Based on clinical experiences as well as an increasing body of literature from around the world, symptoms associated with EoE can be nonspecific and commonplace. Children may experience problems typically associated with gastroesophageal reflux such as vomiting, abdominal pain, regurgitation, and heartburn. They often also present with feeding difficulties or food aversions. Adolescents and adults present with stereotypical symptoms of solid food dysphagia or food impaction [1, 2].

Original clinical descriptions of pediatric patients with EoE recounted histories of children with reflux-like symptoms that did not improve with medical or surgical treatment of GERD, but responded to use of a hypoallergenic, amino acid-based formula [3]. Ten children with reflux-like symptoms were found to have dense esophageal eosinophilia and neither symptoms nor histopathological findings responded to proton pump inhibition or, in some cases, fundoplication. When treated with an elemental formula, all improved clinically and histologically. Clinical experiences and retrospective studies subsequently showed that children with EoE often presented with symptoms of upper abdominal pain, heartburn, or postprandial vomiting that persisted despite treatment with acid inhibition. As experiences grew, clinical reports described feeding difficulties associated with EoE [4, 5]. Symptoms included slow eating, gagging on foods, and lack of interest in trying new foods. More difficult to define were the coping behaviors associated with eating problems. For instance, children developed novel ways to ingest food to maintain nutrition that could also be viewed as troublesome, such as excessively long meals, drinking large amounts of fluids to wash foods down, or avoiding eating certain foods because of swallowing problems. These symptoms can create significant stress at family mealtimes and can alter family dynamics.

Solid food dysphagia and food impaction are typical presenting symptoms in adolescents and adults. While clinical experiences suggest that coping mechanisms likely exist, they are not well defined in the literature to date. Dysphagia is the primary presenting symptom of EoE in adults. In addition, EoE is emerging as the most common cause of food impactions presenting to emergency rooms [6]. Original studies found that up to 55% of patients with food impactions presenting to ERs were thought to have EoE as the underlying cause. Subsequent studies continue to support this estimate. Adults with EoE can also have symptoms of heartburn, but this is less common a presenting complaint.

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As of 2016, the diagnosis of EoE requires the presence of symptoms associated with esophageal dysfunction, dense esophageal eosinophilia on mucosal biopsy and ruling out other potential causes of these findings [7–9]. Upper endoscopy is required for diagnosis of EoE in order to obtain mucosal tissue biopsies. Additional supportive evidence for EoE is the finding of otherwise idiopathic esophageal strictures and improvement upon treatment with either dietary exclusion of food allergens, use of an elemental formula, or swallowed topical corticosteroids [10–14]. Significant controversy is developing regarding the role of proton pump inhibition in making the diagnosis of and treating patients with EoE.

In the early 1990s, two investigators described adults with symptoms of dysphagia and esophageal eosinophilia. Because of the diversity of opinions and lack of a standardized approach, a multidisciplinary group published Consensus Recommendations for the diagnosis of EoE based on the published literature and clinical experiences [8]. This document defined EoE as a clinicopathological disease that required key clinical features and >15 eosinophils per high power field in esophageal mucosal biopsies to make the diagnosis. Other diseases associated with these clinical findings, especially reflux esophagitis, had to be ruled out. Approaches to rule out GERD as a diagnostic possibility included use of pH impedance monitoring of the distal esophagus or a trial of high dose proton pump inhibition.

This document was revised in 2011 to reflect subsequent research findings and clinical advances [9]. Key modifications in the document included a proposed conceptual definition of EoE stating that EoE represents a chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The acronym was changed from EE to EoE because of confusion with erosive esophagitis and chronic was added to the definition because of increasing knowledge of its natural history. A new term, proton pump inhibitor responsive esophageal eosinophilia or PPI-REE, was also introduced. This term described a group of patients who did not have objective evidence of GERD and whose symptoms and esophageal eosinophilia resolved with the use of PPIs .

In the years since the initial description, basic studies have begun to examine additional molecular mechanisms through which PPIs might reduce eosinophil chemotactic events in the esophageal mucosa. In addition, clinical studies have identified EoE-like patients who respond to PPI treatment and controversy has arisen over the role of PPIs in the evaluation of patients with esophageal eosinophilia [15, 16]. Some suggest that PPIs may be used to treat patients with EoE and that these medications should not be used to establish the diagnosis of EoE. In contrast, others suggest that PPI treatment is an effective way to rule out GERD and should be used to do so as suggested in the original Consensus Recommendations. Although molecular studies provide support for the former opinion, more studies to determine the role of PPIs in the evaluation and treatment of adults, and perhaps even more so children, are needed [13].

The three Ds, diet, drugs, and dilation, have all been shown to be effective treatments of EoE in children and adults [17, 18]. Diet and drugs reduce both symptoms and esophageal inflammation and early work suggests they may also improve long-term outcomes. Esophageal dilation improves symptoms and increases luminal diameter, but does not impact the inflammatory process.

Diet: One of the first accounts of EoE demonstrated that esophageal inflammation resolved and symptoms improved with the use of elemental or amino acid-based formula [3]. We now understand EoE is mediated by exposure to certain food allergens in the majority of patients. In fact, dietary therapy for EoE has evolved to include complete elemental diet, empiric food elimination diets, and targeted food elimination diets. Elemental diets in the form of amino acid-based formulas can be highly effective in treating children and adults with EoE but have limited long-term tolerability for patients [19–21].

Targeted approaches to identifying potential offending foods are based on a diet history and results from skin and specific serum IgE (ImmunoCAP) testing. Early studies reported that a targeted approach to developing elimination diets could be effective in reducing eosinophilic density in 53–72% of patients; however a meta-analysis found this approach to be less promising than initial studies [22]. A shortcoming of the targeted approach to diet restriction is that the predictive value of traditional allergy testing is poor in identifying problematic foods in EoE. The potential benefit of the targeted approach is it might reduce the number of excluded foods.

Empiric elimination diets have been based on excluding the six most common food allergens: milk, egg, wheat, soy, peanuts, treenuts, and fish/shellfish. Efficacy at reducing eosinophilic inflammation was 74% in children treated with the six food elimination diet [23]. Studies looking at less restrictive empiric diets including a four food elimination diet (milk, wheat, egg, and legumes), vegan diet, and milk only restriction have demonstrated efficacy in both children and adults [24–26].

In contrast to medications, diet restriction avoids potential steroid side effects. Diet treatment often comes with added cost with respect to groceries and can affect quality of life [27, 28]. Future studies will hopefully help identify an optimal approach to empiric and/or targeted diet restriction in treating EoE.

Drugs: Swallowed topical steroids (STS) and proton pump inhibitors are considered the mainstay of medical treatment for esophageal eosinophilia. Originally EoE was characterized by its lack of response to PPI treatment. However, clinical studies have shown that 25–35% of patients with characteristic esophageal symptoms will have clinical and histologic response to a trial of high dose PPI (PPIREE). Therefore, PPI has been described as a “first line” treatment option for symptomatic patients with esophageal eosinophilia [14]. While controversy exists around the role of PPI in making the diagnosis of EoE, a trial of high dose PPI is practical to rule out PPI responsive inflammation.

STS in the form of swallowed fluticasone and liquid budesonide have been shown to be effective in treating EoE with response rates between 50 and 90%. Metered dose inhalers (MDIs) have been used to deliver medication to the back of the throat where it is then swallowed, coating the esophagus. Viscous preparations of budesonide were developed primarily to treat children who may have difficulty with coordination in taking the MDI. Sucralose was initially proposed and demonstrated 87% efficacy [29]. Since then several other preparations have been described in both children and adults using foods to prepare a viscous vehicle for the budesonide [30, 31]. Randomized clinical trials with a proprietary viscous budesonide slurry are ongoing in treating patients with EoE.

Complications of STS include Candida infections of the mouth or esophagus and adrenal insufficiency (AI) [32–34]. AI has been shown to occur in EoE patients treated with STS ranging from 0 to 45%. The wide range of reported AI associated with STS treatment of EoE exists because of variability in method of testing for AI, lack of control over type and duration of STS, and no control for other forms of steroids used. This later issue may be the most important issue since, in our experience, the use of more than one corticosteroid (e.g., for EoE and asthma) increases susceptibility to developing AI (unpublished data). It is our practice to monitor clinically for signs of AI (decreased height velocity, Cushingoid facies) and screen patients who have been on chronic STS with fasting morning cortisol and if abnormal, refer to an endocrinologist for further evaluation.

Other Drugs: Studies exploring benefits of montelukast to control symptoms and inflammation have been mixed. With the advent of increasing understanding of pathogenetic mechanisms and identification of potential therapeutic targets, antibody-based biologicals have emerged as novel approaches to treatments. Studies examining inhibition of IL-5 and IL-13 demonstrated a positive impact on esophageal eosinophilia but inconsistent findings regarding symptom reduction. Examination of the efficacy, cost benefit, and side effect profile of these approaches will be critical to future care.

Dilation: Dilation should be considered in the setting of severe esophageal narrowing that does not allow passage of a pediatric endoscope or when symptoms of dysphagia persist despite adequate control of inflammation or attempts at medical treatment fail [35–40]. This later circumstance may occur when subepithelial fibrosis has occurred that escapes endoscopic detection. Dilation is effective at improving symptoms by increasing luminal diameter but it does not resolve underlying inflammation that is more appropriately treated with diet restriction or STS. Dilation techniques with wire-guided Savories, bougies, and balloon dilators have all been described in the management of EoE. Although early case series reported high rates of perforations in adult EoE patients treated with dilations, recent studies examining larger numbers of patients as well as children demonstrate the risk of any complications, such as perforation, bleeding requiring transfusion or hospitalization, is low. While risk of serious complications is low, pain is common and has been reported in up to 70% of patients undergoing dilation. Repeat dilation is often needed as a part of long-term management [40]. A careful approach with interval increases in dilator size is often recommended.

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Since EoE is such a “young” disease, treatment goals may vary depending on whether a patient is participating in a therapeutic trial or is receiving treatment in a clinician’s office. For instance, in most industry-sponsored therapeutic trials seeking Food and Drug Administration (FDA) approval, improvement of patient-reported outcomes (PROs) and lowering of eosinophils per high power field (HPF) in a mucosal esophageal biopsy have been used as co-primary endpoints. In contrast, clinicians caring for patients have used a number of different metrics to assess the efficacy of treatment including reduction of primary symptom, decrease in eosinophils/HPF, improvement in endoscopic appearance of the esophageal mucosa, and increase in quality of life. For children, growth and development and balancing risks and benefits of chronic treatment with symptom control and histological improvement remain key considerations.

Assessment of histopathology : The number of eosinophils per high power field has traditionally been the mainstay of establishing the diagnosis of EoE and defining histologic severity. Initial guidelines support the use of >15 eos/HPF to make the diagnosis of EoE, studies have yet to determine the threshold number of eosinophils that defines effective treatment. Other histologic findings that may help better define this include eosinophil degranulation, eosinophil micro-abscesses, basal layer hyperplasia with rete peg elongation, dilated intracellular spaces, and lamina propria fibrosis [41].

Patient-reported outcomes: Goals of treatment from a patient perspective are to reduce symptom severity and frequency and prevent complications of EoE such as food bolus impaction and esophageal narrowing. STS have been shown to reduce the risk of developing food bolus impaction and while not studied, control of inflammation with dietary restriction is presumed to also prevent or delay onset of fibrosis and complications of disease [42].

Patient symptoms do not always correlate with eosinophil density [43, 44]. This may be a result of either patients developing adaptive coping mechanisms to avoid dysphagia symptoms or because long-standing inflammation leads to a “burned out” fibrostenotic esophagus that is devoid of dense eosinophilia [45]. Assessment of patient-reported symptoms therefore has been a challenge for clinical trials in EoE and requires a detailed history. Ongoing studies have developed patient-reported outcomes that provide validated measures of symptoms in therapeutic studies. While some are more practical in the research setting, others may provide a means of more accurately assessing symptoms in the clinical setting and measuring symptom response [43].

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