Animal models of eosinophilic esophagitis,review and perspectives

Eosinophilic oesophagitis(EoE)is an allergen/immune-mediated chronic esophageal disease characterized by esophageal mucosal eosinophilic infiltration and esophageal dysfunction.Although the disease was originally attributed to a delayed allergic reaction to allergens and a Th2-type immune response,the exact pathogenesis is complex,and the efficacy of existing treatments is unsatisfactory.Therefore,the study of the pathophysiological process of EOE has received increasing attention.Animal models have been used extensively to study the molecular mechanism of EOE pathogenesis and also provide a preclinical platform for human clinical intervention studies of novel therapeutic agents.To maximize the use of existing animal models of EOE,it is important to understand the advantages or limitations of each modeling approach.This paper systematically describes the selection of experimental animals,types of allergens,and methods of sensitization and excitation during the preparation of animal models of EoE.It also discusses the utility and shortcomings of each model with the aim of providing the latest perspectives on EoE models and leading to better choices of animal models.

Evolving strategies: Enhancements in managing eosinophilic esophagitis in pediatric patients

Eosinophilic esophagitis is a newly recognized disease first described about 50 years ago.The definition,diagnosis,and management have evolved with new published consensus guidelines and newly approved treatment available to pediatricians,enabling a better understanding of this disease and more targeted treatment for patients.We describe the definition,presentation,and diagnosis of eosinophilic esophagitis including management,challenges,and future directions in children.The definition,diagnosis,and management of eosinophilic esophagitis have evolved over the last 50 years.Consensus guidelines and newly approved biologic treatment have enabled pediatricians to better understand this disease and allow for more targeted treatment for patients.We describe the definition,presentation,diagnosis,management,and treatment in addition to the challenges and future directions of eosinophilic esophagitis management in children.

Eosinophilic esophagitis: Current concepts in diagnosis and treatment

Eosinophilic esophagitis is an immune-allergic pathology of multifactorial etiology(genetic and environmental)that affects both pediatric and adult patients.Its symptoms,which include heartburn,regurgitation,and esophageal stenosis(with dysphagia being more frequent in eosinophilic esophagitis in young adults and children),are similar to those of gastroesophageal reflux disease,causing delays in diagnosis and treatment.Although endoscopic findings such as furrows,esophageal mucosa trachealization,and whitish exudates may suggest its presence,this diagnosis should be confirmed histologically based on the presence of more than 15 eosinophils per high-power field and the exclusion of other causes of eosinophilia(parasitic infections,hypereosinophilic syndrome,inflammatory bowel disease,among others)for which treatment could be initiated.Currently,the 3“D”s(“Drugs,Diet,and Dilation”)are considered the fundamental components of treatment.The first 2 components,which involve the use of proton pump inhibitors,corticosteroids,immunosuppressants and empirical diets or guided food elimination based on allergy tests,are more useful in the initial phases,whereas endoscopic dilation is reserved for esophageal strictures.Herein,the most important aspects of eosinophilic esophagitis pathophysiology will be reviewed,in addition to evidence for the various treatments.

Systematic review:Eosinophilic esophagitis in Asian countries

AIM: to investigate the prevalence and the clinical characteristics of Asian patients with eosinophilic esophagitis.METHODS: We conducted a systematic search of the Pub Med and Web of Science databases for original studies, case series, and individual case reports of eosinophilic esophagitis in Asian countries published from January 1980 to January 2015. We found 66 and 80 articles in the Pub Med and Web of Science databases, respectively; 24 duplicate articles were removed. After excluding animal studies, articles not written in English, and meeting abstracts, 25 articles containing 217 patients were selected for analysis.RESULTS: Sample size-weighted mean values were determined for all pooled prevalence data and clinical characteristics. The mean age of the adult patients with eosinophilic esophagitis was approximately 50 years, and 73% of these patients were male. They frequently presented with allergic diseases including bronchial asthma, allergic rhinitis, food allergy, and atopic dermatitis. Bronchial asthma was the most frequent comorbid allergic disease, occurring in 24% of patients with eosinophilic esophagitis. Dysphagia was the primary symptom reported; 44% of the patients complained of dysphagia. Although laboratory blood tests are not adequately sensitive for an accurate diagnosis of eosinophilic esophagitis, endoscopic examinations revealed abnormal findings typical of this disease, including longitudinal furrows and concentric rings, in 82% of the cases. One-third of the cases responded to proton pump inhibitor administration.CONCLUSION: The characteristics of eosinophilicesophagitis in Asian patients were similar to those reported in Western patients, indicating that this disease displays a similar pathogenesis between Western and Asian patients.

Eosinophilic esophagitis

Eosinophilic esophagitis is increasingly recognized in adults. The diagnosis is based on the presence of both typical symptoms and pathologic findings on esophageal biopsy. Patients usually present with dysphagia, food impaction and/or reflux-like symptoms, and biopsy of the esophagus shows more than 15 eosinophils per high-power fi eld. In addition, it is essential to exclude the presence of known causes of tissue eosinophilia such as gastroesophageal reflux disease, infections, malignancy, collagen vascular diseases, hypersensitivity, and inflammatory bowel disease. There are no standardized protocols for the therapy of eosinophilic esophagitis. A variety of therapeutic approaches including acid suppression, dietary modifications, topical corticosteroids and endoscopic dilation can be used alone or in combination.

Eosinophilic esophagitis: From pathophysiology to treatment

Eosinophilic esophagitis(Eo E) is a chronic immune disease, characterized by a dense eosinophilic infiltrate in the esophagus, leading to bolus impaction and refluxlike symptoms. Traditionally considered a pediatric disease, the number of adult patients with Eo E is continuously increasing, with a relatively higher incidence in western countries. Dysphagia and food impaction represent the main symptoms complained by patients, but gastroesophageal reflux-like symptoms may also be present. Esophageal biopsies are mandatory for the diagnosis of Eo E, though clinical manifestations and proton pump inhibitors responsiveness must be taken into consideration. The higher prevalence of Eo E in patients suffering from atopic diseases suggests a common background with allergy, however both the etiology and pathophysiology are not completely understood. Elimination diets are considered the firstline therapy in children, but this approach appears less effective in adults patients, who often require steroids; despite medical treatments, Eo E is complicated in some cases by esophageal stricture and stenosis, that require additional endoscopic treatments. This review summarizes the evidence on Eo E pathophysiology and illustrates the safety and efficacy of the most recent medical and endoscopic treatments.

Contribution of endoscopy in the management of eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a clinicopathological entity characterized by a set of symptoms similar to gastroesophageal reflux disease and eosinophilic infi ltration of the esophageal epithelium. EoE is an emerging worldwide disease as documented in many countries. Recent reports indicate that EoE is increasingly diagnosed in both pediatric and adult patients although the epidemiology of this new disease entity remains unclear. It is unclear whether EoE is a new disease or a new classification of an old esophageal disorder. Esophagogastroduodenoscopy (EGD) and biopsies with histological examination of esophageal mucosa are required to establish the diagnosis of EoE, verify response to therapy, assess disease remission, document and dilate strictures and evaluate symptom recurrence of EoE. Repeated endoscopies with biopsies are necessary for monitoring of disease progression and treatment effi cacy. EGD has a fundamental role in the diagnosis and management of EoE, forming an essential part of the investigation and follow-up of this condition. EoE is now considered a systemic disorder and not only a local condition with an important immunological back-ground. One of the aims of research in EoE is to study non-invasive markers, such as immune indicators found in plasma, that correlate with local presence of EoE in esophageal tissues. Studies over the next few years will provide new information about diagnosis, pathogenesis, endoscopic/histologic criteria, non-invasive markers, novel and more eff icacious treatments, as well as establishing natural history. Randomized clinical trials are urgently called for to inform non-invasive diagnostic tests, hallmarks of natural history and more eff icacious treatment approaches for patients with EoE. The collaboration between pediatric and adult clinical and experimental studies will be paramount in the understanding and management of this disease.

Recent discoveries and emerging therapeutics in eosinophilic esophagitis

Eosinophilic esophagitis(Eo E) is an allergy-mediated disease culminating in severe eosinophilic inflammation and dysfunction of the esophagus. This chronic disorder of the esophagus causes significant morbidity, poor quality of life, and complications involving fibrosis and esophageal remodeling. Overlapping features between EoE and gastroesophageal reflux disease(GERD) pose great challenges to differentiating the two conditions, although the two disorders are not mutually exclusive. Recent findings suggest that the confounding condition proton pump inhibitor- responsive esophageal eosinophilia(PPI-REE) is likely a subset of EoE. Since PPIs have therapeutic properties that can benefit EoE, PPIs should be considered as a therapeutic option for Eo E rather than a diagnostic screen to differentiate GERD, PPIREE, and EoE. Other current treatments include dietary therapy, corticosteroids, and dilation. Immunomodulators and biologic agents might have therapeutic value, and larger trials are needed to assess efficacy and safety. Understanding the pathophysiology of EoE is critical to the development of novel therapeutics.

Circumferential mucosal dissection and esophageal perforation in a patient with eosinophilic esophagitis

A young man with a previous history of episodes of mild solid food dysphagia was admitted with a total dysphagia. The esophagogastroduodenoscopy (EGDS) showed an extensive disruption of mucosal layer with a cul-de-sac in the lower part of the esophagus. Soon after the procedure, the patient suffered from an acute chest pain and subsequent CT scan demonstrated an intramural circumferential dissection of thoracic esophagus, and a mediastinal emphysema. An emergency right thoracotomy was performed, followed by a total esophagectomy with esophagogastroplasty and jejunostomy. The histopathology confirmed that mucosal and submucosal layers were circumferentially detached from muscular wall and showed an eosinophilic infiltration of the whole organ with necrosis and erosions of mucosal, submucosal and muscular layers. The diagnosis was esophageal perforation in eosinophilic esophagitis.

Overlap of reflux and eosinophilic esophagitis in two patients requiring different therapies:A review of the literature

Eosinophilic esophagitis (EE) and gastroesophageal reflux disease (GERD) have overlapping clinical, manometric, endoscopic and histopathologic features. The diagnosis of EE is nowadays based upon the presence of 15 or more eosinophils per high power field (eo/HPF) in esophageal biopsies. We report the cases of two young males suffering from dysphagia and recurrent food impaction with reflux esophagitis and more than 20 eo/HPF in upper-mid esophagus biopsies, both of which became asymptomatic on proton pump inhibitor (PPI) therapy. The first patient also achieved a histologic response, while EE remained in the other patient after effective PPI treatment, as shown by 24-h esophageal pH monitoring. Topical steroid therapy combined with PPI led to complete remission in this latter patient. GERD and EE may be undistinguishable, even by histology, so diagnosis of EE should only be established after a careful correlation of clinical, endoscopic and pathologic data obtained under vigorous acid suppression. These diagnostic difficulties are maximal when both diseases overlap. Limited data are available about this topic, and the interaction between EE and GERD is a matter of debate. In this setting, upper-mid esophagus step biopsies and esophageal pH monitoring of patients on PPI therapy are pivotal to evaluate the role of each disease. A PPI trial is mandatory in patients with a histopathologic diagnosis of EE; in those unresponsive to PPI treatment, EE should be suggested. However, a clinical response to PPI may not rule out quiescent EE, as shown in this report.

Endoscopic findings in patients with Schatzki rings:Evidence for an association with eosinophilic esophagitis

AIM:To investigate endoscopic findings in patients with Schatzki rings(SRs) with a focus on evidence for eosinophilic esophagitis(EoE).METHODS:We consecutively approached all adult patients scheduled for elective outpatient upper endoscopy for a variety of indications at the German Diagnostic Clinic,Wiesbaden,Germany between July 2007 and July 2010.All patients with endoscopically diagnosed SRs,defined as thin,symmetrical,mucosal structures located at the esophagogastric junction,were prospectively registered.Additional endoscopic findings,clinical information and histopathological findings with a focus on esophageal eosinophilia(≥ 20 eosinophils/high power field) were recorded.The criteria for active EoE were defined as:(1) eosinophilic tissue infiltration ≥ 20 eosinophils/hpf;(2) symptoms of esophageal dysfunction;and(3) exclusion of other causes of esophageal eosinophilia.Gastroesophageal reflux disease was excluded by proton pump inhibitor treatment prior to endoscopy.The presence of ≥ 20 eosinophils/hpf in esophageal biopsies in patients that did not fulfil the criteria of EoE was defined as esophageal hypereosinophilia.RESULTS:A SR was diagnosed in 171(3.3%;128 males,43 females,mean age 66 ± 12.9 years) of the 5163 patients that underwent upper gastrointestinalendoscopy.Twenty of the 116 patients(17%) from whom esophageal biopsies were obtained showed histological hypereosinophilia(≥ 20 eosinophils/hpf).Nine of these patients(8 males,1 female,mean age 49 ± 10 years) did not fulfill all diagnostic criteria of EoE,whereas in 11(9%) patients with ≥ 20 eosinophils/hpf,a definite diagnosis of EoE was made.Three of the 11 patients(27%) with definite EoE had no suspicious endoscopic features of EoE.In contrast,in the 25 patients in whom EoE was suspected by endoscopic features,EoE was only confirmed in 7(28%) patients.Patients with EoE were younger(mean age 41.5 ± 6.5 vs 50.5 ± 11.5 years,P = 0.012),were more likely to have a history of allergies(73% vs 29%,P = 0.007) and complained more often of dysphagia(91% vs 34%,P = 0.004) and food impaction(36% vs 6%,P = 0.007) than patients without EoE.Endoscopically,additional webs were found significantly more often in patients with EoE than in patients without EoE(36% vs 11%,P = 0.04).Furthermore,the SR had a tendency to be narrower in patients with EoE than in those without EoE(36% vs 18%,P = 0.22).The percentage of males(73% vs 72%,P = 1.0) and frequency of heartburn(27% vs 27%,P = 1.0) were not significantly different in both groups.The 9 patients with esophageal hypereosinophilia that did not fulfil the diagnostic criteria of EoE were younger(mean age 49 ± 10 years vs 58 ± 6 years,P = 0.0008) and were more likely to have a history of allergies(78% vs 24%,P = 0.003) than patients with < 20 eosinophils/hpf.Predictors of EoE were younger age,presence of dysphagia or food impaction and a history of allergies.CONCLUSION:A significant proportion of patients with SRs also have EoE,which may not always be suspected according to other endoscopic features.

Eosinophilic esophagitis in patients with esophageal atresia and chronic dysphagia

Esophageal atresia(EA)is defined as a discontinuity of the lumen of the esophagus repaired soon after birth.Dysphagia is a common symptom in these patients,usually related to stricture,dysmotility or peptic esophagitis.We present 4 cases of patients with EA who complained of dysphagia and the diagnosis of Eosinophilic esophagitis(Eo E)was made,ages ranging from9 to 16 years.Although our patients were on acid suppression years after their EA repair,they presented with acute worsening of dysphagia.Esophogastroduodenoscopy and/or barium swallow did not show stricture and biopsies revealed elevated eosinophil counts consistent with Eo E.Two of 4 patients improved symptomatically with the topical steroids.It is important to note that all our patients have asthma and 3 out of 4 have tested positive for food allergies.One of our patients developed recurrent anastomotic strictures that improved with the treatment of the Eo E.A previous case report linked the recurrence of esophageal strictures in patients with EA repair with Eo E.Once the Eo E was treated the strictures resolved.On the other hand,based on our observation,Eo E could be present in patients without recurrent anastomotic strictures.There appears to be a spectrum in the disease process.We are suggesting that Eo E is a frequent concomitant problem in patients with history of congenital esophageal deformities,and for this reason any of these patients with refractory reflux symptoms or dysphagia(with or without anastomotic stricture)may benefit from an endoscopic evaluation with biopsies to rule out Eo E.

Confounding factors affect the pathophysiology of eosinophilic esophagitis

Eosinophilic esophagitis is a newly diagnosed esophageal disease in adult and children. The clinical and pathological characteristics of this disease have been established and were recently summarized in the expert clinical guideline published in 2011. In spite of the wide knowledge accumulated on this disease, there are many areas where scientific data are missing, especially in regard to the disease's pathophysiology. Recent publications have suggested that other confounding factors modify the disease and may affect its clinicalphenotypic presentation. Those factors may include place of living, air pollution, race, genetic factors and other. In the present report we discussed and review those confounding factors, the new developments, and what direction we should go to further advance our knowledge of this disease.

Eosinophilic esophagitis in Egyptian adult patients presenting with upper gastrointestinal symptoms

Background and Study Aim: Eosinophilic esophagitis (EoE) is a clinicopathological disease characterized by esophageal dysfunction and marked esophageal eosinophilic infiltration. It shows a marked increase in incidence and prevalence and has been associated with gastroesophageal reflux disease (GERD). The aim of this work was to detect the prevalence of EoE in Egyptian adult patients presenting with upper gastrointestinal symptoms and to clarify its clinical pattern and the possibility of its overlap with GERD. Patients and Methods: The study included 91 adult patients presenting with various upper gastrointestinal symptoms. Upper gastrointestinal endoscopy was done and esophageal biopsies were taken. The presence of >15 eosinophils per high power field together with a history of intake of proton pump inhibitors for at least 3 weeks without improvement was used as prerequisite diagnostic criteria for EoE. Results: Classification of the patients was based on both endoscopic and histo-pathological findings. Accordingly, out of the 91 patients, 70 had GERD (76.9%);58 of them had erosive reflux disease (ERD) and 12 had endoscopically normal esophagus but with histopathological changes compatible with reflux esophagitis and were classified as non erosive reflux disease (NERD). Eighteen patients had normal endoscopic and histopathological esophagus (19.8%), and 3 patients had EoE (3.3%), with an overlap between ERD and EoE in one patient. The mean age of EoE patients was 41.6 ± 11.7 years. Two of them were males and one was a female. All of the 3 patients complained of dysphagia and none complained of heartburn. The endoscopists did not report any endoscopic findings characteristic of EoE. Conclusion: The prevalence of EoE is low in adult Egyptian patients presenting with upper gastrointestinal symptoms. Dysphagia is the main presenting symptom of EoE while heartburn is not characteristic of the disease. Normal esophagus endoscopically does not exclude EoE.

Eosinophilic esophagitis: A newly established cause of dysphagia

Eosinophilic esophagitis has rapidly become a recognized entity causing dysphagia in young adults. This review summarizes the current knowledge of eosinophilic esophagitis including the epidemiology, clinical presentation, diagnostic criteria, pathophysiology, treatment, and prognosis. An extensive search of PubMed/Medline （1966-December 2005） for available English literature in humans for eosinophilic esophagitis was completed. Appropriate articles listed in the bibliographies were also attained. The estimated incidence is 43/10s in children and 2.5/10s in adults. Clinically, patients have a long history of intermittent solid food dysphagia or food impaction. Some have a history of atopy. Subtle endoscopic features may be easily overlooked, including a ＂feline＂ or corrugated esophagus with fine rings, a diffusely narrowed esophagus that may have proximal strictures, the presence of linear furrows, adherent white plaques, or a friable （crepe paper） mucosa, prone to tearing with minimal contact. Although no pathologic consensus has been established, a histologic diagnosis is critical. The accepted criteria are a dense eosinophilic infiltrate （〉20/high power field） within the superficial esophageal mucosa. In contrast, the esophagitis associated with acid reflux disease can also possess eosinophils but they are fewer in number. Once the diagnosis is established, treatment options may include specific food avoidance, topical corticosteroids, systemic corticosteroids, leukotriene inhibitors, or biologic treatment. The long-term prognosis of EE is uncertain; however available data suggests a benign, albeit inconvenient, course. With increasing recognition, this entity is taking its place as an established cause of solid food dysphagia.

Eosinophilic esophagitis: New insights in pathogenesis and therapy

Eosinophilic esophagitis(Eo E) is a clinico-pathological entity with esophageal symptoms and dense esophageal eosinophilic infiltration throughout the esophagus that may persist despite treatment with proton pump inhibitors. This eosinophilic infiltration is usually absent in the stomach, small intestine and colon, although there are a number of reports of patients with a multiorgan involvement. EoE is associated with abnormalities involving TH2-dependent immunity, with multiple environmental factors strongly contributing to disease expression. The layer of the esophagus affected by the eosinophilic infiltration causes the specific symptoms. Esophageal involvement results mostly in dysphagia for solids that can be severe enough to cause recurrent esophageal obstruction with typical endoscopic features suggesting esophageal remodeling and pathological changes of eosinophilic infiltration of the mucosa, sub-epithelial fibrosis and muscle hypertrophy. This disease is frequently associated with other allergic conditions such as allergic asthma, allergic dermatitis and eosinophilia. The treatment of patients with Eo E depends on the severity of the symptoms and of the inflammatory process as well as to their response to a gradual step-up treatment. The first line of treatment consists of steroid containing local inhalers. If unresponsive they are then treated with oral steroids. Intravenous interleukin blockers seem to have a consistent positive therapeutic effect.

A Novel Therapy of Eosinophilic Esophagitis-Treatment of Eosinophilic Esophagitis Using a Single Dose of Intramuscular Corticosteroid and Proton Pump Inhibitor

Background： Ee （Eosinophilic esophagitis） is an inflammatory condition characterized by a dense eosinophilic infiltrate in the esophageal epithelium. Its pathophysiology mimics that of allergic esophagitis, and evolves clinically as a chronic disease with periods of exacerbation. Symptoms and endoscopic findings are usually non-specific and similar to those of other esophageal illnesses. The mainstay of treatment of Ee is with corticosteroids and/or specific diets, which have been shown to cause symptom remission and histological improvement. Aim： The objective of this study was to demonstrate the efficacy of a novel and promising treatment protocol for Ee. Materials and methods： We prospectively evaluated 24 patients with Ee over two years. Patients were treated with a single intramuscular injection of betamethasone sodium phosphate associated with betamethasone dipropionate and a PPI （proton pump inhibitor） （rabeprazole 20 mg PO）. After 4 weeks of treatment, patients underwent endoscopy and biopsy. We evaluated patients＇ clinical response as well as the results of endoscopic and histological examinations. Results： After 4 weeks of treatment, all patients （100%） are reported significant clinical improvement, which was corroborated by the findings on endoscopy and histology. There were no complications or adverse reactions. Conclusions： In this cohort of patients with eosinophilic esophagitis, treatment with a single intramuscular dose of corticosteroids led to complete remission of symptoms and improvement in endoscopic and histological findings.

Significance of feeding dysfunction in eosinophilic esophagitis

Feeding dysfunction is a frequent presenting symptom of eosinophilic esophagitis(EoE). Here we present 3 children of various ages whose manifestations of EoE associated feeding dysfunction led to significant and life altering impact on their growth and development. Early identification of presenting symptoms of EoE will allow for prompt diagnosis and initiation of appropriate treatments. Recognition of salient features of dysfunction and treatment by feeding therapists and nutritionists led to symptom resolution and growth.

Esophageal squamous papillomas with focal dermal hypoplasia and eosinophilic esophagitis

Focal dermal hypoplasia(FDH) is a rare disorder of the mesodermal and ectodermal tissues. Here we present an eight-year-old female known to have FDH who presents with poor weight gain and dysphagia. She was diagnosed with multiple esophageal papillomas and eosinophilic esophagitis. She was successfully treated with argon plasma coagulation and ingested fluticasone propionate, which has not been described previously in a child.

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 registrybased 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.