Susan Laubach

Oral tolerance, food allergy, and immunotherapy: Implications for future treatment

The lumen of the gastrointestinal tract is exposed daily to an array of dietary proteins. The vast majority of proteins are tolerated through suppression of cellular or humoral responses, a process known as oral tolerance. However, in approximately 6% of children and 4% of adults in the United States, tolerance to a given dietary antigen either is not established or breaks down, resulting in food hypersensitivity. Although food allergies can result in sudden and life-threatening symptoms, their prevalence is remarkably low considering the complexities of the gut-associated mucosal system. Suppression involves signaling by an array of nonprofessional antigen-presenting cells, dendritic cells, and regulatory T cells, as well as lymphocyte anergy or deletion. Several factors, including antigen properties, route of exposure, and genetics and age of the host, contribute to the development of oral tolerance. Although the current standard of care for patients with food allergies is based on avoidance of the trigger, increased understanding of the mechanisms involved in tolerance has shifted focus of treatment and prevention toward inducing tolerance. Data from early-phase clinical trials suggest both sublingual and oral immunotherapy are effective in reducing sensitivity to allergens. In this article we review the mechanisms of tolerance, discuss aberrations in oral tolerance, and provide information on novel prevention and treatment paradigms for food allergy.

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,

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.

Ovalbumin content of 2010-2011 influenza vaccines.

As regards patients 2 and 3, considering negative results of in vivo and in vitro tests as well as the fact that they had not experienced severe reactions, an open food challenge was performed to firmly establish the diagnosis. In accordance with Kanny et al, we administered increasing doses of sesame seeds (0.05, 0.5, 1, 5, and 10 g) every 30 minutes. Both patients experienced urticarial reactions: the first one 20 minutes after the dose of 0.5 g, the second 15 minutes after the dose of 1 g. Consequently, no oral provocation test with sesame oil was performed. We did not perform an oral provocation test in patient 1, because of the previous anaphylactic shock and positivity to SPTs with sesame seeds. Specific IgE was further analyzed by immunoblot experiments with an extract of sesame seeds and sesame oil (Fig 1). All patients’ sera (diluted 1:4 in PBS-Tween 0.5%) showed an IgE binding to several proteins of the oil bodies (membrane lipoproteins), such as oleosins (the band with molecular mass around 15-17 kDa). To our knowledge, these are the first cases of hypersensitivity to sesame diagnosed by a simple immediate-reading contact test with sesame oil. Because oleosins are hydrophobic and can not be solubilized in normal saline, a negative prick-to-prick test with crushed sesame seeds is not sufficient to exclude sesame allergy, especially in subjects in whom specific IgE is directed prevalently to liposoluble proteins. For this reason, patients with histories of adverse reactions to sesame should also be tested with an immediate-reading ‘‘contact test’’ with sesame oil, in which oleosins are anchored onto the surface by its central hydrophobic domain and can easily penetrate the skin. Negative results in SPTs with sesame oil can be explained by the fact that the oil drops were wiped away immediately after testing and there was not enough time to allow oil to penetrate into the skin. The data from Leduc et al and our data indicate that sensitization to oleosins can play an etiologic role in some subjects with immediate reactions to sesame products. Therefore, sensitization to oleosins might constitute a diagnostic problem in both adults and children. In effect, even though all our patients were adults, one of the patients described by Leduc et al was a 9-year-old girl. Few data exist on the allergenicity of other vegetable oils. The presence of oleosins has been shown in some of them. In peanut oil, for example, the allergenicity of oleosins has been established, even though commercially available, refined peanut oil has been proven to be well tolerated by most subjects with peanut allergy. In effect, the major refined oils are not thought to induce symptoms in susceptible individuals. There are commercial available crude and cold-pressed peanut oils that contain proteins. Sesame oil differs from the others because it is typically available as an unrefined, crude oil, which contains a significantly higher amount (3-13 mg/g) of proteins. Our immunoblot experiments detected serum-specific IgE to the oleosins contained in sesame oil. The sera of our patients also displayed a higher IgE-reactivity to other liposoluble proteins not yet characterized (Fig 1, D). Like oleosins, such lipoproteins are hydrophobic, and because they can not be solubilized in normal saline, they are not present in commercial extracts. Our data suggest that patients with histories of immediate reactions to sesame products and positive results in immediate-reading contact tests with sesame oil should be instructed to avoid all sesame products, including oil. However, further studies in larger samples are needed to confirm the usefulness of this immediate-reading contact test and to validate such advice. Cristiana Alonzi, MD Paolo Campi, MD Francesco Gaeta, MD Fernando Pineda, PhD Antonino Romano, MD

Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial

BACKGROUND Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies. OBJECTIVE We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product. METHODS A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. RESULTS Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. CONCLUSIONS In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.

Posttussive emesis as a symptom of asthma in children

BACKGROUND Emesis can be triggered by cough in children, and cough is a common symptom of asthma. OBJECTIVE To explore the association between posttussive emesis and asthma in the pediatric population. METHODS A questionnaire was distributed to parents of children between the ages of 2 and 17 years in the pediatric and allergy-immunology clinics at our institution from August 16 through November 3, 2008. Prevalence of posttussive emesis was determined and compared among children with physician-diagnosed asthma, children with no evidence of asthma, and those not formally diagnosed as having asthma but with surrogate markers suggestive of asthma. The predictive value of posttussive emesis was compared with those of known markers of asthma. The prevalence of gastroesophageal reflux and pertussis was evaluated because these conditions might also cause posttussive emesis. RESULTS The prevalence of posttussive emesis was 33% in our study population of 500 children. Among those with physician-diagnosed asthma (n = 122), 56% reported a history of posttussive emesis. For patients not formally diagnosed as having asthma but with surrogate markers suggestive of asthma (n = 62), 71% had a history of posttussive emesis. Both of these were significantly higher than in those with no evidence of asthma (n = 316), in whom 16% reported a history of posttussive emesis (P < .0005). Children with posttussive emesis were significantly more likely to have asthma than those without posttussive emesis (odds ratio, 7.9; 95% confidence interval, 5.2-12). Neither pertussis nor gastroesophageal reflux accounted for the degree of posttussive emesis reported. CONCLUSIONS Posttussive emesis is more common among children with asthma than among nonasthmatic children. In children with cough and a history of posttussive emesis, asthma should be strongly considered in the differential diagnosis.

Use of Food Allergy Panels by Pediatric Care Providers Compared With Allergists

DR Strukus, E Kempe, A Leber, D Thonrton, R Scherzer. Pediatrics. 2016;138(6):e20161602 To characterize and quantify the use of food-specific serum IgE (sIgE) panels by PCPs and allergists. Clinicians (physicians, nurse practitioners, and physician assistants) who placed orders for food sIgEs at the outpatient laboratory at Nationwide Children’s Hospital in Columbus, Ohio, were classified according to their primary area of clinical expertise, including allergy and immunology, PCP (including pediatricians, family medicine, and internal medicine), and gastroenterology. This was a retrospective review of all food sIgE tests (individual tests and panels) ordered in 2013. In the 1-year study time period, 10 794 single-food sIgE …

The "Tooth" About Wheezing.

FIGURE 1. An anterior-posterior chest x-ray performed during the first week after the child developed a cough. The arrow points to a deciduous tooth lodged in what appears to be the right mainstem bronchus. This finding was missed during the initial read in which the only accompanying history was “wheeze.” A 6-year-old previously healthy nonatopic Caucasian female patient presented to the allergist with a 1-month history of cough. The cough started during a viral upper respiratory infection but progressed to include wheezing and cough. There were no other reported health or environmental changes. A chest x-ray showed “Minimal peribronchial thickening. No evidence of pneumonia or air trapping,” and she was treated with azithromycin, prednisolone, and levalbuterol for 5 days. Her symptoms improved after 5 days, but within 2 weeks, the cough and wheezing had returned and was exacerbated by exercise and talking. She was prescribed a second course of prednisolone and started on fluticasone/salmeterol 100/50 mcg, with minimal improvement. Sinusitis was suspected and she completed a 3-week course of amoxicillin/clavulanic acid. Her wheezing resolved, and the cough slowly improved but did not completely resolve. She and her mother reported a variable clinical response to bronchodilators. Asthma, vocal cord dysfunction, gastroesophageal reflux, and foreign body aspiration were considered. She was referred to Speech Therapy and Pulmonology. Two days before her Pulmonology appointment, she had a coughing fit and post-tussive emesis. In the vomited phlegm, her mother noticed a small tooth. In retrospect, they recalled that just before the onset of her cough, she had lost a tooth and had gasped when it fell out. They never found the tooth and thought she had swallowed it. On further review of the chest x-ray performed at the onset of her cough, the tooth can actually be seen (Figure 1, arrow). Her pediatrician had ordered the x-ray to look for the foreign body after the patient was brought into the clinic shortly after losing her tooth. However, the pediatrician had not specifically mentioned the possibility of aspiration in the radiology requisition, and the foreign body was missed.

Sinusitis and Pneumonia Hospitalization After Introduction of Pneumococcal Conjugate Vaccine

A Lindstrand, R Bennet, I Galanis. Pediatrics. 2014;134(6):e1528–e1536 The purpose of the study was to evaluate the impact of pneumococcal vaccination (PCV) with PCV7 and PCV13 on the incidence of hospitalization due to sinusitis, bacterial pneumonia, and empyema. The study included all children hospitalized with sinusitis, pneumonia, or empyema in Stockholm County between July 2003 and June 2012. This was a retrospective, population based study in which the children were identified by International Classification of Diseases, 10th Revision –coded hospital registries. Discharge codes used were J13–J18 (bacterial pneumonia or pneumonia unspecified), J86 (empyema), or J01 (sinusitis). Pyelonephritis was used as a control for the effect of PCV on number of admissions. The number of children admitted with …

Introduction of Complementary Foods and the Relationship to Food Allergy

KE Grimshaw, J Maskell, EM Oliver. Pediatrics. 2013;132(6). Available at: www.pediatrics.org/cgi/content/full/132/6/e1529 The study analyzed the significance of complementary feeding and breastfeeding in association with allergy development. This study was a nested case-control trial of 41 infants with food allergy diagnosed by age 2 years and 82 matched controls within a cohort study involving 1140 infants. The infants’ food allergies were confirmed by using double-blind, placebo-controlled food challenges, the gold standard for diagnosing food allergies. Infants with food allergies were recruited from the PIFA (Prevalence of Infant Food Allergy) study in the United Kingdom. Parents kept prospective daily food diaries and …