Proton Pump Inhibitor-responsive Esophageal Eosinophilia Research Articles

Proton Pump Inhibitor Therapy for Eosinophilic Esophagitis: History, Mechanisms, Efficacy, and Future Directions.

Over the past decade, the role of proton pump inhibitor (PPI) medication has evolved from a diagnostic tool for Eosinophilic Esophagitis (EoE), by excluding patients with PPI responsive esophageal eosinophilia (PPI-REE), to a therapy for EoE. This transition resulted from the Updated International Consensus Diagnostic Criteria for Eosinophilic Esophagitis: Proceedings of the Appraisal of Guidelines for Research and Evaluation II (AGREE) Conference to support PPI therapy for EoE in children and adults. Additional recent advances have suggested a role for genetic variations that might impact response to PPI therapy for EoE. This review article will explore a brief background of EoE, the evolution of PPI therapy for EoE and its proposed mechanisms, efficacy and safety in children and adults, and considerations for future PPI precision medicine in patients with EoE.

Swallowed Steroids and Adrenal Insufficiency in Eosinophilic Esophagitis

Swallowed Steroids and Adrenal Insufficiency in Eosinophilic Esophagitis

Eosinophilic Esophagitis and Proton Pump Inhibitor-Responsive Esophageal Eosinophilia; Single Center Experience

Objective: Eosinophilic esophagitis is a chronic inflammatory disease characterized by eosinophilic infiltration and esophagus dysfunction symptoms. Proton pump inhibitor responsive esophageal eosinophilia is similar to eosinophilic esophagitis in terms of clinical, laboratory, genetic expression profile, endoscopic and histopathological features. In this study, we aimed to share demographic features, clinical, laboratory and histopathological findings, and treatment outcomes of patient with eosinophilic esophagitis and proton pump inhibitor responsive esophageal eosinophilia. Materials and Methods: Demographic features, laboratory, endoscopic and histopathological findings, and treatment outcomes of patients followed in our clinic were recorded retrospectively since January 2010. Results: Four thousand six hundred fifty five patients underwent esophagogastroscopy since 2010 in our clinic and 0.4% (n=18) of these patients were diagnosed with eosinophilic esophagitis, and 0.2% (n=8) with proton pump inhibitor-responsive esophageal eosinophilia. The main symptom of patients with eosinophilic esophagitis were food impaction/dysphagia (n=5, 27.8%) and chronic abdominal pain (n=5, 27.8%). Allergen sensitization was found in 14 (77.8%), increased IgE in 12 (66.7%), peripheral eosinophilia in 12 (66.7%), and food allergen sensitization in 10 patients (55.6%) with eosinophilic esophagitis. On histopathological examination, the mean intraepithelial eosinophil count was 48.9 ± 30.9 cells / HPF (400x). When patients with eosinophilic esophagitis (group 1) and proton pump inhibitor-responsive esophageal eosinophilia (group 2) were compared, it was found that chronic abdominal pain was more common in the proton pump inhibitor-responsive esophageal eosinophilia group and food allergen sensitization in the eosinophilic esophagitis group (p<0.05). Total IgE, peripheral eosinophil count and intraepithelial eosinophil count were higher in the eosinophilic esophagitis group, but the differences were not statistically significant. Diet (n=11), medical (n=17) and dilatation (n=1) therapies were used in the eosinophilic esophagitis group. Fibrosis was detected on the histopathological examination in two patients who underwent TED and then SED was started. No side effect was seen any group in long term. Conclusion: Eosinophilic esophagitis and proton pump inhibitor-responsive esophageal eosinophilia have similar laboratory and histopathological features but eosinophilic esophagitis should be suspected more frequently in the presence of food allergy. Long-term followup is essential in patients with eosinophilic esophagitis.

Histologic similarities in children with eosinophilic esophagitis and proton pump inhibitor–responsive esophageal eosinophilia

The EPX histologic scoring system can be used to differentiate children with EoE and PPI-REE relative to GERD, supporting the relationship between these 2 groups and enhancing current diagnostic and treatment approaches.

Eosinophilic esophagitis in Japanese patients: A mild and slow-progressing disorder.

Background and aimAwareness of eosinophilic esophagitis (EoE) has gradually increased in Japan, therefore the characteristics of this disease in the Japanese patient population need to be elucidated. This study aimed to investigate the features of EoE in the Japanese population.MethodsDuring a 2-year period, all gastrointestinal endoscopies were performed with maximum attention being paid to identify EoE through endoscopic findings. Clinical features and findings were analyzed among this population.ResultsAmong a total of 8589 patients (general gastrointestinal endoscopy, performed for evaluation of symptoms or disease follow-up: 3669; medical check-up endoscopy, routinely performed in asymptomatic patients: 4920), 17 patients (0.20%) were diagnosed with esophageal eosinophilia (mean age ± standard deviation: 44±11.9 years; 1 female). Only 6 patients with esophageal eosinophilia were diagnosed by general gastrointestinal endoscopy; among them, 3 patients had dysphagia and 3 were asymptomatic. The remaining 11 patients were diagnosed by medical check-up endoscopy. All patients were treated with a proton pump inhibitor (PPI); 5 were diagnosed with EoE and 12 with PPI responsive esophageal eosinophilia. Chronological endoscopy analysis showed that EoE findings could be observed for a mean of 6.1 years prior to diagnosis, and the disease did not significantly progress in severity.ConclusionsMost Japanese patients with EoE have mild and slowly progressing disease, which can be diagnosed when close attention is paid to the endoscopic findings. Medical check-up endoscopy in Japan could be a great opportunity for the early diagnosis of EoE.

Gastro-oesophageal reflux disease and eosinophilic oesophagitis: What is the relationship?

Eosinophilic oesophagitis (EoE) and gastro-oesophageal reflux disease (GORD) are the most common causes of chronic oesophagitis and dysphagia associated with oesophageal mucosal eosinophilia. Distinguishing between the two is imperative but challenging due to overlapping clinical and histological features. A diagnosis of EoE requires clinical, histological and endoscopic correlation whereas a diagnosis of GORD is mainly clinical without the need for other investigations. Both entities may exhibit oesophageal eosinophilia at a similar level making a histological distinction between them difficult. Although the term proton-pump inhibitor responsive oesophageal eosinophilia has recently been retracted from the guidelines, a relationship between EoE and GORD still exists. This relationship is complex as they may coexist, either interacting bidirectionally or are unrelated. This review aims to outline the differences and potential relationship between the two conditions, with specific focus on histology, immunology, pathogenesis and treatment.

Efficacy of Pharmacologic Therapy for Eosinophilic Esophagitis: A Systematic Review and Network Meta-Analysis.

In order to provide a comparative evaluation of available pharmacologic treatments for eosinophilic esophagitis (EoE), we conducted a network meta-analysis. A variety of pharmacologic treatments for EoE have been reported, however there exists a paucity of direct comparisons. We searched randomized controlled trials using MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials database through December 2014. Studies were analyzed using a random-effects network meta-analysis to identify the most effective therapy. Subgroup analysis was performed among studies that excluded gastroesophageal reflux disease or proton-pump inhibitor responsive esophageal eosinophilia, and also among pediatric and adult populations. The ranking probability for the efficacy of each treatment was analyzed. Consistency of the included randomized controlled trials was checked by applying inconsistency and node-splitting models. Eleven studies of a total of 456 patients were identified. Six pharmacologic treatments (budesonide suspension and viscous, fluticasone, prednisone, esomeprazole, and mepolizumab) and placebo were included in our analysis. Meta-analysis showed superiority of budesonide viscous, budesonide suspension, and fluticasone over placebo. Network meta-analysis demonstrated the rank order of efficacy as budesonide viscous, esomeprazole, prednisone, budesonide suspension, fluticasone, mepolizumab, and placebo. The results were consistent from the inconsistency model analysis and node-splitting analysis. Subgroup analysis demonstrated prednisone, budesonide suspension, and esomeprazole were the most effective when network meta-analyses were performed among studies that excluded gastroesophageal reflux disease or proton-pump inhibitor responsive esophageal eosinophilia, and among pediatric and adult populations, respectively. On the basis of this network meta-analysis, viscous budesonide was shown to be the most effective pharmacologic therapy for EoE among the reported pharmacologic treatments.

Eosinophilic esophagitis: latest insights from diagnosis to therapy.

Eosinophilic esophagitis (EoE) represents a chronic, local immune-mediated esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Other systemic and local causes of esophageal eosinophilia should be excluded. Clinical manifestations or pathologic data should not be interpreted in isolation. EoE was first described as a distinct disease entity in 1993. Most patients are diagnosed with underlying food allergies. The first diagnostic and therapeutic guidelines were published in 2007 with a first update in 2011. In 2017, new international guidelines were published based on the GRADE methodology. These guidelines provide, among many other topics, insights on the role of proton pump inhibitor-responsive esophageal eosinophilia. Over the last two decades, considerable progress was made by stakeholders regarding the understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization of assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. This brief review provides further insights into latest diagnostic and therapeutic advances.

The Role of Proton Pump Inhibitors in the Management of Pediatric Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, local, immune-mediated disorder characterized by symptoms of esophageal dysfunction and the presence of a dense eosinophilic infiltrate in the esophageal mucosa. Consensus diagnostic recommendations for EoE diagnosis included absence of histological response to a proton-pump inhibitor (PPI) trial, to exclude gastro-oesophageal reflux disease (GERD)-associated esophagitis. This recommendation exposed an entity known as “proton pump inhibitor-responsive esophageal eosinophilia” (PPI-REE), which refers to patients with EoE phenotype who are PPI-responsive and do not present GERD. In recent years, there is evidence which indicates that PPI-REE is a sub-phenotype of EoE with similar clinical, endoscopic, histological and genetic characteristics, as well as Th2-related inflammatory response. As a result, PPIs should be considered another treatment for EoE and not a diagnostic tool. PPI-REE was originally described in a case series which included two children and in two retrospective pediatric series. Later, a prospective pediatric study showed a high rate of response to PPIs at high doses with long-term maintenance at lower doses. PPI monotherapy in children with esophageal eosinophilia (EE) has been observed to reduce eotaxin-3 expression in epithelial cells and to practically reverse the allergy and inflammatory transcriptome. These data reveal that PPIs are also an effective treatment for EoE in pediatric patients, although more studies are necessary in order to define the best induction and maintenance treatment regimen, the long-term safety profile and their influence on the occurrence of fibrosis and esophageal remodeling.

Impacto Alimentar Esofágico, um Dilema Diagnóstico

O impacto alimentar esofágico é uma situação que na maioria dos casos é secundária a patologia esofágica congénita ou adquirida, podendo constituir a primeira manifestação da doença. Descreve-se um rapaz, 11 anos, saudável, com sialorreia e dor retrosternal que surgiram subitamente durante o jantar. Foi submetido a endoscopia digestiva alta, que revelou um fragmento de carne impactado no terço distal do esófago (que foi extraído) e estrias longitudinais na mucosa. A análise histológica das biópsias esofágicas foi compatível com eosinofilia esofágica. Iniciou terapêutica com inibidor da bomba de protões com melhoria clínica e histológica. O diagnóstico diferencial das principais causas de impacto alimentar associadas a eosinofilia esofágica, nomeadamente esofagite eosinofílica, doença do refluxo gastroesofágico e eosinofilia esofágica respondedora a inibidor da bomba de protões, constitui um desafio clínico.&#x0D; Recebido: 15/10/2016 - Aceite: 11/12/2017

Ankylosaurus back sign: novel endoscopic finding in esophageal eosinophilia patients indicating proton pump inhibitor response

Background and study aims Characteristic endoscopic findings, such as linear furrows, rings, and whitish exudates, indicate the presence of esophageal eosinophilia (EE), though no specific findings are known to distinguish eosinophilic esophagitis (EoE) from proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). Here, we present a novel endoscopic finding in some EE patients possessing a linear longitudinal arrangement of whitish nodules with the appearance of the back of an Ankylosaurus dinosaur, termed Ankylosaurus back sign (ABS), and evaluations of its significance in affected patients. Patients and methods Fifty-five patients diagnosed with EE (≥ 15 eosinophils/high power field) who were treated at our hospital and shown to evaluate a PPI response were enrolled. Endoscopic findings at baseline and clinical parameters were retrospectively reviewed. Furthermore, the clinicopathological features of patients with ABS, as well as the relationship between its presence and PPI response were evaluated. Results Fifty-five patients (47 males, 8 females) with EE (17 with EoE, 38 with PPI-REE) were evaluated, of whom 50 (90.9 %) had linear furrows, the most frequently found feature, while ABS was found in 9 (16.4 %). Inter-observer agreement was substantial for ABS (κ 0.77). Interestingly, all patients with ABS had PPI-REE. Our findings revealed that the presence of ABS was closely associated with reflux esophagitis (RE) in patients with PPI-REE. Conclusions Although ABS was less frequent than typical endoscopic findings such as linear furrows in EE, this novel finding was closely associated with PPI-REE accompanied with RE. The clinical implications of ABS in patients with EE should be investigated further.

A Single-center Experience of Esophageal Eosinophilia.

Esophageal eosinophilia occurs in many conditions, including eosinophilic esophagitis (EoE) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE), which have been increasingly recognized in Western countries. There have been only a few reports in Korea. Here, we evaluated the clinical and endoscopic characteristics of patients with esophageal eosinophilia from our experience. Nineteen patients were diagnosed with esophageal eosinophilia based on typical symptoms, endoscopic features, esophageal eosinophilia with ≥15 eosinophils/high power field, and response to medication by PPI. Symptoms, endoscopic and pathological findings were evaluated. Of the 19 patients, 2 patients were diagnosed with EoE, 7 patients were diagnosed with PPI-REE, and 10 patients were undetermined due to loss to follow-up. Among these 19 patients, dysphagia was present in 11, and heartburn, dyspepsia and refluxin 8. Sixteen patients had common endoscopic features, such as longitudinal furrows, concentric rings, strictures, and white plaques; however, 3 patients had normal findings. Nine patients underwent endoscopy at the time of follow-up. Two patients had complete resolution, and 3 had partial resolution. However, 4 patients showed no endoscopic changes. All patients showed symptom improvements. The clinical and endoscopic characteristics of both groups in Korea were undistinguishable. However, after treatment, endoscopic findings were different between the two groups. Large-scale studies are warranted to confirm our findings.

Lack of proton pump inhibitor trial prior to commencing therapy for eosinophilic esophagitis is common in the community.

Eosinophilic esophagitis is characterized by eosinophil inflammation restricted to the esophagus and the resulting symptoms of esophageal dysfunction. Critical to the diagnosis of eosinophilic esophagitis is a trial of proton pump inhibitor therapy to exclude alternative causes of esophageal eosinophilia such as proton pump inhibitor-responsive esophageal eosinophilia. While consensus guidelines recommend a proton pump inhibitor trial prior to diagnosis, little is known about its implementation in clinical practice. The primary aim of this study is to assess the frequency of proton pump inhibitor trial prior to the diagnosis of eosinophilic esophagitis in community practice. The secondary aim is to assess the frequency of other treatments for eosinophilic esophagitis, including topical steroids and/or dietary therapy, in patients who did not undergo a proton pump inhibitor trial prior to diagnosis or who had an alternative diagnosis to eosinophilic esophagitis upon completed workup. We conducted a single-center, case series of patients referred to the Hospital of the University of Pennsylvania for eosinophilic esophagitis management between 2010 and 2015. This case series consisted of 125 patients who were referred from community practitioners with a presumptive diagnosis of eosinophilic esophagitis. Upon review, 90 out of 125 (72%) patients had not had a proton pump inhibitor trial or esophageal pH testing prior to the diagnosis of eosinophilic esophagitis being made. Of these patients, 77.8% (70/90) had already received either topical steroid or dietary therapy for presumed eosinophilic esophagitis. Of the 125 patients initially diagnosed with eosinophilic esophagitis, 32 (25.6%) were found to have an alternative diagnosis, and 79.2% of this subset of patients (25/32) had previously received topical steroid or dietary therapy. This study demonstrates that a substantial number of patients with presumed eosinophilic esophagitis have not had a proton pump inhibitor trial prior to diagnosis in community practice. This led to the misclassification of patients and potentially to the use of less optimal medical therapies in a substantial number of these patients.

Eosinophilic Esophagitis in Children and Adolescents

Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus characterized by symptoms of esophageal dysfunction in association with histologic evidence of eosinophilic infiltration of the esophageal mucosa. The diagnosis is based on esophageal biopsies showing more than 15 eosinophils per high-power field in the absence of pathologic gastroesophageal reflux. It can present with a wide array of upper gastrointestinal tract symptoms. Babies and toddlers typically present with feeding intolerance or refusal, vomiting, and failure to thrive. Older children often present with abdominal pain and reflux symptoms, whereas adolescents and adults typically present with solid-food dysphagia and/or food impaction. Diagnosis is also supported by a family history of EoE and other allergy-based disorders, such as asthma, seasonal allergies, and atopy. Topical corticosteroids and dietary elimination are acceptable first-line treatment approaches. This review contains 7 figures, 5 tables, and 51 references. Key words: dysphagia, elimination diets, endoscopic dilation, eosinophilic esophagitis, eotaxin-3, feeding dysfunction, interleukin-5, proton pump inhibitor–responsive esophageal eosinophilia, swallowed fluticasone, viscous budesonide

Eosinophilic Esophagitis in Children and Adolescents

Eosinophilic esophagitis (EoE) is an inflammatory disorder of the esophagus characterized by symptoms of esophageal dysfunction in association with histologic evidence of eosinophilic infiltration of the esophageal mucosa. The diagnosis is based on esophageal biopsies showing more than 15 eosinophils per high-power field in the absence of pathologic gastroesophageal reflux. It can present with a wide array of upper gastrointestinal tract symptoms. Babies and toddlers typically present with feeding intolerance or refusal, vomiting, and failure to thrive. Older children often present with abdominal pain and reflux symptoms, whereas adolescents and adults typically present with solid-food dysphagia and/or food impaction. Diagnosis is also supported by a family history of EoE and other allergy-based disorders, such as asthma, seasonal allergies, and atopy. Topical corticosteroids and dietary elimination are acceptable first-line treatment approaches. This review contains 7 figures, 5 tables, and 51 references. Key words: dysphagia, elimination diets, endoscopic dilation, eosinophilic esophagitis, eotaxin-3, feeding dysfunction, interleukin-5, proton pump inhibitor–responsive esophageal eosinophilia, swallowed fluticasone, viscous budesonide

Proton pump inhibitor-responsive esophageal eosinophilia: still a valid diagnosis?

To update rapidly evolving concepts regarding the controversial entity of 'proton pump inhibitor (PPI)-responsive esophageal eosinophilia,' referring to patients with clinical, endoscopic and histologic features of eosinophilic esophagitis (EoE) who achieve remission on PPI therapy. Up to half of pediatric and adult patients with typical EoE symptoms and histology achieve clinico-pathologic remission on PPI therapy, irrespective of whether esophageal pH monitoring demonstrates abnormal acid reflux. In patients with clinical and histologic features of EoE, genotypic and phenotypic features of PPI responders and nonresponders are virtually indistinguishable, and different from those of patients with gastroesophageal reflux disease. In PPI responders, PPIs effects on esophageal Th2 inflammation and gene expression are similar to those of topical steroids in PPI nonresponders. These therapies, along with diets, recently have been shown to be potentially interchangeable in two small series. Proton pump inhibitor-responsive esophageal eosinophilia is an inappropriate disease descriptor, arbitrarily based on a response to a single drug, and should be abandoned. Patients who have esophageal eosinophilia and esophageal symptoms that resolve with PPI therapy have phenotypic, molecular, mechanistic, and therapeutic features indistinguishable from similar patients who do not respond to PPIs. These patients with PPI responsiveness should be considered within the spectrum of EoE.

Eosinophilic Esophagitis: Latent Disease in Patients with Anaphylactic Reaction to Cow's Milk

Food allergy and eosinophilic esophagitis are a substantial and evolving public health issue. Clinicians should know the relationship between these diseases and how one may predispose to the other. This can help minimize misdiagnosis. The objective of this study was to assess esophageal eosinophilia and eosinophilic esophagitis frequency in patients with persistent cow's milk allergy and anaphylaxis manifestations. Patients with persistent cow's milk allergy with anaphylaxis manifestations were enrolled from 2012 through 2016 at the São Paulo University Hospital, Brazil. All of them were submitted to endoscopy despite the presence or absence of gastrointestinal symptoms. Demographics data, atopic comorbidities, medication use, endoscopic findings, and esophageal eosinophilia frequency were evaluated. Eighty-nine patients were selected. The median age was 8 years. It was observed that 34 of 89 patients (38.2%; 95% confidence interval [CI]: 28.14%-49.16%) presented with esophageal eosinophilia. Five patients (7.1%) presented proton pump inhibitor-responsive esophageal eosinophilia, and 10 patients (14.2%) presented eosinophilic esophagitis. We found that 29.4% were asymptomatic patients, 23.5% had nonspecific symptoms, 23.5% had persistent typical symptoms, and 23.5% had intermittent typical symptoms. There was an association with inflammatory endoscopy findings in 21 patients (61.7%). This description demands scientific attention because it is the highest frequency of esophageal eosinophilia yet described in a group of patients with cow's milk allergy presenting with anaphylaxis. Eosinophilic esophagitis is a condition that can coexist "silently" with an IgE-mediated food allergy and is most often underestimated and underdiagnosed.

Tu1105 - Differences in Clinical and Endoscopic Features Between Eosinophilic Esophagitis and Proton Pump Inhibitor-Responsive Esophageal Eosinophilia in Japan

Tu1105 - Differences in Clinical and Endoscopic Features Between Eosinophilic Esophagitis and Proton Pump Inhibitor-Responsive Esophageal Eosinophilia in Japan

Application of Clinical Scoring System to Distinguish Eosinophilic Esophagitis vs. Proton Pump Inhibitor-Responsive Esophageal Eosinophilia

Application of Clinical Scoring System to Distinguish Eosinophilic Esophagitis vs. Proton Pump Inhibitor-Responsive Esophageal Eosinophilia

Cohort Profile: The Swiss Eosinophilic Esophagitis Cohort Study (SEECS)

Background and Aims: The prospective, observational Swiss Eosinophilic Esophagitis Cohort Study (SEECS) was set up in 2015 with the following goals in mind: (1) to provide up-to-date epidemiologic data; (2) to assess the appropriateness of care; (3) to evaluate the psychosocial impact; and (4) to foster translational research projects. Data capture relies on validated instruments to assess disease activity and focuses on epidemiologic variables and biosamples (esophageal biopsies and blood specimens). An annual inclusion of 70 new patients with eosinophilic esophagitis (EoE) or proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is intended. We herein describe the SEECS cohort profile. Methods: The SEECS includes adult patients (age ≥18 years) with EoE or PPI-REE diagnosed according to published criteria. After inclusion, the patients are typically seen once a year for a clinical and endoscopic/histologic follow-up examination. Data are captured using validated questionnaires. Biosamples from patients with gastroesophageal reflux disease (GERD) and controls with a healthy esophagus are collected as well. Results: From January 2016 to July 2017, a total of 111 patients with EoE and 10 patients with PPI-REE were recruited. In addition, esophageal biopsies and blood samples from 11 patients with GERD and 20 controls with a healthy esophagus were collected. The mean age of the patients with EoE and those with PPI-REE was 39.6 ± 12.9 and 44.6 ± 15.6 years, respectively. A male predominance was found among both the patients with EoE (77.5%) and those with PPI-REE (70%). Concomitant allergic disorders were found in 79.3% of the patients with EoE and 90% of the patients with PPI-REE. At inclusion, the EoE patients were treated with the following therapeutic regimens: no therapy (0.9%), PPI (36%), swallowed topical corticosteroids (82.9%), elimination diets (15.3%), and esophageal dilation (19.8%). Conclusions: The SEECS is the first national cohort study of patients with EoE or PPI-REE. The SEECS will provide up-to-date epidemiologic data and foster translational research projects.