Terri F. Brown-Whitehorn

Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.

BACKGROUND Eosinophilic esophagitis (EE) is a recently described disorder identified in patients with symptoms suggestive of gastroesophageal reflux disease (GERD) but unresponsive to conventional reflux therapies. Therapies have included corticosteroids, elemental diet, and diet restriction. We report our experience with skin prick and atopy patch testing and food elimination diets in patients diagnosed as having EE. OBJECTIVE To identify food antigens that cause EE and the characteristics of patients who respond to food elimination vs those who are unresponsive. METHODS Patients diagnosed as having EE had restricted diets based on skin prick and atopy patch testing results. Additional biopsies were performed after 4 to 8 weeks of restricted diet. Demographics, atopic tendencies, and food antigens were identified retrospectively in our food allergy database. RESULTS A total of 146 patients diagnosed as having EE were evaluated with skin prick and atopy patch testing. Thirty-nine patients had unequivocal demonstration of food causing EE, with normalization of biopsy results on elimination and reoccurrence on reintroduction. An additional 73 patients, for a total 112 (77%) of 146 patients, had resolution of their EE as demonstrated by biopsy results. Fifteen (10%) of 146 patients were nonresponders manifested by no significant reduction in esophageal eosinophils despite restricted diet based on skin prick and atopy patch testing. Egg, milk, and soy were identified most frequently with skin prick testing, whereas corn, soy, and wheat were identified most frequently with atopy patch testing. CONCLUSION In more than 75% of patients with EE, both symptoms and esophageal inflammation can be significantly improved with dietary elimination of foods. Skin prick and atopy patch testing can help identify foods in most patients.

14 years of eosinophilic esophagitis: clinical features and prognosis.

Objective: To determine the natural history of treated and untreated eosinophilic esophagitis (EE) and examine the presenting symptoms of EE. Patients and Methods: Retrospective and prospective chart review of all patients diagnosed with EE at The Childrens Hospital of Philadelphia. EE was defined as greater than 20 eosinophils per high power field after treatment with reflux medications. Results: We identified 620 patients in our database in the last 14 years and 330 patients with greater than 1 year of follow-up for analysis. The number of new EE patients has increased on an annual basis. Of the patients presenting with EE, 68% were younger than 6 years old. Reflux symptoms and feeding issues/failure to thrive were the most common presenting symptoms for EE. Eleven patients had resolution of all of their food allergies and 33 patients had resolutions of some of their food allergies. No patients have progression of EE into other gastrointestinal disorders. Conclusions: EE is a chronic disease with less than 10% of the population developing tolerance to their food allergies. EE does not progress into other gastrointestinal diseases.

Common variants at 5q22 associate with pediatric eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 × 10−9). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.

Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease.

Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet.

BACKGROUND Eosinophilic esophagitis (EoE) is a chronic inflammatory disease with isolated eosinophils in the esophagus predominantly triggered by foods. The optimal testing to identify inciting foods remains unclear. OBJECTIVES We sought to determine the effectiveness of allergy testing-directed diets in patients with EoE. METHODS A retrospective analysis of all children with EoE seen at the Childrens Hospital of Philadelphia between 2000 and 2011 identified 941 patients with EoE. Skin prick tests (SPTs) and atopy patch tests (APTs) were conducted, and predictive values were calculated. IgE-mediated food reactions were also identified. A food was considered to cause EoE if its elimination led to resolution of esophageal eosinophilia or reintroduction led to reoccurrence of EoE. The effectiveness of the various elimination diets was compared with targeted food antigen elimination. RESULTS Definitive foods causing EoE were identified, with milk, egg, wheat, and soy as the most common foods in 319 patients. IgE-mediated reactions (urticaria and anaphylaxis) were seen in 15%. The negative predictive value for the combination of SPTs and APTs averaged 92%, with the exception of milk at 44%, and the positive predictive value averaged 44%. An empiric 6-food elimination diet or removal of positive foods on allergy testing (SPTs/APTs) both had a histologic success rate of 53%. Removal of foods identified on SPTs/APTs plus empiric elimination of milk leads to resolution in 77% of patients. CONCLUSION An elimination diet based on SPT/APT results leads to resolution of esophageal eosinophilia in a similar proportion of patients as empiric removal of foods but required that fewer foods be removed. These observations suggest that both methods are acceptable options.

Food Protein-induced Enterocolitis Syndrome: Insights from Review of a Large Referral Population

BACKGROUND Food protein-induced enterocolitis (FPIES) is a rare non-IgE mediated disease. Most studies have been limited in nature, with the largest cohort being 66 patients. The most common foods that have been reported are milk and soy. OBJECTIVE A retrospective chart review of patients seen in the Allergy Section at The Childrens Hospital of Philadelphia with International Classification of Diseases Ninth Revision code of 558.3 (Allergic Gastroenteritis and Colitis) between 2007 and 2012 was conducted to identify patients with suspected FPIES. Diagnosis of FPIES was confirmed based on meeting clinical criteria of delayed reaction with pronounced vomiting and/or diarrhea. Data regarding patient characteristics and features of their reactions were collected for analysis and comparison with existing studies. RESULTS A total of 462 cases were identified in our chart review. Patients had a similar demographic profile to the normal allergy patients seen in our clinic. The most common foods identified were milk (67%), soy (41%), rice (19%), oat (16%), and egg (11%). Patients had onset of FPIES to milk and soy around 7 months of age compared with 12 months of age for solid foods. FPIES reactions were identified to meats, tree nuts, peanuts, fruits, and vegetables; 70% of the patients reacted to one or two foods. Skin prick testing and atopy patch testing were not helpful in identifying the foods. CONCLUSION FPIES reactions were seen more frequently than previously described. However, the presentation and clinical features were similar to previous reports. Milk- and soy-triggered FPIES were common, and 43.5% of patients who had a milk trigger reacted to soy. There is no laboratory test to identify foods that cause FPIES, and clinician-supervised oral food challenge is the only definitive test available.

The link between allergies and eosinophilic esophagitis: implications for management strategies.

Eosinophilic esophagitis (EE) has an increased incidence of diagnosis similar to other atopic diseases. We present a recent literature review of the common features between atopic diseases (i.e., asthma, allergic rhinitis and atopic dermatitis) and EE. All of the disorders have allergen triggers and evidence of a possible Th2 inflammation at the site of disease. Murine models have also shown similar features with the importance of T cells and Th2 cytokines for the development of disease. The diseases share underlying inflammation with the potential for remodeling with an increase in TGF-β expression in asthma and EE. However, differences do exist between the diseases in treatment and pathogenesis. For EE, there are two basic treatment options: avoidance of the food triggers or treatment of the eosinophilic inflammation with corticosteroids.

Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity : A randomized clinical trial

Importance Epicutaneous immunotherapy may have potential for treating peanut allergy but has been assessed only in preclinical and early human trials. Objective To determine the optimal dose, adverse events (AEs), and efficacy of a peanut patch for peanut allergy treatment. Design, Setting, and Participants Phase 2b double-blind, placebo-controlled, dose-ranging trial of a peanut patch in peanut-allergic patients (6-55 years) from 22 centers, with a 2-year, open-label extension (July 31, 2012-July 31, 2014; extension completed September 29, 2016). Patients (n = 221) had peanut sensitivity and positive double-blind, placebo-controlled food challenges to an eliciting dose of 300 mg or less of peanut protein. Interventions Randomly assigned patients (1:1:1:1) received an epicutaneous peanut patch containing 50 &mgr;g (n = 53), 100 &mgr;g (n = 56), or 250 &mgr;g (n = 56) of peanut protein or a placebo patch (n = 56). Following daily patch application for 12 months, patients underwent a double-blind, placebo-controlled food challenge to establish changes in eliciting dose. Main Outcomes and Measures The primary efficacy end point was percentage of treatment responders (eliciting dose: ≥10-times increase and/or reaching ≥1000 mg of peanut protein) in each group vs placebo patch after 12 months. Secondary end points included percentage of responders by age strata and treatment-emergent adverse events (TEAEs). Results Of 221 patients randomized (median age, 11 years [quartile 1, quartile 3: 8, 16]; 37.6% female), 93.7% completed the trial. A significant absolute difference in response rates was observed at month 12 between the 250-&mgr;g (n = 28; 50.0%) and placebo (n = 14; 25.0%) patches (difference, 25.0%; 95% CI, 7.7%-42.3%; P = .01). No significant difference was seen between the placebo patch vs the 100-&mgr;g patch. Because of statistical testing hierarchical rules, the 50-&mgr;g patch was not compared with placebo. Interaction by age group was only significant for the 250-&mgr;g patch (P = .04). In the 6- to 11-year stratum, the response rate difference between the 250-&mgr;g (n = 15; 53.6%) and placebo (n = 6; 19.4%) patches was 34.2% (95% CI, 11.1%-57.3%; P = .008); adolescents/adults showed no difference between the 250-&mgr;g (n = 13; 46.4%) and placebo (n = 8; 32.0%) patches: 14.4% (95% CI, −11.6% to 40.4%; P = .40). No dose-related serious AEs were observed. The percentage of patients with 1 or more TEAEs (largely local skin reactions) was similar across all groups in year 1: 50-&mgr;g patch = 100%, 100-&mgr;g patch = 98.2%, 250-&mgr;g patch = 100%, and placebo patch = 92.9%. The overall median adherence was 97.6% after 1 year; the dropout rate for treatment-related AEs was 0.9%. Conclusions and Relevance In this dose-ranging trial of peanut-allergic patients, the 250-&mgr;g peanut patch resulted in significant treatment response vs placebo patch following 12 months of therapy. These findings warrant a phase 3 trial. Trial Registration clinicaltrials.gov Identifier: NCT01675882

Biphasic reactions in children undergoing oral food challenges.

Literature regarding biphasic reactions in the pediatric population is sparse. We aimed to determine the prevalence of biphasic reactions in children with food allergies undergoing oral food challenges (OFCs) and examine whether any clinical or treatment factors are associated with biphasic reactions. A retrospective chart review of OFCs conducted between July 2007 and March 2011 was performed. Charts were reviewed from time of challenge to 48 hours after challenge to capture data on any biphasic reactions. Uniphasic and biphasic reactions were compared in terms of specific clinical features and treatments. Of 614 positive challenges, 9 resulted in a biphasic reaction (1.5%). Six of the biphasic reactions occurred in challenges where the initial reaction met anaphylaxis criteria. The biphasic reactions were to eggs (4), peanuts (3), and milk (2). The symptom-free interval ranged from 2 to 24 hours. There were no statistically significant differences in clinical features between uniphasic and biphasic reactions, but there appeared to be a higher percentage of initial reactions with multiple organ involvement and meeting anaphylaxis criteria in the biphasic group. Biphasic reactors were significantly more likely to have received steroids for their initial reaction. A higher percentage of biphasic reactors also appeared to have received epinephrine, multiple doses of epinephrine, and antihistamines for their initial reactions. Biphasic reactions are rare in children undergoing OFCs and may be associated with more severe allergic reactions. Children with severe reactions may benefit from a 24-hour period of observation.

Oral viscous budesonide can be successfully delivered through a variety of vehicles to treat eosinophilic esophagitis in children

Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized by eosinophilic infiltration of the esophagus. Symptoms vary, with infants and young children typically presenting with feeding difficulties or failure to thrive, older children presenting with abdominal pain or vomiting, and adolescents and adults presenting with dysphagia or food impaction. Diagnosis must be confirmed on esophagogastroduodenal endoscopy, with esophageal biopsy showing at least 15 eosinophils (eos)/hpf. Gastroesophageal reflux disease and proton pump inhibitoreresponsive esophageal eosinophilia must be excluded with high-dose proton pump inhibitor therapy. The main treatments currently available for EoE are dietary therapy and corticosteroids. Systemic corticosteroids are reserved for emergency cases such as severe dysphagia or stricture and weight loss, whereas swallowed topical corticosteroids comprise the main pharmacologic therapy for EoE. One option is oral viscous budesonide (OVB), created typically by mixing liquid budesonide (Pulmicort Respule) intended for nebulized administration with sucralose (Splenda) to create a slurry consistency. Some patients, however, are wary of using artificial sweeteners such as Splenda. A recent study compared the use of Splenda and Neocate Nutra, a hypoallergenic food powder, as the vehicle for delivering OVB and found that they were similarly effective. We report the various vehicles that have been used by patients with EoE at the Children’s Hospital of Philadelphia. The study protocol was approved by the Institutional Review Board of the Children’s Hospital of Philadelphia. We reviewed the electronic medical records of all patients with EoE treated with OVB during a 5.5-year period between November 2008 and May 2014. Charts were reviewed for demographic data, the vehicle used to mix budesonide, and esophageal biopsy data. Active EoE was defined as a peak esophageal eosinophil count of 15 eos/hpf or more. We compared the peak esophageal eosinophil count on the biopsies performed immediately before and after the initiation of OVB. All follow-up biopsies were performed at least 6 weeks after initiation. Some patients did not respond by the first biopsy following OVB initiation but did show response on a subsequent biopsy after the dose of OVB was increased. For these patients, we used the peak eosinophil count from the biopsy showing response. Patients were considered responsive if peak eosinophil count improved from 15 eos/hpf or more to less than 15 eos/hpf. The starting dose of OVB was determined by a standardized dosing schedule based on the patient’s weight: 0.5 mg daily for less than 20 kg, 1 mg daily for 20 to 40 kg, and 2 mg daily for more than 40 kg. Seventy patients were treated with OVB during the time period studied. Three patients were excluded because the vehicle used to mix budesonide could not be confirmed. Six patients were excluded because they were started on OVB during a time of inactive EoE (<15 eos/hpf) because of unavailability of previous therapy or desire to switch from dietary therapy. Of the 61 remaining patients, 49 were male (80%). Ages ranged from 1 to 17 years (median, 8 years) at the time of OVB initiation. The various vehicles with associated budesonide doses used by all 61 patients are presented in Table I. The most frequently used vehicle was Splenda (N 1⁄4 30 [49%]). Twenty-seven of the 30 patients using Splenda responded (90%), demonstrating improvement in their peak eosinophil count to less than 15 eos/ hpf. The 3 patients without response did have decreased peak eosinophil counts but not less than 15 eos/hpf. The mean peak eosinophil count for all 30 patients using Splenda decreased from 56.5 eos/hpf to 3.9 eos/hpf after the initiation of OVB. Following Splenda, applesauce (N 1⁄4 19) and honey (N 1⁄4 7) were the next most commonly used vehicles. Fifteen of the 19 patients using applesauce responded (79%). Of the 4 patients without response, 1 patient did ultimately respond when switched to honey. The mean peak eosinophil count for all patients using applesauce decreased from 56.3 eos/hpf to 9.8 eos/ hpf after the initiation of OVB. Six of the 7 patients started on OVB using honey responded (86%). The patient without response had documented poor compliance. The mean peak eosinophil count for all patients using honey decreased from 53.7 eos/hpf to 8.6 eos/hpf after the initiation of OVB. The following vehicles were also used, by 1 patient each: hot cocoa mix, pear sauce, xanthan gum, and rice cereal. One patient used a compounded formulation of OVB prepared by a compounding pharmacy. The patient using rice cereal did show some improvement from more than 100 eos/hpf to 40 eos/hpf but not to less than 15 eos/hpf. The patients using hot cocoa mix, pear sauce, xanthan gum, and a compounded formulation all responded. The specific peak eosinophil counts for each of these patients are presented in Table I. In summary, we report success using various vehicles to deliver OVB to treat EoE in children. Similar to previous findings, we show that there are promising alternatives to Splenda. Although Splenda remains the standard and is highly successful, most of the patients using applesauce and honey have also been effectively treated with OVB. In addition, individual patients using hot cocoa mix, pear sauce, xanthan gum, and a compounded formulation have responded to OVB.