Significant Esophageal Eosinophilia Research Articles

A Multicenter Long-Term Cohort Study of Eosinophilic Esophagitis Variants and Their Progression to Eosinophilic Esophagitis Over Time.

Eosinophilic esophagitis (EoE) variants have been recently characterized as conditions with symptoms of esophageal dysfunction resembling EoE, but absence of significant esophageal eosinophilia. Their disease course and severity have yet to be determined. Patients from 6 EoE centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <15/hpf in esophageal biopsies and absence of gastroesophageal reflux disease with at least one follow-up visit were included. Clinical, (immuno)histological, and molecular features were determined and compared with EoE and healthy controls. We included 54 patients with EoE variants (EoE-like esophagitis 53.7%; lymphocytic esophagitis 13.0%; and nonspecific esophagitis 33.3%). In 8 EoE-like esophagitis patients, EoE developed after a median of 14 months (interquartile range 3.6-37.6). Such progression increased over time (17.6% year 1, 32.0% year 3, and 62.2% year 6). Sequential RNA sequencing analyses revealed only 7 genes associated with this progression (with TSG6 and ALOX15 among the top 3 upregulated genes) with upregulation of a previously attenuated Th2 pathway. Immunostaining confirmed the involvement of eosinophil-associated proteins (TSG6 and ALOX15) and revealed a significantly increased number of GATA3-positive cells during progression, indicating a Th1/Th2 switch. Transition from one EoE variant (baseline) to another variant (during follow-up) was seen in 35.2% (median observation time of 17.3 months). Transition of EoE variants to EoE suggests the presence of a disease spectrum. Few genes seem to be associated with the progression to EoE with upregulation of a previously attenuated Th2 signal. These genes, including GATA3 as a Th1/Th2 switch regulator, may represent potential therapeutic targets in early disease pathogenesis.

Characterization of eosinophilic esophagitis variants by clinical, histological, and molecular analyses: A cross-sectional multi-center study.

ObjectivePhysicians are increasingly confronted with patients presenting with symptoms of esophageal dysfunction resembling eosinophilic esophagitis (EoE), but absence of significant esophageal eosinophilia. The purpose of this study was to characterize and classify this group of EoE variants.DesignPatients from six EoE‐centers with symptoms of esophageal dysfunction, but peak eosinophil counts of <60/mm2 (<15/hpf) in esophageal biopsies and absence of gastro‐esophageal reflux disease (GERD) were included. Clinical, endoscopic, (immuno)‐histological, and molecular features were determined and compared with EoE, GERD, and healthy controls.ResultsWe included 69 patients with EoE variants. Endoscopic abnormalities were found in 53.6%. We identified three histological subtypes: EoE‐like esophagitis (36/69, 52.2%), lymphocytic esophagitis (14/69, 20.3%), and non‐specific esophagitis (19/69, 27.5%). Immunohistochemistry revealed—in contrast to EoE—no significant increase in inflammatory cell infiltrates compared with GERD and healthy controls, except for lymphocytes in lymphocytic esophagitis. EoE‐typical Th2‐response was absent in all EoE variants. However, considerable structural changes were detected based on histology and protein expression. Using next generation mRNA sequencing, we found the three EoE variants to have distinct molecular fingerprints partially sharing pronounced traits of EoE. Hierarchical sample clustering of RNA sequencing data confirmed the presence of an EoE‐like (characterized by eotaxin‐3 expression), non‐specific, and lymphocytic variant cluster (characterized by CD3 cells and TSLP expression).ConclusionAll EoE variants are clinically and histologically active conditions despite the absence of esophageal eosinophilia. EoE variants appear to be part of a disease spectrum, where classical EoE represents the most common and apparent phenotype.

Esophageal Fibrosis in Eosinophilic Gastrointestinal Diseases.

Eosinophilic esophagitis (EoE), the most common eosinophilic gastrointestinal disease (EGID), is associated with lamina propria (LP) fibrosis. The relationship of EoE to other EGIDs is still unclear. We frequently observe cases of concurrent esophageal eosinophilia and extra-esophageal mucosal eosinophilia. The purpose of this study was to compare clinical, endoscopic, and histologic features, as well as the prevalence of esophageal LP fibrosis in children with EGID and concurrent esophageal eosinophilia to children with EoE. We also examine the current practices of pathologists in evaluating fibrosis. We reviewed esophageal biopsies from index cases of EoE (N = 38), EGID with significant esophageal eosinophilia (≥15 eos/hpf) (EGID-SEE, N = 38), EGID with mild esophageal eosinophilia (1-14 eos/hpf) (EGID-MEE, N = 12), and EGID with no esophageal eosinophilia (EGID-NEE, N = 12) for LP presence, adequacy, and fibrosis. EoE and EGID-SEE cases share similar demographics, esophageal endoscopic features, and symptoms. A majority of EGID-SEE cases (71%) had adequate LP for the evaluation of fibrosis, similar to EoE cases (87%). The prevalence of esophageal fibrosis in EoE (79%) and EGID-SEE (55%) cases were similar, whereas no fibrosis was detected in the EGID-MEE and EGID-NEE cases. The fibrosis was patchy and often detected in the distal esophagus. Fourteen cases were reclassified from their original clinical diagnosis as having fibrosis by the study pathologists. Cases of EGID-SEE have overlapping features with EoE, suggesting that all EGIDs are part of a disease continuum. A consensus for the evaluation of LP fibrosis is needed.

Esophageal Biopsies for All? The Diagnostic Yield of Esophageal Biopsies in Patients Referred for EGD to Investigate Dysphagia in Excluding Significant Esophageal Eosinophilia When No Other Cause Is Apparent

Esophageal Biopsies for All? The Diagnostic Yield of Esophageal Biopsies in Patients Referred for EGD to Investigate Dysphagia in Excluding Significant Esophageal Eosinophilia When No Other Cause Is Apparent

Eosinophilic esophagitis: current perspectives from diagnosis to management

Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disease of the esophagus characterized by symptoms related to esophageal dysfunction, as well as significant esophageal eosinophilia. Although dense eosinophilia is the hallmark of EoE, other characteristic histologic features have been described that may help distinguish EoE from other competing diagnoses, although none are specific to EoE. One or more foods and, at times, environmental allergens trigger EoE. Left untreated, esophageal inflammation in EoE may lead to esophageal remodeling and stricture formation. Symptoms in EoE vary with age, as they relate to the progression of the disease from an inflammatory to a fibrostenotic phenotype over time. There are currently no U.S. Food and Drug Administration-approved therapies for EoE. Current options include various dietary-restriction therapies, topical corticosteroids, and esophageal dilations. Several emerging therapies aiming at restoring the esophageal barrier function or targeting various inflammatory cells or their mediators are under investigation.

Transcriptome analysis of proton pump inhibitor–responsive esophageal eosinophilia reveals proton pump inhibitor–reversible allergic inflammation

Esophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery. In this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities. We evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE. The EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment. These findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.

Letter: Epstein–Barr virus status may be especially important in paediatric IBD populations

Remission in proton pump inhibitor-responsive esophageal eosinophilia correlates with down regulation of eotaxin-3 and TH2 cytokines, similarly to eosinophilic esophagitis after steroids. Gastroenterology 2013; 144(Suppl. 1): S-484. 7. Dranove JE, Horn DS, Davis MA, et al. Predictors of response to proton pump inhibitor therapy among children with significant esophageal eosinophilia. J Pediatr 2009; 154: 96–100. 8. Sayej WN, Patel R, Baker RD, et al. Treatment with high-dose proton pump inhibitors helps distinguish eosinophilic esophagitis from noneosinophilic esophagitis. J Pediatr Gastroenterol Nutr 2009; 49: 393–9. 9. Peterson KA, Thomas KL, Hilden K, et al. Comparison of esomeprazole to aerosolized, swallowed fluticasone for eosinophilic esophagitis. Dig Dis Sci 2010; 55: 1313–9. 10. Abe Y, Iijima K, Ohara S, et al. A Japanese case series of 12 patients with esophageal eosinophilia. J Gastroenterol 2011; 46: 25–30. 11. Francis DL, Foxx-Orenstein A, Arora AS, et al. Results of ambulatory pH monitoring do not reliably predict response to therapy in patients with eosinophilic oesophagitis. Aliment Pharmacol Ther 2012; 35: 300–7. 12. Schroeder S, Capocelli KE, Masterson JC, et al. Effect of proton pump inhibitor on esophageal eosinophilia. J Pediatr Gastroenterol Nutr 2013; 56: 166–72. 13. Fujiwara Y, Sugawa T, Tanaka F, et al. A multicenter study on the prevalence of eosinophilic esophagitis and PPI-responsive esophageal eosinophilic infiltration. Intern Med 2012; 51: 3235–9. 14. Moawad FJ, Schoepfer A, Ally MR, et al. Eosinophilic esophagitis and proton pump inhibitor responsive esophageal eosinophilia: are they one and the same? Gastroenterology 2013; 144(Suppl. 1): S489 (Su1845). 15. Mangla S, Singal G, Hornick JL, et al. Clinical predictors of response to proton pump inhibitors in patients with esophageal eosinophilia. Gastroenterology 2013; 144(Suppl. 1): S495–6 (Su1866). 16. Dellon ES, Speck O, Woodward K, et al. Clinical and endoscopic characteristics do not reliably differentiate PPIresponsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: a prospective cohort study. Am J Gastroenterol 2013; doi: 10.1038/ajg.2013.363 [Epub ahead of print].

880 Acid Suppression Restores Impaired Esophageal Mucosal Integrity in Patients With Esophageal Eosinophilia

Introduction: Gastroesophageal reflux and allergies are both thought to play a role in the pathophysiology of eosinophilic esophagitis (EoE). It has been suggested that acid-induced esophageal mucosal damage promotes transepithelial allergen flux. Anecdotal evidence suggests that patients with typical signs and symptoms of EoE benefit from acid-suppressive therapy. The aim of our study was to evaluate esophageal mucosal integrity in patients with significant esophageal eosinophilia (SEE) and to study the effects of acid-suppressive therapy with PPI on symptoms, endoscopic signs, mucosal integrity, dilation of epithelial intercellular spaces (DIS), and peak eosinophilia and mastocytosis. Methods: We included 11 untreated adults with SEE (.15 eosinophils/hpf) and predominant symptoms of dysphagia and/or food impaction and typical endoscopic signs of EoE, and 11 controls. All study subjects underwent endoscopy at baseline; in SEE patients endoscopy was repeated after 8 weeks of esomeprazole 40 mg BID. Esophageal mucosal integrity was measured in vivo during endoscopy with a through-the-scope electrical tissue impedance spectroscopy probe (ETIS) at 5 cm proximal of the LES. At the same location, we obtained 2 biopsies for electron microscopic analysis of DIS and 4 biopsies for mucosal integrity experiments in Ussing chambers. In the Ussing chambers, we measured transepithelial electrical resistance (TER) and transmucosal flux of fluorescently-labelled molecules sized 0.3 and 40 kDa (size of food allergens) during 1 hour. In SEE patients, we additionally scored symptoms and endoscopic signs of EoE. Furthermore, eosinophilia and mastocytosis were scored in biopsies taken at the proximal, midand distal esophagus of SEE patients at each endoscopy. Results: Both structural (DIS) and in vivo and in vitro functional measurements (ETIS, TER, and molecule flux) of mucosal integrity showed significant impairment in SEE patients compared to HC (table 1). After acid-suppressive therapy, mucosal integrity was significantly improved in patients with SEE, but still did not reach the levels seen in controls. Esophageal peak eosinophilia andmastocytosis as well as dysphagia and endoscopic signs of EoE also decreased after acid-suppressive therapy. Conclusion: Patients with SEE have an impaired esophageal mucosal integrity, which is partially restored after acid-suppressive therapy. The observed reduction of transmucosal flux of molecules with a similar size as food allergens after acidsuppressive therapy supports the hypothesis that acid-induced mucosal damage facilitates transepithelial food allergen flux, which results in esophageal eosinophilia. Study parameters in HC and SEE patients

S1093 Significant Esophageal Eosinophilia and Typical Endoscopic Features are Highly but Not Exclusively Specific for Eosinofilic Esophagitis

S1093 Significant Esophageal Eosinophilia and Typical Endoscopic Features are Highly but Not Exclusively Specific for Eosinofilic Esophagitis

Predictors of Response to Proton Pump Inhibitor Therapy Among Children With Significant Esophageal Eosinophilia

Dranove JE, Horn DS, Davis MA, Kernek KM, Gupta SK. J Pediatr . 2009;154(1):96–100 PURPOSE OF THE STUDY. To determine predictors of the histologic response to proton pump inhibitor (PPI) therapy among children with significant esophageal eosinophilia (SEE), defined as ≥15 eosinophils per high-powered field (hpf) on esophageal mucosal biopsy (EMB). STUDY POPULATION. Patients between the ages of 1 and 18 years who underwent esophagogastroduodenoscopy between 1999 and 2006 were eligible for the study. Indications for esophagogastroduodenoscopy included regurgitation, vomiting, heartburn, abdominal pain, dysphagia, …

Predictors of Response to Proton Pump Inhibitor Therapy among Children with Significant Esophageal Eosinophilia

To determine predictors of histological response to proton pump inhibitor (PPI) therapy among children with significant esophageal eosinophilia (SEE), defined as >or=15 eosinophils per high powered field (eos/hpf) on esophageal mucosal biopsy (EMB). Response to PPI therapy among children with SEE treated with PPI who underwent repeat EMB was studied retrospectively. Response was defined as <5 eos/hpf on repeat EMB. Characteristics of responders and nonresponders were analyzed. Of 326 patients (ages 1 through 18 years) diagnosed with SEE over a 7-year period, 43 (mean age, 8.5 years; 67% males) met inclusion criteria. After PPI therapy, 17 patients (40%) were responders. There were no significant differences in demographics, presenting symptoms, endoscopic, or histological findings between responders and nonresponders. Among patients with 15 to 20 eos/hpf on EMB, 50% were responders; among patients with >20 eos/hpf on EMB, 29% were responders. Seven of 17 (41%) patients with abnormal pH monitoring and 5 of 11 (45%) patients with normal monitoring were responders. Forty percent of patients with SEE demonstrated histological response to PPI therapy. None of the clinical characteristics evaluated predicted response, and response was not dependent on results of pH study. The role of PPI therapy in treating SEE warrants further prospective investigation.

Primary Eosinophilic Esophagitis in Children: SuccessfulTreatment With Oral Corticosteroids

Liacouras CA, Wenner WJ, Brown K, Ruchelli EJ Pediatr Gastroenterol Nutr.261998380To describe a group of children with gastroesophageal reflux disease (GERD) and persistent esophageal eosinophilia despite traditional antireflux therapy.From a total of 1809 children evaluated prospectively over a 2.5-year period for symptoms of GERD, 20 were identified with persistent symptoms and esophageal eosinophilia despite aggressive therapy with omeprazole and cisapride.The 20 children were treated with 1.5 mg/kg/d of oral methylprednisolone for 4 weeks. All patients underwent an extensive evaluation before treatment, including questionnaires about symptoms, blood counts, serum chemistries, immunoglobulin E (IgE) level, pH probe, and endoscopy. After treatment the questionnaires and endoscopy with biopsies of the esophagus, stomach, and duodenum were repeated.Histologic findings in pretreatment esophageal biopsies in the 20 children diagnosed with primary eosinophilic esophagitis revealed significantly greater eosinophilia (34.2 ± 9.6 eosinophils per high power field [HPF]) compared with biopsies from children with GERD who responded to medical therapy (2.26 ± 1.16 eosinophils per HPF, P < .001). After corticosteroid therapy, 19 of 20 children with primary eosinophilic esophagitis had dramatic clinical and histological improvement (1.5 ± 0.9 eosinophils per HPF). After 12 months of follow-up, 10 patients had remained asymptomatic and 9 redeveloped symptoms. In those with a recurrence of symptoms, treatment with an elemental diet lead to an improvement in 7, while 2 remained symptomatic and required further corticosteroid therapy.Children with GERD who were unresponsive to aggressive medical treatment and who displayed significant esophageal eosinophilia had both clinical and histologic improvement after oral corticosteroid therapy.This is a very useful study from a large pediatric gastroenterology clinic. It points out that the presence of significant eosinophilia in the esophagus may be a very different entity than standard GERD. Although the major conclusion that corticosteroids are helpful in this population is justified, from an allergist's viewpoint I would rather look for a dietary cause before embarking on a course of steroids. Their approach, however, of looking for food allergy only in those whose symptoms recurred after steroid therapy is also reasonable, especially because they found that a relatively short course of corticosteroid therapy was effective. In any event, we should not lose sight of the fact that the presence of significant eosinophilia is commonly associated with allergy, no matter where the eosinophils are located.