Corinne A. Keet

The natural history of wheat allergy

BACKGROUND Wheat allergy is 1 of the most common food allergies in children, yet few data are available regarding its natural history. OBJECTIVES To define the natural course of wheat allergy and identify factors that help predict outcome in a large referral population of children with wheat allergy. METHODS Patients were included in the study if they had a history of a symptomatic reaction to wheat and a positive wheat IgE test result. Clinical history, laboratory results, and final outcome were recorded for 103 patients who met the inclusion criteria. Resolution of wheat allergy was determined based on food challenge results. Kaplan-Meier survival curves were generated to depict resolution of wheat allergy. RESULTS Rates of resolution were 29% by 4 years, 56% by 8 years, and 65% by 12 years. Higher wheat IgE levels were associated with poorer outcomes. The peak wheat IgE level recorded was a useful predictor of persistent allergy (P < .001), although many children outgrew wheat allergy with even the highest levels of wheat IgE. CONCLUSION The median age of resolution of wheat allergy is approximately 6 1/2 years in this population. In a significant minority of patients, wheat allergy persists into adolescence.

Urinary levels of triclosan and parabens are associated with aeroallergen and food sensitization

BACKGROUND Endocrine-disrupting compounds (EDCs) have immune-modulating effects. We were interested in determining their association with allergic sensitization. OBJECTIVE We sought to determine the association between EDCs and allergic sensitization and whether this relationship depends on the antimicrobial properties of the EDCs, sex, or both. METHODS Data were obtained from the 2005-2006 National Health and Nutrition Examination Survey in which urinary bisphenol A; triclosan; benzophenone-3; propyl, methyl, butyl, and ethyl parabens; and specific IgE levels were available for 860 children. Aeroallergen and food sensitizations were defined as having at least 1 positive (≥ 0.35 kU/L) specific IgE level to an aeroallergen or a food. Logistic regression was used to determine the association of EDCs and sensitization. Analyses were adjusted for urinary creatinine level, age, sex, ethnicity, and poverty index ratio. RESULTS The odds of aeroallergen sensitization significantly increased with the level of the antimicrobial EDCs triclosan and propyl and butyl parabens (P ≤ .04). The odds of food sensitization significantly increased with the level of urinary triclosan among male subjects (odds ratio for third vs first tertiles, 3.9; P= .02 for trend). There was a significant interaction between sex and triclosan level, with male subjects being more likely to be food sensitized with exposure (P= .03). Similar associations were not identified for the nonantimicrobial EDCs bisphenol A and benzophenone-3 (P > .2). CONCLUSIONS As a group, EDCs are not associated with allergen sensitization. However, levels of the antimicrobial EDCs triclosan and parabens were significantly associated with allergic sensitization. The potential role of antimicrobial EDCs in allergic disease warrants further study because they are commonly used in Western society.

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,

Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.

Neighborhood poverty, urban residence, race/ethnicity, and asthma: Rethinking the inner-city asthma epidemic.

BACKGROUND Although it is thought that inner-city areas have a high burden of asthma, the prevalence of asthma in inner cities across the United States is not known. OBJECTIVE We sought to estimate the prevalence of current asthma in US children living in inner-city and non-inner-city areas and to examine whether urban residence, poverty, or race/ethnicity are the main drivers of asthma disparities. METHODS The National Health Interview Survey 2009-2011 was linked by census tract to data from the US Census and the National Center for Health Statistics. Multivariate logistic regression models adjusted for sex; age; race/ethnicity; residence in an urban, suburban, medium metro, or small metro/rural area; poverty; and birth outside the United States, with current asthma and asthma morbidity as outcome variables. Inner-city areas were defined as urban areas with 20% or more of households at below the poverty line. RESULTS We included 23,065 children living in 5,853 census tracts. The prevalence of current asthma was 12.9% in inner-city and 10.6% in non-inner-city areas, but this difference was not significant after adjusting for race/ethnicity, region, age, and sex. In fully adjusted models black race, Puerto Rican ethnicity, and lower household income but not residence in poor or urban areas were independent risk factors for current asthma. Household poverty increased the risk of asthma among non-Hispanics and Puerto Ricans but not among other Hispanics. Associations with asthma morbidity were very similar to those with prevalent asthma. CONCLUSIONS Although the prevalence of asthma is high in some inner-city areas, this is largely explained by demographic factors and not by living in an urban neighborhood.

Prevalence of self-reported food allergy in the National Health and Nutrition Examination Survey (NHANES) 2007-2010.

Symptoms Feeding dysfunction 8 (73%) 3 (75%) 0% 0% 0% 0% Vomiting 5 (45%) 2 (50%) 0% 0% 0% 0% Abdominal pain 7 (64%) 2 (50%) 0% 0% 0% 1 (25%) Dysphagia 5 (45%) 2 (50%) 0% 0% 0% 2 (50%) Food impaction 3 (27%) 2 (50%) 0% 0% 0% 0% Endoscopic findings Furrows 9 (81%) 1 (25%) 1 (9%) 0% 1 (9%) 3 (75%) Rings 5 (45%) 2 (50%) 0% 2 (50%) 0% 2 (50%) Whitish papules 6 (55%) 1 (25%) 0% 0% 0% 2 (50%) Edema 4 (36%) 2 (50%) 0% 0% 0% 0% Small-caliber esophagus 0% 1 (25%) 0% 0% 0% 0% Stricture 9% 0% 0% 0% 0% 0%

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.

The natural history of persistent peanut allergy.

BACKGROUND Peanut allergy affects 1% of children, and for those with persistent disease, few data have been published on trends in peanut-specific immunoglobulin E (P-IgE) levels or the value of P-IgE in predicting reaction severity. OBJECTIVE The primary outcome was the frequency of inadvertent peanut exposure. Secondary outcomes included clinical characteristics, trends in P-IgE, characteristics of accidental exposures, and predictors of reaction severity in patients with persistent peanut allergy. METHODS Records of patients with persistent peanut allergy were reviewed. Other allergic conditions, P-IgE levels, and peanut exposures were documented. RESULTS Seven hundred eighty-two patients were studied, 524 of them male. The median age at initial observation was 1.4 years; the median duration of follow-up was 5.3 years. Of the 782 patients, 93.1% were avoiding other foods, 70.8% had atopic dermatitis, 57.3% allergic rhinitis, and 55.8% asthma. The median initial P-IgE was 28.0 kU/L, and the median peak P-IgE was 68.1. Six hundred eighty-five exposures were seen among 455 patients: 75.9% ingestion, 13.6% contact, 4.5% airborne. 73.7% resulted in urticaria/angioedema, 22.2% lower respiratory symptoms, 21.2% gastrointestinal symptoms, and 7.7% oral erythema/pruritus. Treatment included antihistamines (33.4%), emergency department visits (16.5%), epinephrine (13.1%), corticosteroids (7.7%), albuterol (3.2%), no treatment (26.3%), and not recorded (29.6%). The rate of postdiagnosis ingestion was 4.7%/year; exposures with severe reactions, 1.6%/year; reactions treated with epinephrine, 1.1%/year. Reaction severity did not change with repeated exposure. Severe reactions were associated with higher P-IgE, but not with age, sex, or asthma. CONCLUSION In this referral population, the rates of accidental peanut exposures and severe reactions were low. There was a strong association between higher P-IgE levels and reaction severity.

Long-term treatment with egg oral immunotherapy enhances sustained unresponsiveness that persists after cessation of therapy

BACKGROUND We previously reported the results of a randomized placebo-controlled study of egg oral immunotherapy (eOIT) in which 27.5% of subjects achieved sustained unresponsiveness (SU) after 2 years. Here we report the results of treatment through 4 years and long-term follow-up. OBJECTIVE We sought to evaluate the efficacy and safety of eOIT in participants treated up to 4 years. METHODS Children with egg allergy (5-18 years old) received eOIT (n = 40) for up to 4 years or placebo (n = 15) for 1 year or less. The key outcome was the percentage of subjects achieving SU by year 4. Safety and immunologic assessments were performed, and long-term follow-up questionnaires (LFQs) were administered after study conclusion (LFQ-1) and 1 year later (LFQ-2). RESULTS Of 40 eOIT-treated subjects, 20 (50.0%) of 40 demonstrated SU by year 4. For those subjects still dosing during years 3 and 4, mild symptoms were present in 12 (54.5%) of 22 subjects. At the time of the LFQ, more subjects receiving eOIT (LFQ-1, 23/34 [68%]; LFQ-2, 21/33 [64%]) were consuming unbaked and baked egg versus placebo (LFQ-1, 2/11 [18%], P = .006; LFQ-2, 3/12 [25%], P = .04). Of subjects achieving SU, 18 (90%) of 20 completed the LFQ, with 18 (100%) of 18 reporting consumption of all forms of egg. When compared with subjects not achieving SU, subjects achieving SU had higher IgG4 values (P = .001) and lower egg skin prick test scores (P = .0002) over time and a lower median baseline ratio of egg-specific IgE to total IgE (1.1% vs 2.7%, P = .04). CONCLUSIONS SU after eOIT is enhanced with longer duration of therapy and increases the likelihood of tolerating unbaked egg in the diet.