagnostic assay for multiple allergen-specific IgEs.

BACKGROUND: Eosinophilic esophagitis (EoE) is considered to be an immunoglobulin E (IgE)-mediated allergic disorder. Our goal was to examine IgE-mediated allergic sensitization patterns in patients with esophageal eosinophilia (EE). METHODS: We enrolled subjects with EE who underwent evaluation with a diagnostic panel to document multiple allergen-specific IgEs. Statistically significant groups were identified by cluster analysis. We also defined allergens based on their characteristics including outdoor, indoor, plant, and animal allergens. RESULTS: We classified patients with EE into 3 distinct groups, including cluster 1 (n = 62) who were minimally sensitized to most allergens except pollen and house dust, cluster 2 (n = 30) who were hypersensitized to outdoor and plant allergens, and cluster 3 (n = 15) who were hypersensitized to most allergens, most notably to indoor and animal allergens. Dysphagia reported among those in clusters 1, 2, and 3 at 35.5%, 46.7%, and 73.3%, respectively, (p = 0.028) and EoE endoscopic reference scores (EREFS) at 3.0, 6.0, and 8.0, respectively, (p < 0.001) differed significantly between the 3 clusters. Those in cluster 3 had a significantly higher prevalence of dysphagia (35.5% vs. 73.3%, p = 0.030), and higher EREFS with respect to rings (0.3 vs. 0.9, p = 0.003) and strictures (0.0 vs. 0.13, p = 0.011) compared to those in cluster 1. CONCLUSIONS: IgE-mediated allergic sensitization patterns are associated with clinical features of patients with EE. Use of a diagnostic panel that detects multiple allergen-specific IgEs can help to explain the heterogeneous phenotype of this patient cohort.

Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study.

BACKGROUND: Eosinophilic oesophagitis is understood in terms of quantifiable histological, endoscopic, and molecular features. Data are scant for inter-relations of these features and their potential to identify distinct disease endotypes. We aimed to identify clinical-pathological correlations between endoscopic and histological disease variables by transcription profiling of the oesophagus of patients with eosinophilic oesophagitis of varying severity and disease activity states. METHODS: We did a cross-sectional study across ten hospital sites in the USA associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. We analysed oesophageal biopsy specimens taken from paediatric and adult patients with eosinophilic oesophagitis (discovery cohort), using the eosinophilic oesophagitis diagnostic panel (EDP), a set of 96 informative transcripts. Histological and endoscopic features were assessed by quantification of oesophageal eosinophils and use of the eosinophilic oesophagitis histology scoring system (HSS) and the eosinophilic oesophagitis endoscopic reference score (EREFS). Associations among the various histological, endoscopic, and molecular features were analysed by Spearman correlation. Results were replicated in a biologically independent, single-centre, validation cohort of patients with active eosinophilic oesophagitis. FINDINGS: The discovery cohort contained 185 samples and the validation cohort comprised 100 specimens. In the discovery cohort, EDP showed intersite consistency, significant correlation with oesophageal eosinophils (p<0·0001), and similar findings between paediatric and adult patients. Of eight HSS domains, basal zone hyperplasia correlated with the EDP (median Spearman ρ 0·47 [IQR 0·36-0·60]). Of five EREFS features, distal furrows correlated with the EDP (median Spearman ρ 0·42 [0·32-0·50]). By analysing active eosinophilic oesophagitis in the discovery cohort, the EDP identified three clusters associated with distinct endotypes (termed EoEe1-3) despite similar eosinophil levels. EoEe1 was associated with a normal-appearing oesophagus (risk ratio [RR] 3·27, 95% CI 1·04-10·27; p=0·0443), an inverse association with a history of oesophageal dilation (0·27, 0·09-0·82; p=0·0105) and showed relatively mild histological, endoscopic, and molecular changes. EoEe2 showed an inflammatory and steroid-refractory phenotype (RR 2·77, 95% CI 1·11-6·95; p=0·0376) and had the highest expression of inflammatory cytokines and steroid-responding genes. EoEe3 was associated with a narrow-calibre oesophagus (RR 7·98, 95% CI 1·84-34·64; p=0·0013) and adult onset (2·22, 1·19-4·12; p=0·0155), and showed the highest degree of endoscopic and histological severity and the lowest expression of epithelial differentiation genes. These endotypes were replicated in the validation cohort by clustering and with an eosinophilic oesophagitis endotype-prediction algorithm. INTERPRETATION: Our new disease classification stratifies patients with eosinophilic oesophagitis into subgroups with potential clinical and therapeutic significance and provides a framework for a precision medicine approach to eosinophilic oesophagitis. FUNDING: National Institutes of Health.

Pediatric Eosinophilic Esophagitis Endotypes: Are We Closer to Predicting Treatment Response?

Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven gastrointestinal disease that is characterized by esophageal eosinophilia. Currently, there are no Food and Drug Administration (FDA)-approved treatments for EoE, but the two most commonly prescribed therapies include topical corticosteroids and food elimination diets. Clinical trials have revealed a significant proportion of cases that are resistant to topical corticosteroids, and although we define EoE as a food antigen-driven disease, not all patients with EoE respond to elimination diets or even elemental diets. The varied response to treatments highlights the heterogeneity of EoE and the need for new treatment strategies. Despite the clinical differences in treatment response, predicting the outcome remains difficult since factors including age, histologic severity at diagnosis, atopic history, and anthropometrics are not predictive of treatment response. In our practice at an academic pediatric referral center, we observe distinct clinical EoE phenotypes, including cases with atopy, connective tissue disorders, or responsiveness to a proton pump inhibitor. Similar to the work in progress with asthma, stratification of patients with EoE by clinical phenotypes and/or molecular endotypes will likely assist with therapy selection and prediction of natural history. Molecular analysis with gene expression panels also shows promise in helping us classify patients based on molecular endotypes. In additional to the clinical and molecular classifications, more accurate histologic diagnostic criteria for EoE may help us tease out small differences between patient cohorts. Despite the leaps in knowledge over the past decade regarding EoE pathogenesis, it remains a challenge to predict the response to treatment. Future studies focused on molecular, genetic, and immunologic analyses of larger patient cohorts are needed to assist in identifying EoE phenotypes and endotypes as we attempt to improve patient outcomes in pediatric EoE.

Eosinophilic esophagitis in Japan: Focus on response to acid suppressive therapy.

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by esophageal dysfunction and dense eosinophilic infiltration of esophageal epithelium. According to clinical consensus and guidelines published in 2011, esophageal eosinophilia was classified into two entities based on response to proton pump inhibitor (PPI) administration: EoE and PPI-responsive esophageal eosinophilia (PPI-REE). We have performed a series of investigations to determine whether EoE is actually different from PPI-REE. Consistent with Western reports, more than half of our examined patients with symptomatic esophageal eosinophilia suggestive of EoE achieved histological remission with single PPI therapy. Furthermore, our comparisons of clinical, endoscopic, and histopathological findings between patients with EoE and those with PPI-REE revealed nearly no differences between them. We also compared gene expression profiles in mucosal biopsy specimens between those groups and found that microarray findings obtained from PPI-REE patients substantially overlapped with those from EoE patients, suggesting that both represent the same condition or are variations of a single disease. In addition, we have noted that more than half of EoE patients who show resistance to a PPI therapy respond to vonoprazan, a novel potassium-competitive acid blocker that has been shown to provide more potent and sustained suppression of gastric acid secretion than PPIs. Our results indicate that PPI-REE may constitute a subtype of EoE. Based on novel evidence including results obtained in our studies, the most recently updated guidelines have included responders to PPI therapy within the spectrum of EoE, abandoning the term PPI-REE.

Proposed criteria to differentiate heterogeneous eosinophilic gastrointestinal disorders of the esophagus, including eosinophilic esophageal myositis.

AIM: To define clinical criteria to differentiate eosinophilic gastrointestinal disorder (EoGD) in the esophagus. METHODS: Our criteria were defined based on the analyses of the clinical presentation of eosinophilic esophagitis (EoE), subepithelial eosinophilic esophagitis (sEoE) and eosinophilic esophageal myositis (EoEM), identified by endoscopy, manometry and serum immunoglobulin E levels (s-IgE), in combination with histological and polymerase chain reaction analyses on esophageal tissue samples. RESULTS: In five patients with EoE, endoscopy revealed longitudinal furrows and white plaques in all, and fixed rings in two. In one patient with sEoE and four with EoEM, endoscopy showed luminal compression only. Using manometry, failed peristalsis was observed in patients with EoE and sEoE with some variation, while EoEM was associated with hypercontractile or hypertensive peristalsis, with elevated s-IgE. Histology revealed the following eosinophils per high-power field values. EoE = 41.4 ± 7.9 in the epithelium and 2.3 ± 1.5 in the subepithelium; sEoE = 3 in the epithelium and 35 in the subepithelium (conventional biopsy); EoEM = none in the epithelium, 10.7 ± 11.7 in the subepithelium (conventional biopsy or endoscopic mucosal resection) and 46.8 ± 16.5 in the muscularis propria (peroral esophageal muscle biopsy). Presence of dilated epithelial intercellular space and downward papillae elongation were specific to EoE. Eotaxin-3, IL-5 and IL-13 were overexpressed in EoE. CONCLUSION: Based on clinical and histological data, we identified criteria, which differentiated between EoE, sEoE and EoEM, and reflected a different pathogenesis between these esophageal EoGDs.

Impact of Diagnostic Delay and Other Risk Factors on Eosinophilic Esophagitis Phenotype and Esophageal Diameter.

GOALS: Endoscopic features of eosinophilic esophagitis (EoE) are variable with at least 2 phenotypes. The goal of this study was to classify adult EoE patients based on esophageal phenotype and diameter, and assess an association between demographical and clinical histories to define EoE phenotypes and overall disease progression. METHODS: All consecutive patients with a confirmed diagnosis of EoE from 1988 to 2013 treated at University of South Florida were included. Patients were grouped into inflammatory or fibrostenotic phenotype, and further characterized by esophageal diameter: group 1 (6 to 9.9 mm), group 2 (10 to 16.9 mm), and group 3 (>17 mm-control). Significance level was set at 5%. RESULTS: Sixty-four adult patients met inclusion criteria. Sixty-one percent of patients (39/64) were defined as fibrostenotic and 39% (25/64) as inflammatory phenotype. There was a significant difference in mean time of delayed diagnosis in patients with <10 mm esophageal diameter (14.8 y) and patients with a diameter of 10 to 16.9 mm (11.1 y) compared with patients with an esophageal diameter of ≥17 mm (5 y); P=0.002 and 0.006, respectively. Patients on aspirin with delayed diagnosis (>7 y) were significantly more likely to present with strictures (<10 mm) compared with nonaspirin users [odds ratio (OR=7.0; 95% confidence interval (CI), 7.2-31.3; P=0.008]. Similar results were found with non-steroid anti-inflammatory drugs, smoking, and alcohol (OR=6.4; 95% CI, 1.6-26.4; P=0.01, OR=5.2; 95% CI, 1.4-20.1; P=0.02, and OR=6.4; 95% CI, 1.6-26.0; P=0.009), respectively. CONCLUSIONS: In our US population, a delay in diagnosis was shown to be associated with stricture formation in EoE confirming the Swiss experience. The results show the importance of reducing the diagnostic delay in EoE as there appears to be progression to fibrosis over time, aggravated by common medications and social habits.

Intrabolus pressure on high-resolution manometry distinguishes fibrostenotic and inflammatory phenotypes of eosinophilic esophagitis.

The aim of this investigation was to determine the motility patterns of inflammatory and fibrostenotic phenotypes of eosinophilic esophagitis (EoE) utilizing high-resolution manometry (HRM). Twenty-nine patients with a confirmed diagnosis of EoE according to clinicopathological criteria currently being managed at the Joy McCann Culverhouse Swallowing Center at the University of South Florida were included in the retrospective analysis. Only patients who completed HRM studies were included in the analysis. Patients were classified into inflammatory or fibrostenotic subtypes based on baseline endoscopic evidence. Their baseline HRM studies prior to therapy were analyzed. Manometric data including distal contractile integral, integrated relaxation pressure, and intrabolus pressure (IBP) values were recorded. HRM results were interpreted according to the Chicago Classification system. Statistical analysis was performed with SPSS software (Version 22, IBM Co., Armonk, NY, USA). Data were compared utilizing Student's t-test, χ(2) test, Pearson correlation, and Spearman correlation tests. Statistical significance was set at P < 0.05. A total of 29 patients with EoE were included into the retrospective analysis. The overall average age among patients was 40 years. Male patients comprised 62% of the overall population. Both groups were similar in age, gender, and overall clinical presentation. Seventeen patients (58%) had fibrostenotic disease, and 12 (42%) displayed inflammatory disease. The average IBP for the fibrostenotic and inflammatory groups were 18.6 ± 6.0 mmHg and 12.6 ± 3.5 mmHg, respectively (P < 0.05). Strictures were only seen in the fibrostenotic group. Of the fibrostenotic group, 6 (35%) demonstrated proximal esophageal strictures, 7 (41%) had distal strictures, 3 (18%) had mid-esophageal strictures, and 1 (6%) patient had pan-esophageal strictures. There was no statistically significant correlation between the level of esophageal stricture and degree of IBP. Integrated relaxation pressure, distal contractile integral, and other HRM metrics did not demonstrate statistical significance between the two subtypes. There also appeared no statistically significant correlation between patient demographics and esophageal metrics. Patients with the fibrostenotic phenotype of EoE demonstrated an IBP that was significantly higher than that of the inflammatory group.

Distinguishing GERD from eosinophilic oesophagitis: concepts and controversies.

Over the past three decades, the detection of oesophageal mucosal eosinophils has transitioned from a biomarker of GERD to a diagnostic criterion for eosinophilic oesophagitis (EoE). In GERD, oesophageal eosinophils are considered part of the chronic inflammatory response to acid reflux, whereas the marked eosinophilia in EoE is viewed as a central feature of the immune response to ingested food and/or environmental antigen stimulation. Descriptions of a considerable subset of patients with symptomatic, endoscopic and histological findings of EoE that resolve with PPI therapy has led to confusion and controversy regarding the distinction of EoE from GERD. Study findings indicate that PPI-responsive oesophageal eosinophilia (PPI-REE) more closely resembles EoE than GERD, both from a clinical and immunological aspect. Although responsiveness to PPI therapy should not be utilized to exclude EoE, PPI therapy is effective at reducing oesophageal eosinophilia in ∼40% of patients, and PPI therapy is both a safe and practical initial step in the management of patients with oesophageal eosinophilia. Ongoing studies elucidating the mechanism behind PPI-REE will improve our understanding and management of EoE. In this Review, the mechanisms and evidence that underlie the controversy in the distinction between GERD and EoE are evaluated.

Proton pump inhibitor responsive esophageal eosinophilia, a distinct disease entity?

Recent studies have suggested the existence of a patient population with esophageal eosinophilia that responds to proton pump inhibitor therapy. These patients are being referred to as having proton pump inhibitor responsive esophageal eosinophilia (PPI-REE), which is currently classified as a distinct and separate disease entity from both gastroesophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). The therapeutic effect of proton pump inhibitor (PPI) on PPI-REE is thought to act directly at the level of the esophageal mucosa with an anti-inflammatory capacity, and completely independent of gastric acid suppression. The purpose of this manuscript is to review the mechanistic data of the proposed immune modulation/anti-inflammatory role of the PPI at the esophageal mucosa, and the existence of PPI-REE as a distinct disease entity from GERD and EoE.

Administrative coding is specific, but not sensitive, for identifying eosinophilic esophagitis.

The use of administrative databases to conduct population-based studies of eosinophilic esophagitis (EoE) in the United States is limited because it is unknown whether the International Classification of Diseases, Ninth Revision (ICD-9) code for EoE, 530.13, accurately identifies those who truly have the disease. The aim of this retrospective study was to validate the ICD-9 code for identifying cases of EoE in administrative data. Confirmed cases of EoE as per consensus guidelines (symptoms of esophageal dysfunction and ≥15 eosinophils per high-power field on biopsy after 8 weeks of twice daily proton pump inhibitor therapy) were identified in the University of North Carolina (UNC) EoE Clinicopathologic Database from 2008 to 2010; 2008 was the first year in which the 530.13 code was approved. Using the Carolina Data Warehouse, the administrative database for patients seen in the UNC system, all diagnostic and procedure codes were obtained for these cases. Then, with the EoE cases as the reference standard, we re-queried the Carolina Data Warehouse over the same time frame for all patients seen in the system (n=308,372) and calculated the sensitivity and specificity of the ICD-9 code 530.13 as a case definition of EoE. To attempt to refine the case definition, we added procedural codes in an iterative fashion to optimize sensitivity and specificity, and restricted our analysis to privately insured patients. We also conducted a sensitivity analysis with 2011 data to identify trends in the operating parameters of the code. We identified 226 cases of EoE at UNC to serve as the reference standard. The ICD-9 code 530.13 yielded a sensitivity of 37% (83/226; 95% confidence interval: 31-43%) and specificity of 99% (308,111/308,146; 95% confidence interval: 98-100%). These operating parameters were not substantially altered if the case definition required a procedure code for endoscopy or if cases were limited to those with commercial insurance. However, in 2011, the sensitivity of the code had increased to 61%, while the specificity remained at 99%. The ICD-9 code for EoE, 530.13, had excellent specificity for identifying cases of EoE in administrative data, although this high specificity was achieved at an academic center. Additionally, the sensitivity of the code appears to be increasing over time, and the threshold at which it will stabilize is not known. While use of this administrative code will still miss a number of cases, those identified in this manner are highly likely to have the disease.

Development and validation of a registry-based definition of eosinophilic esophagitis in Denmark.

AIM: To develop and validate a case definition of eosinophilic esophagitis (EoE) in the linked Danish health registries. METHODS: For case definition development, we queried the Danish medical registries from 2006-2007 to identify candidate cases of EoE in Northern Denmark. All International Classification of Diseases-10 (ICD-10) and prescription codes were obtained, and archived pathology slides were obtained and re-reviewed to determine case status. We used an iterative process to select inclusion/exclusion codes, refine the case definition, and optimize sensitivity and specificity. We then re-queried the registries from 2008-2009 to yield a validation set. The case definition algorithm was applied, and sensitivity and specificity were calculated. RESULTS: Of the 51 and 49 candidate cases identified in both the development and validation sets, 21 and 24 had EoE, respectively. Characteristics of EoE cases in the development set [mean age 35 years; 76% male; 86% dysphagia; 103 eosinophils per high-power field (eos/hpf)] were similar to those in the validation set (mean age 42 years; 83% male; 67% dysphagia; 77 eos/hpf). Re-review of archived slides confirmed that the pathology coding for esophageal eosinophilia was correct in greater than 90% of cases. Two registry-based case algorithms based on pathology, ICD-10, and pharmacy codes were successfully generated in the development set, one that was sensitive (90%) and one that was specific (97%). When these algorithms were applied to the validation set, they remained sensitive (88%) and specific (96%). CONCLUSION: Two registry-based definitions, one highly sensitive and one highly specific, were developed and validated for the linked Danish national health databases, making future population-based studies feasible.

Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and grading system.

OBJECTIVE: Abnormalities are commonly identified during endoscopy in eosinophilic oesophagitis (EoE). There is no standardised classification to describe these features. This study aimed to evaluate the interobserver agreement of a grading system for the oesophageal features of EoE. METHOD: The proposed system incorporated the grading of four major oesophageal features (rings, furrows, exudates, oedema) and the presence of additional features of narrow calibre oesophagus, feline oesophagus, stricture and crepe paper oesophagus. Endoscopic videos from 25 patients with EoE and controls were reviewed by 21 gastroenterologists. Interobserver agreement was assessed by estimating multi-rater κ and the proportion of pairwise agreement. RESULTS: Using the original grading system, agreement for rings, furrows and exudates was moderate (κ=0.38-0.46, 56-65% agreement) but poor for oedema (κ=0.23, 51% agreement). Identification of narrow calibre oesophagus had fair agreement (κ=0.30, 74% agreement) while feline oesophagus had poor agreement (κ=0.15, 68% agreement). After collapsing the severity grading for oedema and furrows and eliminating poorly performing features of feline oesophagus and narrow calibre oesophagus, a modified grading system demonstrated good agreement for the four major features of EoE (κ=0.40-0.54, 71-81% agreement) and additional features of stricture and crepe paper oesophagus (κ=0.52 and 0.58, 79% and 92% agreement). CONCLUSIONS: The proposed system for endoscopically-identified oesophageal features of EoE defines common nomenclature and severity scores for the assessment of EoE disease activity. The system has good interobserver agreement among practising and academic gastroenterologists.