Summary of the First International Gastrointestinal Eosinophil Research Symposium

INTRODUCTION Chris A. Liacouras, MD, and Glenn T. Furuta, MD The last decade raised eosinophilic esophagitis (EE) from a clinical curiosity to a recognized disease. The care of the patient with EE demands an extraordinary attention to detail; the diagnosis must be made in the proper fashion, and then consistent collaboration between multiple subspecialists is required to provide outstanding longitudinal care. Eosinophilic esophagitis is no longer an emerging diagnosis, but rather a distinct clinicopathological disease. Its natural history, pathophysiology, and treatments are undergoing discovery and refinement that have been reviewed in a number of recent articles. In January 2006 the North American Society of Pediatric Gastroenterology convened a steering committee to develop an international conference focusing on EE. The overall goals of the symposium were to present new data regarding clinical and basic elements of the disease, engage new investigators to enter into research focusing on EE, and initiate an international research consortium. To that end, the First International Gastrointestinal Eosinophil Researcher Symposium was organized and held October 17–18, 2006, in Orlando, FL. Young investigators presented abstracts focusing on EE. More than 300 pediatric and adult pathologists, allergists/immunologists, and gastroenterologists shared experiences and data derived from their area of expertise. During the first day of the symposium, 5 subcommittees (clinical symptoms, endoscopy, histology, allergy, and treatment) presented their review of the world's literature. This work is being synthesized into a consensus statement. The next day, the symposium was divided into 3 sections: EE natural history, pathogenesis, and treatments. The following summaries provide the current state of knowledge as it was presented at the symposium. I. NATURAL HISTORY OF EE EPIDEMIOLOGY Peter Bonis, MD The epidemiology of EE is incompletely understood. Available data suggest that the disease is new (perhaps first arising in the 1970s) and the worldwide incidence is rising in both adults and children, although the extent to which increased recognition accounts for the rising incidence is uncertain. A more complete understanding of its incidence, geographic variability, and associated burden of disease is still evolving. Few population-based studies have evaluated the epidemiology of EE. Available reports suggest that the incidence has been increasing in recent years, although in some regions it may have stabilized. The prevalence in children living in Western Australia was estimated to have increased from 0.5 cases to 0.89 cases per 10,000 children between 1995 and 2004 (1). The incidence was estimated to be 0.6/10,000 population in adults in a separate report from Australia, (2) and 0.15/10,000 population in a study from Olten County, Switzerland (3). In all of these reports, the authors noted a marked increase in recent years, which did not appear to be related to changes in referral patterns or increased recognition. A report from the United States of children and adolescents (up to ages 19) estimated an incidence of 1.3/10,000 population in 2003 (4), which the authors point out exceeded that of inflammatory bowel disease (IBD) in children (0.7/10,000 population in a report from Wisconsin) (5). The prevalence was estimated to be 4.3/10,000 population in 2003. However, in contrast to the studies above, the authors note that the incidence has remained stable in recent years (M.E. Rothenberg, personal communication, October 2006). All of these reports are limited by the potential for ascertainment bias because the estimates were based upon patients who were recognized clinically. A population-based study of adults from Sweden attempted to define the prevalence of esophageal eosinophilia in the general population (6). Eosinophils are not normally present in the esophagus, and thus any esophageal eosinophilia is abnormal. Interestingly, some degree of esophageal eosinophilia was present in about 5% of the population, whereas 1% had more severe esophageal eosinophilia with a density consistent with EE. The study did not perform objective testing for gastroesophageal reflux disease (GERD), however, thus the degree to which these findings may have been attributed to GERD (or other causes) is unclear. The geographic distribution of the disease has not been well established, although reports have emerged from many regions of the world. It is possible that a better understanding of the disease distribution could help uncover etiologic associations. Such an understanding will require the establishment of systematic surveillance and consensus on its definition. Several reports have established familial clustering of the disease (3,4,7); however, the degree to which these represent a genetic predisposition versus common environmental conditions is unclear. Morbidity and costs related to the disease (and its treatment) are incompletely understood. Presentation has been sufficiently severe to warrant an elimination or elemental diet in children, which may have a substantial impact on quality of life for patients and their families. By contrast, many adults with EE do not have severe symptoms, even without treatment (8). Emerging data, however, suggest that EE is an important cause of dysphagia and food impaction in adults (9). An improved understanding of the natural history of the disease and endpoints of treatment will help to define morbidity related to the disease. For example, it remains unclear whether EE in children persists into adulthood. Whether persistent esophageal eosinophilia in patients who have minimal or no symptoms is associated with adverse health outcomes also is unknown. NATURAL HISTORY IN CHILDREN AND ADULTS Phil E. Putnam, MD, and Alex Straumann, MD Eosinophilic esophagitis is a “young” disorder. The first comprehensive descriptions of the adult form of this inflammatory esophageal disease were published in the early 1990s (10–12). We have come to recognize that EE is a clearly defined clinicopathological entity, characterized by esophagus-related symptoms in combination with a dense esophageal eosinophilia, both of which persist despite treatment with prolonged proton pump inhibitors (13). Initially thought to be rare, EE has emerged as 1 of the most common causes of dysphagia and esophageal food impaction in adults (9). Despite enormous research activity, the natural history of EE remains poorly understood. The natural history of a disease describes the expected course followed by the given disease over time, its characteristic pattern, and its time-intensity gradient. This, in turn, supplies answers for research purposes, to lay the foundation for the evaluation of any therapeutic measure; patient care, to provide a prognosis to an affected individual; and socioeconomic considerations, to estimate the burden of illness. The natural history of a disease can be studied by observing the course of the illness if left untreated. Various outcomes can occur, including spontaneous permanent resolution, remission with relapse, relentless progression, or a progression to a fixed stable state. With regard to EE in children, there is little published data regarding the long-term outcome of this disease when it has its onset in childhood. In addition, the literature that has been reported has generally included information regarding treated individuals who are observed only for short periods. Because of these brief periods of observation, it is still not known whether children with EE grow up to become adults with EE or whether pediatric EE is the same disease as adult EE. With regard to EE in infants, children, and adolescents, there have been several studies that have provided information regarding clinical symptoms seen at various ages. Studies by Liacouras et al (14) and Noel et al (15) demonstrate that infants with EE generally present with symptoms of reflux, feeding disorder, or irritability. School-age and older children generally continue to complain of symptoms similar to gastroesophageal reflux. In addition, they also exhibit signs of vomiting, regurgitation, and abdominal pain. Older children and adolescents present more often with signs and symptoms of dysphagia, swallowing difficulties, and possible food impaction. At this point, investigators are unsure whether these various symptoms represent different subtypes or phenotypes of EE, or whether they manifest a progression of the disease. It is interesting to note that the majority of the pediatric EE literature relates to children who present to their physician with clinical symptoms. These chronic symptoms eventually prompt evaluation, including upper endoscopy with biopsy leading to the diagnosis of EE. Frequently, the symptoms of EE can be intermittent or sporadic. Clinicians are now histologically identifying many asymptomatic children who have severe EE. These patients are typically either found incidentally during evaluation for another disorder or found at endoscopic follow-up after therapy for EE has been instituted. Because they have minimal or no symptoms, many of these children are either lost to follow-up or discharged from care. Thus, the question exists as to what happens to the disease in these children over time. The treatment for asymptomatic children with histological EE is controversial. With regard to children, EE appears to be a chronic disease at best and a progressive disease at worst. Spontaneous remission and resolution of the disease seem unlikely. Histological relapse is extremely common when treatment such as dietary therapy or corticosteroids is withdrawn. In addition, the absence of clinical symptoms does not predict an absence of histological inflammation. In individuals who have been treated, the question remains whether treatment with either dietary therapy or medical therapy will result in permanent resolution or control of the inflammatory process. In general, effectively treated individuals have not been observed to develop dysphagia or fibrosis. Moreover, will aggressive therapy alter the natural history of esophageal fibrosis? Based on previously published studies (8), it has been established that in adults, EE is a chronic disease with persistence of symptoms and eosinophilic-tissue infiltration for years; unequivocally restricted to the esophagus without a risk of extension to eosinophilic gastroenteritis; a localized disease, given that no cases with development of hypereosinophilic syndrome have been observed; likely a benign disease because so far no EE patient has experienced an esophageal malignancy; a nonfatal disease, given that no EE-related deaths have been reported; and a disease that substantially impairs the quality of life. Recent publications, as well as clinical observations, suggest that the inflammatory activity of EE may be exogenously influenced by aeroallergens, such as pollen (16). In contrast, EE may fluctuate spontaneously, independently of aero- or food allergens. EE may persist for years in a “stand-by mode.” In contrast, chronic EE may lead to a remodeling of the esophagus, may predispose to viral and/or fungal superinfections, or may lead to an emesis-induced perforation of the esophagus. EE also has been shown to be a risk factor for procedure-induced perforation with the potential for a fatal outcome, and may impair the function of the lower esophagus sphincter and consecutively lead to gastroesophageal reflux. There are no specific markers or presenting factors that can predict the outcome of EE; however, features such as the age of presentation, response to steroids, and the response to an elemental or elimination diet may be important criteria that may predict the outcome of EE in the future. Additionally, current research suggests that there may be specific phenotypes that may allow for gene chips or biomarkers to be developed. We need better “instruments” to assess the natural history of EE. We propose that a prospective, long-term, multicenter trial should be initiated, one that includes a substantial number of patients. In this study clinical findings, laboratory analyses, endoscopic findings, and histological as well as immunological and genetic markers must be assessed according to a study protocol using clearly defined criteria. EOSINOPHILS IN THE ESOPHAGUS: HOW MANY ARE TOO MANY? Eduardo Ruchelli, MD Except in the esophagus, eosinophils are present normally in variable numbers in the mucosa of the entire gastrointestinal (GI) tract (17,18). The squamous epithelium of the normal esophagus is completely devoid of eosinophils. When present, intraepithelial eosinophils are considered a sign of esophagitis. Their presence, however, is not diagnostic of any particular etiology. Several types of esophagitis frequently include eosinophils as part of the inflammatory changes. In children, the most common causes of esophagitis include gastroesophageal reflux, allergic response, Crohn disease, and infections such as those caused by Candida species and herpesviruses. In general, infections tend to be associated with a predominantly neutrophilic response, whereas the inflammation in gastroesophageal reflux disease (GERD) and allergen exposure is primarily eosinophilic in nature. Eosinophilic esophagitis has emerged in the last 10 years as a distinct type of esophagitis (4,13,19–22). It is characterized not only by its association with food or airborne allergens but also by the large number of eosinophils that are usually present in the esophagus of these patients (>15–20 eosinophils per high power field). Although biopsies from patients with GERD usually have a lower number of eosinophils, the distinction between these 2 types of esophagitis on histological grounds alone is frequently difficult. In some biopsies the eosinophil count is within a “borderline” range. Because the inflammation is often patchy, the number of eosinophils varies significantly, even among samples taken from relatively close areas. Therefore, the eosinophil count may be affected by sampling. Because of this variability from 1 area to another, eosinophils should be counted in the most intensely inflamed high power field (peak count) and multiple biopsies should be obtained. Although infrequent, there are well-documented cases of severe eosinophilia with complete response to antireflux medication (23), and conversely, there are some patients who have typical clinical and endoscopic features of EE in whom the biopsy fails to demonstrate a large number of eosinophils. Despite these limitations, numerous studies and our own experience indicate that patients with EE tend to have a larger number of eosinophils than patients with GERD, and at a minimum, a peak eosinophil count >15 eosinophils per high power field should raise the possibility of EE. However, a pathognomonic eosinophil count identifying EE does not exist. The distinction between EE and GERD rests on both histological and clinical findings. In addition to the large number of eosinophils, other histopathological features have been observed in patients with EE. These features include a superficial distribution of eosinophils along the luminal surface of the mucosa (superficial layering), superficial aggregates of eosinophils (eosinophilic microabscesses), and detached fragments of squamous cells admixed with numerous eosinophils (9,24,25). These pathological changes explain the endoscopic appearance of the esophagus in some patients with EE, in whom white plaques are observed. Other features include prominent basal layer hyperplasia and fibrosis of the lamina propria. It is unclear whether prominent basal layer hyperplasia is merely secondary to an inflammatory process involving a large number of eosinophils, or whether it is driven by other mediators, particularly when in some instances the degree of basal layer hyperplasia is out of proportion to the number of eosinophils. Only a few reports have described the presence of lamina propria fibrosis in patients with EE (8). The rarity of this finding may be due to the fact that most esophageal biopsies do not include the lamina propria. Despite the limited number of well-documented cases, fibrosis may explain the narrowing of the esophagus or motility abnormalities that cause dysphagia or food impaction in patients with EE, particularly older children and adults. It is also possible that eosinophils infiltrate deeper layers of the esophagus leading to edema, fibrosis, and/or muscle thickening, which contribute to altered motility. Documentation of such a finding, however, is extremely rare in the literature (26,90). In summary, mucosal biopsies should be obtained from all patients undergoing evaluation for GERD-like symptoms that do not respond to acid blockade, or who present with dysphagia or food impaction. Biopsies should be obtained regardless of the gross appearance of the mucosa, and multiple biopsies should be obtained. Biopsies should also be obtained from stomach and duodenum to rule out other diseases such as eosinophilic gastroenteritis and IBD. Currently, in the proper clinical context (lack of response to proton pump inhibition or normal pH monitoring of the distal esophagus), the number of intraepithelial eosinophils is the primary histological feature distinguishing EE from GERD. The number of eosinophils should be determined in the most intensely inflamed high power field. Additional features such as eosinophilic microabscesses, surface layering of eosinophils, basal layer hyperplasia, and lamina propria fibrosis and inflammation should be assessed in all biopsies. Esophageal biopsy histology is critical for the diagnosis, but ultimately the diagnosis rests on both histological and clinical findings. NONINVASIVE MARKERS Sandeep K. Gupta, MD EE is a chronic condition with periods of exacerbation and remission. Esophagogastroduodenoscopy and histological examination of esophageal mucosal biopsies are required to establish the diagnosis, assess response to therapy, document disease remission, and evaluate symptom recurrence. Because of the invasiveness of esophagogastroduodenoscopy and the costs associated with repeated procedures, there is an acute need to identify noninvasive biomarkers that correlate with disease presence, remission, severity, and response to therapy. Biomarkers may be broadly divided into 3 groups (Table 1) (27). The following lists the characteristics of an ideal biomarker for EE:TABLE 1: Types of biomarkers Correlates with EE state Connects with EE severity Reflects changes due to therapy High sensitivity High specificity Reproducible Performed on specimens which are noninvasively obtained and relatively easy to obtain Simple methodology Cost effective Identification of an EE Biomarker Although there are gaps in our understanding of EE, the underlying pathogenesis is thought to be related to a Th2 response that is controlled by cytokines including interleukin (IL)-5, IL-13, and eotaxin (13). In addition, a number of studies have identified the pluripotent potential of eosinophils and have documented the fact that they contain a number of cytokines, chemokines, and granular proteins (28). These biologically active mediators are released upon activation, and likely participate in the inflammatory cascade. Thus, future identification of novel EE biomarkers likely will be related to mediators dictating the influx of eosinophils into the esophageal mucosa or those mediators that are released by the eosinophils themselves. These biomarkers could be obtained from a number of different sources including sputum, breath, blood, stool, and urine. This section focuses on biomarkers studied in a number of eosinophilic diseases, including EE. Well-designed studies that take into account severity of concomitant atopic diseases, proper controls, treatment interventions, and the influence of preservative, fixation, and storage will be critical to of these Eosinophil eosinophil have not been studied in a to as a Studies to demonstrate that eosinophil may be in as many as to of but no Eosinophils in the have been as a of disease activity in patients with and eosinophilic but have not been in patients with EE. 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