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Eosinophililc esophagitis is a clinicopathologic disease characterized clinically by dysphagia and food impaction in adults and nonspecific symptoms of gastroesophageal reflux disease in children, and histologically by large numbers of eosinophils in the proximal and distal esophageal epithelium. Importantly, these symptoms and histologic abnormalities appear to be unresponsive to proton pump inhibition. Recent clinical and basic studies suggest an allergic etiology but the precise allergen remains unknown and is likely unique for each patient. Endoscopic features suggest ongoing inflammation and range from linear furrowing with whitish exudation to long-segment stricture formation, to a fragile, crepe paper–like mucosa that is easily split open. Treatments include nutritional restrictions, medical management with topical steroids, and, in stenotic circumstances, esophageal dilation. The long-term outcome is still not certain.
Since 1879, when Paul Erhlich originally identified the eosinophil (named after Eos, the Greek goddess of dawn), clinicians and scientist have puzzled over the nature of this enigmatic cell. Little is known about its overall role in bodily function but the recognition of eosinophilic infiltrates in several gastrointestinal diseases has sparked a recent upsurge in interest in the association of eosinophil with specific diseases. In the past 5 years, we have witnessed a number of studies focusing on the clinicopathologic disease eosinophilic esophagitis (EOE). The recognition of this disease introduces a new era in understanding the biology of the eosinophil in the gastrointestinal tract. This review will focus on identifying clinicopathologic features of EOE in adults and children.
Once considered a rarity, EOE is now increasingly recognized, with some studies suggesting a prevalence reaching near epidemic proportions. Whether this increased recognition is due to enhanced awareness or genuinely greater incidence is unclear. The first pediatric demographic data by Noel and associates,1 from the United States, identified an over four-fold increase in the prevalence of EOE in children during the period from 1998 to 2002. In order to obtain adult demographic data, Straumann and colleagues2 prospectively analyzed the number of patients with EOE from a demographically stable catchment area in Switzerland. Throughout a 16-year observation period, an average annual incidence of 1.438 cases per 100,000 inhabitants was noted, resulting in an increasing prevalence from initially 2 to actually 27 patients per 100,000 inhabitants. Given the stability of the demographic conditions and the unchanged recording principles in both of these studies, it is very likely that this remarkable trend reflects an increase in EOE and not just enhanced awareness.
As with many other noninfectious inflammatory gastrointestinal diseases, EOE appears to be a disease of Westernized cultures. Case series originate in urban settings and have described patients from all continents except Africa.1-3 All ages are affected and in the majority of adult studies, symptoms developed between adolescence and the fourth decade of life. For unknown reasons, over 70% of affected individuals are male.4
Symptoms associated with EOE vary according to the age of presentation. As an example, adults most commonly complain of a narrow range of symptoms including dysphagia or food impaction.5,6 In a recent series that identified 22 adults with EOE, at an average age of 32 years, all were found to have dysphagia lasting from several seconds to several hours. Desai and coworkers7 found that over half of adults presenting with food impaction in a private practice setting were found to have EOE. A minority of adults present with nonspecific reflux or dyspepsia-like symptoms.
In contrast, children with EOE present with a wide variety of symptoms, including abdominal and chest pain, failure to thrive, vomiting, and gastroesophageal reflux disease (GERD)-like symptoms.8-10 This might be related to the lack of specificity with which children can communicate their discomfort or because the inflammatory response leads to a nonobstructive pattern of symptoms.
It is increasingly clear that EOE is a chronic disease, but little data document its natural history. To date, the only known complication of EOE is narrowing of the esophageal lumen. This finding is manifest from several different endoscopic findings. Strictures can occur in any part of the esophagus and can extend longitudinally to encompass much of the esophageal length or, alternatively, a patient may present with small-caliber esophagus. These observations lead to speculation that longstanding eosinophilic inflammation can potentially lead to collagen deposition, fibrous remodeling, and fixed esophageal narrowing. Straumann and colleagues11 reported the longest follow-up in adults and found that 13 of 30 patients had strictures. The fixed nature of these strictures is further emphasized by the fact that they are often resistant to medical management. So far no reports of esophageal carcinoma in patients with EOE have been published, suggesting it is not a premalignant lesion but that more long-term follow-up is required. Finally, by definition, eosinophilic inflammation is confined to the esophagus and does not manifest in the stomach or duodenum. It is unusual for young children to develop long strictures or fixed narrowings but this has been reported.12
The impact of EOE on daily function was examined in one prospectively conducted observational study including 30 adult patients with EOE. After a mean of 7.2 years, dysphagia persisted in almost all patients and exerted a negative impact on socioprofessional activities of more than half of those studied.11 No single case evolved to eosinophilic gastroenteritis or to a hypereosinophilic syndrome. Taken together, these studies suggest that EOE is a chronic esophageal disease that can potentially lead to longstanding dysphagia and structural esophageal alterations.
To date, many different endoscopic signs have been reported in the literature. Unspectacular reddish longitudinal furrows,3,7 white nodule- or plaque-like exudates that mimic topical anesthetic spray or fungal infection of the esophagus,13-15 transient or fixed corrugated rings,16 crêpe paper–like mucosa due to a loss of mucosal elasticity,17 and strictures of variable length3,18 have all been described in adults and children with EOE (Figure 1). It is likely that certain endoscopic findings in children are related to consequences of acute inflammation and local edema such as whitish exudates and longitudinal furrowing. Other endscopic findings in adults are likely the impact of chronic eosinophilic inflammation. For instance, crêpe paper–like mucosa and strictures are more frequently thought to occur in adults than in children.
No studies have demonstrated the specificity of endoscopic findings. In fact, white exudates and longitudinal furrows can occur in peptic esophagitis in children.19 In other circumstances, the endoscopic signs of EOE are often subtle6,3,20 or even absent,5 requiring a high degree of clinical suspicion and the procurement of multiple mucosal biopsies.
To date, no definitive, consensual diagnostic criteria exist for EOE. In reviewing the published literature and clinical experience, EOE can be defined as a clinicopathologic disease that requires both symptoms and characteristic histologic findings that are resistant to proton pump inhibition. The diagnostic hallmark is a dense mucosal eosinophilic infiltration of the esophagus, a tissue normally void of these inflammatory cells (Figure 2).21,22 Basal-zone hyperplasia and increased papillary size are further histomorphologic alterations, but these findings are nonspecific and induced by several other chronic inflammatory mucosal processes. Eosinophilic microabscesses and superficial layering of eosinophils along the luminal surface are other characteristic, but not pathognomonic, features. It is important to recognize that eosinophilic infiltration may be present in a heterogeneous pattern (ie, with a patchy distribution along the circumference or longitudinal extension of the esophagus). Therefore, when considering EOE as a diagnosis, it is critical to obtain multiple biopsies from different sections of the proximal and distal esophagus.23 Importantly, gastric and duodenal biopsies are normal in patients with EOE.
No consensus has been reached on an optimal treatment for EOE. The degree of symptomatology, age of the patient, endoscopic findings, social history, and comorbid diseases all contribute to treatment decision-making. Standard recommendations for EOE-induced dysphagia include systemic24,25 or topical corticosteroids,25-29 a specific elimination diet,9,10 an elemental diet,30,31 and dilation.5,17
Only a minority of adults with EOE develop such severe disturbances that therapy is desired.11 When obstructive symptoms and an esophageal stricture are present, medical management should be strongly considered, and if it is not effective, dilation is indicated. Adults have also received treatment with topical corticosteroids leading to remission of symptoms and normalization of histopathology. This treatment involves spraying an actuation of fluticasone from a metered-dose inhaler into the mouth and having the patient swallow. The mouth should be closed and no spacer should be used. The patient should not eat or drink for 30 minutes following the actuation. Previous studies in older children have found success with a dose of fluticasone of 220 μg/actuation, two puffs twice daily for 2 months.
Treatment for younger children can be more challenging. Optimal treatment involves identification of an offending allergen, typically food-associated. In consultation with the allergist, single foods are eliminated to see if symptoms and histopathology improve. In certain circumstances, an elemental diet with a formula composed of free amino acids is required to induce a remission. Subsequently, single foods can be added back with close observation of symptoms and histopathology.
To date, the ultimate goal of treatment is to provide symptom relief and, in the opinion of these authors, significant improvement of mucosal inflammation. Because the long-term outcome suggests that some patients may develop strictures, we currently will provide dietary or topical steroid treatment to resolve symptoms and then repeat the endoscopy to insure mucosal healing. Others feel that this approach to treatment is overly aggressive and will address symptoms only.
Recently, beneficial effects of mepolizumab (GlaxoSmithKline), a humanized antibody against interleukin-5, were reported in two open label studies with various hypereosinophilic disorders, including one patient with EOE.32,33 An adolescent boy with significant upper esophageal narrowing, whose symptoms were refractory to all medical and nutritional management, received mepolizumab and achieved both symptomatic and histologic remission. The role of this medication in the management of adults and children with EOE awaits further study and definition.