Management of proton pump inhibitor responsive-esophageal eosinophilia and eosinophilic esophagitis: Controversies in treatment approaches

Abstract

Eosinophilic esophagitis (EoE) is a chronic immune mediated clinicopathologic disease. The prevalence of EoE is approximately 1/2000 persons, EoE is now the most common cause of food impactions, and health care expenditures approach $1 billion annually. This paper will discuss challenges related to proton pump inhibitor responsive esophageal eosinophilia (PPI-REE), including distinguishing this condition from EoE and understanding mechanisms of the PPI response. For EoE, we will review multiple ongoing debates about treatment and monitoring strategies, including selecting treatment outcomes, optimizing medication formulations, approaching the steroid-refractory patient, conducting dietary elimination, prescribing long-term maintenance therapy, and performing esophageal dilation.

Introduction

Eosinophilic esophagitis (EoE) is a chronic immune-mediated clinicopathologic disease. Patients presenting with evidence of esophageal dysfunction with at least 15 eosinophils per high power field (eos/hpf) after a high-dose proton pump inhibitor (PPI) trial and in the absence of other known causes of eosinophilia meet diagnostic criteria for EoE [1,2]. However, the presence of high intraepithelial eosinophils in an esophageal biopsy is not specific to EoE, but can be present in gastroesophageal reflux disease (GERD), PPI-responsive esophageal eosinophilia (PPI-REE) and other disorders with systemic eosinophilia or inflammation [2,3]. The prevalence of EoE has been recently estimated to be at least 56.7/100,000 persons, with a peak prevalence of 114.6/100,000 in men between the ages of 35 – 39 years [4], EoE is now the most common cause of food impactions [5], and health care expenditures approach $1 billion annually [6]. Given the rising prevalence of EoE, understanding the controversies in management of EoE is beneficial to patients, clinicians and researchers alike. This paper will therefore discuss challenges related to PPI-REE, including distinguishing this condition from EoE and understanding mechanisms of the PPI response. For EoE, we will review multiple ongoing debates about treatment and monitoring strategies, including selecting treatment outcomes, optimizing medication formulations, approaching the steroid-refractory patient, conducting dietary elimination, prescribing long-term maintenance therapy, and performing esophageal dilation.

Proton pump inhibitor-responsive esophageal eosinophilia

PPI-REE is a condition where patients have esophageal eosinophilia and clinical and endoscopic features that are consistent with EoE, but have symptom improvement and resolution of eosinophilia after PPI treatment [2]. In retrospect, this entity was first described in 2006 in a case series posing the question of whether three patients which esophageal eosinophilia who responded to PPI treatment had peptic or allergic esophagitis [7,8]. However, prior to the recognition of EoE and PPI-REE, the presence of eosinophils in the esophageal mucosa had largely been attributed to GERD [9], and the first EoE diagnostic guidelines required either a PPI trial or negative pH-testing to distinguish EoE from GERD [10]. Since then, a much more complex relation between EoE and GERD has been described [11]. Multiple prospective and retrospective studies in both children and adults have shown that at least one third of patients with esophageal eosinophilia will respond to PPI treatment [12-19]. With this increasing evidence, the more recent EoE diagnostic guidelines have required exclusion of PPI-REE with a high-dose PPI trial prior to the diagnosis of EoE [1,2]. However, as of yet there are no clinical, endoscopic, histologic, immunohistochemical, cytokine, or gene expression differences at baseline prior to the PPI trial that distinguish EoE from PPI-REE [17,19-24]. Therefore, it is possible that PPI-REE is a phenotype of EoE, instead of being a distinctly different disease [21,25,26], but further studies are needed to better elucidate this dilemma.

Mechanism of PPI response in PPI-REE

If PPI-REE is difficult to distinguish from EoE at baseline, and if GERD is not the cause of esophageal eosinophilia in PPI-REE, what acid-independent mechanisms might explain the PPI response in these patients? Available evidence suggests that in patients with a clinical EoE phenotype who respond to PPI therapy and are diagnosed with PPI-REE, allergic and immune mediators are elevated at levels similar to what would be seen in EoE [20,22,24]. Moreover, a study of genetic expression in patients with EoE and PPI-REE, prior to the PPI trial, revealed that patients in both groups had a similar molecular signature. However, in the population with PPI-REE, PPI monotherapy almost completely reversed the molecular signature. This suggests that PPIs play an anti-inflammatory role in treating PPI-REE [24]. In vitro and in vivo models have demonstrated anti-oxidant and anti-inflammatory effects of PPIs [27]. In recent work in EoE cell lines, PPIs have been shown to decrease eotaxin-3 expression by blocking the promotor region of that gene, a mechanism that can directly explain the PPI response seen clinically [28,29]. Another proposed mechanism of PPI responsiveness is through the mucosal barrier. The esophageal mucosal barrier is impaired in both EoE and PPI-REE. However, in the patients with PPI-REE, PPIs partially restored mucosal integrity [30]. A final possible mechanism relates to polymorphisms in the CYP2C19 gene, the principle enzyme involve in hepatic activation of PPIs. Preliminary data presented in abstract form suggest that those who are rapid metabolizers may have less PPI response than slow metabolizers, as well as less durable response [31].

With these emerging novel mechanisms of PPI-response in esophageal eosinophilia, a remaining question is whether patients maintain a response on these medications or do they evolve into EoE over time. This issue requires further study, but some early data are instructive. A pediatric study presented four patients with a transient PPI response [32]. However, newer data with 46 patients suggest that 72% of patients with PPI-REE have a sustained response to PPIs [31]. Further investigation is required to determine the optimal dose of PPIs and duration of treatment [26].

Eosinophilic Esophagitis

EoE is a chronic disease, and symptoms are varied based on age. In the pediatric population, symptoms tend to be non-specific, including failure to thrive, feeding intolerance, food aversion, abdominal pain, nausea, vomiting, regurgitation or reflux [33]. In adults, dysphagia is the prominent symptom, and EoE is the most common cause of food impactions [34-36]. These differences in symptoms may reflect progression of disease and endoscopic findings, from more of an inflammatory-predominant condition in the pediatric population as manifest by esophageal furrows, edema, and exudates, to a fibrotic condition in adults as esophageal remodeling, narrowing, and stricturing complicate chronic inflammation [5,37-39]. A Swiss retrospective cohort study of diagnostic delay in EoE concluded that for every increased decade of untreated EoE, the odds of having an esophageal stricture doubled [37]. A case series similarly highlighted that patients with long standing untreated EoE are more likely to have endoscopic complications during the removal of their food impaction [40]. Furthermore, as EoE is now the leading cause of food impactions in the United States [5], treating EoE will presumably result in decreased incidence of food impactions and associated costs. In this context, there are several rationales for treating EoE: first is to improve symptoms and help patients feel better; second is to prevent complications, such as food impactions and esophageal strictures; and third is to prevent possible progression of disease manifest by esophageal remodeling.

Selection of treatment outcomes in EoE

Therapeutic endpoints in EoE are not well established, and understanding when EoE treatment is “successful” is a major challenge both in clinical practice and in research studies. Symptoms and histology are the most widely used endpoints in the study of EoE, but these are not the only potential endpoints. Others could include quality of life, complications, endoscopic findings, esophageal compliance, and biomarkers [41-43] and after treatment ideally all of these components would improve or normalize.

In practice, however, these outcomes can be difficult to assess. Symptoms do not always correlate with histologic response [44-48]. Symptoms can improve despite persistent inflammation if patients modify their diet by being careful with what they eat and by chewing slowly and thoroughly, or if they undergo esophageal dilation. Conversely, symptoms can persist despite resolution of inflammation if a stricture is present but has not been dilated, if there is an infection complicating treatment, or if there is a superimposed functional gastrointestinal disorder. Because there are few data examining the decrease in eosinophil density needed to prevent the progression of esophageal injury or improve symptoms [49], studies have used varying and empirically determined histologic endpoints based on number of eosinophils per high power field or percent decline in the eosinophil count to define response to therapy [42]. Some studies also use the concept of a partial historic response, again with variable definitions.

Recognizing the need for validated outcomes for EoE, there has been a major effort by researchers over the past several years to develop measures specifically for EoE [41]. Symptom based patient reported outcomes, quality of life measures, and endoscopic scoring systems have been developed and validated for EoE [50-56] and are currently being assessed in ongoing trials. A validated histologic score is also under development [57] and the utility of the functional luminal impedance probe on measuring esophageal compliance is under investigation [58]. Having well defined treatment outcomes will aid practitioners to assess the efficacy of therapy and will allow use of comparable outcomes in clinical trials.

Optimizing topical steroid treatment for EoE

Swallowed topical steroids are an effective therapy for EoE, but it is important to note that there is no Food and Drug Administration (FDA) approved steroid formulation for the treatment of EoE and therefore steroid use is off-label at this time. Fluticasone and budesonide are commonly used steroid formulations in EoE [2] and have been shown in meta-analyses to markedly decrease esophageal eosinophilia [59]. In the pediatric EoE population, swallowed fluticasone has been proven to improve histology in more than 50% of patients [60-62]. However, for very young children with EoE, delivery of fluticasone via a multi-dose inhaler may not be feasible. Placebo controlled trials of swallowed fluticasone in adults with EoE also demonstrated histologic remission thought symptom response was not consistent [44,62]. Oral budesonide has been shown to improve EoE from histologic, clinical and endoscopic standpoints in both children and adults [63,64]. As of yet, there are no completed trials directly comparing fluticasone to budesonide. In a trial comparing budesonide formulations, oral viscous budesonide was found to decrease esophageal eosinophil counts significantly more than nebulized budesonide [65]. This was because oral viscous budesonide was found to have more contact time with the esophageal mucosa [65], highlighting the point that more effective methods are needed to deliver medication topically to the esophagus.

Several recent studies have explored ways to optimize topical steroid delivery to the esophagus. One study in children showed that mixing aqueous budesonide with elemental formula powder to form a thick slurry was effective for decreasing eosinophil counts [66]. In a randomized trial where a viscous budesonide suspension was compared to an effervescent budesonide tablet that dissolved on the tongue and was then swallowed, both were found to be superior to placebo and comparable to each other in inducing histologic remission as well as improving endoscopic severity [47]. Interestingly, however, symptoms improved equally in the placebo and active treatment arms after the two week induction course. A different randomized trial compared oral budesonide suspension, a formulation previously studied in children [67] to placebo using validated symptom and endoscopic metrics [51,52,68]. Here, there was concordant improvement in symptoms of dysphagia, eosinophil counts, and endoscopic appearance compared with placebo. These investigations into novel medication formulations show that more effective targeted medications can lead to improved clinical outcomes.

Approaching patients refractory to topical steroids

There are few studies that have specifically addressed non-response to topical steroids in EoE [69]. In reviewing published clinical trials, rates of non-response range from 0 – 50% [44,47,60,62,63]. It is important to note, however, that the definition of steroid non-response is variable across studies. There are a number of possible reasons why steroids may not be effective in inducing remission in EoE. The dosage may be too low, the formulation may be sub-optimal, the patient may not be using the formulation appropriately and, of course, there may be unreported medication non-adherence. Non-medication related reasons for persistent symptoms after topical steroid use include a superimposed infection, persistent allergen exposure, a concomitant functional GI disorder or that the diagnosis is not EoE.

Clinically, it would be helpful to predict which patient might respond to topical steroid treatment, but there are few data informing this issue. In one large retrospective analysis, 48% of EoE patients receiving topical corticosteroids were defined as non-responders as defined by post-treatment histology revealing >15 eos/hpf [69]. Analysis revealed that esophageal dilation at baseline and abdominal pain were clinical predictors of non-response, but that there were no other clinical, endoscopic, or histologic predictors. These results are similar to those presented in abstract form at a different center [70]. This study of predictors also conducted an immunohistochemical analysis demonstrating that patients who responded to topical corticosteroids had higher baseline levels of tryptase and eotaxin-3, but not major basic protein [69]. Of the patients who were steroid-refractory, 47% underwent second line therapy, and the overall response rate to second line therapies for steroid-refractory patients was 48% [69]. In a prospective randomized trial of high dose swallowed fluticasone, molecular gene expression profiles of responders to therapy and non-responders were evaluated [62]. In those patients who responded to steroids, the molecular signature normalized, although it was still significantly different from healthy controls. This group identified a small subset of genes that may predict steroid efficacy, but additional studies are required to validate this approach.

Optimizing dietary therapy in EoE

Because EoE is thought to be caused by food antigens in a majority of patients [71], dietary elimination has been extensively tested for EoE. The current guidelines suggest that dietary therapy is a first line treatment option, and should also be used for those patients who failed topical corticosteroids [2]. There are three strategies for dietary therapy in EoE: elemental formulas which completely eliminate all food allergens; a targeted elimination diet guided by allergy testing; and an empiric elimination diet of the six foods most commonly known to be triggers of EoE (wheat, milk, eggs, soy, nuts and seafood) [42,72].

In pediatric case series, elemental diets have been shown to be an effective method of improving histology in EoE [73,74], and this has recently been confirmed in adults [75]. Despite its efficacy, elemental formulas are expensive and difficult to tolerate. Therefore, allergy testing directed elimination was studied and found to be effective in inducing histologic remission in EoE and triggers could be identified upon reintroduction of the food [76-79]. Such studies revealed commonly implicated foods. Because there was no good agreement or reproducibility for skin-based allergy testing, the six food elimination diet (SFED) was developed and was found to be equally or more effective, as well as more palatable than the very restrictive elemental diets [80-83].

Though effective, the SFED and other restrictive diets can still be rather limiting, and food reintroduction process is cumbersome, time-intensive, and expensive, with a follow-up endoscopy often required after every food or food group has been reintroduced. Therefore, less restrictive empiric elimination diets are currently being studied. A diet eliminating four of the more commonly implicated food groups, dairy, wheat, egg and legumes, was prospectively tested in Spain and demonstrated a 54% clinicopathologic remission rate in adult patients [84]. Non-responders were then offered a SFED, which was effective in one third of non-responders to the four food elimination diet [84]. A subsequent study of the four food elimination diet in adults in the U.S. where dairy, wheat, egg, and soy were eliminated had comparable results, with a 46% response rate [85]. In children, responses might be better for the four food elimination, with one study reporting response rates of 71% [86]. To simplify dietary elimination more, there have been studies of dairy elimination alone, given that dairy appears to be the most common trigger of EoE. Two studies of cow's milk elimination in children have both shown a 65% rate of clinical and histologic remission [87,88].

Once identified, long term exclusion of trigger foods from the diet is recommend [2]. Food re-introduction after histologic remission has been studied most commonly with single-food reintroduction, followed by endoscopy with biopsies after each reintroduction, but this process is not standardized and remains somewhat controversial [42]. While this method allows one to determine the specific food trigger in the development of EoE [81,89], it can be challenging both for patients and physicians as noted above. This remains an area where additional research is required to guide practice, and emerging non-invasive or minimally invasive techniques may change paradigms in the future [90-92].

The role of esophageal dilation in EoE

Fibrostenotic complications of EoE such as strictures and narrow caliber esophagus may not be adequately treated with diet elimination or pharmacotherapy, [2,93] treatments which primarily are anti-inflammatory rather than anti-fibrotic. Because esophageal dilation is effective in increasing the esophageal luminal diameter as well as improving dysphagia for as long as one year [94-98], it has become an important treatment option for EoE. It must be noted, however, that while symptoms improve post-dilation, eosinophilic inflammation persists so should still be separately addressed [94]. Both though-the-scope balloon dilators and wire- and non-wire-guided dilators have been used and shown to be safe, though there are no head-to-head comparisons of these techniques [94-99]. Dilation in EoE is relatively safe; a 2-9% rate of deep mucosal tears is reported, the risk of major bleeding is <1%, but the perforation rate is 1% or lower, with many reviews reporting no perforations in their cohorts, and this safety has been confirmed in meta-analyses [96-103]. Novel techniques for dilation, such as the pull through technique, have been proposed to better appreciate subtle luminal narrowing that may be present in EoE [99]. As the fibrostenotic complications of EoE tend to occur with longer duration of disease [37], esophageal dilation is primarily studied in the adults, however a recent abstract presented the first evidence that dilation can be safely performed in children [104]. A retrospective analysis of the risk factors associated with endoscopic complications revealed that luminal narrowing in the upper or middle third of the esophagus or esophageal stricture that cannot be traversed with a standard upper endoscope increases the risk of complications [100]. Overall, the complication rate of dilation in eosinophilic esophagitis can be low and endoscopic therapy should be considered as an adjunct for the management of dysphagia in patients with EoE.

What is the best first line therapy for EoE?

The current guidelines state that either topical corticosteroids or dietary elimination can be considered first line treatment option for EoE [2] based on the studies reviewed above. However, to date there are no prospective studies directly comparing these two modalities for inducing remission in EoE. Therefore, the choice of therapy should be guided by patient preference, tailored to the clinical scenario, and take into account local provider expertise and resources [105]. A recent cost-utility analysis has attempted to inform this decision making, and shows that even after accounting for the multiple endoscopies required for food trigger identification, dietary elimination is cost-effective compared to topical steroids, primarily related to the ongoing requirement for and high cost of these medications [106].

Endoscopic therapy with dilation is considered adjunctive in the treatment of EoE to address the fibrostenotic aspect of the disease, which is predominantly in adult patients [2]. Some research suggested that esophageal dilation alone may effectively treat symptoms related to EoE, specifically dysphagia [94,97], and it is reasonable to perform dilation even at the diagnostic endoscopic if there is a critical stricture. A cost analysis of fluticasone as first line therapy with subsequent dilation if needed and dilation as first line therapy with subsequent fluticasone if needed revealed that the cost of both modalities is nearly the same [107]. Further data are needed to support the decision making process for the optimal first line therapy in EoE.

Long-term therapy to maintain remission

Because EoE is a chronic disease, symptoms, endoscopic signs, and eosinophilic inflammation tend to recur when treatment is discontinued [33,61,108-113]. Moreover, recent studies demonstrate that a longer symptom duration prior to diagnosis of EoE, a proxy for untreated eosinophilic inflammation, is associated with the increasing of strictures over time [37,38]. These findings support the need for maintaining remission with ongoing treatment, but data on long-term outcomes remain somewhat limited.

There is only one prospective randomized trial on this topic, but it has confirmed that oral budesonide use is effective in maintaining remission with one year of use [112]. Furthermore, long term topical steroid use in patients with EoE has been shown to decrease the occurrence of complications such as food impactions in adults [114] and suppress symptoms and endoscopic findings in children [115]. While long term safety data are lacking, topical corticosteroid therapy for the treatment of EoE has also been shown to be relative safe in the short and mid-term. Studies reported 0 - 30% rates of esophageal candidiasis, the majority of which were mild, asymptomatic and detected on routine endoscopy [44,47,59,62,64,67,111-113]. Furthermore, endoscopy did not reveal signs of esophageal atrophy [111,112]. A recently published small pilot study of pediatric patients with EoE receiving oral viscous budesonide for more than three months revealed that there may be a risk of adrenal insufficiency [116]. However, larger studies of adults and children did not observe an effect on the adrenal axis [44,62,63,67,68,117]. Clinical and histologic remission can also be maintained in both children and adults with long term avoidance of the identified food trigger [33,74,81,82]. When either diet or steroid therapy decreases esophageal inflammation, esophageal fibrosis and remodeling improve as well, shown either by a decrease in lamina propria fibrosis, a decrease in esophageal wall thickness as measured by endoscopic ultrasound, or by an increase in esophageal compliance [58,112,118-122]. Therefore, current guidelines support the use of maintenance therapy for EoE, and particularly recommend this approach for patients who have had food impactions, development of esophageal strictures or other signs of remodeling, and symptoms that rapidly recur after initially stopping treatment [2]. As with inducing remission, there are no studies comparing the efficacy and long term safety of pharmacotherapy and diet elimination strategies for maintenance therapy.

Emerging pharmacologic agents

At this time, there are no FDA approved medical therapies for the treatment of eosinophilic esophagitis. Therefore, there is a pressing need for drug development in this field. Novel steroid delivery vehicles are under development and have been previously discussed. Another topical steroid that holds some promise is ciclesonide. It has been shown to bind to esophageal glucocorticoid receptors with more affinity than budesonide, and requires activation by an epithelial esterase [123]. Furthermore, it is rapidly metabolized, minimizing systemic side effects [124]. However, there are only two small cases series of patients who were treated with ciclesonide. In one series, all four patients had clinical and histologic responses [125]. In another series of four patients who did not respond to topical budesonide or fluticasone, only 50% of the patients demonstrated a histologic response to ciclesonide [126].

Novel biologic agents, immunomodulators, and leukotriene antagonists are also being studied for the treatment of EoE [127]. Since EoE is thought to be a Th2 lymphocyte mediated process, a suppressor of T cell proliferation such as 6-mercaptopurine (6-MP), or its prodrug azathioprine, have been proposed for the treatment of EoE. A case series of two patients on azathioprine and one patient on 6-MP for treatment of corticosteroid dependent EoE reported that these agents were able to induce and maintain remission in EoE [128], but there are no other studies examining these agents in EoE.

Biologics offer a promising approach to target key cytokines in the Th2 pathway. Reslizumab and mepolizumab are monoclonal antibodies against IL-5 that have been studied for treating EoE. There are three published RCTs studying these agents, two large studies in children and a smaller one in adults [43,46,129]. While these agents were able to significantly improve eosinophil counts, there was not a clear symptom benefit, these agents are not currently available, and there are no active protocols with them currently. A small phase II proof of principle study of the efficacy of an anti-IL-13 antibody in EoE did not achieve the primary end point, but did significantly decrease esophageal eosinophilia and demonstrate a trend toward an improvement in dysphagia [130]. This class of medication is currently under further investigation [131]. There is also a study underway examining whether an anti-IL-4 antibody is effective for EoE [132].

Leukotriene D4 is a known eosinophil chemoattractant. Montelukast is a leukotriene D4 receptor antagonist that is widely used in treatment of pulmonary disease, and has been studied for use in EoE. While an initial prospective observational study reported that patients had symptomatic improvement with montelukast treatment [133], subsequent pediatric and adult data failed to show that montelukast was effective in inducing or maintaining remission [134,135]. There are two ongoing trials to study montelukast in EoE [136,137].

Th-2 cells express prostaglandin-D2 receptors which mediate eosinophil chemotaxis and activation. OC000459 is a prostaglandin-D2 receptor antagonist which has been studied in the treatment of steroid-dependent and steroid-refractory EoE. When compared to placebo, OC000459 significantly decreased esophageal eosinophilia and resulted in an improvement in the physician's global assessment of disease activity [138]

Expert commentary

Eosinophilic esophagitis is a newly described chronic disease with an increasing incidence and prevalence. While great strides have been made to characterize EoE and understand its pathogenesis, there are a number of challenges to accurate diagnosis and optimal management of EoE. First, the distinction between PPI-REE and EoE is critical and needs to be better understood. If new data continue to support what has already been reported, we would predict that in the future PPI-REE may be defined as a phenotype of EoE, and PPI use may shift from a diagnostic maneuver to a therapeutic option. Second, the optimal treatment endpoints for EoE need to be defined. Current studies use varying symptoms and histologic cutoffs to define successful therapy, but symptom and histologic responses can be discordant. Advances in the development of validated symptom, quality of life, endoscopic, and histologic outcome measures present the opportunity to bring much needed consistency to the field.

Finally, a careful and deliberate approach is needed when treating EoE, but additional data are needed to inform the choice of a first line approach, be it diet or steroids, to understand why some patients are refractory to topical steroid treatment, dietary elimination, or both approaches, and to determine predictors of response. Novel and emerging therapeutic options hold promise not only that there will be approved medications for treatment of EoE, but by targeting pathogenic mechanisms the natural history of the disease can be altered. We would predict that certain clinical, endoscopic, histologic, molecular, or genetic markers will be identified to aid in characterizing clinical phenotypes, selecting appropriate therapies, and predicting treatment response.

Eosinophilic esophagitis, as a field, has made tremendous advances in a short time, from being first described two decades ago to having phenotypes characterized and novel therapeutics developed in this decade. The field continues to be rapidly evolving and therefore, guidelines, diagnostic modalities and management strategies may change in the future.

Five Year View.

Eosinophilic esophagitis has rapidly emerged as an important cause of upper gastrointestinal morbidity in both children and adults. As with any new field of study, there are many questions raised by the existing knowledge base, and multiple challenges associated with management. Over the next five years, it seems likely that PPI-REE may be reclassified as a subset of EoE rather than a different disease process. Currently, endoscopy is the mainstay of monitoring disease activity, but this is both expensive and invasive. In the near future, minimally invasive and non-invasive methods of monitoring disease activity will be established. As therapeutic endpoints are better defined, drug development can progress and novel treatment options can be can brought to market. These endpoints will not only help determine which agents are most effective in the management of EoE, but will also help establish the comparative efficacy of topical corticosteroids, dietary therapies and new therapeutics. Finally, it is possible that in five years, a patient's diagnosis, prognosis, and treatment options will be determined by molecular and genetic profiling techniques.

Key Issues.

• PPI-REE and EoE may be a spectrum of the same disease

• Topical corticosteroids are first line therapy for the management of EoE

• Dietary therapies can also be first line agents for the management of EoE or can be used as second line treatment or adjunctively with steroid therapy

• Esophageal dilation is a safe and effective adjunctive tool in the management of EoE

• Maintenance therapy is typically required for EoE

• Many novel therapeutics are being studied for the treatment of EoE

• Treatment endpoints need to be better defined