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Background Childhood food allergy is a serious health problem. However, little is known about the frequency and manner in which it is currently diagnosed. Objective To describe parent report of physician practices in the diagnosis of pediatric food allergy. Methods Data from children with food allergy were identified for analysis from a representative survey administered in US households with children from June 2009 to February 2010. Analyses were performed at the level of the allergy. Demographic characteristics, symptom prevalence, and diagnostic methods were calculated as weighted proportions. Adjusted models were estimated to examine the association of reaction history and allergenic food with odds of physician diagnosis and testing. Results Food allergies (n = 3,218) to 9 common allergens were reported among 2,355 children in a sample of 38,480. We found that 70.4% of reported food allergy was diagnosed by a physician. Among physician-diagnosed food allergy, 32.6% was not evaluated with diagnostic testing, 47.3% was assessed with a skin prick test, 39.9% with a serum specific IgE test, and 20.2% with an oral food challenge. Odds of physician diagnosis and testing were significantly higher for severe versus mild/moderate food allergy. Urticaria and angioedema were not reported as symptoms in 40.7% and 34.6% of severe food allergies, respectively. Conclusion Thirty percent of parent-reported food allergies in this study were not diagnosed by a physician. One in 5 physician-diagnosed allergies was evaluated with oral food challenge. Understanding parent report of practices in food allergy provides insight into ways in which to streamline the diagnosis and management of care.

Objective: To evaluate a brief educational tool for pediatricians developed to address known gaps in food allergy knowledge. Study Design: Pre- and post-assessments were administered to a convenience sample of 61 US pediatricians completing the Food Allergy Comprehension Tool between February and March of 2010. McNemar’s and Wilcoxon signed rank tests were used to determine whether clinical knowledge of food allergy and level of comfort in caring for food-allergic children increased significantly after reviewing the tool. Logistic regression models were used to measure the association of participant characteristics with increased knowledge and comfort. Results: Sixty-one percent of surveyed physicians answered more knowledge questions correctly after reviewing the tool. Significantly more participants correctly indicated that anaphylaxis poses the greatest threat to teenagers rather than young children, and correctly rejected chronic nasal problems as a symptom of food allergy (p

Objective The aim of this study was to describe the distribution of childhood food allergy in the United States. Methods A randomized survey was administered electronically from June 2009 to February 2010 to adults in US households with at least 1 child younger than 18 years. Data were analyzed as weighted proportions to estimate prevalence and severity of food allergy by geographic location. Multiple logistic regression models were constructed to estimate the association between geographic location and food allergy. Results Data were analyzed for 38 465 children. Increasing population density corresponded with increasing prevalence, from 6.2% in rural areas (95% confidence interval [CI] = 5.6-6.8) to 9.8% in urban centers (95% CI = 8.6-11.0). Odds of food allergy were graded, with odds in urban versus rural areas highest (odds ratio [OR] = 1.7, 95% CI = 1.5-2.0), followed by metropolitan versus rural areas (OR = 1.4, 95% CI = 1.2-1.5), and so on. Significance remained after adjusting for race/ethnicity, gender, age, household income, and latitude. Conclusions An association between urban/rural status and food allergy prevalence was observed.

Background Recently, the Cystic Fibrosis Foundation developed a consensus report recommending diagnostic criteria for allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis that includes a serum IgE level greater than 500 IU/mL as the "minimal diagnostic criterion." Objective To describe a 7-year-old girl with ABPA whose serum IgE level increased to only 398 IU/mL. Methods Total IgE and anti- Aspergillus serologic measurements were performed using enzyme-linked immunosorbent assay and standard laboratory techniques; HLA analysis was performed; interleukin 4 receptor α single nucleotide polymorphisms were performed using polymerase chain reaction and DNA sequencing; CD23 + B cells were measured using flow cytometry; and cytokine synthesis to Aspergillus purified antigens was assessed using flow cytometry. Results A 7-year-old girl with cystic fibrosis who had mild pulmonary disease and well-controlled asthma developed pulmonary infiltrates, increased wheezing, and decreased pulmonary function. Additional studies demonstrated peripheral blood eosinophilia (eosinophil count, 1,807 cells/mm 3 [19%]) and an increase in IgE and IgG anti- Aspergillus serology; bronchoalveolar lavage revealed septate hyphae with 45° branching subsequently identified as A fumigatus and pulmonary eosinophilia. Previous HLA typing revealed that the patient was HLA-DR2+, DRB*1501, HLA-DQ2−, a pattern associated with increased risk of ABPA. In addition, there was increased up-regulation of CD23 molecules by interleukin 4 stimulation on the patient's B cells, as observed in ABPA. The patient was treated with corticosteroids and itraconazole with resolution of symptoms and pulmonary infiltrates. Conclusions Examination of the pulmonary inflammatory response using bronchoalveolar lavage, genetic risk with HLA-DR2+DQ2– typing, and increased interleukin 4 sensitivity are useful adjunctive studies in the diagnosis of ABPA.

Background Milk is one of the most common food allergies in US children, yet little is known about its distribution and diagnosis. Objective To better understand current pediatric milk allergy distribution and diagnosis trends in the United States. Methods A randomized, cross-sectional survey was administered to parents belonging to a representative sample of US households with children from June 2009 to February 2010. Data from 38,480 parents regarding demographic characteristics, allergic symptoms associated with food ingestion, and methods used to diagnose food allergy were collected and analyzed as weighted proportions. Adjusted models were estimated to examine association of these aspects with odds of milk allergy. Results Of the 3,218 children identified with food allergy, 657 (19.9%) were reported to have milk allergy. Asian (odds ratio [OR], 0.5) and black (OR, 0.4) children were half as likely as white children to develop milk allergy. The highest percentage of milk-allergic children (23.8%) were aged 6 to 10 years, and the lowest percentage of milk-allergic children (15.0%) were aged 11 to 15 years. Nearly one-third (31.4%) of children with milk allergy had a history of severe reactions. Compared with children with other food allergies, children with milk allergy had a higher odds of having physician-diagnosed allergy (OR, 1.7) and were twice as likely (OR, 2.1) to outgrow their milk allergy. Conclusion Childhood milk allergy, which accounts for one-fifth of US food allergies, is less prevalent among Asian and black children than white children. Although less than half of children with milk allergy received confirmatory testing, it is the most commonly diagnosed food allergy.

To evaluate a brief educational tool for pediatricians developed to address known gaps in food allergy knowledge.Pre- and post-assessments were administered to a convenience sample of 61 US pediatricians completing the Food Allergy Comprehension Tool between February and March of 2010. McNemar's and Wilcoxon signed rank tests were used to determine whether clinical knowledge of food allergy and level of comfort in caring for food-allergic children increased significantly after reviewing the tool. Logistic regression models were used to measure the association of participant characteristics with increased knowledge and comfort.Sixty-one percent of surveyed physicians answered more knowledge questions correctly after reviewing the tool. Significantly more participants correctly indicated that anaphylaxis poses the greatest threat to teenagers rather than young children, and correctly rejected chronic nasal problems as a symptom of food allergy (p0.05). Comfort in caring for food-allergic children increased significantly on all items post-intervention (p0.05). Odds of increased knowledge and comfort were significantly higher among pediatricians without previous training in food allergy.The Food Allergy Comprehension Tool is a rapid way to address known knowledge gaps among pediatricians and to identify areas in need of further intervention. We recommend integration of the tool with current food allergy guidelines.

OBJECTIVE: The goal of this study was to better estimate the prevalence and severity of childhood food allergy in the United States. METHODS: A randomized, cross-sectional survey was administered electronically to a representative sample of US households with children from June 2009 to February 2010. Eligible participants included adults (aged 18 years or older) able to complete the survey in Spanish or English who resided in a household with at least 1 child younger than 18 years. Data were adjusted using both base and poststratification weights to account for potential biases from sampling design and nonresponse. Data were analyzed as weighted proportions to estimate prevalence and severity of food allergy. Multiple logistic regression models were constructed to identify characteristics significantly associated with outcomes. RESULTS: Data were collected for 40 104 children; incomplete responses for 1624 children were excluded, which yielded a final sample of 38 480. Food allergy prevalence was 8.0% (95% confidence interval [CI]: 7.6–8.3). Among children with food allergy, 38.7% had a history of severe reactions, and 30.4% had multiple food allergies. Prevalence according to allergen among food-allergic children was highest for peanut (25.2% [95% CI: 23.3–27.1]), followed by milk (21.1% [95% CI: 19.4–22.8]) and shellfish (17.2% [95% CI: 15.6–18.9]). Odds of food allergy were significantly associated with race, age, income, and geographic region. Disparities in food allergy diagnosis according to race and income were observed. CONCLUSIONS: Findings suggest that the prevalence and severity of childhood food allergy is greater than previously reported. Data suggest that disparities exist in the clinical diagnosis of disease.

IL-13 receptor alpha2 (IL-13R alpha 2) is a high-affinity receptor for IL-13, a central mediator of allergic asthma. It acts predominantly as a decoy receptor but can also contribute to IL-13 responses under certain conditions. IL-13R alpha 2 exists in soluble and membrane forms, which can both bind IL-13 and modulate its activity. Yet the proteolytic processes that contribute to the generation of soluble IL-13R alpha 2 are largely unknown.We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13R alpha 2.Acellular cleavage assays by MMPs were performed by using glutathione-S-transferase fusion proteins of murine or human IL-13R alpha 2. IL-13R alpha 2 stable-transfected cells were used for analysis of surface expression and release of soluble IL-13R alpha 2. Wild-type and MMP-8-deficient mice were used for analysis of allergen-induced airway hyperresponsiveness and solubilization of IL-13R alpha 2.Among several MMPs tested, only MMP-8 cleaved IL-13R alpha 2. Treatment of transfected human or murine cells expressing high levels of surface IL-13R alpha 2 with MMP-8 resulted in release of soluble IL-13R alpha 2 into the supernatants, with a concomitant decrease in surface IL-13R alpha 2 levels. The IL-13R alpha 2 solubilized by MMP-8 retained IL-13 binding activity. In an asthma model MMP-8-deficient mice displayed increased airway hyperresponsiveness and decreased soluble IL-13R alpha 2 protein levels in bronchoalveolar lavage fluid compared with those seen in wild-type mice after house dust mite challenge.MMP-8 cleaves IL-13R alpha 2 in vitro and contributes to the solubilization of IL-13R alpha 2 in vivo.

BackgroundAllergic bronchopulmonary aspergillosis occurs in 7–10% of cystic fibrosis (CF) and 1–2% of asthmatic patients. HLA-DR restriction and increased sensitivity to IL-4 stimulation have been proposed as risk factors in these populations.ObjectiveWe examined for the presence of IL-4 receptor alpha chain (IL-4Rα) single nucleotide polymorphisms (SNPs) in ABPA and whether these accounted for increased sensitivity to IL-4 stimulation.MethodsOne extracellular (ile75val) and four cytoplasmic IL-4Rα SNPs were analyzed in 40 CF and 22 asthmatic patients and in 56 non-ABPA CF and asthmatic patients. Sensitivity to IL-4 stimulation was measured by induction of CD23 expression on B cells.ResultsIL-4Rα SNPs were observed in 95% of ABPA patients. The predominant IL-4Rα SNP was the extracellular IL-4Rα SNP, ile75val, observed in 80% of ABPA patients.ConclusionThe presence of IL-4Rα SNPs, principally ile75val, appears to be a genetic risk for the development of ABPA.

Background Atopic individuals are predisposed to mounting vigorous T H 2-type immune responses to environmental allergens. The skin is often the first organ that manifests allergic disease and may provide an early entry point for antigen sensitization. Objective We sought to determine whether epicutaneous exposure to the aeroallergen Aspergillus fumigatus induces nasal allergic responses. Furthermore, we aimed to examine the mechanism involved. Methods Wild-type and signal transducer and activator of transcription 6 (STAT6)–deficient mice were exposed to epicutaneous A fumigatus and control antigen ovalbumin. Nasal inflammation and responsiveness to methacholine were monitored. Results Exposure to epicutaneous A fumigatus antigen induced a marked atopic dermatitis-like phenotype in a manner significantly more efficient than epicutaneous ovalbumin. A single A fumigatus intranasal challenge induced clinical nasal responses and hyperresponsiveness to methacholine in the nose as manifested by nasal symptoms, accompanied by allergic airway and nasal inflammation. Mechanistic analysis using gene-targeted mice revealed that the clinical nasal responses and hyperresponsiveness were STAT6-dependent. Although STAT6 was required for changes in nasal responses, it was not required for epicutaneous pathology except eosinophilia. Conclusion Epicutaneous exposure to the aeroallergen A fumigatus potently primes for STAT6-dependent nasal responses. These results draw attention to the cooperative interaction between the nasal tract and skin. Clinical implications The skin is a potent site for antigen sensitization in the development of experimental allergic rhinitis.

Rationale Single nucleotide polymorphisms (SNPs) in the coding region of the IL-4Rα gene resulting in amino acid substitutions have been associated with atopic phenotypes. We report on the presence of 4 SNPs, E375A, C406R, S478P, and Q551R, (numbering including the 25-amino-acid signal peptide), of the IL-4Rα intracellular domain associated with increased IL-4 stimulated CD23 expression in a CF patient with ABPA. Methods DNA was extracted from cultures of B-cell lines of our patient with a diagnosis of CF and ABPA and from controls (non-ABPA with CF and non-ABPA without CF). Subjects were genotyped for the region of the IL-4Rα containing the desired 4 polymorphisms. IL-4 stimulated PBLs from our patient and controls were also examined for the expression of CD23, the low affinity IgE receptor, on B-cells. Results In our patient we found that the portion of the gene coding for the intracellular domain of the IL-4Rα contained all 4 of the SNPs for which we searched. This is in comparison to control subjects in whom no SNPs were found. Our patient also had significantly increased expression of CD23 molecules/B-cell of IL-4 stimulated PBL cultures compared to controls but similar to other patients with ABPA. Conclusions Thus multiple polymorphisms in the IL-4Rα gene may not only confer susceptibility to atopic diseases such as asthma, but also play a role in the risk of developing ABPA in certain patients with cystic fibrosis.

Rationale ABPA is characterized by a heightened Th2 response to A. fumigatus allergens and a hyper-IgE state compared to patients without ABPA. We hypothesize that one reason for this response is increased sensitivity to IL-4 in ABPA resulting in increased expression of CD23 and CD86 and leading to a positive amplification mechanism that increases Th2 CD4+ T cell responses. Methods PBLs were stimulated with rIL-4 (1-10 ng/ml) and rIL-13 (1-10 ng/ml) for 48 hours. The number of CD23 molecules and percentages of CD23+ B cells were quantified by flow cytometry. Results Following IL-4 stimulation in vitro, the numbers and percentages of CD23 expression on B-cells and CD86+ B-cells were significantly up-regulated in ABPA CF patients compared to non-ABPA CF patients and controls. The slope of increase of CD23 molecules on B-cell was significantly increased in ABPA patients compared to non-ABPA patients. The percentages of CD86+ and CD23+CD86+ B-cells were significantly elevated on Day 0 in ABPA CF patients compared to non-ABPA CF patients. Furthermore, during flares of ABPA compared to remissions the number of CD23 molecules increased on total and CD86+ B-cells. Blockade of CD86 activation with anti-CD86 mAb inhibited IL-4 induced CD23 expression by 50%. With IL-13 stimulation, CD23 expression was up-regulated; however, there was no significant difference in ABPA patients compared to non-ABPA patients and controls. Conclusions ABPA CF patients have increased sensitivity to IL-4 stimulation with up-regulation of CD23 molecules compared to non-ABPA CF patients. During flares of ABPA, there is increased expression of CD23+ on B-cells.