Justin M. Skripak

A randomized, double-blind, placebo-controlled study of milk oral immunotherapy for cow's milk allergy.

BACKGROUND Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals. OBJECTIVE We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cows milk allergy. METHODS Twenty children were randomized to milk or placebo OIT (2:1 ratio). Dosing included 3 phases: the build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg), daily doses with 8 weekly in-office dose increases to a maximum of 500 mg, and continued daily maintenance doses for 3 to 4 months. Double-blind, placebo-controlled food challenges; end-point titration skin prick tests; and milk protein serologic studies were performed before and after OIT. RESULTS Nineteen patients, 6 to 17 years of age, completed treatment: 12 in the active group and 7 in the placebo group. One dropped out because of persistent eczema during dose escalation. Baseline median milk IgE levels in the active (n = 13) versus placebo (n = 7) groups were 34.8 kUa/L (range, 4.86-314 kUa/L) versus 14.6 kUa/L (range, 0.93-133.4 kUa/L). The median milk threshold dose in both groups was 40 mg at the baseline challenge. After OIT, the median cumulative dose inducing a reaction in the active treatment group was 5140 mg (range 2540-8140 mg), whereas all patients in the placebo group reacted at 40 mg (P = .0003). Among 2437 active OIT doses versus 1193 placebo doses, there were 1107 (45.4%) versus 134 (11.2%) total reactions, with local symptoms being most common. Milk-specific IgE levels did not change significantly in either group. Milk IgG levels increased significantly in the active treatment group, with a predominant milk IgG4 level increase. CONCLUSIONS Milk OIT appears to be efficacious in the treatment of cows milk allergy. The side-effect profile appears acceptable but requires further study.

Open-label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy.

Maria D. Rivas, PhD Javier Molina-Infante, MD Maria A. Gonzalez-Nuñez, MD Moises Perez-G, BSc Juan F. Masa, MD Juan F. Sanchez, MD Jose Zamorano, PhD From Unidad de Investigación, Servicio de Digestivo, Servicio de Anatomia Patologica, Servicio de Neumologia-Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CiberRes), and Servicio de Medicina Interna, Hospital San Pedro de Alcantara, Caceres, Spain. E-mail: jose.zamorano@ses.juntaextremadura.net. Supported by Fondo Europeo Desarrollo Regional (FEDER) Funds, Spanish public funds Fondo de Investigacion Sanitaria 06/1431, and Junta de Extremadura PRI06A035 and SCSS0744. M.D.R. was supported by Subdireccion General de Investigacion Sanitaria CA06/0110. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

Long-term follow-up of oral immunotherapy for cow's milk allergy

To the Editor: Oral immunotherapy (OIT) for food allergy is currently under active investigation, and its use in clinical practice is spreading despite important concerns(1, 2). Among the many reasons for caution is the paucity of data on long-term outcomes. One study in Italy found that although 18/21 (86%) subjects were initially partially or completely desensitized to cows milk (CM) with OIT, this dropped to 14/20 (70%) after 4 ½ years(3). Other studies have generally reported limited or no follow-up data. Here, we report follow-up of two studies of CM OIT after up to five years in order to evaluate ongoing CM consumption, symptoms, and potential predictors of long-term outcomes. Both previously published studies enrolled CM allergic children at Johns Hopkins and Duke Universities after a double-blind placebo-controlled oral food challenge (OFC) (4-6). The first study was a double-blind placebo-controlled trial in 20 children (4). Dose escalation to 0.5 grams CM protein lasted approximately eight weeks, followed by three month maintenance. All placebo treated children were offered active OIT after the final OFC. The second study was an open label randomized trial of OIT versus sublingual immunotherapy (SLIT) in 30 children (6). Dose escalation, lasting approximately 30 weeks, started with a short course of SLIT, followed by OIT to a goal dose of 1 or 2 grams. After three months of maintenance, an OFC was administered and the dose was potentially adjusted to a maximum of 4 grams. Maintenance totaled 15 months and was followed by another OFC. For subjects who passed that challenge, tolerance challenges were done at one and six weeks later. In both studies, individualized recommendations regarding milk consumption after study completion were provided based on OFC results. Follow-up data were collected by standardized questionnaire and/or clinical follow-up for all 32 subjects treated with active OIT at Johns Hopkins, and 26/32 participated in a follow-up visit including phlebotomy and skin testing. Subjects were asked about CM consumption and symptoms with CM ingestion in the past year. Symptoms were classified as frequent or predictable if they typically occurred with CM consumption or sporadic if there were no frequent or predictable symptoms but definite reactions occurred on at least one occasion. In order to assess predictors of outcome, subjects were split into two groups: those who consumed at least one serving of CM daily with no more than oral/pharyngeal symptoms, and those who either consumed less CM or reported symptoms. Differences were evaluated by Fischers exact test for dichotomous variables or Wilcoxan rank sums for continuous variables. Sixteen subjects were eligible from each study, including 5 subjects who did not complete the questionnaire but for whom clinical data were available (including three who withdrew during active treatment). Subjects were followed-up after a median of 4.5 years (range 1.3-5.3) and 3.2 years (range 2.6-3.4) from end of dose escalation, in study 1 and study 2, respectively. Because outcomes were similar between studies, and between OIT randomization groups in the second study, data were combined for further analysis. Table 1 shows current CM consumption status and symptoms with CM ingestion. Twenty-two percent reported limiting their consumption because of symptoms, 9% because of anxiety and 13% because of taste. In addition, 25% limited CM with exercise and 6% with illness. Most reactions were not attributed to cofactors, but 13% reported increased symptoms with exercise, 9% with illness and 6% after missing several days of CM. Notably, some subjects who initially did well, and passed interim OFCs, subsequently had increased symptoms and began to restrict CM. Disturbingly, some subjects had significant symptoms after study completion of which we were unaware, with one subject reporting using epinephrine at least twice per month for reactions to CM. (Supplemental Table 1 describes types of symptoms with CM consumption). Table 1 Characteristics by long-term outcome category Baseline and follow-up characteristics and their relationship to long-term outcomes are shown in Table 2. Of note, several characteristics were associated with long-term outcome, including baseline CM-IgE, gastrointestinal and lower respiratory symptoms with OIT, food challenge threshold at three months of maintenance, amount of CM recommended for daily intake and SPT wheal size in follow-up. No subject with baseline CM IgE over 75 kU/L (n=8), respiratory symptoms with more than 2% of doses (n=8), or who had a post-treatment food-challenge threshold of less than 4 grams (n=7) was consuming at least one serving of milk in follow-up without symptoms. In addition, 7 (88%) of those with baseline CM IgE over 75 kU/L either had anaphylaxis or consumed no more than trace or baked milk in follow-up. (Supplemental Tables 2-3 and Figures 1-3) However, collectively these predictors identified only 48% of subjects in the poorer outcome group, and given the relatively small sample size, we would be hesitant to suggest that these specific cut-offs would necessarily apply to other studies. Table 2 Milk consumption status and symptoms during follow-up. This report has several important limitations. First, we do not have follow-up serology or skin prick testing on most subjects with the worst outcome – those who were avoiding milk – which may underestimate the discriminative capacity of these parameters. Second, we do not have a control group that was not treated to compare long-term outcomes. Third, these subjects may represent an especially severe phenotype of CM allergy. Most importantly, our data do not answer the question of whether subjects who continue to have symptoms are actually better off than they were before treatment. However, while we hope that newer OIT protocols that include higher doses and/or longer periods of maintenance will lead to better results, it is clear from these preliminary data that long-term outcomes following CM immunotherapy are decidedly mixed, with some subjects losing desensitization over time, and no more than 31% of subjects tolerating at least full servings of CM with minimal or no symptoms. These findings are particularly concerning for the future of OIT because, unlike most other allergenic foods, CM is typically consumed in diverse forms several times a day. Even young children are generally very motivated to incorporate CM into their diets. For foods like peanut, where aversion among formerly allergic children is common(7), results may be far worse than we have found here. It is therefore clear that more research into the long-term outcomes of OIT for food allergy is necessary and, most importantly, that OIT for food allergy is far from ready for clinical practice.

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,

Potential mechanisms for the association between fall birth and food allergy

Season of birth has been reported as a risk factor for food allergy, but the mechanisms by which it acts are unknown.

Peanut and tree nut allergy in childhood

Peanut and tree nut allergies present multiple challenges in their presentation and management. These challenges have become increasingly relevant in recent years, as these allergies appear to have become more common. An estimated 1–2% of the population in the USA is allergic to peanut or tree nuts. Peanut allergy typically presents with symptoms in one of the first few exposures to peanut. Diagnosis is based on clinical history along with skin prick test, or quantitation of allergen‐specific immunoglobulin E (IgE), and oral food challenges when indicated. Once the diagnosis is confirmed, the only current management approach is strict avoidance of the food. This is clearly an imperfect option as it can be difficult to avoid completely peanut and tree nuts and accidental exposures are not uncommon. Only about 20% of those with peanut allergy, and <10% of those with tree nut allergy, are reported to acquire tolerance. Additionally, peanut allergy can recur, with one study finding a recurrence rate of 8%. Peanut and tree nuts are the foods most frequently associated with fatal episodes of anaphylaxis. This is of particular concern in adolescents and young adults, among whom life‐threatening and fatal food allergy‐related reactions are most common.

Mammalian milk allergy: avoidance strategies and oral desensitization.

Purpose of reviewTo address what is currently the most significant, fundamental question in the management of milk-allergic patients: is the best pathway to developing tolerance to milk via complete avoidance or by regular intentional exposure to the offending agent? Recent findingsThe current standard of care for the management of milk-allergic patients, and food-allergic patients in general, remains avoidance of suspected allergens. However, there is growing evidence that regular oral exposure to gradually increasing amounts of an allergenic food can lead to a desensitized state in most food-allergic children. A limited number of studies have attempted to demonstrate permanent tolerance induction. In those cases, a minority of participants has achieved this. Mechanisms of action have not been extensively evaluated, but when serologic studies have been reported, changes have been similar to those seen with standard subcutaneous immunotherapy. That is, food-specific IgE is typically unchanged or slightly decreased, whereas food-specific IgG4 increases substantially. SummaryConsumption of extensively heated cows milk and treatment with orally or sublingually administered milk immunotherapy are promising therapeutic approaches. It remains to be determined whether or not the majority of milk-allergic patients can be permanently tolerized through these methods and what the mechanisms of action are for both desensitization and tolerization.

Persistent Effects of Maternal Smoking During Pregnancy on Lung Function and Asthma in Adolescents

EM Hollams, NH de Klerk, PG Holt, PD Sly. Am J Respir Crit Care Med. 2014;189(4):401–407 The study was conducted to determine if the negative effects of maternal smoking during pregnancy on respiratory health persist into adolescence and, if so, to identify a mechanism. The study population included 1129 Australian children, age 14 years, seen for one of multiple scheduled follow-up visits as part of a birth cohort study. …

Exposure to Pets, and the Association With Hay Fever, Asthma, and Atopic Sensitization in Rural Children

Purpose of the Study. To evaluate the effect of exposure to animals on the development of hay fever, asthma, and atopy. Study Population. Cross-sectional study of 2618 families of Swiss, German, and Austrian decent, living in a rural location. Families were assigned to 1 of 2 categories: farming and nonfarming. Methods. Information was collected by standardized questionnaire and interview. Mattress dust was collected and measured for content of endotoxin and cat allergen. Specific immunoglobulin E levels to multiple common allergens and immunoglobulin G4 to cat were measured. Results. Complete data were available for 812 children. Among them, 319 were farmers’ children and 493 were nonfarmers’ children. In the entire group, early (<1-year-old) and current exposure to cats was associated with a reduced risk of wheezing and grass pollen sensitization. Current contact with dogs was inversely associated with hay fever, asthma, and sensitization to cat allergen and grass pollen. Early exposure to dog did not have any significant effects. When farm-animal contact was controlled for, most of these associations were weakened but were strongest in farmers’ children. Conclusions. There was an inverse relationship between dog exposure and asthma, hay fever, and allergy. However, much of this protective effect was explained by exposure to farm animals. Reviewer Comments. There are several studies that report pet exposure to be associated with a reduced risk for atopic disease. In this study, the primary outcome of decreased clinical manifestations of atopy was confounded by exposure to farm animals. Although the exposure to pets did not show an overall statistically significant association, the results approached significance, and a larger study population may have revealed significant differences. Also, the study ultimately found that animal exposure is most likely to provide a protective effect when the total level of exposure is highest (ie, those children exposed to pets and farm animals).

Effects of Childhood Asthma on the Development of Obesity Among School-Aged Children

Z Chen, MT Salam, TL Alderete. Am J Respir Crit Care Med. 2017;195(9):1181–1188 To determine what effect asthma has on the development of obesity. A total of 3474 children from 8 different southern California communities were enrolled and followed prospectively. A total of 2706 of these children were nonobese at study entry and were included in the primary analysis. Nonobese children were followed and examined annually or biannually from kindergarten or first grade through high school. Questionnaires were completed …