Showing papers in "The Journal of Allergy and Clinical Immunology in 2011"

Guidelines for the Diagnosis and Management of Food Allergy in the United States: Summary of the NIAID-Sponsored Expert Panel Report

Abstract: Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.

Eosinophilic esophagitis: Updated consensus recommendations for children and adults

Abstract: Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.

Prevalence of challenge-proven IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants.

Abstract: Background: Several indicators suggest that food allergy in infants is common and possibly increasing. Few studies have used oral food challenge to measure this phenomenon at the population level. Objective: To measure the prevalence of common IgE-mediated childhood food allergies in a population-based sample of 12-month-old infants by using predetermined food challenge criteria to measure outcomes. Methods: A sampling frame was used to select recruitment areas to attain a representative population base. Recruitment occurred at childhood immunization sessions in Melbourne, Australia. Infants underwent skin prick testing, and those with any sensitization (wheal size ≥1 mm) to 1 or more foods (raw egg, peanut, sesame, shellfish, or cow's milk) were invited to attend an allergy research clinic. Those who registered a wheal size ≥1 mm to raw egg, peanut, or sesame underwent oral food challenge. Results: Amongst 2848 infants (73% participation rate), the prevalence of any sensitization to peanut was 8.9% (95% CI, 7.9-10.0); raw egg white, 16.5% (95% CI, 15.1-17.9); sesame, 2.5% (95% CI, 2.0-3.1); cow's milk, 5.6% (95% CI, 3.2-8.0); and shellfish, 0.9% (95% CI, 0.6-1.5). The prevalence of challenge-proven peanut allergy was 3.0% (95% CI, 2.4-3.8); raw egg allergy, 8.9% (95% CI, 7.8-10.0); and sesame allergy, 0.8% (95% CI, 0.5-1.1). Oral food challenges to cow's milk and shellfish were not performed. Of those with raw egg allergy, 80.3% could tolerate baked egg. Conclusion: More than 10% of 1-year-old infants had challenge-proven IgE-mediated food allergy to one of the common allergenic foods of infancy. The high prevalence of allergic disease in Australia requires further investigation and may be related to modifiable environmental factors.

Epidemiology of food allergy.

Abstract: Adverse reactions to foods can occur for a variety of reasons, but a food allergy is caused by a specific immune response. Challenges to determine the prevalence of food allergy include misclassification, biased participation, lack of simple diagnostic tests, rapid evolution of disease, large numbers of potential triggers, and varied clinical phenotypes. Nonetheless, it is clear that this is a common disorder, with studies suggesting a cumulative prevalence of 3% to 6%, representing a significant impact on quality of life and costs. The inclusion of mild reactions to fruits and vegetables could result in calculation of prevalence exceeding 10% in some regions. There are data from numerous studies to suggest an increase in prevalence, but methodologic concerns warrant caution. Prevalence varies by age, geographic location, and possibly race/ethnicity. Many childhood food allergies resolve. Population-based epidemiologic studies have generated numerous novel theories regarding risks, including modifiable factors such as components of the maternal and infant diet, obesity, and the timing of food introduction. Recent and ongoing studies provide insights on risk factors, prevalence, and natural course that may inform clinical trials to improve diagnosis, prevention, and treatment.

Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases

Abstract: Advancing our understanding of mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections could lead to effective and targeted therapies. Subsets of immune and inflammatory cells interact via ILs and IFNs; reciprocal regulation and counter balance among T(h) and regulatory T cells, as well as subsets of B cells, offer opportunities for immune interventions. Here, we review current knowledge about ILs 1 to 37 and IFN-γ. Our understanding of the effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs. Studies of transgenic or knockout mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided important information about IL and IFN functions. We discuss their signaling pathways, cellular sources, targets, roles in immune regulation and cellular networks, roles in allergy and asthma, and roles in defense against infections.

Reduced Diversity of the Intestinal Microbiota During Infancy Is Associated With Increased Risk of Allergic Disease at School Age

Abstract: Background Changes in the human microbiome have been suggested as a risk factor for a number of lifestyle-related disorders, such as atopic diseases, possibly through a modifying influence on immune maturation in infancy. Objectives We aimed to explore the association between neonatal fecal flora and the development of atopic disorders until age 6 years, hypothesizing that the diversity of the intestinal microbiota influences disease development. Methods We studied the intestinal microbiota in infants in the Copenhagen Prospective Study on Asthma in Childhood, a clinical study of a birth cohort of 411 high-risk children followed for 6 years by clinical assessments at 6-month intervals, as well as at acute symptom exacerbations. Bacterial flora was analyzed at 1 and 12 months of age by using molecular techniques based on 16S rRNA PCR combined with denaturing gradient gel electrophoresis, as well as conventional culturing. The main outcome measures were the development of allergic sensitization (skin test and specific serum IgE), allergic rhinitis, peripheral blood eosinophil counts, asthma, and atopic dermatitis during the first 6 years of life. Results We found that bacterial diversity in the early intestinal flora 1 and 12 months after birth was inversely associated with the risk of allergic sensitization (serum specific IgE P = .003; skin prick test P = .017), peripheral blood eosinophils ( P = .034), and allergic rhinitis ( P = .007). There was no association with the development of asthma or atopic dermatitis. Conclusions Reduced bacterial diversity of the infant's intestinal flora was associated with increased risk of allergic sensitization, allergic rhinitis, and peripheral blood eosinophilia, but not asthma or atopic dermatitis, in the first 6 years of life. These results support the general hypothesis that an imbalance in the intestinal microbiome is influencing the development of lifestyle-related disorders, such as allergic disease.

Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma.

Abstract: Background Improvement in lung function after macrolide antibiotic therapy has been attributed to reduction in bronchial infection by specific bacteria. However, the airway might be populated by a more diverse microbiota, and clinical features of asthma might be associated with characteristics of the airway microbiota present. Objective We sought to determine whether relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria. Methods In this pilot study bronchial epithelial brushings were collected from 65 adults with suboptimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control and 10 healthy control subjects. A combination of high-density 16S ribosomal RNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements. Results Compared with control subjects, 16S ribosomal RNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae, and other bacterial families were highly correlated with the degree of bronchial hyperresponsiveness. Conclusion: The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with suboptimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis.

Costs of asthma in the United States: 2002-2007

Abstract: Background The economic burden of asthma is an important measure of the effect of asthma on society. Although asthma is a costly illness, the total cost of asthma to society has not been estimated in more than a decade. Objective The purpose of this study is to provide the public with current estimates of the incremental direct medical costs and productivity losses due to morbidity and mortality from asthma at both the individual and national levels for the years 2002-2007. Methods Data came from the Medical Expenditure Panel Survey. Two-part models were used to estimate the incremental direct costs of asthma. The incremental number of days lost from work and school was estimated by negative binomial regressions and valued following the human capital approach. Published data were used to value lives lost with an underlying cause of asthma. Results Over the years 2002-2007, the incremental direct cost of asthma was $3,259 (2009 dollars) per person per year. The value of additional days lost attributable to asthma per year was approximately $301 for each worker and $93 for each student. For the most recent year available, 2007, the total incremental cost of asthma to society was $56 billion, with productivity losses due to morbidity accounting for $3.8 billion and productivity losses due to mortality accounting for $2.1 billion. Conclusion The current study finds that the estimated costs of asthma are substantial, which stresses the necessity for research and policy to work toward reducing the economic burden of asthma.

Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis.

Abstract: Background Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. Objective We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. Methods Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. Results Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. Conclusion Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.

Defective epithelial barrier function in asthma.

Abstract: Background Asthma is a complex disease involving gene and environment interactions. Although atopy is a strong predisposing risk factor for asthma, local tissue susceptibilities are required for disease expression. The bronchial epithelium forms the interface with the external environment and is pivotally involved in controlling tissue homeostasis through provision of a physical barrier controlled by tight junction (TJ) complexes. Objectives To explain the link between environment exposures and airway vulnerability, we hypothesized that epithelial TJs are abnormal in asthma, leading to increased susceptibility to environmental agents. Methods Localization of TJs in bronchial biopsies and differentiated epithelial cultures was assessed by electron microscopy or immunostaining. Baseline permeability and the effect of cigarette smoke and growth factor were assessed by measurement of transepithelial electrical resistance and passage of fluorescently labeled dextrans. Results By using immunostaining, we found that bronchial biopsies from asthmatic subjects displayed patchy disruption of TJs. In differentiated bronchial epithelial cultures, TJ formation and transepithelial electrical resistance were significantly lower ( P P P Conclusions Our results show that the bronchial epithelial barrier in asthma is compromised. This defect may facilitate the passage of allergens and other agents into the airway tissue, leading to immune activation and may thus contribute to the end organ expression of asthma.

Tight junction defects in patients with atopic dermatitis.

Abstract: Background Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. Objective We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Methods Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. Results We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with T H 2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Conclusion Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.

World Allergy Organization anaphylaxis guidelines: Summary

Abstract: The uniqueWorld Allergy Organization (WAO) Guidelines for the Assessment and Management of Anaphylaxis were created in response to the absence of global guidelines for anaphylaxis. They were developed after documenting that essential medications, supplies, and equipment for assessment andmanagement of anaphylaxis are not universally available worldwide. Additionally, they were developed with the awareness that any health care professional might, at some time, have to assess and manage anaphylaxis in a low-resource environment, whether this be a country, a region, or a specific location, such as an aircraft cabin or a remote area. They incorporate contributions frommore than 100 allergy/immunology specialists on 6 continents received through the WAO member societies and the WAO Board of Directors. In order to transcend language barriers, the principles of anaphylaxis assessment and management set forth in the guidelines are summarized in 5 comprehensive illustrations. The guidelines review patients’ risk factors for severe or fatal anaphylaxis, cofactors that amplify anaphylaxis, and anaphylaxis in vulnerable patients, such as pregnant women, infants, and the

A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response.

Abstract: Background Open-label oral immunotherapy (OIT) protocols have been used to treat small numbers of patients with peanut allergy. Peanut OIT has not been evaluated in double-blind, placebo-controlled trials. Objective To investigate the safety and effectiveness of OIT for peanut allergy in a double-blind, placebo-controlled study. Methods In this multicenter study, children ages 1 to 16 years with peanut allergy received OIT with peanut flour or placebo. Initial escalation, build-up, and maintenance phases were followed by an oral food challenge (OFC) at approximately 1 year. Titrated skin prick tests (SPTs) and laboratory studies were performed at regular intervals. Results Twenty-eight subjects were enrolled in the study. Three peanut OIT subjects withdrew early in the study because of allergic side effects. During the double-blind, placebo-controlled food challenge, all remaining peanut OIT subjects (n = 16) ingested the maximum cumulative dose of 5000 mg (approximately 20 peanuts), whereas placebo subjects (n = 9) ingested a median cumulative dose of 280 mg (range, 0-1900 mg; P Conclusion These results conclusively demonstrate that peanut OIT induces desensitization and concurrent immune modulation. The current study continues and is evaluating the hypothesis that peanut OIT causes long-term immune tolerance.

Remodeling in asthma

Abstract: Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.

The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose

Abstract: Background: In 2009, we reported a novel form of delayed anaphylaxis to red meat that is related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Most of th ...

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Abstract: Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL −1 ) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients ( P = 3.0 × 10 −6 ; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study ( P = 5.4 × 10 −5 ; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant ( P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy

Abstract: BACKGROUND: Both gastrointestinal microbiota composition and cesarean section have been linked to atopic manifestations. However, results are inconsistent, and the hypothesized intermediate role of the microbiota in the association between birth mode and atopic manifestations has not been studied yet. OBJECTIVES: We sought to investigate the relationship between microbiota composition, mode and place of delivery, and atopic manifestations. METHODS: The Child, Parent and Health: Lifestyle and Genetic Constitution Birth Cohort Study included data on birth characteristics, lifestyle factors, and atopic manifestations collected through repeated questionnaires from birth until age 7 years. Fecal samples were collected at age 1 month (n = 1176) to determine microbiota composition, and blood samples were collected at ages 1 (n = 921), 2 (n = 822), and 6 to 7 (n = 384) years to determine specific IgE levels. RESULTS: Colonization by Clostridium difficile at age 1 month was associated with wheeze and eczema throughout the first 6 to 7 years of life and with asthma at age 6 to 7 years. Vaginal home delivery compared with vaginal hospital delivery was associated with a decreased risk of eczema, sensitization to food allergens, and asthma. After stratification for parental history of atopy, the decreased risk of sensitization to food allergens (adjusted odds ratio, 0.52; 95% CI, 0.35-0.77) and asthma (adjusted odds ratio, 0.47; 95% CI, 0.29-0.77) among vaginally home-born infants was only found for children with atopic parents. Mediation analysis showed that the effects of mode and place of delivery on atopic outcomes were mediated by C difficile colonization. CONCLUSION: Mode and place of delivery affect the gastrointestinal microbiota composition, which subsequently influences the risk of atopic manifestations.

Histamine and H1-antihistamines: celebrating a century of progress.

Abstract: In this review we celebrate a century of progress since the initial description of the physiologic and pathologic roles of histamine and 70 years of progress since the introduction of H(1)-antihistamines for clinical use. We discuss histamine and clinically relevant information about the molecular mechanisms of action of H(1)-antihistamines as inverse agonists (not antagonists or blockers) with immunoregulatory effects. Unlike first (old)-generation H(1)-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)-generation H(1)-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. Important advances include improved nasal and ophthalmic H(1)-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H(1)-antihistamines for chronic urticaria treatment. New H(1)-antihistamines introduced for clinical use include oral formulations (bilastine and rupatadine), and ophthalmic formulations (alcaftadine and bepotastine). Clinical studies of H(3)-antihistamines with enhanced decongestant effects have been conducted in patients with allergic rhinitis. Additional novel compounds being studied include H(4)-antihistamines with anti-inflammatory effects in allergic rhinitis, atopic dermatitis, and other diseases. Antihistamines have a storied past and a promising future.

Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis.

Abstract: Background Epidemiologic studies suggest that deficiencies of the nutrients selenium; zinc; vitamins A, C, D, and E; and low fruit and vegetable intake may be associated with the development of asthma and allergic disorders. Objectives To investigate the evidence that nutrient and food intake modifies the risk of children developing allergy. Methods We systematically searched 11 databases. Studies were critically appraised, and meta-analyses were undertaken. Results We identified 62 eligible reports. There were no randomized controlled trials. Studies used cohort (n = 21), case-control (n = 15), or cross-sectional (n = 26) designs. All studies were judged to be at moderate to substantial risk of bias. Meta-analysis revealed that serum vitamin A was lower in children with asthma compared with controls (odds ratio [OR], 0.25; 95% CI, 0.10-0.40). Meta-analyses also showed that high maternal dietary vitamin D and E intakes during pregnancy were protective for the development of wheezing outcomes (OR, 0.56, 95% CI, 0.42-0.73; and OR, 0.68, 95% CI, 0.52-0.88, respectively). Adherence to a Mediterranean diet was protective for persistent wheeze (OR, 0.22; 95% CI, 0.08-0.58) and atopy (OR, 0.55; 95% CI, 0.31-0.97). Seventeen of 22 fruit and vegetable studies reported beneficial associations with asthma and allergic outcomes. Results were not supportive for other allergic outcomes for these vitamins or nutrients, or for any outcomes in relation to vitamin C and selenium. Conclusion: The available epidemiologic evidence is weak but nonetheless supportive with respect to vitamins A, D, and E; zinc; fruits and vegetables; and a Mediterranean diet for the prevention of asthma. Experimental studies of these exposures are now warranted.

Heterogeneity of severe asthma in childhood: confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program.

Abstract: Background Asthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to school-age children with persistent asthma across a wide range of severities. Objectives This study determined how children with severe asthma are distributed across a cluster analysis and how well these clusters conform to current definitions of asthma severity. Methods Cluster analysis was applied to 12 continuous and composite variables from 161 children at 5 centers enrolled in the Severe Asthma Research Program. Results Four clusters of asthma were identified. Children in cluster 1 (n = 48) had relatively normal lung function and less atopy. Children in cluster 2 (n = 52) had slightly lower lung function, more atopy, and increased symptoms and medication use. Cluster 3 (n = 32) had greater comorbidity, increased bronchial responsiveness, and lower lung function. Cluster 4 (n = 29) had the lowest lung function and the greatest symptoms and medication use. Predictors of cluster assignment were asthma duration, the number of asthma controller medications, and baseline lung function. Children with severe asthma were present in all clusters, and no cluster corresponded to definitions of asthma severity provided in asthma treatment guidelines. Conclusion Severe asthma in children is highly heterogeneous. Unique phenotypic clusters previously identified in adults can also be identified in children, but with important differences. Larger validation and longitudinal studies are needed to determine the baseline and predictive validity of these phenotypic clusters in the larger clinical setting.

Dietary baked milk accelerates the resolution of cow’s milk allergy in children

Abstract: Background The majority (approximately 75%) of children with cow's milk allergy tolerate extensively heated (baked) milk products. Long-term effects of inclusion of dietary baked milk have not been reported. Objective We report on the outcomes of children who incorporated baked milk products into their diets. Methods Children evaluated for tolerance to baked milk (muffin) underwent sequential food challenges to baked cheese (pizza) followed by unheated milk. Immunologic parameters were measured at challenge visits. The comparison group was matched to active subjects (by using age, sex, and baseline milk-specific IgE levels) to evaluate the natural history of development of tolerance. Results Over a median of 37 months (range, 8-75 months), 88 children underwent challenges at varying intervals (range, 6-54 months). Among 65 subjects initially tolerant to baked milk, 39 (60%) now tolerate unheated milk, 18 (28%) tolerate baked milk/baked cheese, and 8 (12%) chose to avoid milk strictly. Among the baked milk–reactive subgroup (n = 23), 2 (9%) tolerate unheated milk, and 3 (13%) tolerate baked milk/baked cheese, whereas the majority (78%) avoid milk strictly. Subjects who were initially tolerant to baked milk were 28 times more likely to become unheated milk tolerant compared with baked milk–reactive subjects ( P P 4 levels in the baked milk–tolerant group increased significantly ( P Conclusions Tolerance of baked milk is a marker of transient IgE-mediated cow's milk allergy, whereas reactivity to baked milk portends a more persistent phenotype. The addition of baked milk to the diet of children tolerating such foods appears to accelerate the development of unheated milk tolerance compared with strict avoidance.

Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.

Abstract: Background Atopic dermatitis (AD) is a common inflammatory skin disease with a T(H)2 and "T22" immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. An extensive study of nonlesional AD (ANL) skin is necessary to explore whether there is an intrinsic predisposition to barrier abnormalities, background immune activation, or both in patients with AD. Objective We sought to characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) skin are also reflected in ANL skin. Methods We performed genomic and histologic profiling of both ANL and AL skin lesions (n = 12 each) compared with normal human skin (n = 10). Results We found that ANL skin is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities and that it has a cutaneous expansion of T cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the "background skin phenotype," increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the "clinical disease phenotype." Conclusion Our study implies that systemic immune activation might play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with the disease severity index.

Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation

Abstract: Background Asthma in obese subjects is poorly understood, and these patients are often refractory to standard therapy. Objectives We sought to gain insights into the pathogenesis and treatment of asthma in obese subjects by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation. Methods We performed a prospective study of (1) asthmatic and nonasthmatic patients undergoing bariatric surgery compared at baseline and (2) asthmatic patients followed for 12 months after bariatric surgery. Results We studied 23 asthmatic and 21 nonasthmatic patients undergoing bariatric surgery. At baseline, asthmatic patients had lower FEV 1 and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P P 20 , 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness ( P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4 + T cells increased significantly. Conclusions Bariatric surgery improves AHR in obese asthmatic patients with normal serum IgE levels. Weight loss has dichotomous effects on airway physiology and T-cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.

Anaphylaxis during anesthesia in France: An 8-year national survey

Abstract: Background More attention should be paid to rare serious adverse events such as anaphylaxis to increase the safety of anesthesia. Objective To report the results of an 8-year survey of anaphylaxis during anesthesia in France. Methods Data from patients who experienced anaphylaxis between January 1, 1997, and December 31, 2004, were analyzed. Estimated incidences were obtained by combining this database with data from the French pharmacovigilance system by using a capture-recapture method. The number of patients exposed to the offending agents was obtained from data collected during the national survey of anesthesia practice. Results A total of 2516 patients was included. A diagnosis of IgE-mediated reaction was established in 1816 cases (72.18%). The most common causes were neuromuscular blocking agents ([NMBAs]; n = 1067; 58.08%), latex (n = 361; 19.65%), and antibiotics (n = 236; 12.85%). The median annual incidence per million procedures was higher for females 154.9 (5th-95th percentile, 117.2-193.1) than for males 55.4 (5th-95th percentile, 42.0-68.0). It reached 250.9 (5th-95th percentile, 189.8-312.9) for women in cases of allergic reactions to NMBAs. In children, a diagnosis of IgE-mediated reactions was obtained in 122 cases (45.9%). The most common causes were latex (n = 51; 41.8%), NMBAs (n = 39; 31.97%), and antibiotics (n = 11; 9.02%). In contrast with adults, no female predominance was observed. Conclusion The incidence of allergic reactions during anesthesia, estimated on a national basis, is higher than previously estimated. These results should be taken into account in the evaluation of the benefit-to-risk ratio of the various anesthetic techniques in individuals. The similar incidence of reactions according to sex before adolescence suggests a role for sex hormones in the increase of anaphylaxis observed in women.

Chronic rhinosinusitis: Epidemiology and medical management

Abstract: Chronic rhinosinusitis (CRS) affects 12.5% of the US population. On epidemiologic grounds, some association has been found between CRS prevalence and air pollution, active cigarette smoking, secondhand smoke exposure, perennial allergic rhinitis, and gastroesophageal reflux. The majority of pediatric and adult patients with CRS are immune competent. Data on genetic associations with CRS are still sparse. Current consensus definitions subclassify CRS into CRS without nasal polyposis (CRSsNP), CRS with nasal polyposis (CRSwNP), and allergic fungal rhinosinusitis (AFRS). Evaluation and medical management of CRS has been the subject of several recent consensus reports. The highest level of evidence for treatment for CRSsNP exists for saline lavage, intranasal steroids, and long-term macrolide antibiotics. The highest level of evidence for treatment of CRSwNP exists for intranasal steroids, systemic glucocorticoids, and topical steroid irrigations. Aspirin desensitization is beneficial for patients with aspirin-intolerant CRSwNP. Sinus surgery followed by use of systemic steroids is recommended for AFRS. Other modalities of treatment, such as antibiotics for patients with purulent infection and antifungal drugs for patients with AFRS, are potentially useful despite a lack of evidence from controlled treatment trials. The various modalities of medical treatment are reviewed in the context of recent consensus documents and the author's personal experience.

Rapid oral desensitization in combination with omalizumab therapy in patients with cow’s milk allergy

Abstract: To the Editor: We conducted a pilot phase I study in 11 children (age, 7-17 years) with cow’s milk allergy by using omalizumab (anti-IgE mAb; Xolair; Genentech, South San Francisco, Calif) in combination with relatively rapid oral milk desensitization. We hypothesized that oral desensitization might occur rapidly and with few side effects when performed with omalizumab. Our primary objectives were to examine the safety of this approach and to determine whether subjects could be dosed up to 2000 mg milk within 7 to 11 weeks of initiating the desensitization. Eleven patients with a history of IgE-mediated milk allergy were enrolled in the study at 2 sites—Children’s Hospital Boston and Stanford University—under institutional review board and US Food and Drug Administration approval. All subjects had histories of acute clinical reactions to milk, including immediate reactions (urticaria, vomiting, and/or anaphylaxis) after ingestion of milk, as well as elevated milk-specific IgE (median, 50 kilounits of antibody (kUA)/L; range, 41.6-342 kUA/L; Table I). At entry, the median wheal/flare skin prick test to milk was 20/50 mm (wheal/erythema diameter; range, 11-45/20-52 mm), and the median total serum IgE was 349 kU/L (range, 148-2593 kU/L). The median age was 8 years (range, 7-17 years). Seven subjects had a diagnosis of asthma and/or eczema. For children with IgE levels 700 kU/L, the dose was 225 to 300 mg (approximately 0.016 mg/kg/IgE [U/ mL]) every 2 to 4 weeks. During the course of the study, subjects were asked to exclude all dairy products from their diets except what was given as the study milk dose. TABLE I Characteristics of enrolled subjects Nine weeks after the start of omalizumab treatment, oral cow’s milk desensitization was performed in 2 phases. Rush oral desensitization occurred on the first day of desensitization, starting with 0.1 mg of milk powder (dried nonfat powdered cow’s milk, Carnation Instant Milk; Nestle, San Francisco, Calif), with doses every 30 minutes to a maximum dose of 1000 mg (cumulative dose, 1992 mg). One subject (subject 7; Table I) voluntarily discontinued the study because of abdominal migraines; eosinophilic esophagitis and other allergic disorders were ruled out. Nine of the 10 remaining subjects reached the 1000-mg dose on the first day of desensitization. However, 1 subject, subject 5 (Table I), after administration of the 1000-mg dose, received epinephrine for nasal obstruction and generalized urticaria refractory to diphenhydramine and cetirizine. Subject 8 reacted at the 7-mg dose on the first day. Desensitization with daily doses of milk continued in the 10 subjects, with weekly increases in the dose of milk over the next 7 to 11 weeks (all dose increases were given in the clinical research unit, and if the dose was tolerated, the dose was then given daily at home). During the study, subjects were asked to take the study milk dose on a full stomach and to half the study milk dose during a viral infection. Nine of the 10 patients reached the maximum daily dose of 2000 mg milk (the primary end point of the study); the subject who received epinephrine during the rush phase of desensitization achieved a daily dose of 1200 mg when the omalizumab was stopped (end of the weekly dose escalation phase, week 16). Omalizumab treatment was then discontinued at week 16, whereas daily oral milk was continued at home. A double-blind, placebo-controlled food challenge (DBPCFC) was performed 8 weeks later (week 24 of the study). The DBPCFC consisted of 5 doses (milk or placebo, eg, rice or soy beverage) administered orally every 15 minutes: 500 mg, 750 mg, 1000 mg, 2000 mg, and 3000 mg (cumulative dose, 7250 mg, equivalent to 220 mL milk). Allergic reactions occurring during the protocol were scored by using the system developed by Bock et al.1 All 9 patients who had reached a daily dose of 2000 mg passed the DBPCFC and an open challenge (for subjects taking their oral food challenge on the same day of the DBPCFC [n = 4], 4000 mg was given as the open challenge; for subjects taking their open challenge on the day after the DBPCFC [n = 5], 8000 mg was given). All 9 patients continued with daily milk ingestion >8000 mg/d, which included different types of milk products. In terms of overall safety, the mean frequency for total reactions reported by week 24 was 1.6% (32 reactions of 2199 doses total for all 11 subjects; Table II). All patients experienced some adverse events, though most reactions were defined as mild1 (1%) and needed no treatment. There were moderate reactions (0.3%), and these included abdominal pain and vomiting, which responded within 1 hour to oral antihistamine dosing. Severe reactions (0.1%) included swelling of the tongue in 1 subject during the initial rush desensitization day, which responded to oral antihistamines. Another subject developed rhinitis and urticaria after the 1000-mg dose during the rush desensitization and responded to epinephrine. The most common types of reactions were local (mostly pruritus or urticaria) and/ or gastrointestinal (eg, abdominal pain), occurring with a frequency of 1%. No reactions occurred that involved the cardiovascular system or that failed to respond rapidly to treatment. There were 2 other subjects who were given epinephrine at home by their guardians during the maintenance phase of dosing. One received epinephrine for a moderate reaction that was manifested by upper lip swelling and urticaria (7.5 cm × 5cm) on the left upper leg; the second received epinephrine for urticaria (2.5 cm × 5 cm) on the right upper arm. In addition, this subject had wheezing, which began before the milk ingestion that day, and which most likely was a result of a viral infection. Overall, the reaction rate in our study was relatively low given the rapidity of the desensitization, although the rate of epinephrine use was similar to that in previous desensitization studies. All subjects tolerated omalizumab treatment with no signs of allergic reactions. TABLE II Overall safety data Previous studies of slow, deliberate oral milk desensitization in patients with cow’s milk allergy showed that desensitization can increase the amount of milk tolerated by many of the treated subjects.2-6 We now show that milk desensitization can be performed relatively rapidly with minimal hospitalization time when combined with omalizumab treatment. The limitations of our study include the small sample size, the lack of a placebo group, and lack of a baseline oral food challenge. In addition, it is possible that our desensitization protocol with omalizumab might be further optimized by limiting the number of milk doses during the rush phase; by extending the dose escalation phase over a longer period, beyond the 7 to 11 weeks used in our current protocol; and by performing the DBPCFC 12 or more weeks after discontinuation of omalizumab. In summary, we demonstrated that omalizumab treatment combined with oral milk desensitization in children with clinical reactions to cow’s milk permitted rapid milk dose escalation in the majority of subjects. This study is the first to use omalizumab in combination with oral desensitization and demonstrates a potential value of this approach for the treatment of food allergy, a major public health problem,7-9 although it must be first confirmed by future phase II and III trials. Nine of the 11 patients achieved the primary objective, tolerating desensitization to a dose of 2000 mg/d within a period of 7 to 11 weeks. Moreover, 9 of the 10 patients who completed the study passed a DBPCFC and an open challenge of milk without symptoms. Importantly, the 9 patients, after passing the DBPCFC, began tolerating almost normal amounts of milk in their diet (≥240 mL, equivalent to ≥8000 mg/d). The tenth patient is tolerating 4000 mg/d.

Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of desensitization.

Abstract: Background There are no treatments currently available for peanut allergy. Sublingual immunotherapy (SLIT) is a novel approach to the treatment of peanut allergy. Objective We sought to investigate the safety, clinical effectiveness, and immunologic changes with SLIT in children with peanut allergy. Methods In this double-blind, placebo-controlled study subjects underwent 6 months of dose escalation and 6 months of maintenance dosing followed by a double-blind, placebo-controlled food challenge. Results Eighteen children aged 1 to 11 years completed 12 months of dosing and the food challenge. Dosing side effects were primarily oropharyngeal and uncommonly required treatment. During the double-blind, placebo-controlled food challenge, the treatment group safely ingested 20 times more peanut protein than the placebo group (median, 1,710 vs 85 mg; P = .011). Mechanistic studies demonstrated a decrease in skin prick test wheal size ( P = .020) and decreased basophil responsiveness after stimulation with 10 −2 μg/mL ( P = .009) and 10 −3 μg/mL ( P = .009) of peanut. Peanut-specific IgE levels increased over the initial 4 months ( P = .002) and then steadily decreased over the remaining 8 months ( P = .003), whereas peanut-specific IgG4 levels increased during the 12 months ( P = .014). Lastly, IL-5 levels decreased after 12 months ( P = .015). No statistically significant changes were found in IL-13 levels, the percentage of regulatory T cells, or IL-10 and IFN-γ production. Conclusion Peanut SLIT is able to safely induce clinical desensitization in children with peanut allergy, with evidence of immunologic changes suggesting a significant change in the allergic response. Further study is required to determine whether continued peanut SLIT is able to induce long-term immune tolerance.

A randomized, placebo-controlled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine–refractory chronic idiopathic urticaria

Abstract: Background Proof-of-concept studies with omalizumab in patients with chronic idiopathic urticaria (CIU) have shown significant decreases in mean urticaria activity scores (UASs). Objective We sought to evaluate the efficacy and safety of omalizumab in patients with CIU who remain symptomatic despite concomitant H 1 -antihistamine therapy. Methods This phase II, prospective, double-blind, placebo-controlled, dose-ranging study investigated omalizumab in patients aged 12 to 75 years in the United States and 18 to 75 years in Germany with a UAS over 7 days (UAS7) of 12 or greater despite antihistamine therapy. Patients were randomized 1:1:1:1 to receive a single subcutaneous dose of 75, 300, or 600 mg of omalizumab or placebo added to a stable dose of H 1 -antihistamine. The primary efficacy outcome was change from baseline to week 4 in UAS7. Patients were followed for an additional 12 weeks to monitor safety. Results Ninety patients from the United States or Germany were enrolled. Both the 300-mg omalizumab group (−19.9 vs −6.9, P P = .047) showed greater improvement versus the placebo group in UAS7. No meaningful difference was observed for the 75-mg omalizumab group. Similar results were seen for key secondary end points of weekly hive and itch scores. Onset of effect occurred after 1 to 2 weeks. Omalizumab was well tolerated, and the incidence of adverse events was similar across treatment groups. Conclusion This study demonstrated that a fixed dose of 300 or 600 mg of omalizumab provides rapid and effective treatment of CIU in patients who are symptomatic despite treatment with H 1 -antihistamines.

Pathogenesis of chronic rhinosinusitis: Inflammation

Abstract: Chronic rhinosinusitis (CRS) is a heterogeneous group of inflammatory diseases of the nasal and paranasal cavities either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP and CRSwNP are prevalent medical conditions associated with substantial impaired quality of life, reduced workplace productivity, and serious medical treatment costs. Despite recent research evidence that contributes to further unveiling the pathophysiology of these chronic airway conditions, the cause remains poorly understood and appears to be multifactorial. A diverse spectrum of alterations involving histopathology, inflammatory cell and T-cell patterns, remodeling parameters (eg, TGF-β), eicosanoid and IgE production, microorganisms, and epithelial barrier malfunctions is reported in the search to describe the pathogenesis of this heterogeneous group of upper airway diseases. Furthermore, novel evidence indicates considerable heterogeneity within the CRSwNP subgroup determining the risk of comorbid asthma. The characterization of specific disease subgroups is a challenging scientific and clinical task of utmost importance in the development of diagnostic tools and application of individualized treatments. This review focuses on recent evidence that sheds new light on our current knowledge regarding the inflammatory process of CRS to further unravel its pathogenesis.

Obesity and asthma, an association modified by age of asthma onset

Abstract: Background Studies of asthma phenotypes have identified obesity as a component of a group characterized by a high proportion of subjects with adult-onset asthma. However, whether age of asthma onset modifies the association between obesity and asthma is unknown. Objectives We sought to compare the associations between body mass index (BMI) categories with physiological, inflammatory, and clinical parameters across age of asthma onset phenotypes; and to compare the rate of BMI change in relation to asthma duration, by age of onset asthma phenotypes. Methods From the Severe Asthma Research Program, we defined age of asthma onset as early ( Results The study population consisted of 1049 subjects, and the median age for asthma onset was 10 years (interquartile range, 4-25 years); 48% had late-onset asthma (≥12 years of age), and 52% had early-onset asthma ( Conclusion Asthmatic subjects are differentially affected by obesity based on whether they had asthma early (