Caitlin M. Burk

Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy

BACKGROUND Although peanut oral immunotherapy (OIT) has been conclusively shown to cause desensitization, it is currently unknown whether clinical protection persists after stopping therapy. OBJECTIVE Our primary objective was to determine whether peanut OIT can induce sustained unresponsiveness after withdrawal of OIT. METHODS We conducted a pilot clinical trial of peanut OIT at 2 US centers. Subjects age 1 to 16 years were recruited and treated for up to 5 years with peanut OIT. The protocol was modified over time to permit dose increases to a maximum of 4000 mg/d peanut protein. Blood was collected at multiple time points. Clinical end points were measured with 5000-mg double-blinded, placebo-controlled food challenges once specific criteria were met. RESULTS Of the 39 subjects originally enrolled, 24 completed the protocol and had evaluable outcomes. Twelve (50%) of 24 successfully passed a challenge 1 month after stopping OIT and achieved sustained unresponsiveness. Peanut was added to the diet. At baseline and the time of challenge, such subjects had smaller skin test results, as well as lower IgE levels specific for peanut, Ara h 1, and Ara h 2 and lower ratios of peanut-specific IgE/total IgE compared with subjects not passing. There were no differences in peanut IgG₄ levels or functional activity at the end of the study. CONCLUSIONS This is the first demonstration of sustained unresponsiveness after peanut OIT, occurring in half of subjects treated for up to 5 years. OIT favorably modified the peanut-specific immune response in all subjects completing the protocol. Smaller skin test results and lower allergen-specific IgE levels were predictive of successful outcome.

Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective

Background: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. Objective: We sought to test the safety, effectiveness, and feasibility of early OIT (E‐OIT) in the treatment of peanut allergy. Methods: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block‐randomized 1:1 to receive E‐OIT at goal maintenance doses of 300 or 3000 mg/d in a double‐blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4‐SU), was assessed by double‐blinded, placebo‐controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut‐specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard‐care controls. Results: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent‐to‐treat analysis achieved 4‐SU (300‐mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per‐protocol, the overall proportion achieving 4‐SU was 29 of 32 (91%). Peanut‐specific IgE levels significantly declined in E‐OIT‐treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard‐care controls, in whom peanut‐specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7‐43.7; P < .001). Allergic side effects during E‐OIT were common but all were mild to moderate. Conclusions: At both doses tested, E‐OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.

Outcomes of Esophageal Dilation in Eosinophilic Esophagitis: Safety, Efficacy, and Persistence of the Fibrostenotic Phenotype

Objectives:Esophageal dilation is commonly performed in eosinophilic esophagitis (EoE), but there are few long-term data. The aims of this study were to assess the safety and long-term efficacy of esophageal dilation in a large cohort of EoE cases, and to determine the frequency and predictors of requiring multiple dilations.Methods:We conducted a retrospective cohort study in the University of North Carolina EoE Clinicopathological Database from 2002 to 2014. Included subjects met consensus diagnostic criteria for EoE. Clinical, endoscopic, and histologic features were extracted, as were dilation characteristics (dilator type, change in esophageal caliber, and total number of dilations) and complications. Patients with EoE who had undergone dilation were compared with those who did not and also stratified by whether they required single or multiple dilations.Results:Of 509 EoE patients, 164 were dilated a total of 486 times. Those who underwent dilation had a longer duration of symptoms before diagnosis (11.1 vs. 5.4 years, P<0.001). Ninety-five patients (58%) required >1 dilation (417 dilations total, mean of 4.4±4.3 per patient). The only predictor of requiring multiple dilations was a smaller baseline esophageal diameter. Dilation was tolerated well, with no major bleeds, perforations, or deaths. The overall complication rate was 5%, primarily due to post-procedural pain. Of 164 individuals dilated, a majority (58% or 95/164) required a second dilation. Of these individuals, 75% required repeat dilation within 1 year.Conclusions:Dilation in EoE is well-tolerated, with a very low risk of serious complications. Patients with long-standing symptoms before diagnosis are likely to require dilation. More than half of those dilated will require multiple dilations, often needing a second procedure within 1 year. These findings can be used to counsel patients with fibrostenotic complications of EoE.

Modified peanut oral immunotherapy protocol safely and effectively induces desensitization

Peanut oral immunotherapy (OIT) has been shown to effectively induce desensitization in the majority of peanut-allergic individuals who receive therapy. However, questions exist regarding its safety and the optimal dose of peanut protein to administer. Studied maintenance doses range from 800 mg daily to 4000 mg daily. Side effects, which are typically mild, are most often seen during the build-up phase of therapy; therefore, we hypothesized that minimizing time to maintenance dosing may be favorable for the safety of individuals over the course of the therapy. We designed an unblinded peanut OIT pilot study that shortened time to maintenance by incorporating (1) a modified entry dose protocol and (2) a 2000 mg maintenance dose. Desensitization endpoints comparable to previously published protocols utilizing a 4000 mg maintenance dose were used for comparison. Inclusion and exclusion criteria are outlined in Table E1 (available in this article’s Online Repository at www.jaciinpractice.org) and required objective symptoms of allergic reactivity within 60 minutes of peanut ingestion during a double-blind, placebo-controlled food challenge (DBPCFC) to 2000 mg of peanut protein. Dose initiation was performed as outlined in Table I, utilizing lightly roasted peanut flour (partially defatted 12% fat; Golden Peanut Co., Alpharetta, Ga; 2 g flour 1⁄4 1 g peanut protein). A modified entry dose was based on the threshold dose of reactivity. Build-up dosing occurred approximately every 2 weeks. After dose initiation, doses were increased as previously described. A 5000 mg DBPCFC was performed after approximately 4 months of maintenance dosing (median 105 days, range 83 to 181 days). Subjects were instructed to resume 2000 mg daily dosing after the DBPCFC. Titrated skin prick tests (SPTs) were performed every 6 months with peanut extract (Greer Laboratories, Lenoir, NC). Peanutspecific IgE and IgG4 levels were measured using the ImmunoCAP 100 instrument (Phadia AB, Uppsala, Sweden) according to the manufacturer’s instructions. Approval for this study was obtained through the University of Texas Southwestern Institutional Review Board. Differences in the values over time compared with baseline were analyzed by using the Wilcoxon rank-sum tests (GraphPad Prism version 6.00 for Windows, GraphPad Software, La Jolla, Calif) on matched data. P values <.05 were considered significant. Twelve subjects were screened and 11 met entry criteria (see Table E2 in this article’s Online Repository at www.jaciinpractice.org). Of the 11 subjects, 9 were able to safely ingest the 2000 mg daily maintenance dose. Details regarding the 2 subjects unable to achieve maintenance are included in Table E2. The median time to maintenance was 41 weeks (28-48 weeks) (Table E2). The most common reason to delay up-dosing was related to convenience (eg, inability to miss school, study staff vacation, etc.). Adjusting the time to maintenance with removal of convenience factors yields a median time to maintenance of 36 weeks (26-45 weeks). All 9 subjects who achieved maintenance dosing passed the 5000 mg peanut DBPCFC (Figure 1). Three subjects experienced transient symptoms during the challenge, which were not deemed significant enough to discontinue the challenge. From entry to the 5000 mg DBPCFC, 3265 total doses were administered. Only 7.9% of doses (264/3265) were associated with a reported side effect. All side effects were mild except for 2 severe reactions (see Table E3 in this article’s Online Repository at www.jaci-inpractice.org). The majority of reactions, 94% (249/ 264), occurred during the build-up phase. The most common complaints during build-up included skin reactions, followed by throat clearing and sneezing (see Figure E1 in this article’s Online Repository at www.jaci-inpractice.org). The skin prick test wheal diameter decreased significantly in all subjects after 6 months of therapy (see Figure E2A in this article’s Online Repository at www.jaci-inpractice.org). Peanutspecific IgE, IgG4, and IgE/IgG4 changed significantly after 6 weeks of therapy (see Figure E2B-D in this article’s Online Repository at www.jaci-inpractice.org), similar to findings from investigators using other protocols. Secondary to our modified entry dose protocol with a lower maintenance dose, our subjects were able to achieve maintenance dosing in a shorter time frame, and with comparable levels of desensitization and similar effects on the immune response as reported by previous investigators. Making head-to-head comparisons between existing peanut OIT studies is difficult secondary to the varied approaches investigators have taken. Begin et al recently reported successful acquisition of maintenance dosing by an average of 18 weeks with 4000 mg dosing per allergen for multiple allergen OIT; however, omalizumab is given adjunctively during up-dosing. Our up-dosing regimen was longer, but we did not use omalizumab. Our reaction rate was similar (5.3% [Begin] vs 7.9% [Bird]) without the protective benefits of omalizumab. We have now shown that 9/9 children who received a 2000 mg maintenance dose were able to pass a 5000 mg challenge with 6/9 (66%) having no symptoms during the challenge, and they were able to achieve maintenance dosing in a median time of 41 weeks. Because of differences in time receiving maintenance, total time on therapy, and differences in the amount of protein given during the desensitization challenge, we cannot directly compare our study with the recent study by Anagnostou et al. It

Utility of component analyses in subjects undergoing sublingual immunotherapy for peanut allergy

Sublingual immunotherapy (SLIT) with peanut changes clinical and immune responses in most peanut‐allergic individuals, but the response is highly variable.

Causes and Outcomes of Esophageal Perforation in Eosinophilic Esophagitis.

Goals: To characterize patients who suffer perforation in the context of eosinophilic esophagitis (EoE) and to identify predictors of perforation. Background: Esophageal perforation is a serious complication of EoE. Materials and Methods: We conducted a retrospective cohort study of the University of North Carolina EoE clinicopathologic database from 2001 to 2014. Subjects were included if they had an incident diagnosis of EoE and met consensus guidelines, including nonresponse to a PPI trial. Patients with EoE who had suffered perforation at any point during their course were identified, and compared with EoE cases without perforation. Multiple logistic regression was performed to determine predictors of perforation. Results: Out of 511 subjects with EoE, 10 (2.0%) had experienced an esophageal perforation. Although those who perforated tended to have a longer duration of symptoms before diagnosis (11.4 vs. 7.0 y, P=0.13), a history of food impaction (odds ratio, 14.9; 95% confidence interval, 1.7-129.2) and the presence of a focal stricture (odds ratio, 4.6; 95% confidence interval, 1.1-19.7) were the only factors independently associated with perforation. Most perforations (80%) occurred after a prolonged food bolus impaction, and only half of individuals (5/10) carried a diagnosis of EoE at the time of perforation; none occurred after dilation. Six patients (60%) were treated with nonoperative management, and 4 (40%) required surgical repair. Conclusions: Esophageal perforation is a rare but serious complication of eosinophilic esophagitis, occurring in ∼2% of cases. Most episodes are due to food bolus impaction or strictures, suggesting that patients with fibrostenotic disease due to longer duration of symptoms are at increased risk.

Strategies to Mitigate Peanut Allergy: Production, Processing, Utilization, and Immunotherapy Considerations

Peanut (Arachis hypogaea L.) is an important crop grown worldwide for food and edible oil. The surge of peanut allergy in the past 25 years has profoundly impacted both affected individuals and the peanut and related food industries. In response, several strategies to mitigate peanut allergy have emerged to reduce/eliminate the allergenicity of peanuts or to better treat peanut-allergic individuals. In this review, we give an overview of peanut allergy, with a focus on peanut proteins, including the impact of thermal processing on peanut protein structure and detection in food matrices. We discuss several strategies currently being investigated to mitigate peanut allergy, including genetic engineering, novel processing strategies, and immunotherapy in terms of mechanisms, recent research, and limitations. All strategies are discussed with considerations for both peanut-allergic individuals and the numerous industries/government agencies involved throughout peanut production and utilization.

Tree nut- and sesame-specific IgE do not decrease from baseline with peanut oral immunotherapy (OIT)

Figure 1. Peanut-specific IgE decreased significantly between all measured time points (0e12 months, P 1⁄4 .019; 0e24 months, P 1⁄4 .0005, 12e24 months, P 1⁄4 .0005, denoted by *). Serum levels of sesameand almond-specific IgE are significantly increased during the first 12 months of peanut OIT (P1⁄4 .03 and P1⁄4 .01, respectively) and almond-specific IgE decreases significantly between 12 and 24months (P1⁄4 .03). Significant changes in cashewand walnut-specific IgE were not measured at any time point. Median values are represented by black horizontal lineswithin the scatter plot. peanut-specific immunoglobulin E (IgE) in peanut-allergic subjects, and most peanut-allergic individuals completing therapy safely ingest approximately 20 peanuts.1,2 Approximately one third of peanut-allergic individuals are allergic to tree nuts,3 and the effect of peanut OIT on other allergen-specific IgE is unknown. Because cross-reactivity exists between seed storage proteins in peanut and allergens present in almond4 and sesame,5 we hypothesized that peanut OIT would induce a significant decrease in almondand sesame-specific IgE but would not affect cashewand walnutspecific IgE. Serum samples from our original peanut OIT cohort1 were retrospectively analyzed for almond-, sesame-, cashew-, and walnut-specific IgE. Sixteen subjects (ages 26 to 112 months at enrollment, mean age 67 months 24.7 months, 10 male, all white) with convincing clinical history of peanut allergy1 were included in the analysis based on specific IgE greater than 0.01 kU/ L to almond, sesame, cashew, and walnut at the beginning of treatment. Serum was collected at 0, 12, and 24 months on OIT. Skin testing and oral food challenges to tree nuts and sesame were not performed, and only one subject had a history of reacting after tree nut ingestion. Data regarding tree nut and sesame consumption throughout the study were not recorded. Specific IgE was quantified using ImmunoCAP 100 (Phadia AB, Uppsala, Sweden) according to the manufacturer’s instructions. Analysis was performed using the 2-tailed Wilcoxon signed rank test to compare IgE values at 0 and 12 months, 0 and 24 months, and 12 and 24 months. Peanut-specific IgE significantly decreased between all time points (Fig 1), and all subjects were desensitized to peanut. Sesameand almond-specific IgE increased significantly between 0 and 12 months, and almond-specific IgE decreased significantly between 12 and 24 months (Fig 1). There were no significant changes between the other measured time points. Significant changes in cashewand walnut-specific IgE were not detected (Fig 1). Our data show that, in contrast to its effect on peanut IgE, peanut OIT does not significantly decrease IgE to almond, cashew, sesame, or walnut compared with baseline values, despite the known crossreactivity between peanut and sesame and peanut and almond. The clinical significance and changes observed between 0 and 12 or 12 and 24 months on treatment is uncertain. The small sample size,