Parent report of physician diagnosis in pediatric food allergy.

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.

The epidemiology of milk allergy in US children.

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.

A brief intervention to improve food allergy knowledge among US pediatricians: lessons learned.

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 < 0.05). Comfort in caring for food-allergic children increased significantly on all items post-intervention (p < 0.05). Odds of increased knowledge and comfort were significantly higher among pediatricians without previous training in food allergy. CONCLUSION: 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.

IL-13Rα2 has a protective role in a mouse model of cutaneous inflammation.

IL-13 is expressed in lesions of atopic dermatitis (AD) and has been associated with increased disease severity. IL-13 has two cognate receptors: IL-13Rα1 and IL-13Rα2. Although IL-13Rα2 expression is known to be induced in response to IL-13 in keratinocytes, its function in AD has never been evaluated. We characterized the loss of skin barrier function and the development of cutaneous inflammation in IL-13Rα2-null versus wild-type BALB/c mice following an epicutaneous allergen-sensitization/challenge model that shares similarities with human AD. Mice lacking IL-13Rα2 had significantly increased transepidermal water loss, cutaneous inflammation, peripheral eosinophilia, and IgG1 and IgE levels compared with wild-type mice. The rate of resolution of the cutaneous inflammation was not significantly altered in the IL-13Rα2-null mice. IL-13 induced expression of IL-13Rα2 in keratinocyte cell lines and primary human keratinocytes. Depletion of IL-13Rα2 in a keratinocyte cell line resulted in increased STAT6 signaling in response to IL-13. In conclusion, IL-13Rα2 serves a protective role in the pathogenesis of allergic inflammation and loss of skin barrier function in a mouse model of AD, suggesting that it may be an important endogenous regulator of IL-13-induced cutaneous inflammation in humans.

Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor alpha2 in vivo.

BACKGROUND: 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. OBJECTIVE: We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13R alpha 2. METHODS: 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. RESULTS: 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. CONCLUSION: MMP-8 cleaves IL-13R alpha 2 in vitro and contributes to the solubilization of IL-13R alpha 2 in vivo.

Asthma genetics: personalizing medicine.

Asthma is a chronic inflammatory lung disease that leads to significant morbidity, mortality, and economic burden. The clinical symptoms, which are a result of airway inflammation and reversible airway obstruction, have led to the mainstay of therapies for asthma: anti-inflammatory medications and bronchodilators. However, the efficacies of the various classes of medications are not equal among all patients and may be affected by asthma phenotypes, environmental exposures, and genetic differences. Similarly, the risk for developing asthma and the natural history of the disease show great inter-individual variability due to these same factors. Over the past few decades, much effort has been focused on the genetics of asthma, and investigators have identified more than one hundred potential asthma susceptibility genes, of which at least ten have been replicated in numerous independent studies. In parallel, researchers have also identified genetic factors that impact the pharmacotherapeutic responses to the major classes of asthma medications. While the results of previous studies have been promising, future investigations need to combine genetics, pharmacogenetics, accurate disease phenotyping, and environmental exposures to build the foundation for personalized and predictive medicine for the 21st century. The ultimate goal is to enable physicians to identify those at risk for asthma, intervene to prevent or attenuate the disease, and select the optimal medical regimen for each individual patient. If successful, the resulting paradigm shift in medical practice will lead to improved clinical outcomes and decreased health care expenditures.

IL-4 alpha chain receptor (IL-4Ralpha) polymorphisms in allergic bronchopulmonary sspergillosis.

BACKGROUND: Allergic 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. OBJECTIVE: We examined for the presence of IL-4 receptor alpha chain (IL-4Ralpha) single nucleotide polymorphisms (SNPs) in ABPA and whether these accounted for increased sensitivity to IL-4 stimulation. METHODS: One extracellular (ile75val) and four cytoplasmic IL-4Ralpha 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. RESULTS: IL-4Ralpha SNPs were observed in 95% of ABPA patients. The predominant IL-4Ralpha SNP was the extracellular IL-4Ralpha SNP, ile75val, observed in 80% of ABPA patients. CONCLUSION: The presence of IL-4Ralpha SNPs, principally ile75val, appears to be a genetic risk for the development of ABPA.

Geographic variability of childhood food allergy in the United States.

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.

The prevalence, severity, and distribution of childhood food allergy in the United States.

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.

Allergen-dependent solubilization of IL-13 receptor alpha2 reveals a novel mechanism to regulate allergy.

BACKGROUND: Allergic sensitization affects half of western populations and often precedes the development of allergic disorders including asthma. Despite the critical role of allergens in the pathogenesis of these disorders, little is known about how allergens modulate the immune response. IL-13 receptor alpha2 (IL-13Ralpha2) is a decoy receptor for IL-13. OBJECTIVE: Although the existence of soluble IL-13Ralpha2 has been documented, the mechanisms underlying its generation are unknown. Many allergens possess protease activity; we investigated whether IL-13Ralpha2 is solubilized in response to allergen treatment. METHODS: We evaluated the ability of allergens to solubilize IL-13Ralpha2 in vitro and in vivo and examined the effect on IL-13 signaling and responses. RESULTS: We determined that treatment of cells with house dust mite (HDM) allergen or purified Dermatophagoides pteronyssinus or Dermatophagoides farinae, but not other allergens, resulted in release of soluble IL-13Ralpha2 that was biologically active and inhibited IL-13 signaling. Prolonged exposure to HDM or treatment with mold allergens resulted in IL-13Ralpha2 degradation. This was associated with increased IL-13 signaling. A single treatment of HDM in vivo resulted in release of IL-13Ralpha2 into the bronchoalveolar lavage (BAL) fluid. BAL fluid from humans also contained IL-13Ralpha2; BAL fluid from individuals with asthma contained less IL-13Ralpha2 than that from controls. CONCLUSION: Allergen exposure can directly affect the level of soluble IL-13Ralpha2 in a way that affects IL-13 signaling and responses. CLINICAL IMPLICATIONS: Soluble IL-13Ralpha2 may be an important biomarker of environmental allergen exposure and asthma.

Allergy-driven alternative splicing of IL-13 receptor alpha2 yields distinct membrane and soluble forms.

IL-13 is a key mediator of allergic inflammation. Its diverse functions are mediated by a complex receptor system including IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2. IL-4Ralpha and IL-13Ralpha1 form a high-affinity signaling heterodimer. IL-13Ralpha2 binds IL-13 with high affinity and has been found to exist in membrane and soluble forms. Soluble IL-13Ralpha2 has been postulated as a critical endogenous modulator of IL-13 responses. However, the mechanism of generation for the soluble form remains unclear. We present the initial study that a mechanism for generation of the soluble form is alternative splicing and that alternative splicing yields a distinct form of soluble IL-13Ralpha2. We found that several mouse organs expressed two IL-13Ralpha2 transcripts, the 1152-bp transcript encoding the full-length protein and the 1020-bp transcript lacking exon10, which encodes the transmembrane region. Deletion of exon 10 (DeltaEx10) caused a frameshift resulting in a different amino acid sequence from position 327 to position 339 and early termination. Constructs encoding both splice variants were transfected into WEHI-274.1 cells. Transfectants expressing the full-length transcript had IL-13Ralpha2 on the cell surface but produced minimal soluble IL-13Ralpha2 in the supernatants. In contrast, transfectants expressing the DeltaEx10 transcript displayed no membrane IL-13Ralpha2 but secreted high levels of soluble IL-13Ralpha2 capable of inhibiting IL-13 signaling. Both variants bound IL-13, but the DeltaEx10 variant displayed approximately 2-fold increase in IL-13 binding activity. Expression of the two IL-13Ralpha2 transcripts was differentially regulated in vivo in an experimental allergic asthma model. Thus, alternatively spliced variants of IL-13Ralpha2 may have a distinct biologic function in vivo.

Level of expression of IL-13R alpha 2 impacts receptor distribution and IL-13 signaling.

IL-13, a critical cytokine for allergic inflammation, exerts its effects through a complex receptor system including IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2. IL-4Ralpha and IL-13Ralpha1 form a heterodimeric signaling receptor for IL-13. In contrast, IL-13Ralpha2 binds IL-13 with high affinity but does not signal. IL-13Ralpha2 exists on the cell surface, intracellularly, and in soluble form, but no information is available regarding the relative distributions of IL-13Ralpha2 among these compartments, whether the compartments communicate, and how the relative expression levels impact IL-13 responses. Herein, we investigated the distribution of IL-13Ralpha2 in transfected and primary cells, and we evaluated how the total level of IL-13Ralpha2 expression impacted its distribution. Our results demonstrate that the distribution of IL-13Ralpha2 is independent of the overall level of expression. The majority of the IL-13Ralpha2 protein existed in intracellular pools. Surface IL-13Ralpha2 was continually released into the medium in a soluble form, yet surface expression remained constant supporting receptor trafficking to the cell surface. IL-13Ralpha2 inhibited IL-13 signaling proportionally to its level of expression, and this inhibition could be overcome with high concentrations of IL-13.

Epicutaneous aeroallergen exposure induces systemic TH2 immunity that predisposes to allergic nasal responses.

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.

Allergic bronchopulmonary aspergillosis in a patient with cystic fibrosis: diagnostic criteria when the IgE level is less than 500 IU/mL.

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 alpha 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, 1807 cells/mm3 [19%]) and an increase in IgE and IgG anti-Aspergillus serology; bronchoalveolar lavage revealed septate hyphae with 45 degrees 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.

Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema.

BACKGROUND: Angioedema, particularly of the head and neck, is a well-recognized adverse effect of angiotensin-converting enzyme (ACE) inhibitors. Most cases respond to conventional therapy, including antihistamines and corticosteroids. Severe episodes may require epinephrine and intubation. OBJECTIVE: To report the case of a patient with ACE inhibitor-induced angioedema treated with fresh frozen plasma (FFP). METHODS: The patient is a 43-year-old, white woman who first received the ACE inhibitor ramipril in March 2002. After 3 weeks, she developed angioedema of her lips and fingers, which resolved with antihistamines, corticosteroids, and one dose of epinephrine. A low dose of ramipril was restarted 4 days later, which was increased throughout 4 days. In late August 2002, she developed severe upper lip and tongue edema recalcitrant to conventional therapy. Her C1 esterase inhibitor level was normal. RESULTS: After 4 days of treatment with antihistamines, corticosteroids, epinephrine, antileukotrienes, cyclosporine, and intravenous immunoglobulins, the patient's tongue swelling continued to recur and became more severe. Two units of intravenous FFP was given, with rapid improvement and no further recurrence of tongue swelling. CONCLUSIONS: In our patient, FFP was highly successful in the treatment of resistant, life-threatening angioedema due to an ACE inhibitor. The benefit of FFP in this setting might be due to the effect of kininase II in breaking down accumulated bradykinin.