EoE in Evolution

The Search Continues for Better Treatments and Diagnostics

Much has been learned about eosinophilic esophagitis since the early-to-mid 1990s when the chronic immune-mediated clinicopathologic condition was first described in a number of case series. Since then, EoE has become increasingly recognized as a cause of dysphagia distinct from GERD, as consensus guidelines clarified its definition and standardized the field.

While numerous advances in understanding EoE’s etiology — as well as diagnosing, monitoring and treating the disease — have been made over the past 2 decades, there is still no FDA-approved drug, challenges to diagnosis persist and the mechanism of allergy remains unknown. Experts interviewed by Healio Gastroenterology, however, have been involved with promising developments on all of these fronts and all agreed the future for patients with EoE looks encouraging.

Standardizing the Field

Until the first guidelines for the diagnosis and management of EoE were published in 2007, consensus on the definition of this “new” disease was lacking, while diagnostic criteria, treatment approaches and research priorities varied. According to Evan S. Dellon, MD, MPH, from the University of North Carolina, the literature before that time was difficult to compare and review, as at least 10 histologic thresholds were used to diagnose EoE.

“What the first guidelines did were standardize the field diagnostically and help give a blueprint, not only for where treatment currently was, but where researchers needed to go,” Dellon said.

The 2007 guidelines defined EoE as a clinicopathologic disease characterized by symptoms of food impaction and dysphagia in adult patients, and by feeding intolerance, heartburn, vomiting, and abdominal pain in pediatric patients, with a histologic cut-off point of at least 15 eosinophils per high-power field (eos/hpf) in esophageal biopsies, and the exclusion of similar disorders, especially GERD. These guidelines also established food allergen-eliminating dietary interventions and topical corticosteroids as appropriate first-line therapies.

What has evolved the most since the 2007 guidelines is the exclusion of GERD, Dellon said. “At the time it was believed GERD and EoE could not overlap; if you had eosinophils and you got better with GERD treatment, that was GERD, regardless of the rest of the clinical picture, and if you didn’t get better, that was EoE.”

By 2011, when Chris A. Liacouras, MD, from The Children’s Hospital of Philadelphia and Perelman School of Medicine at University of Pennsylvania, Dellon and colleagues developed updated guidelines, the complex relationship between GERD and EoE became more recognized. “Just by odds, GERD is so common that EoE and GERD can coexist in the same patient,” Dellon said. By this point, it was also recognized that some individuals who fit the criteria for EoE, and in whom GERD was ruled out, improved with proton pump inhibitor therapy.

“One of the main changes in the 2011 consensus statement was this new entity that was termed PPI-responsive esophageal eosinophilia [PPI-REE], which appeared at that time to be separate from EoE and separate from GERD,” Dellon said. At that point it became clear that a PPI trial was an important part of diagnosing EoE, not only to rule out GERD, but also to determine if the diagnosis may be PPI-REE. Researchers then began to study this PPI-responsive category of patients, leading up to the 2013 guidelines, which “emphasized that when you find esophageal eosinophilia on biopsy during an endoscopy, you have to work through a differential that it isn’t just EoE or GERD, but could be PPI-REE.”

According to William Asher Wolf, MD, also from UNC, these guidelines established an effective standard for diagnosing the disease, but a well-defined EoE treatment target is still lacking.

“First, Dellon and others had to work hard just to define the disease, and to create an understanding of what pathological cutpoint would represent EoE,” Wolf said. “They identified 15 eos/hpf as an optimal cutpoint, and they standardized the size of that high-powered field, which has given us a good starting point for how to make the diagnosis. I would highlight that we don’t have a comparable standard for treatment. Different researchers define successful treatment of EoE in different ways, and we’re still working hard to figure out what represents treated disease. Is it the disappearance of eosinophils in the esophagus or is reduction enough? Is it the disappearance of symptoms? Of endoscopic changes? Is it some combination of those, or some other entity entirely?”

According to a review article by Dellon and Liacouras, “the ideal treatment endpoint in EoE would be complete resolution of clinical symptoms, eosinophilic inflammation, and esophageal remodeling,” but this may be difficult to achieve in clinical practice. Further complicating the issue are varying treatment endpoints used in clinical trials, “with nearly every study having a different threshold of histological response.” Additionally, there can often be a “dissociation between symptomatic and histological response.”

“The most appropriate treatment outcome is of clinical, research, and regulatory interest, and multiple studies are under way to help define this,” Dellon and Liacouras wrote in the review.

According to Wolf, he and colleagues have an article on such a study currently in process, which confirms “that less than 15 [eos/hpf] is probably representative of effective treatment and a pathologic cutoff, [but] we still need to work to integrate that with endoscopic appearance and symptomatic response to create a complete picture of EoE.” Some researchers in the field, however, argue “very reasonably ... that we should treat to zero eosinophils in the esophagus,” he said.

The limitations to arriving at a consensus on a treatment target are three-fold, Wolf said. “First, there’s some new research suggesting that we finally have good symptomatic measures for EoE, but previously most patients using the symptomatic measures we had available often got symptomatically better without improvement in their eosinophil counts ... or the endoscopic appearance of their esophagus. Patients felt better over time, regardless of the direction their disease was going, and that has made it very hard to identify clinical outcomes. Second, we don’t have a clear picture of the long term course of EoE yet,” so it remains uncertain “if chronic low grade inflammation in the esophagus carries risks like cancer or fibrosis.” Third, it also remains uncertain “how much inflammation creates risk over time.”

Marc E. Rothenberg, MD, PhD, director of the Cincinnati Center for Eosinophilic Disorders at Cincinnati Children’s Hospital, agreed that good clinical outcome metrics are needed to standardize the measurement of patient well-being, and he has been instrumental in developing patient reported outcome measures that are currently available for use in clinical practice. “There are two basic types that have been developed; one is for the adult, called the EEsAI,” or EoE Activity Index, “and there’s also the Pediatric EoE Symptoms Score, or PEESS version 2.0,” he said. “Both of these have now been validated; the PEESSv2 can be used both by the patients and by proxy with parents to monitor clinical activity, they’ve been shown to correlate with histology, and they can be used to monitor effectiveness of therapy, particularly following drug trial interventions, and that’s going to be important for ultimate monitoring effectiveness of interventions including drugs.”

Wolf agreed this lack of consensus on what effective treatment looks like has been the real challenge to bringing an FDA-approved drug to market in the U.S. “It’s very hard to produce convincing data that a drug has effectively treated the disease without a consensus on treatment,” he said. “I certainly want drugs to be thoroughly vetted and appropriately approved before they come to market ... [but], in particular, there seems to be reluctance at the FDA level to accept just pathologic changes, the decrease in eosinophils, as an appropriate outcome measure. It’s going to take work from the scientific community, but I think it’s also going to take some increased flexibility from the FDA.”

A number of recent and ongoing studies on experimental steroid formulations have demonstrated efficacy, but none have yet received FDA approval. “They all work great,” Wolf said. “The drugs exist, they just aren’t being sold ... It’s definitely a disease in search of a drug,” and once one becomes available, “it would be transformative.”

‘A Disease in Search of a Drug’

Because no drugs have been approved by the FDA for the treatment of EoE, off-label use of the topical corticosteroids fluticasone, delivered by a multidose inhaler and swallowed, and budesonide, delivered by a swallowed nebulized vapor or a viscous slurry, are the mainstay first-line therapies. A number of randomized controlled trials have demonstrated good efficacy of both of these medications; but, because their methods of delivery are not officially approved for treatment of EoE, there is currently active investigation on new steroid formulations specifically developed for the esophagus.

Results from a randomized controlled trial of such a formulation, oral budesonide suspension, were presented by Dellon at DDW 2015.

“This was a phase 2 study looking at oral budesonide suspension, which is a specifically formulated muco-adherent solution for treatment of EoE,” Dellon said. The syrup was developed by Meritage and was tested in children in a previous dose-ranging randomized controlled trial by Sandeep K. Gupta, MD, from Indiana University School of Medicine, which found it was “incredibly effective for inducing histologic remission, but the symptoms improved similarly in both the treatment and the placebo group.” Because they were basing their evaluation on a general symptom score in children, “it was difficult to move that drug forward in development, because you need to show that there’s a symptom benefit as well as a histology benefit,” Dellon said.

Dellon and colleagues’ 12-week study was therefore designed to assess the safety and efficacy of twice-daily 2-mg oral budesonide suspension compared with placebo for decreasing symptoms of dysphagia and esophageal eosinophil counts in adolescents and adults with EoE (n = 87), “not only to confirm that you get a histological response, but to show that symptoms would improve if you can use a validated symptom measure for dysphagia in EoE.” The primary outcomes were change in Dysphagia Short Questionnaire (DSQ) score and the proportion of patients with histologic response defined as 6 eos/hpf or less.

“The results were pretty striking,” Dellon said. “There was almost no histologic response in the placebo group compared to almost 40% in the budesonide group [P < .0001] and with that the symptoms decreased significantly more in the budesonide group than in the placebo group [P = .0096]. This is the first time that a concordant symptom-histology improvement has been shown using a validated dysphagia measure, so it’s really a step forward in the field in terms of treatment outcome measures. ... Hopefully this medicine will continue to proceed into development and eventually will be available for patients, as it certainly seems like a very viable treatment option.”

“This data substantiates what we’ve known for a long time,” Rothenberg said, which is that “topical steroids in the formulation of asthma inhalers that are basically swallowed instead of inhaled are very effective for treating EoE. This does not mean that this is a long-term great option, but it does work acutely in clinical trials and in practice to induce remission, and these results are encouraging as we seek to ultimately get more accepted usage of steroids in this indication.”

Data on a number of other esophagus-specific formulations of topical corticosteroids have also been recently published. For example, a dose-ranging randomized controlled trial of an effervescent budesonide tablet compared with a viscous budesonide suspension, performed by Stephan Miehlke, MD, from the Centre for Digestive Diseases Eppendorf, in Germany, and colleagues, showed both formulations were safe and effective for short-term treatment of EoE, but patients preferred the effervescent tablet.

According to Rothenberg, however, topical corticosteroids are limited by their failure to treat all patients. “The current treatments are all temporary ... as soon as the treatment is withdrawn, the patient relapses. So steroids have a substantial rate of nonresponsiveness, there seems to be bona fide steroid resistance, and there is steroid phobia present. [There is thus, an] overall need for additional therapies, both in nonresponders and for long-term maintenance,” he said.

As a result, there is also active investigation on novel biologics agents for the treatment of EoE, and according to Dellon’s review article, two promising agents previously studied in clinical trials are antibodies against interleukin (IL)-5 (mepolizumab and reslizumab). “These antibodies were initially tested in a case series and a small pilot RCT,” he and colleagues wrote. “Findings from larger RCTs of both antibodies were recently reported.”

The RCT of mepolizumab, performed by Amal H. Assa’ad, MD, from Cincinnati Children’s Hospital, and colleagues, showed the anti-IL-5 antibody reduced esophageal eosinophilic inflammation in children with EoE (P < .0001). The RCT of reslizumab, performed by Rothenberg and colleagues, showed this medication reduced intraepithelial esophageal eosinophil counts in children and adolescents with EoE (P < .001), but symptom improvements occurred in all groups and were not associated with changes in esophageal eosinophil counts. Rothenberg and colleagues also recently demonstrated the efficacy of QAX576, a monoclonal antibody against IL-13, in reducing tissue eosinophilia, as well as a variety of pathological processes defined by esophageal transcript analysis, in a pilot study.

“Despite encouraging histological improvements, the clinical (symptomatic) response was disappointing compared with placebo,” Dellon and colleagues wrote in their review. “Because of these mixed results, further studies are in progress.”

In addition to new topical corticosteroid formulations, biologics and other medications, ongoing research on dietary interventions is also an area of great interest, according to Wolf, with the ultimate goal of making dietary therapies for EoE patients less restrictive.

Less Restrictive Dietary Interventions

Unlike topical corticosteroid therapies, dietary interventions allow patients to “enter long-term remission without medication,” Dellon and colleagues wrote in their review, adding that “dietary therapy has also been shown to improve esophageal fibrosis and remodeling.” Dietary interventions for EoE include amino acid-based elemental diets, directed elimination diets based on allergy test results, and nondirected elimination diets that empirically exclude common food antigens.

According to Wolf, there has been an increase in acceptance of dietary therapy and good efficacy data supporting its use as a first-line treatment for EoE. “Dietary therapy had been used successfully in pediatric patients, though some of the diets that were used were pretty restrictive, including the elemental diet. Now we’re seeing somewhat less restrictive diets showing good efficacy in adults.”

“Most of our patients still get steroids first-line,” Wolf said, “but we’re now at a point where we can confidently tell them they can choose either dietary therapy or steroid therapy and expect similar effectiveness.”

While the best benefit from dietary therapy still comes from the highly restrictive elemental diet, Wolf said, much work is being done to reduce the restrictiveness of dietary therapies. “To the extent that we can reduce the restrictiveness of an effective therapeutic diet, that’s in the best interest of the patient and patient compliance, which should increase the effectiveness of therapy.”

One such study presented at DDW was a multicenter prospective study comparing the clinical, endoscopic and histologic efficacy of a four-food elimination diet (milk, wheat, egg and soy) vs. a six-food elimination diet in 55 children with EoE. Histologic remission was achieved with four-food elimination diet in 71% of patients, and symptoms and endoscopic abnormalities were significantly improved. The researchers concluded that four-food elimination diet for EoE was noninferior to six-food elimination diet.

A similar study in adults by Molina-Infante and colleagues published in 2014 showed a 54% success rate in achieving clinicopathologic remission with the four-food elimination diet (although soy was replaced by legumes in this model). “Children may be more responsive to a less restrictive diet and respond better to it, but in adults [the results are] not quite as good,” Dellon said.

“This study reinforces what we’ve known for a long time,” Rothenberg said, “that EoE is a food antigen-driven process, that the top allergens are driving the disease, and that going from four to six foods is not necessarily associated with a better outcome. That doesn’t rule out that six is better than four, but it does indicate, consistent with the data, that the top four allergens are the primary driver in many of the patients.”

The results are nevertheless encouraging and may lead to improved interventions, Rothenberg said, adding that the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), which is part of the NIH’s Rare Disease Clinical Research Network (supported by the NCAT, NIAID and NIDDK institutes of the NIH), is currently involved in a prospective trial of a one-food vs. six-food elimination diet, which seeks to determine which patients only respond to the one-food elimination diet, which is driven by milk. Those results are expected in about 2 years, he said.

Another study in which Dellon and Wolf were both involved, presented at DDW by their colleague Cary C. Cotton, MD, was a cost-utility analysis of a six-food elimination diet vs. topical steroids for first-line treatment of EoE, which demonstrated that dietary intervention was actually more cost-effective.

It is important to note that this study was done from the payer’s perspective, Dellon said, and it showed that “diet was actually cost effective even from year one,” which is primarily related to the cost of the topical steroids.

“My expectation was that steroid therapy would be much less expensive,” Wolf said. “Based on previous work that Dellon and I had done, it was clear that a patient going through dietary elimination therapy required something in the range of 5 to 6 endoscopies, as they serially reintroduced foods, and that in my mind is a really expensive and invasive approach to care. ... It turned out that the opposite was true, that the up-front costs of those endoscopies is more than offset by the long-term cost of medications in patients taking steroid therapy. I think it’s a surprising and counterintuitive result, but it makes me feel even better about the benefits of dietary therapy.

“Underlying all of this is the fact that while we believe this is an allergic disease, we still have not clearly defined a mechanism of allergy,” Wolf said. “I’m really interested in better understanding the mechanism of this disease. I think that’s the first step to moving toward a more targeted individualized therapy. Right now we use a shotgun approach diet, the six-food elimination diet, and we use a really broad acting medication, a steroid, and I think that there’s an opportunity for much more tailored medication or dietary therapy once we understand what is driving this disease.”

Indeed, Rothenberg and colleagues have shown that EoE susceptibility is linked with a number of genetic variants, particularly those involving epithelial gene products involved with allergic sensitization (eg 5q22 at the TSLP gene and 2p23 at the esophageal specific gene CAPN14). However, genetics is not the full story, as Rothenberg’s research team have shown that only 40% of identical twins have concordance for EoE.

Diagnostics and Monitoring

The investigation of more efficient and less invasive diagnostic modalities for EoE is also an active area of study. According to Dellon’s review article, several symptom scores and predictive models have been developed but not validated. Since then, however, Dellon presented data validating a predictive tool based on clinical and endoscopic features whose accuracy would permit the omission of biopsies.

“I had performed a retrospective study in 2009 that looked at GERD patients and EoE patients, and tried to separate them out by clinical and endoscopic and histologic features, and it turned out that no single feature at that time could do it,” Dellon said. “But if you combine eight or nine features into a single model, you actually have a good ability ... to discriminate the two conditions. So what that led to was designing and conducting this prospective study over 3 years to collect similar data to validate that predictive model.”

Dellon and colleagues consecutively enrolled a total of 81 EoE cases and 144 controls with symptoms of dysphagia or heartburn between 2011 and 2013. They were enrolled at the time of endoscopy before their diagnosis was known, “and then after all the data were back we could separate people who had EoE and people who did not have EoE, and using the values on the model from the retrospective study, apply it to this prospective set to really validate those models,” he said. It turned out that a model using just a few simple features — age, sex, dysphagia, symptoms, heartburn or food allergy — and then a few endoscopic findings, was very predictive of EoE case status. ... It can be a useful tool and we actually have a website now people can go to and actually use this model in practice to help inform their clinical decision making and get a sense of the possibility of EoE in certain patients.” The website has several predictive models available, depending on the clinical circumstance, Dellon said.

EoE biomarkers are another active area of investigation, although noninvasive biomarkers like blood, urine or stool tests are currently unavailable for the diagnosis of EoE. A DDW poster presented by Dellon, for example, evaluated a panel of 14 different serum cytokines, “and unfortunately, none seemed to have any utility,” he said.

“It would be great to have noninvasive markers for the disease,” Wolf said, “but at this point I think we’re still stuck with using symptoms to guide us toward endoscopy.”

The Rothenberg Laboratory website provides a resource about currently available biomarkers and genetic tests for EoE.

While “the search is still on” for a noninvasive biomarker, Dellon said, molecular analysis of gene expression patterns in esophageal tissues, which was pioneered by Rothenberg, is among the more exciting diagnostic developments.

“Probably the most exciting advancement is the definitive molecular diagnostics that can now be performed in EoE, where you can take a biopsy and molecularly characterize the gene expression profile called the EoE Diagnostic Panel, or EDP,” Rothenberg said. “This test works with one biopsy compared to the conventional biopsies requiring microscopy, which requires five biopsies. This test not only tells you with 100% accuracy based on the latest report by Dellon, et al, but it also tells you the patients’ prognosis in terms of both response to therapy but also the degree of fibrosis and involvement of specific types of effector cells, particularly TH2 cells and their cytokines.”

According to Dellon’s review article, “the initial description of the EoE-associated transcriptome was a major advance; changes in expression of a subset of 94 genes can identify patients with EoE with high levels of sensitivity and specificity. Although additional studies are required to confirm the utility of this test, EoE might one day be diagnosed based on genetic rather than clinicopathologic features.”

This has not been widely clinically adopted yet, Dellon said, but research is ongoing to validate it “in external patient population sources, and to determine exactly where in the clinical diagnostic pathway you could use molecular diagnosis that would be best and most cost effective.”

However, biomarkers and genetic analysis on the tissue level still require an endoscopy, which is where the interest in minimally invasive and noninvasive monitoring comes from, Dellon said. Recent developments on this front include the esophageal string test, the cytosponge, transnasal endoscopy and tethered capsule technology.

The esophageal string test is a novel, minimally invasive device for measuring esophageal eosinophilic inflammation. According to Dellon, it entails a string inside a capsule which is held while swallowing, after which it then unfurls in the esophagus. Furuta, Ackerman and colleagues have previously shown it “can measure a number of eosinophil-related factors that correlate incredibly well with what’s going on in the biopsy,” he said. A phase 2 trial of this device is currently underway.

The cytosponge, developed by Covidien for less invasive Barrett’s esophagus and esophageal cancer screening, is an ingestible gelatin capsule containing compressed mesh attached to a string, and once swallowed, the gelatin dissolves in the stomach, releasing the spherical mesh, which collects the tissue specimen when withdrawn. A pilot study by David A. Katzka, MD, from Mayo Clinic in Rochester, Minn., and colleagues, demonstrated its diagnostic potential for EoE.

“This pilot study shows the cytosponge to be a safe, easy to perform, inexpensive, and accurate test to monitor patients with EoE without the need for endoscopy and biopsy, but larger multicenter studies are needed to confirm its efficacy,” Katzka told Healio Gastroenterology.

The cytosponge is “now being rolled out in a larger study to validate the measure compared to traditional endoscopy to see how best to use that technique,” Dellon said. “I would say both of those techniques are very exciting, hold a lot of promise for the future.”

Another minimally invasive technique is unsedated transnasal endoscopy, which was shown to be a safe, well-tolerated and lower-cost alternative to esophagogastroduodenoscopy for evaluating pediatric EoE in a recent study by Joel A. Friedlander, DO, MBe, from Children’s Hospital Colorado, and colleagues.

“Those patients are awake but their nasal passages are given topical anesthesia, and then you can pass a very small endoscope through the nose down into the esophagus and stomach and take biopsy samples,” Dellon said.

“Our study provides strong support for larger studies to validate this approach,” Friedlander said in a press release. “This technique has the potential to significantly improve the lives of children with EoE in a safer, cost-effective and efficacious manner.”

Finally, tethered capsule technology involves a capsule containing a confocal laser microscopy system, which is swallowed and pulled back through the esophagus, during which time it takes microscopy images of the esophagus, Dellon said. “This is still in an experimental pilot phase, but that may hold some promise for the future as well. So there’s quite a lot of work in trying to make this a less invasive process.”

A Multidisciplinary Effort

Although EoE was still not widely recognized just a little over decade ago, the research has increased exponentially since, though not without the unique challenges posed by the multidisciplinary nature of managing and studying the disease.

“This is a complex disease characterized by low quality of life, chronicity, allergies, and requires a holistic treatment approach, involving allergists, gastroenterologists, social workers, psychologists, pathologists and dieticians,” Rothenberg said. “So you need to have a whole team in place.”

“These teams, working with patients and advocacy groups, have made great strides in increasing our understanding of this disease, and ongoing collaborations hold great promise for the future,” Dellon concluded in his review.

According to Wolf, the “first and most significant challenge with the diagnosis of this disease” — which is in the midst of being overcome — “is community awareness; having people recognize that EoE should be considered as a cause of dysphagia.”

Rothenberg agrees that “the most important thing is to recognize that the disease exists, and it should be in the differential of upper GI complaints.” – by Adam Leitenberger

• References:
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• Cotton C, et al. Abstract 4. Presented at: 2015 Digestive Disease Week; May 16-19; Washington, D.C.
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• For more information:
• Evan S. Dellon, MD, can be reached at evan_dellon@med.unc.edu.
• Marc E. Rothenberg, MD, can be reached at marc.rothenberg@cchmc.org.
• W. Asher Wolf, MD, MPH, can be reached at william.wolf@unchealth.unc.edu.

Disclosures: Dellon reports he has received research funding from NIH, ACG, AGA, CURED Foundation, UNC, Meritage, Miraca Life Sciences, Receptos and Regeneron; and has served as a consultant for Aptalis, Novartis, Receptos, Regeneron, Roche. Rothenberg reports he has received research support from the NIH (DK076894, DK076893, AI070235, AI066738, TR000078, AI045898, AI060515, AI117804), the CURED Foundation, the Buckeye Foundation, and FARE; has received consultancy fees from Immune Pharmaceuticals, Receptos, Novartis, Genetech/Roche, and Celsus Therapeutics; is an inventor for patents submitted and owned by CCHMC; has received royalties from Teva Pharmaceuticals (royalty interest in reslizumab); and has stock/stock options in Immune Pharmaceuticals, Receptos, NKT Therapeutics, and Celsus Therapeutics. Wolf reports a financial relationship with Nestle HealthCare Nutrition.