J. Andrew Bird

Adverse reactions during peanut oral immunotherapy home dosing

To The Editor: Oral immunotherapy (OIT) is increasingly being investigated as a potential treatment for peanut and other food allergies, with a recent study demonstrating evidence of clinical desensitization and immunologic changes suggesting the development of long-term tolerance1. Unlike traditional subcutaneous immunotherapy for inhalant allergens, peanut OIT is administered daily, with the vast majority of doses given at home. In our peanut OIT protocols, subjects are seen in the research unit for observed dose escalations every two weeks, and subsequent doses are given at home. In the open-label study of peanut OIT, home doses were generally well-tolerated2. The incidence of allergic reactions with any home dose was 3.5%, with mild upper respiratory and skin symptoms being the most common complaints. Despite the infrequent incidence of symptoms with peanut OIT home dosing, certain patterns of reactions have surfaced during this phase. Characterizing these reactions and identifying potential triggers or factors which predispose to reactions may improve the safety of home dosing. Reactions occurring during investigational OIT or any immunotherapy protocol are challenging to study prospectively, due to ongoing modifications in the protocol and recommendations that are instituted to prevent further reactions. In subcutaneous aeroallergen immunotherapy, asthma has been identified as a risk factor for systemic reactions, prompting recommendations to evaluate respiratory symptoms and consider objective measures of airway function during administration3. Researchers studying milk and egg OIT noted certain “augmentation factors” that lowered threshold doses – namely, infection, exercise, pollen allergy, and irregular intake4 – and identifying these factors and reducing the immunotherapy dose prevented further allergic reactions. We have noted five patterns associated with a propensity to react to a previously tolerated dose of peanut OIT, including several not previously described. It is interesting that these factors would provoke symptoms after a given OIT dose when, in many of the examples noted, the dose had been tolerated for weeks to months without symptoms. Table I lists selected examples illustrating the observed patterns – (1) concurrent illness, (2) suboptimally-controlled asthma, (3) timing of dose administration after food ingestion, (4) physical exertion after dosing, and (5) dosing during menses. Addressing these factors (see Table II) has improved the safety profile of our peanut OIT protocol. While some of our recommendations mirror those instituted in subcutaneous immunotherapy protocols, most are unique to OIT administration. We expand on reports from other research centers4, 5, which have described triggers such as infection, exercise, pollen allergy, and irregular intake, and this is the first report involving protocols for peanut allergy. Table I Examples of Reactions during Peanut OIT Home Dosing Table II Recommendations for Future OIT Investigations We have observed that dosing during febrile illnesses has been associated with systemic reactions to previously tolerated peanut OIT doses. We recommend withholding OIT during acute illnesses and advise subjects to resume dosing at home if fewer than three doses are missed. If three to five doses are missed, subjects return to the research unit for observed dosing. Those who miss more than five days of dosing may require significant dose reduction or repeat desensitization. In our open-label study2, asthma was associated with a higher rate of chest symptoms during OIT. Of the subjects reporting chest symptoms during home dosing, 82% had co-existing asthma. Several subjects receiving peanut OIT noted cough and wheezing after doses. Some also had chronic cough or exercise-induced respiratory symptoms. Although we did not observe changes in pulmonary function in these subjects, their symptoms improved with the initiation of asthma controller medications (see Table I), highlighting the importance of diagnosing and treating co-morbid atopic conditions. Regular peak flow measurements and pulmonary function testing has been implemented to optimize asthma control. It has not been uncommon for a subject taking a daily OIT dose without eating a meal or snack in the two hours before dosing to have symptoms with a dose that has been previously tolerated; taking the same dose with food the next day and thereafter prevents further reactions. Additionally, several subjects have experienced allergic symptoms with exercise after OIT dosing, and we advise these individuals to avoid exertion for two hours after dosing. Finally, one subject had several systemic reactions when menses was coupled with exercise despite no symptoms with daily dosing in the interval between episodes and was eventually withdrawn from the study. She was not taking other medications (e.g. non-steroidal anti-inflammatory drugs). Of note, she did not have systemic reactions each time she exercised during menses. At this time, the role of menses is unclear, and further study is needed. In the studies to date, peanut and food OIT have a good safety profile, and home dosing is infrequently associated with adverse reactions2, 6. However, allergic symptoms should be expected, and subjects and their families should be counseled about circumstances associated with an increased possibility of reacting to previously tolerated OIT doses. As OIT for food allergy becomes increasingly studied in research settings, implementing these recommendations and modifications can improve the safety of these experimental protocols.

Section on allergy and immunology

Founded in 1948, the Section on Allergy and Immunology is dedicated to ensuring that children receive the highest quality of allergy and immunology care. To accomplish its mission, the Section provides a number of educational, training, and research programs and continually advocates for improved allergy and immunology care and services. The Section sponsors educational programs for both pediatric generalists and subspecialists at the American Academy of Pediatrics (AAP) National Conference and Exhibition (NCE) each fall and at the American Academy of Allergy Asthma & Immunology annual meeting each spring. The Section’s other educational endeavors include this annual “Best Articles Relevant to Pediatric Allergy and Immunology” supplement to Pediatrics, Visiting Professor Program, Pediatric Asthma Speaker’s Kit, online continuing medical education course on “asthma gadgets,” electronic quality improvement in practice program on asthma diagnosis and management (Education in Quality Improvement for Pediatric Practice [eQIPP], which meets the American Board of Pediatrics maintenance-ofcertification criteria), school nurse allergy tool kit, and a number of public education materials. The Section is also active in contributing to educational programs and resources such as AAP News, educational brochures, clinical reports, and many other endeavors. To support training and promote research in pediatric allergy and immunology, the Section awards travel grants to residents and training fellows to participate and present cases at the AAP NCE and provides outstanding abstract awards for training fellows and junior faculty for presentation at the American Academy of Allergy Asthma & Immunology annual meeting. In close collaboration with other subspecialty societies, the Section is actively involved with initiatives to improve subspecialty education such as the American Board of Allergy and Immunology maintenance-of-certification requirements. Section members represent the AAP in national and government conferences and provide input on federal legislation on behalf of the AAP. For more information on all AAP allergy and immunology resources and initiatives, visit www.aap.org/sections/allergy. The reviews contained in the 2011 synopsis were written by Fellows of the AAP Section on Allergy and Immunology and fellows in allergy and immunology training programs who contributed reviews with their mentors. The editor selected the journals to be reviewed on the basis of the likelihood that they would contain articles on allergy and immunology that would be of value and interest to the pediatrician. Each journal was assigned to a voluntary reviewer who was responsible for selecting articles and writing reviews of their articles. Only articles of original research were selected for review. Final selection of the articles to be included was made by the editor. The 2010–2011 journals chosen for review were Allergy, American Journal of Asthma & Allergy for Pediatricians, Archives of Pediatric and Adolescent Medicine, American Journal of Medicine, American Journal of Respiratory and Critical Care Medicine, Annals of Allergy, Asthma, and Immunology, Annals of Internal Medicine, Archives of Disease in Childhood, Archives of Internal Medicine, Blood, British Journal of Dermatology, British Medical Journal, Chest, Clinical and Experimental Allergy, Clinical Pharmacology and Therapeutics, Critical Care Medicine, European Journal of Pediatrics, European Respiratory Journal, Immunology, Journal of Allergy and Clinical Immunology, Journal of the American Academy of Dermatology, Journal of the American Medical Association, Journal of Applied Physiology, Journal of Experimental Medicine, Journal of Immunology, Journal of Infectious Diseases, Journal of Pediatric Gastroenterology and Nutrition, Journal of Pediatrics, Journal of Pharmacology and Experimental Therapeutics, Lancet, Nature, New England Journal of Medicine, Pediatrics, Medicine, Pediatric Allergy and Immunology, Pediatric Asthma, Allergy & Immunology, Pediatric Dermatology, Pediatric Infectious Disease Journal, and Science. The editor and the Section on Allergy and Immunology gratefully acknowledge the work of the reviewers and their trainees who assisted. The reviewers were Stuart L. Abramson, MD, PhD, Sugar Land, TX; James R. Banks, MD, Arnold, MD; Theresa A. Bingemann, MD, Rochester,

Increased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy

Capsule Summary Peanut-specific IgA in saliva correlates with DBPCFC outcomes following peanut SLIT, suggesting that peanut-specific salivary IgA may be a potential biomarker for SLIT used to treat peanut allergy.

Letter to the editorIncreased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy

Capsule Summary Peanut-specific IgA in saliva correlates with DBPCFC outcomes following peanut SLIT, suggesting that peanut-specific salivary IgA may be a potential biomarker for SLIT used to treat peanut allergy.

Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy

BACKGROUND Anaphylaxis to egg or severe egg allergy has been considered a contraindication to receiving trivalent seasonal influenza vaccine (TIV). OBJECTIVE To evaluate the safety of TIV among severely egg allergic children. METHODS A 2-phase, multicenter study at 7 sites was conducted between October 2010 and March 2012. Inclusion criteria included a history of a severe reaction, including anaphylaxis, to the ingestion of egg and a positive skin test result or evidence of serum specific IgE antibody to egg. Phase 1 consisted of a randomized, prospective, double-blind, placebo controlled trial of TIV administration to egg allergic children, using a 2-step approach; group A received 0.1 mL of influenza vaccine, followed in 30 minutes if no reaction with the remainder of an age-appropriate dose, whereas group B received an injection of normal saline followed in 30 minutes if no reaction with the full 100% of the age-appropriate dose. Phase 2 was a retrospective analysis of single dose vs split-dose administration of TIV in eligible study participants who declined participation in the randomized controlled trial. RESULTS Thirty-one study participants were prospectively evaluated in the randomized controlled trial (group A, 14; group B, 17); 45.1% had a history of anaphylaxis after egg ingestion. A total of 112 participants were retrospectively evaluated (87 with the single dose and 25 with the split dose); 77.6% of participants had a history of anaphylaxis after egg ingestion. All participants in both phases received TIV without developing an allergic reaction. CONCLUSION TIV administration is safe even in children with histories of severe egg allergy. Use of 2-step split dosing appears unnecessary because a single dose was well tolerated.

Single-dose influenza vaccination of patients with egg allergy in a multicenter study

Institutes of Health (NIH); is a consultant and scientific advisor for the Food Allergy Initiative; is a medical advisor for the Food Allergy & Anaphylaxis Network; is a scientific advisor for the University of Nebraska–FARRP; and is 45% owner of Herbal Springs, LLC. S. H. Sicherer is a consultant for the Food Allergy Initiative and has received research support from the NIAID/NIH. The rest of the authors have declared that they have no conflict of interest.

Misdiagnosed Food Allergy Resulting in Severe Malnutrition in an Infant

As food allergies become increasingly prevalent and testing methods to identify “food allergy” increase in number, the importance of careful diagnosis has become even more critical. Misdiagnosis of food allergy and inappropriate use of unproven testing modalities may lead to a harmful food-elimination diet. This case is an example of an infant who was placed on an overly restrictive elimination diet at the recommendation of her health care providers, resulting in kwashiorkor and acquired acrodermatitis enteropathica.

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

Clinical Management of Food Allergy

Food allergies are commonly seen by the practitioner, and managing these patients is often challenging. Recent epidemiologic studies report that as many as 1 in 13 children in the United States may have a food allergy, which makes this an important disease process to appropriately diagnose and manage for primary care physicians and specialists alike. Having a understanding of the basic immunologic processes that underlie varying presentations of food-induced allergic diseases will guide the clinician in the initial workup. This review will cover the basic approach to understanding the immune response of an individual with food allergy after ingestion and will guide the clinician in applying appropriate testing modalities when needed by conducting food challenges if indicated and by educating the patient and his or her guardian to minimize the risk of accidental ingestion.

Food allergen panel testing often results in misdiagnosis of food allergy

OBJECTIVE To determine the utility of food allergy panel testing among patients referred to a pediatric food allergy center. STUDY DESIGN Retrospective chart review of all new patients seen between September 2011 and December 2012 by 1 provider in a tertiary referral pediatric food allergy center. A cost analysis was performed to calculate the estimated cost of evaluation for patients who have received a food allergy panel. RESULTS Of 797 new patient encounters, 284 (35%) patients had received a food allergy panel. Only 90 (32.8%) individuals had a history warranting evaluation for food allergy; 126 individuals were avoiding a food based on recommendations from the referring provider and 112 (88.9%) were able to re-introduce at least 1 food into their diet. The positive predictive value of food allergy panel testing in this unselected population was 2.2%. The estimated cost of evaluation for this population was