Key points

Introduction

During the last two decades, a new disease, eosinophilic esophagitis (EoE) emerged as one of the leading causes of food impaction and dysphagia in adults and vague reflux-like symptoms in children. Early case series describing adult patients indicated that this disease possessed distinct features that differentiated it from gastroesophageal reflux disease (GERD). Following these early descriptions, a tide of reports provided a clearer symptom complex in children and adults that ultimately helped to define EoE as a clinicopathological condition characterized by symptoms of esophageal dysfunction and dense esophageal epithelial eosinophilia (>15 eosinophils per high-power field [eos/HPF]). Clinical, basic, and translational studies have provided a deeper understanding of this somewhat enigmatic disease that mechanistically is defined as an antigen-driven condition limited to the esophagus. This article summarizes many of the key historical features of EoE and provides a glimpse of potential future developments.

Introduction

During the last two decades, a new disease, eosinophilic esophagitis (EoE) emerged as one of the leading causes of food impaction and dysphagia in adults and vague reflux-like symptoms in children. Early case series describing adult patients indicated that this disease possessed distinct features that differentiated it from gastroesophageal reflux disease (GERD). Following these early descriptions, a tide of reports provided a clearer symptom complex in children and adults that ultimately helped to define EoE as a clinicopathological condition characterized by symptoms of esophageal dysfunction and dense esophageal epithelial eosinophilia (>15 eosinophils per high-power field [eos/HPF]). Clinical, basic, and translational studies have provided a deeper understanding of this somewhat enigmatic disease that mechanistically is defined as an antigen-driven condition limited to the esophagus. This article summarizes many of the key historical features of EoE and provides a glimpse of potential future developments.

Initial descriptions of esophageal eosinophilia

Although eosinophils reside in most the gastrointestinal mucosae, they are not present in the normal esophageal epithelia. Initial reports of esophageal eosinophilia associated this histologic finding with GERD. How and why acid affected the esophageal epithelium in some but not all patients still escapes our understanding; however, the association of GERD with esophageal eosinophilia held firm for several years. Interestingly, these early reports characterized eosinophilia as more than 1 eos/HPF and the size of the HPF was not standardized. In 1985, Lee reported eosinophilic infiltration in esophageal mucosal biopsy in 11 patients with average age of 14.6 years; these patients had reflux symptoms and their eosinophil density was low. In retrospect, these were probably patients with GERD.

GERD is not the only disease associated with esophageal eosinophilia

Although GERD-associated eosinophilia was thought to be the predominant cause of esophagitis for years, several case series began to report clinical features that were somewhat different from those associated with classic GERD. In 1978, Landres and colleagues reported an isolated case of vigorous achalasia in a patient with marked smooth muscle hypertrophy and eosinophilic infiltration of esophagus. He concluded that this patient likely represented a variant of eosinophilic gastroenteritis, which predisposed to esophageal motor disorder. This case is unusual in that large numbers of eosinophils are not commonly found in esophageal tissues affected by achalasia or other defined motor disorders. In 1981, Picus and Frank reported a case of 16-year-old boy with progressive dysphagia for 1.5 years and dense esophageal eosinophilia. Endoscopic findings revealed multiple 1 mm nodular filling defects near a stricture and proximal dilation. Radiological studies showed luminal narrowing and wall rigidity; peripheral blood showed high circulating eosinophil count. Again, the investigators assumed it was a variant of eosinophilic gastroenteritis. Following this, a series of case reports provided more details of patients who presented with dysphagia and esophageal eosinophilia, some of who developed esophageal strictures.

Critical observations of new clinical disorder: EoE

In 1989, Attwood and colleagues published an abstract in Gut , describing “Oesophageal Asthma—an episodic dysphagia with eosinophilic infiltrates.” These investigators compared a group of 15 adults who presented with dysphagia without esophageal obstruction and normal pH monitoring with a group of 100 adults with GERD as defined by increased acid exposure in the distal esophagus. Differences between the two groups were that the group without increased acid exposure was found to have significantly greater number of eosinophils than the group with GERD. The key finding of this case series was that it identified patients with dysphagia, with severity up to complete bolus obstruction, who presented with dense esophageal eosinophilia. In 1993, they published these key findings that described adults with dysphagia, normal pH monitoring, and dense esophageal eosinophilia (>20 eos/HPF) and termed this esophageal eosinophilia with dysphagia, a distinct clinicopathological syndrome. Importantly, control patients with proven GERD had a mean of 3.3 eos/HPF in the esophageal epithelium. Endoscopic appearances using fiberoptic technology likely limited descriptions of the full details now observed in this disease and may partially explain why no endoscopic abnormalities were visualized in this series. Seven patients had food hypersensitivity and all required advanced intervention (dilatation and/or steroids in one case) for resolution of symptoms.

In 1994, Straumann and colleagues described a series of 10 patients with acute recurrent dysphagia seen over a 4-year period, who showed discrete endoscopic changes and high concentrations of epithelial esophageal eosinophils, who improved following systemic steroid and antihistamine treatment. From this series, it was clear that the endoscopic findings, including rings, white exudates, and furrows, were variably expressed because some patients’ esophageal mucosae appeared relatively normal. The investigators termed this idiopathic EoE.

Taken together, these two reports from two different investigators, described key clinical findings observed in adults with dysphagia who had dense mucosal eosinophilia that was limited to the esophagus who did not have GERD. Importantly, endoscopic findings were variable, leading to the necessity of procuring endoscopic pinch biopsy to make the diagnosis. Because this practice was not widespread and because of the lack of diagnostic usefulness, larger recognition of this newfound disease remained somewhat limited.

These two series, published by a gastroenterologist in private practice, Straumann, and a surgeon, Attwood, formed the beginnings of their quest to define key clinical features and therapeutic approaches during the next 20 years.

Increasing awareness of EoE in the pediatric gastroenterology community

With the emergence of improved sedation practices in the early 1990s, pediatric gastroenterologists began to perform fiberoptic endoscopy with increased frequency. Coincident with this increased practice, was the recognition that histologic evidence of inflammation could be present despite an endoscopically normal appearing mucosa. This observation lead to the practice of procuring mucosal samples as a standard of care for children undergoing endoscopic assessment of symptoms, a key difference from adult practice.

During this time, an increasing number of children were observed to have symptoms that persisted despite antacid blockade. Children ranging from toddlers to teenagers presented with a wide range of symptoms, including vomiting, regurgitation, feeding problems, and abdominal pain, that were unresponsive to H2 receptor antagonists or proton pump inhibitors (PPIs) and who, at the time of endoscopy, were found to have dense mucosal eosinophilia limited to the esophagus. Associated clinical features observed in these patients included a male predominance, radiologic evidence of strictures, and endoscopic findings of white exudates, edema, and rings. Consistent with the initial reports in adults, some children seemed to experience a high degree of concomitant atopic diseases, including food allergy, eczema, and asthma.

EoE may be a food allergy disease

With the increasing clinical descriptions, lack of therapeutic approaches, and potential allergic mechanism underlying this disease, Kelly and colleagues took a novel approach in 1995. They provided a detailed description of 10 children who experienced vomiting and abdominal pain, dense esophageal eosinophilia (>20/HPF), and lack of response to either acid blockade or fundoplication (n = 2), who responded clinically and histologically to an amino acid–based formula. Strict use of the formula lead to normalization of the esophagus and, when allergenic food was added back into the diet, symptoms and esophageal eosinophilia returned. This study set the stage for several future studies that have examined the allergic diathesis and mechanisms of EoE. Development of therapeutic regimens included removing the six most common food allergens and instituting a diet based on the removal of foods based on food allergy testing. In addition, the global concept of EoE being a chronic disease was initiated because patients relapsed once foods were added back into the diet.

Alternative approaches to treat EoE

Because of difficulties adhering to diet restriction and the impact of steroids in other eosinophilic diseases, investigators took two different approaches. In 1998, Liacouras and colleagues demonstrated that subjects with EoE responded clinically and histologically to prednisone but that symptoms recurred when the medication was stopped. In the same year, Faubion and colleagues adapted a novel approach to provide topical steroids to the esophageal mucosa. They hypothesized that steroid sprayed from the metered dose inhaler used for asthma could be delivered by the saliva to the esophageal mucosa, leading to an antiinflammatory response. In their series of four patients, they found that this delivery mechanism was effective in relieving symptoms and, when examined, diminished esophageal eosinophilia. Subsequent studies using a variety of different preparations in adults and children have shown this approach to significantly decrease symptoms and mucosal eosinophilia. Other approaches toward modulating the immune system to treat EoE include leukotriene antagonist as described by Attwood and colleagues, antibody-based approaches to block interleukin (IL)-5, and a chemoattractant receptor-homologous molecule on Th2 cells (CRTH2) antagonist.

With the increasing identification of fixed narrowings in patients with EoE, dilatation has been very helpful in EoE management. Some early reports of perforation risk were perhaps overstated, which may be accounted for by the use of rigid esophagoscopy and bougie dilatation. However, the increased use of flexible endoscopic approaches with either balloon or bougie have shown to provide safe outcomes with a risk of perforation less than 1% per procedure, a risk similar to dilatation of peptic stricture.

More clinical experiences and prospective research studies continue to emphasize the chronic nature of EoE in that when treatments are stopped symptoms and inflammation return.

Wider acceptance of EoE and increasing frequency of diagnosis

Following these articles, there was a nearly logarithmic rise in articles focusing on the new entity, EoE. Within these bodies of works, reports surfaced that documented EoE as a disease occurring primarily in white males with an overall incidence of 1 in 10,000. From 2003 to 2007, work began to focus on defining the clinical phenotype of EoE. Symptoms in children included vomiting, abdominal pain, and feeding difficulties; adults were characterized by the stereotypical features of food impaction, dysphagia, and, in some circumstances, chest pain. Endoscopic patterns of linear furrows, circular ridges, and more defined rings (trachealization); the presence of white microabscesses; and the complication of severe strictures in some patients, were all manifestations of EoE. Retrospective studies detailing experiences with diet elimination, topical steroids, and other treatments emerged. Overall, a growing acceptance of a “new” disease became manifest and patient diagnoses and treatments ensued.

Development of consensus recommendations for diagnosis and treatment

Despite this increased recognition, several problems emerged that stymied not only clinical care but also an emerging research interest in this disease. How many eosinophils were required to make the diagnosis? What is the size of diagnostic HPF? What symptoms are necessary to diagnose a patient with EoE? Most problematic was determining the criteria necessary to make a diagnosis of EoE. To address this, the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition held the First International Gastrointestinal Eosinophil Research Symposium in Orlando, Florida, in 2006. This meeting represented the culmination of a multidisciplinary team of experts’ yearlong work to develop diagnostic recommendations and treatment approaches. The following year, the first consensus recommendations were published founded on expert clinical experience as well as the published literature, works that consisted primarily of case series, and retrospective analyses. This multidisciplinary team of physicians and clinical scientists determined that EoE was a clinicopathological disease that required symptoms characterizing esophageal dysfunction and dense esophageal eosinophilia (>15 eos/HPF) to make the diagnosis. Alternative causes for eosinophilia were ruled out and other parts of the gastrointestinal tract were normal. This publication provided strong support for the efforts of the advocacy organization, the American Partnership for Eosinophilic Disorders ( APFED.org ) to spearhead efforts in 2008, 15 years after the first case series was published, to obtain approval for the International Classification of Diseases, Ninth Revision classification (530.13) for EoE. Since then, three more guidelines have been published, each with new and improved recommendations based on expert opinion and, even more, on prospective studies. During that time, the original acronym EE was changed to EoE to avoid confusion with the previous use of EE to describe erosive esophagitis. Taken together, these guidelines provide a basis for both clinical care and research studies.

Defining EoE phenotypes

With increased clinical experiences, the clinical diversity of EoE continues to undergo definition. For instance, EoE is likely the most common cause of food impaction in adults and children. A range of features characterize luminal narrowings associated with EoE, including isolated esophageal strictures and rings, long segment narrowings, and crepe paper esophagus. Although rare, esophageal perforation can occur because of dilation or as a spontaneous event. In fact, EoE is now likely the most common cause of spontaneous perforation of the esophagus, although it is usually a partial perforation and treated differently than the original complete disruption originally described by Boorhaeve. In addition, clinical phenotypes related to therapeutic responses have been identified. For instance, patients with an FK506-binding protein 5 (FKBP51) genotype are steroid responsive thus pointing to a future role for molecular techniques to define personalized medicine.

Histologic conundrums: what is PPI-responsive esophageal eosinophilia?

One of the more confounding clinical problems that has arisen relates to determining whether the primary driver of esophageal eosinophilia is related to peptic or allergic causes. To address this, clinicians either have treated patients with high-dose PPIs or performed pH monitoring of the distal esophagus. These practices have revealed a group of patients with symptoms of esophageal dysfunction, dense esophageal eosinophilia, and normal pH monitoring who respond clinically and histologically to PPIs. For instance, Molina-Infante and colleagues, and Molina-Infante and Zamorano, identified many patients thought to not have GERD who responded to PPI therapy. Cheng and colleagues provide a potential mechanism for this finding in studies in which omeprazole was shown to downregulate EoE-related cytokines, including IL-4, IL-13, and eotaxin-3 signaling in esophageal epithelial cells through a signal transducer and activator of transcription factor 6 (STAT6)-dependent process. Whether this represents undocumented GERD or an alternative action of PPIs related to its potential antiinflammatory effect is not yet certain. Further studies defining the molecular features of EoE may lend insights into this clinical finding.

Understanding of chronicity

Following these initial case series, very little progress was apparent in the literature until the detailed description of the chronic nature and natural history of EoE. Straumann described the longest follow-up of 30 adults with EoE (22 men, mean age, 40.6 years; range, 16–71 years). The presenting symptom was almost exclusively dysphagia with food impaction and diagnosis was delayed an average of 4.6 years (range, 0–17 years). During the follow-up period of 1.4 to 11.5 years, 23% of patients reported increasing dysphagia and 36.7% reported stable symptoms. No change in endoscopic features was identified in six of seven patients in whom a subepithelial component could be analyzed but an increase in fibrosis and thickening was documented. Follow-up studies by the same group demonstrated that delay in diagnosis increased risk for stricture formation.

Molecular techniques advance care and pathogenetic understanding

In 2006, Blanchard reported the seminal finding that EoE was defined by a uniquely conserved gene-expression profile that included overexpression of eotaxin-3. Work from this group and others has defined several gene profiles for children and adults with EoE that have identified novel therapeutic targets. In addition, murine models and ex vivo systems continue to dissect pathogenetic pathways, in particular, those associated with IL-5, IL-13, and thymic stromal lymphopoietin (TSLP). Most recently, Wen and colleagues described a novel molecular testing that provides a diagnostic platform for patients with EoE in a rapid and objective manner using mucosal biopsies. These approaches will likely pave the way for future diagnostic and therapeutic approaches leading to a more personalized approach to care.

Future concerns and directions