Development of the First Disease Activity Index for Eosinophilic Esophagitis: Update on the EEsAI in 2011

Background a nd Aims: T he international E EsAI study g roupis currently developing the first activity index (EEsAI) specificfor Eosinophilic Esophagitis (EoE). Goal: To develop, evaluateand validate the EEsAI.Methods: T he d evelopment comprises three phases: 1.Selection of candidate items; 2. Evaluation of the activity indexin a f irst patient cohort; and 3. V alidation in a s econd EoEpatient cohort. Focus group interviews with patients were usedin p hase 1 to generate p atient r eported outcomes ( PRO)according to guidelines o f regulatory authorities ( FDA andEMA), whereas the section of biologic items was developed byDelphi r ounds of i nternational E oE experts from E urope andNorth America.Results: The EEsAI has a modular composition to assess thefollowing components o f EoE activity: p atient reportedoutcomes, endoscopic activity, histologic activity, laboratoryactivity, a nd quality of life. D efinitions f or all aspects o fendoscopic and histologic appearance were established byconsensus rounds among EoE experts. Symptom assessmenttools were created that take into account d ifferent foodconsistencies as w ell as f ood avoidance and specificprocessing strategies. T he EEsAI is evaluated in a c ohort ofadult EoE patients since March 2011.Conclusions: After successful validation, the EEsAI will allowto standardize outcome assessment in E oE t rials which w illlikely lead to its wide applicability.

Development of the first disease activity index for eosinophilic esophagitis: update on the EEsAI in 2012

Background and Aims: The international E EsAI s tudy g roup is currently d eveloping the first activity index ( EEsAI) specific for E osinophilic Esophagitis (EoE). G oal: T o develop, e valuate and validate the EEsAI. Methods: T he development c omprises three p hases: 1. Selection of c andidate items ( completed); 2. Evaluation of t he activity index i n a first patient cohort (in progress, p atient recruitment completed); and 3. Validation in a s econd EoE patient cohort. F ocus group interviews with patients were used in p hase 1 to g enerate patient r eported outcomes (PRO) according to g uidelines o f regulatory authorities (FDA a nd EMA), whereas the section of biologic items was developed by Delphi rounds o f international E oE experts from E urope and North America. Results: T he EEsAI has a modular c omposition to a ssess the following components o f EoE activity: p atient r eported outcomes, e ndoscopic activity, histologic activity, laboratory activity, a nd quality of l ife (QoL). Definitions for a ll aspects o f endoscopic and histologic appearance were e stablished by consensus r ounds a mong E oE experts. S ymptom a ssessment tools were c reated that t ake into account d ifferent food consistencies as w ell as f ood avoidance and specific processing strategies. The EEsAI i s currently e valuated in a cohort of a dult EoE patients since M arch 2 011 (patient recruitment completed). Conclusions: The EEsAI standardizes outcome assessment in EoE t rials. T he collaboration with i nternational E oE e xperts a s well as f ollowing o f the guidelines f rom regulatory authorities will lead to its wide applicability.

Eosinophilic esophagitis: Updated consensus recommendations for children and adults.

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.

Fixed rings and strictures in Eosinophilic Esophagitis develop due to continuing inflammation over time

Background and Aims: Two distinct e ndoscopic phenotypes of E osinophilic Esophagitis (EoE) h ave been identified: t he inflammatory (IP) a nd the stenosing (SP) p henotype. I t is not known whether these EoE-associated phenotypes are reflective of different phases during disease course. We aimed to assess the phenotype a t initial EoE p resentation and d iagnosis and to evaluate if SP increases over time. Methods: R etrospective a nalysis of t he Swiss EoE Database (SEED) extended b y a review of p atients charts, endoscopy and pathology records. Results: F orty-four E oE p atients were a nalyzed (33 males, mean age at index visit 41 ± 14 years, all Caucasians). Median follow-up t ime was 3.1 years (IQR 1-4, r ange 1 -18 years). Median diagnostic delay w as 5 y ears (IQR 2-16, range 0-34 years). A t first diagnosis, 3 2% ( 14/44) o f EoE patients h ad already presented w ith a stenosis. T he mean d iameter o f the stenoses w as 1 0 ± 2 mm, and the mean length was 2 .8 ± 2 .9 cm. Peak e osinophil count d id n ot c hange over t ime (48 ± 39 eos/HPF at index visit vs. 59 ± 41 eos/HPF at end of follow-up, n=44). The risk of the presence of a stenosis at index visit was 0% f or a d isease duration of 0 -4 y ears, 37% f or a d isease duration between 5-10 years and 67% f or a d isease duration >10 years (p = 0.0035, trend test). Conclusions: T he frequency of e sophageal stenoses i s proportional to the disease duration, whereas the inflammatory activity does n ot s ignificantly c hange over t ime. O ur f indings underscore the necessity to reduce diagnostic delay in EoE and to control the underlying inflammatory processes to prevent esophageal remodeling.

Escalating epidemiology of eosinophilic esophagitis: 21 years of prospective population-based documentation in Olten county

Background and Aims: Eosinophilic Esophagitis (EoE) is detected with a dramatically increasingfrequency during the last decades. However, it is still unknown whether this reflects atrue increase in incidence or just an increased awareness by gastroenterologists. We therefore,prospectively assessed incidence and prevalence of EoE in an epidemiologically well definedindicator area over the last 21 years. Methods: Olten County is an area of approximately90,000 inhabitants without pronounced demographic changes during the last two decades.Two EoE-experienced gastroenterologists and one pathology centre are responsible forcovering the gastroenterological service of the area. No public programs for increasingawareness of EoE were implemented in this region. Since 1989 all individuals with confirmeddiagnosis of EoE living in Olten County were entered prospectively into the database. Results:Forty-six patients (76% males, mean age 41±16 yrs) were diagnosed with EoE between1989 and 2009. Ninety-four percent of patients presented with dysphagia. An average annualincidence rate of 1.88/100,000 was found (range 0-8) with a marked increase in the periodfrom 2004 to 2009. The cumulative EoE prevalence rose up to 35.1/100,000 inhabitantsin 2009. No significant change was observed for the median diagnostic delay, as it was 3years from 1989 to 1998 and 2 years from 1999 to 2009 with age < 40 years representinga risk factor for retarded diagnosis. The number of upper endoscopies per year increasedby 63% in the period from 1999 to 2009 compared to the years 1989 to 1998 which ismarkedly less then the increase in the incidence rate of 150% for the same periods. Conclusions:Over the last 21 years, a significant increase in EoE incidence and prevalence wasfound in an epidemiologically stable indicator region of Switzerland. The constant diagnosticdelay, the number of newly diagnosed EoE cases that was much more pronounced thanthe modest increase of performed upper endoscopies, as well as the lack of EoE awarenessprograms in Olten County indicates a true increase in EoE incidence.

Severity of endoscopically detected esophageal inflammatory and fibrostenotic features correlates with degree of esophageal eosinophilia in adults with eosinophilic esophagitis

Background: Eosinophilic esophagitis (EoE) has emerged as a leading cause of dysphagia in adults. Characteristic esophageal features on endoscopy include structural/fibrostenotic (rings, narrow caliber, strictures) and inflammatory manifestations (longitudinal furrows, exudates, edema). Aim: The purpose of this study was to correlate the clinical, endoscopic and histopathologic features in adult EoE patients. Methods: A total of 106 encounters of 81 patients with EoE were analyzed. Data included an EoE-directed symptom-severity patient questionnaire evaluating symptoms of dysphagia (frequency, intensity, duration), meal duration, chest pain, and overall symptom severity. Video recordings of endoscopies were reviewed in a blinded manner using a classification and grading scheme for the esophageal features of EoE. Histopathology was reviewed for peak eosinophil count/high power field by pathologists blinded to the patients' clinical status. Associations between endoscopic features, histology and symptoms were evaluated using the Spearman rank correlation analysis. Results: The endoscopic severity of both structural and inflammatory esophageal features of EoE, including rings, exudates, longitudinal furrows, and edema, correlated significantly with peak eosinophil counts (see Table 1). Presence of "crepe paper mucosa" did not demonstrate significant association with peak eosinophil counts. Both structural (rings, narrow-caliber esophagus and strictures) and inflammatory (furrows, exudates and edema) composite endoscopic scores demonstrated a strong correlation with peak eosinophil counts. The strongest association with the degree of esophageal eosinophilia was found with a combination of both structural and inflammatory findings (p < 0.0001). The esophageal diameter (in mm) was negatively correlated with overall symptom severity (Spearman's rho = -0.4883, P = 0.0339). None of the individual or combined patient reported symptoms correlated significantly with either endoscopic or histopathologic findings. Conclusion: The severity of both structural and inflammatory endoscopic features associated with EoE is significantly associated with the degree of esophageal eosinophilia. Patient reported symptom severity was not associated with the degree of esophageal eosinophilia. Esophageal stricture diameter was inversely correlated with EoE symptom severity. The prognostic and therapeutic implications of these observations need to be determined.

Update on basic and clinical aspects of eosinophilic oesophagitis.

The identification of a distinct syndrome, designated eosinophilic oesophagitis (EoE), with its own clinical and histopathological characteristics, was first described in the early 1990s. Meanwhile intense research has uncovered many molecular, immunological and clinical aspects of this chronic-inflammatory disorder. This article focuses exclusively on basic and clinical insights of EoE gathered during the last few years. Regarding aetiopathogenesis it has become clear that EoE is a food-triggered disease with milk and wheat as the dominant culprit food categories. However, it is still debated whether a disturbed mucosal integrity allowing allergens to cross the mucosal barrier, or changes in wheat and milk manufacturing might induce these inflammatory responses. Furthermore, basic science and clinical studies have accordingly confirmed that a chronic eosinophilic inflammation leads to a remodelling of the oesophagus with micro- and macro-morphological alterations, ending in a strictured oesophagus with impaired function. Fortunately, long-term therapeutic trials, using either topical corticosteroids or dietary allergen avoidance, have demonstrated that this sequela can be prevented or even reversed. This finding is of clinical relevance as it supports the initiation of a consistent anti-inflammatory therapy. Nevertheless, EoE is still an enigmatic disease and the long list of unanswered questions will certainly stimulate further research.

Eosinophilic oesophagitis: latest intelligence.

Eosinophilic oesophagitis (EoE), first described in the early 1990s, has rapidly evolved as a distinctive chronic inflammatory oesophageal disease with increasing incidence and prevalence in the westernized countries. Currently, EoE represents the main cause of dysphagia in adult patients. This disease is more prevalent in males and is frequently associated with allergies. The diagnosis is established based on the presence of oesophageal symptoms and dense eosinophilic oesophageal infiltration once other conditions leading to oesophageal eosinophilia are excluded. It is currently under discussion to what extent and by which methods allergic testing should be performed. Topical corticosteroids lead to a rapid improvement of active EoE clinically and histologically. Especially in children, elimination diets can have similar efficacy as topical corticosteroids. Oesophageal dilation of EoE-induced oesophageal strictures can also be effective in improving symptoms, but this therapy has no effect on the underlying inflammation. Neither the diagnostic nor the long-term therapeutic strategies are as yet defined. Cite this as: A. M. Schoepfer, D. Simon and A. Straumann, Clinical & Experimental Allergy, 2011 (41) 630-639.

Eosinophilic esophagitis: overview of clinical management.

A validated disease-specific symptom-assessment tool for eosinophilic esophagitis (EoE) has yet to be approved by regulatory authorities for use in clinical trials. Relevant end points for daily practice include EoE-related symptoms and esophageal eosinophilic inflammation. Endoscopic features should also be taken into account when establishing a therapy plan. A reasonable clinical goal is to achieve a reduction in EoE-related symptoms and esophageal eosinophilic inflammation. Evidence is increasing to support an anti-inflammatory maintenance therapy, as this can reduce esophageal remodeling. In EoE patients in clinical remission, annual disease monitoring with symptom, endoscopic, and histologic assessments of sustained treatment response is recommended.

Long-term treatment of eosinophilic esophagitis esophagitis with budesonide

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic-inflammatory disease of the esophagus, characterized by esophagus-related symptoms and a dense tissue eosinophilia, both refractory to proton pump inhibitors. Topical corticosteroids have proven effective in inducing clinical and histologic remission. However, a long-term strategy for the management of this chronic disease is not yet defined. METHODS: In a randomized, double-blind, placebocontrolled, long-term trial, we evaluated the efficacy of twice-daily 0.25 mg swallowed budesonide in maintaining a remission in adult EoE with prior response to induction therapy. Pre- and post-treatment disease activity was assessed clinically, endoscopically, histologically, by immunofluorescence and by high-resolution endosonography. The primary end point was the ability to maintain histologic remission (<5 eos/hpf) of EoE in. Secondary end points were the efficacy on symptom control and on tissue remodeling as well as the determination of the safety of long-term esophageal administration of topical corticosteroids. RESULTS: During a 50-week therapy of quiescent EoE with low-dose budesonide the esophageal eosinophil load (ECP staining) increased from 1.1 to 29.9 eos/hpf, but under placebo the increase was significantly larger (0.5 to 51.1 eos/hpf; p=0.01). At the end of the studyperiod, 35.7% (5/14) of the budesonide patients were in complete and 14.3% (2/14) in partial histologic remission; with placebo no patient was in complete and 28.6% (4/14) were in partial remission (p=0.0647). The increase of the symptom score was markedly lower in budesonide- (0.79 to 2.29 points) than in placebo-patients (0.71 to 4.00 points; p=0.0875). The median time to relapse of symptoms was >125 days in the budesonide and 95 days in the placebo group (p = 0.14). Measured by high-resolution endosonography, all EoE patients had pre-treatment a highly thickened esophageal wall compared with healthy controls (3.05±1.08 mm vs. 2.18±0.35 mm; p<0.0001). Long-term topical budesonide reduced mainly the thickness of the superficial wall layers (mucosa, 0.75 mm to 0.45 mm; p=0.025) whereas the response of the deeper layers was less pronounced (submucosa 1.31 to 1.08 mm; p=0.19 and muscularis 0.82 to 0.76 mm; p=0.72). Budesonide did not evoke any mucosal atrophy. CONCLUSIONS: This study clearly demonstrates that 1) Untreated eosinophil inflammation results in an impressive remodeling of the esophagus; 2) A therapy is therefore needed; 3) The high relapse rate after short-term therapy requires a long-term management and 4) Maintenance treatment with budesonide is well tolerated and keeps half of the patients in remission.

Oesophagite a eosinophiles: mise a jour 2011 [Eosinophilic esophagitis: update 2011].

Eosinophilic esophagitis (EoE) shows an increasing incidence and prevalence in western countries and is currently the main cause of dysphagia in adults. This disease is more prevalent in males and is frequently associated with allergies. Diagnosis is based on the presence of esophageal symptoms, dense eosinophilic esophageal infiltration, and the exclusion of other conditions associated with esophageal eosinophilia. Topical corticosteroids lead to a rapid clinical and histological improvement of active EoE. Especially in children, elimination diets can have similar efficacy as topical corticosteroids. Esophageal dilation of EoE-induced strictures can also be effective in improving symptoms, but this therapy has no effect on the underlying inflammation. Long-term therapeutic strategies have yet to be defined.

Oesophagite à éosinophiles [Eosinophilic esophagitis].

Eosinophilic esophagitis is a recent diagnosis, of growing interest and prevalence. It has to be considered by every physician when facing any adult or pediatric case of dysphagia, food impaction, and symptoms of GERD (gastroesophageal reflux disease) resistant to proton-pump inhibitor treatment. The diagnosis is made by combining clinical symptoms and endoscopic signs, supported by biopsies of the mucosa, which should show more than 15 eosinophils per high power field. The etiology seems to be of allergic origin, and a full immuno-allergic testing should be made. Recommendations for the treatment are to calm down the inflammatory process by proton-pump inhibitors, and to give topical steroids, keeping the systemic treatment for acute severe cases. In cases of esophageal stenoses, dilations can be undertaken, but with a high risk of recurrence.

Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.

BACKGROUND & AIMS: Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. METHODS: We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). RESULTS: Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. CONCLUSIONS: We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.

Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.

BACKGROUND & AIMS: Development of strictures is a major concern for patients with eosinophilic esophagitis (EoE). At diagnosis, EoE can present with an inflammatory phenotype (characterized by whitish exudates, furrows, and edema), a stricturing phenotype (characterized by rings and stenosis), or a combination of these. Little is known about progression of stricture formation; we evaluated stricture development over time in the absence of treatment and investigated risk factors for stricture formation. METHODS: We performed a retrospective study using the Swiss EoE Database, collecting data on 200 patients with symptomatic EoE (153 men; mean age at diagnosis, 39 ± 15 years old). Stricture severity was graded based on the degree of difficulty associated with passing of the standard adult endoscope. RESULTS: The median delay in diagnosis of EoE was 6 years (interquartile range, 2-12 years). With increasing duration of delay in diagnosis, the prevalence of fibrotic features of EoE, based on endoscopy, increased from 46.5% (diagnostic delay, 0-2 years) to 87.5% (diagnostic delay, >20 years; P = .020). Similarly, the prevalence of esophageal strictures increased with duration of diagnostic delay, from 17.2% (diagnostic delay, 0-2 years) to 70.8% (diagnostic delay, >20 years; P < .001). Diagnostic delay was the only risk factor for strictures at the time of EoE diagnosis (odds ratio = 1.08; 95% confidence interval: 1.040-1.122; P < .001). CONCLUSIONS: The prevalence of esophageal strictures correlates with the duration of untreated disease. These findings indicate the need to minimize delay in diagnosis of EoE.