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Background: There is no accepted grading system classifying the severity of immediate reactions to drugs., Objective: The purpose of this article is to present a proposed grading system developed through the consensus of drug allergy experts from the United States Drug Allergy Registry (USDAR) Consortium., Methods: The USDAR investigators sought to develop a consensus severity grading system for immediate drug reactions that is applicable to clinical care and research., Results: The USDAR grading scale scores severity levels on a scale of 0 to 4. A grade of no reaction (NR) is used for patients who undergo challenge without any symptoms or signs, and it would confirm a negative challenge result. A grade 0 reaction is indicative of primarily subjective complaints that are commonly seen with both historical drug reactions and during drug challenges, and it would suggest a low likelihood of a true drug allergic reaction. Grades 1 to 4 meet the criteria for a positive challenge result and may be considered indicative of a drug allergy. Grade 1 reactions are suggestive of a potential immediate drug reaction with mild symptoms. Grade 2 reactions are more likely to be immediate drug reactions of moderate severity. Grade 3 reactions have features suggestive of a severe allergic reaction, whereas grade 4 reactions are life-threatening reactions such as anaphylactic shock and fatal anaphylaxis., Conclusion: This proposed grading schema for immediate drug reactions improves on prior schemata by being developed specifically for immediate drug reactions and being easy to implement in clinical and research practice., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Inborn errors of immunity are traditionally best known for enhancing susceptibility to infections. However, allergic inflammation, among other types of immune dysregulation, occurs frequently in patients with inborn errors of immunity. As such, the term primary atopic disorders (PADs) was recently coined to describe the group of heritable monogenic allergic disorders. It is becoming increasingly important for clinicians to recognize that allergic diseases such as food allergy, atopic dermatitis, and allergic asthma are expressions of misdirected immunity, and in patients who present with severe, early-onset, or coexisting allergic conditions, these can be indications of an underlying PAD. Identifying monogenic allergic disease through next-generation sequencing can dramatically improve outcomes by allowing the use of precision-based therapy targeting the patient's underlying molecular defect. It is therefore imperative that clinicians recognize PADs to be able to provide informed therapeutic options and improve patient outcomes. Here, we summarize the clinical features commonly seen with each of the currently known PADs, identify clinical warning signs that warrant assessment for PADs, and lastly, discuss the benefits of timely diagnosis and management of these conditions., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Electronic noses (eNoses) are emerging point-of-care tools that may help in the subphenotyping of chronic respiratory diseases such as asthma., Objective: We aimed to investigate whether eNoses can classify atopy in pediatric and adult patients with asthma., Methods: Participants with asthma and/or wheezing from 4 independent cohorts were included; BreathCloud participants (n = 429), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adults (n = 96), Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes pediatric participants (n = 100), and Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory Effects 2 participants (n = 30). Atopy was defined as a positive skin prick test result (≥3 mm) and/or a positive specific IgE level (≥0.35 kU/L) for common allergens. Exhaled breath profiles were measured by using either an integrated eNose platform or the SpiroNose. Data were divided into 2 training and 2 validation sets according to the technology used. Supervised data analysis involved the use of 3 different machine learning algorithms to classify patients with atopic versus nonatopic asthma with reporting of areas under the receiver operating characteristic curves as a measure of model performance. In addition, an unsupervised approach was performed by using a bayesian network to reveal data-driven relationships between eNose volatile organic compound profiles and asthma characteristics., Results: Breath profiles of 655 participants (n = 601 adults and school-aged children with asthma and 54 preschool children with wheezing [68.2% of whom were atopic]) were included in this study. Machine learning models utilizing volatile organic compound profiles discriminated between atopic and nonatopic participants with areas under the receiver operating characteristic curves of at least 0.84 and 0.72 in the training and validation sets, respectively. The unsupervised approach revealed that breath profiles classifying atopy are not confounded by other patient characteristics., Conclusion: eNoses accurately detect atopy in individuals with asthma and wheezing in cohorts with different age groups and could be used in asthma phenotyping., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Persistent childhood asthma is mainly atopy driven. However, limited data exist on the risk factors for childhood asthma phenotypes., Objective: We sought to identify risk factors at the first severe wheezing episode for current asthma 7 years later and separately for atopic and nonatopic asthma., Methods: One hundred twenty-seven steroid-naive children with the first severe wheezing episode (90% hospitalized/10% emergency department treated) were followed for 7 years. The primary outcome was current asthma at age 8 years, which was also analyzed separately as atopic and nonatopic asthma. Risk factors, including sensitization, viral cause, and other main asthma risk factors, were analyzed., Results: At study entry, median age was 11 months (interquartile range, 6-16 months); 17% were sensitized, and 98% were virus positive. Current asthma (n = 37) at 8 years was divided into atopic (n = 19) and nonatopic (n = 18) asthma. The risk factors for current atopic asthma at study entry were sensitization (adjusted odds ratio [OR], 12; P < .001), eczema (adjusted OR, 4.8; P = .014), and wheezing with rhinovirus (adjusted OR, 5.0; P = .035). The risk factors for nonatopic asthma were the first severe respiratory syncytial virus/rhinovirus-negative wheezing episode (adjusted OR, 8.0; P = .001), first wheezing episode at age less than 12 months (adjusted OR, 7.3; P = .007), and parental smoking (adjusted OR, 3.8; P = .028)., Conclusions: The data suggest diverse asthma phenotypes and mechanisms that can be predicted by using simple clinical markers at the time of the first severe wheezing episode. These findings are important for designing early intervention strategies for secondary prevention of asthma., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Disadvantaged urban children have high rates of allergic diseases and wheezing, which are diseases associated with type 2-biased immunity., Objective: We sought to determine whether environmental exposures in early life influence cytokine responses that affect the development of recurrent wheezing illnesses and allergic sensitization., Methods: A birth cohort of 560 urban families was recruited from neighborhoods with high rates of poverty, and 467 (83%) children were followed until 3 years of age. Cytokine responses were measured in blood cell samples obtained at birth (cord blood) and ages 1 and 3 years. Cytokine responses were examined in relation to personal characteristics and environmental exposures to allergens and endotoxin and to the development of allergic sensitization and recurrent wheeze assessed at age 3 years., Results: Cytokine responses generally increased with age, but responses at birth were poorly predictive for those at ages 1 and 3 years. Exposure to certain allergens (cockroach, mouse, dust mite) was significantly associated with enhanced cytokine responses at age 3 years, including IFN-α and IL-10 responses to certain stimulants and responses to phytohemagglutinin. Regarding the clinical outcomes, reduced LPS-induced IL-10 responses at birth were associated with recurrent wheeze. In contrast, reduced respiratory syncytial virus-induced IL-8 responses and increased 5'-cytosine-phosphate-guanine-3' (CpG)-induced IL-12p40 and allergen-induced IL-4 responses were associated with atopy., Conclusions: These findings suggest that diverse biologic exposures, including allergens and endotoxin, in urban homes stimulate the development of cytokine responses in early life, and that cytokine responses to specific microbial and viral stimuli are associated with the development of allergic sensitization and recurrent wheeze., (Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: The term atopic disorder is an early attempt to define specific endotypes of children with asthma, eczema, or both and increased IgE levels., Objective: We performed a longitudinal analysis of the relevance of the atopic endotype from birth to age 13 years., Methods: Allergic sensitization against 28 inhalant and food allergens was assessed at ½, 1½, 4, 6, and 13 years of age in 399 children from the Copenhagen Prospective Study on Asthma in Childhood2000 birth cohort by using both skin prick test responses and specific IgE levels. Asthma and eczema were diagnosed longitudinally by strictly adhering to predefined algorithms. Associations between allergic sensitization, asthma, and eczema were estimated by means of logistic regression, and a machine learning approach was used to identify temporal phenotype clusters of these traits., Results: Allergic sensitization showed no association with asthma through early childhood (0-6 years) when analyzed as any sensitization (odds ratio [OR] range, 0.78-1.29; P ≥ .48). However, at 13 years of age, any sensitization was associated with asthma (OR range, 4.02-5.94; all P < .001). In contrast, any sensitization was associated with eczema at ½, 1½, and 6 years of age (OR range, 2.06-6.02; P ≤ .01) and borderline associated at 4 years of age (OR, 1.61 [95% CI, 0.96-2.69]; P = .07) but not at 13 years of age (OR, 1.57 [95% CI, 0.78-3.16]; P = .21). We identified 4 latent patterns of disease development that were either dominated by sensitization (37%), eczema (26%), asthma (14%), or healthy status (24%)., Conclusion: We found very little interdependency between asthma, eczema, and allergic sensitization through childhood. The associations between those entities were strongly dependent on age, type of allergens, and method of testing for sensitization. Therefore, atopy in children is unlikely to represent a true endotype., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Late allergic reactions are common in the course of allergen-specific immunotherapy and even occur with allergy vaccines with reduced IgE reactivity., Objective: We sought to study atopy patch test (APT) reactions and T-cell responses to the recombinant birch pollen allergen Bet v 1 and recombinant hypoallergenic T-cell epitope-containing Bet v 1 fragments in patients with birch pollen allergy with and without atopic dermatitis (AD)., Methods: A clinical study was conducted in 15 patients with birch pollen allergy with AD (group 1), 5 patients with birch pollen allergy without AD (group 2), 5 allergic patients without birch pollen allergy (group 3), and 5 nonallergic subjects (group 4) by performing skin prick tests and APTs with rBet v 1 and hypoallergenic rBet v 1 fragments. T-cell, cutaneous lymphocyte antigen (CLA)(+) and CCR4(+) T-cell and cytokine responses were studied by thymidine uptake, carboxyfluorescein diacetate succinimidyl ester staining, and Luminex technology, respectively., Results: rBet v 1 and hypoallergenic rBet v 1 fragments induced APT reactions in not only most of the patients with birch pollen allergy with AD (11/15) but also in most of those without AD (4/5). Patients with birch pollen allergy with AD had higher Bet v 1-specific proliferation of CLA(+) and CCR4(+) T cells compared with patients with birch pollen allergy without AD. There were no differences in Bet v 1-specific CLA(+) and CCR4(+) proliferation and cytokine secretion in patients with and without APT reactions., Conclusion: Hypoallergenic rBet v 1 fragments induce T cell-dependent late reactions not only in patients with birch pollen allergy with AD but also in those without AD, which can be determined based on APT results but not based on in vitro parameters., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although most children with asthma and rhinitis are sensitized to aeroallergens, only a minority of sensitized children are symptomatic, implying the underlying operation of efficient anti-inflammatory control mechanisms., Objective: We sought to identify endogenous control mechanisms that attenuate expression of IgE-associated responsiveness to aeroallergens in sensitized children., Methods: In 3 independent population samples we analyzed relationships between aeroallergen-specific IgE and corresponding allergen-specific IgG (sIgG) and associated immunophenotypes in atopic children and susceptibility to asthma and rhinitis, focusing on responses to house dust mite and grass., Results: Among mite-sensitized children across all populations and at different ages, house dust mite-specific IgG/IgE ratios (but not IgG4/IgE ratios) were significantly lower in children with asthma compared with ratios in those without asthma and lowest among the most severely symptomatic. This finding was mirrored by relationships between rhinitis and antibody responses to grass. Depending on age/allergen specificity, 20% to 40% of children with allergen-specific IgE (sIgE) of 0.35 kU/L or greater had negative skin test responses, and these children also expressed the high sIgG/sIgE immunophenotype. sIgG1 from these children inhibited allergen-induced IgE-dependent basophil activation in a dose-dependent fashion. Profiling of aeroallergen-specific CD4(+) TH memory responses revealed positive associations between sIgG/sIgE ratios and IL-10-dependent gene signatures and significantly higher IL-10/TH2 cytokine (protein) ratios among nonsymptomatic children., Conclusion: In addition to its role in blocking TH2 effector activation in the late-phase allergic response, IL-10 is a known IgG1 switch factor. We posit that its production during allergen-induced memory responses contributes significantly to attenuation of inflammation through promoting IgG1-mediated damping of the FcεRI-dependent acute-phase reaction. sIgG1/sIgE balance might represent a readily accessible therapeutic target for asthma/rhinitis control., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Local allergic rhinitis (LAR) is a common disease that affects 25.7% of the rhinitis population and more than 47% of patients previously diagnosed with nonallergic rhinitis. Whether LAR is the first step in the natural history of allergic rhinitis (AR) with systemic atopy or a consistent entity is unknown., Objective: The aim was to evaluate the natural history of a population with LAR of recent onset and the development of AR and asthma., Methods: A prospective 10-year follow-up study with initial cohorts of 194 patients with LAR of recent onset and 130 healthy controls is being undertaken. A clinical-demographic questionnaire, spirometry, skin prick test, and specific IgE to aeroallergens were done yearly. Nasal allergen provocation tests with Dermatophagoides pteronyssinus, Alternaria alternata, Olea europea, and a mix of grass pollen were performed at baseline and after 5 years., Results: At disease onset, most of the patients with LAR had moderate-to-severe persistent-perennial rhinitis; conjunctivitis and asthma were the main comorbidities (51.1% and 18.8%, respectively), and D pteronyssinus was the most relevant aeroallergen (51.1%). After 5 years of follow-up, a worsening of rhinitis was detected in 26.2%, with an increase in symptom persistence and severity, and new associations with conjunctivitis and asthma. Atopy was detected by skin prick test and/or serum specific-IgE in patients with LAR (6.81%) and in controls (4.5%)., Conclusions: This study shows a similar rate of development of systemic atopy in LAR and controls, which suggests that LAR is an entity well differentiated from AR. To determine the natural course of LAR more precisely, this study is in progress to complete 10 years of follow-up., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: European cross-sectional studies have suggested that prenatal and postnatal farm exposure decreases the risk of allergic diseases in childhood. Underlying immunologic mechanisms are still not understood but might be modulated by immune-regulatory cells early in life, such as regulatory T (Treg) cells., Objective: We sought to assess whether Treg cells from 4.5-year-old children from the Protection against Allergy: Study in Rural Environments birth cohort study are critical in the atopy and asthma-protective effect of farm exposure and which specific exposures might be relevant., Methods: From 1133 children, 298 children were included in this study (149 farm and 149 reference children). Detailed questionnaires until 4 years of age assessed farming exposures over time. Treg cells were characterized as upper 20% CD4(+)CD25(+) forkhead box protein 3 (FOXP3)(+) (intracellular) in PBMCs before and after stimulation (with phorbol 12-myristate 13-acetate/ionomycin or LPS), and FOXP3 demethylation was assessed. Atopic sensitization was defined by specific IgE measurements; asthma was defined by a doctor's diagnosis., Results: Treg cells were significantly increased in farm-exposed children after phorbol 12-myristate 13-acetate/ionomycin and LPS stimulation. Exposure to farm milk was defined as a relevant independent farm-related exposure supported by higher FOXP3 demethylation. Treg cell (upper 20% CD4(+)CD25(+), FOXP3(+) T cells) numbers were significantly negatively associated with doctor-diagnosed asthma (LPS stimulated: adjusted odds ratio, 0.26; 95% CI, 0.08-0.88) and perennial IgE (unstimulated: adjusted odds ratio, 0.21; 95% CI, 0.08-0.59). Protection against asthma by farm milk exposure was partially mediated by Treg cells., Conclusions: Farm milk exposure was associated with increased Treg cell numbers on stimulation in 4.5-year-old children and might induce a regulatory phenotype early in life, potentially contributing to a protective effect for the development of childhood allergic diseases., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors., Objective: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma., Methods: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models., Results: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62-5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[β] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[β] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin., Conclusions: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

This parameter was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "Environmental assessment and remediation: a practice parameter." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single person, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC)., (Published by Mosby, Inc.)

Background: Childhood wheezing and asthma vary greatly in clinical presentation and time course. The extent to which phenotypic variation reflects heterogeneity in disease pathways is unclear., Objective: We sought to assess the extent to which single nucleotide polymorphisms (SNPs) associated with childhood asthma in a genome-wide association study are predictive of asthma-related phenotypes., Methods: In 8365 children from a population-based birth cohort, the Avon Longitudinal Study of Parents and Children, allelic scores were derived based on between 10 and 215,443 SNPs ranked according to the inverse of the P value for their association with physician-diagnosed asthma in an independent genome-wide association study (6176 cases and 7111 control subjects). We assessed the predictive value of allelic scores for asthma-related outcomes at age 7 to 9 years (physician's diagnosis, longitudinal wheezing phenotypes, and measurements of pulmonary function, bronchial responsiveness, and atopy)., Results: Scores based on the 46 highest-ranked SNPs were associated with the symptom-based phenotypes early onset persistent wheeze (P< 10(-11); area under the receiver operating characteristic curve [AUC], 0.59) and intermediate-onset wheeze (P< 10(-3); AUC, 0.58). Among lower-ranked SNPs (ranks, 21,545-46,416), there was evidence for associations with diagnosed asthma (P< 10(-4); AUC, 0.54) and atopy (P< 10(-5); AUC, 0.55). We found little evidence of associations with transient early wheezing, reduced pulmonary function, or nonasthma phenotypes., Conclusion: The genetic origins of asthma are diverse, and some pathways are specific to wheezing syndromes, whereas others are shared with atopy and bronchial hyperresponsiveness. Our study also provides evidence of etiologic differences among wheezing syndromes., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Specific IgE (sIgE) antibodies to both bee and wasp venom can be due to a sensitivity to both insect venoms or due to cross-reactive carbohydrate determinants (CCDs)., Objective: Investigating whether a basophil activation test (BAT) with both venoms as well as with bromelain and horseradish peroxidase (HRP) or recombinant allergen-based IgE testing can improve the diagnostic procedure., Methods: Twenty-two Hymenoptera-venom allergic patients with sIgE antibodies to both bee and wasp venom were studied. sIgE antibodies to MUXF3 CCD, bromelain, HRP, rApi m 1, and rVes v 5 were determined, and a BAT (Flow2 CAST) with venom extracts, bromelain, and HRP was performed. Further recombinant allergen-based IgE testing was done by using an ELISA, if required. The reactivity of basophils was calculated from the insect venom concentration at half-maximum stimulation., Results: Double positivity/double negativity/single positivity to rApi m 1 and rVes v 5 was seen in 12/1/9 patients. Further recombinant allergen-based IgE testing in the last ones revealed positive results to the other venom in all cases except one. BAT was double positive/double negative/single positive in 6/2/14 patients. Four patients with negative results in sIgE antibodies to CCDs had positive results in BAT. BAT with bromelain/HRP showed a sensitivity of 50%/81% and a specificity of 91%/90%., Conclusion: Component-resolved IgE testing elucidates the pattern of double positivity, showing a majority of true double sensitizations independent of CCD sensitization. BAT seems to add more information about the culprit insect even if the true clinical relevance of BAT is not completely determined because of ethical limitations on diagnostic sting challenges. BAT with HRP is a good method to determine sensitivity to CCDs., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects., Objective: National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies., Methods: We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011., Results: Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures., Conclusion: The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories., (Published by Mosby, Inc.)

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., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Sex-related differences in bronchial hyperresponsiveness (BHR) have been reported in adolescents, but the mechanisms remain obscure., Objective: To investigate the risk factors for BHR in the Raine Study, a community-based longitudinal birth cohort., Methods: At 14 years of age, children underwent a respiratory assessment including a questionnaire, lung function testing, methacholine challenge, and determination of atopic status., Results: A total of 1779 children provided data for assessment, with 1510 completing lung function and methacholine challenge testing. Current asthma was present in 152 (10.4%), 762 (50.5%) were atopic, and 277 (18.6%) had BHR. BHR was more common in girls, whereas atopy was more common in boys, with no sex differences in asthma or current wheeze. Independent risk factors for BHR were being female (odds ratio [OR], 3.45; P < .001), atopy at 14 years (OR, 1.27; P = .004), and current asthma (OR, 2.15; P = .005). Better lung function was protective against BHR (forced expiratory flow between 25% and 75% of forced vital capacity/forced vital capacity, OR, 0.09; P < .001). Risk factors differed with sex and atopic status. Early-life factors were generally not independent risk factors for BHR at 14 years of age, with the exception of being smaller at birth in boys (birth length, OR, 6 × 10(-9); P = .017) and maternal asthma in girls (OR, 1.84; P = .041). Current asthma was not a risk for BHR in nonatopic children., Conclusion: Bronchial hyperresponsiveness was more common and more severe in girls. These differences could not be explained by differences in lung function or atopic status., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Asthma prevalence varies widely among neighborhoods within New York City. Exposure to mouse and cockroach allergens has been suggested as a cause., Objective: To test the hypotheses that children living in high asthma prevalence neighborhoods (HAPNs) would have higher concentrations of cockroach and mouse allergens in their homes than children in low asthma prevalence neighborhoods (LAPNs), and that these exposures would be related to sensitization and asthma., Methods: In the New York City Neighborhood Asthma and Allergy Study, a case-control study of asthma, children 7 to 8 years old from HAPNs (n = 120) and LAPNs (n = 119) were recruited through the same middle-income health insurance plan. Children were classified as asthma cases (n = 128) or controls without asthma (n = 111) on the basis of reported symptoms or medication use. Allergens were measured in bed dust., Results: HAPN homes had higher Bla g 2 (P = .001), Mus m 1 (P = .003), and Fel d 1 (P = .003) and lower Der f 1 (P = .001) than LAPN homes. Sensitization to indoor allergens was associated with asthma, but relevant allergens differed between LAPNs and HAPNs. Sensitization to cockroach was more common among HAPN than LAPN children (23.7% vs 10.8%; P = .011). Increasing allergen exposure was associated with increased probability of sensitization (IgE) to cockroach (P < .001), dust mite (P = .009), and cat (P = .001), but not mouse (P = .58) or dog (P = .85)., Conclusion: These findings further demonstrate the relevance of exposure and sensitization to cockroach and mouse in an urban community and suggest that cockroach allergen exposure could contribute to the higher asthma prevalence observed in some compared with other New York City neighborhoods., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Exposure to solid food or cow's milk (complementary food) before age 4 months may confer immune protection (tolerance) or detriment (allergy)., Objective: We explored the relationship between introduction of complementary food <4 months and IgE to egg, milk, and peanut allergen at 2 years in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study birth cohort of Detroit, Mich., Methods: At infant ages 1, 6, and 12 months, mothers were interviewed about feeding practices. Blood samples were collected at age 2 to 3 years to assess sensitization (IgE ≥ 0.35 IU/mL) to egg, milk, or peanut., Results: For the 594 maternal-infant pairs analyzed, maternal mean age was 29.7 years, and 60.6% self-reported as African American or black. Infant exposure to complementary food <4 months was reported by 39.7% of mothers. IgE ≥0.35 IU/mL for egg, milk, or peanut allergen at age 2 years was observed in 23.9% (95% CI, 20.5% to 27.6%), 30.6% (26.9% to 34.5%), and 11.4% (8.9% to 14.3%) of children, respectively. The association between early feeding and sensitization was modified by parental history of asthma or allergy. In multivariable analysis, early feeding reduced the risk of peanut sensitization among children with a parental history (adjusted odds ratio, 0.2 [95% CI, 0.1-0.7]; P = .007). The relationship also became significant for egg when a cutoff for IgE of ≥0.70 IU/mL was used (adjusted odds ratio, 0.5 [95% CI, 0.3-0.9]; P = .022)., Conclusion: In this cohort, complementary food introduced <4 months was associated with a reduced risk of peanut (and perhaps egg) sensitization by age 2 to 3 years, but only for children with a parental history of asthma or allergy., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Studies on airway inflammation, measured as fraction of exhaled nitric oxide (FENO), have focused on its relation to control of asthma, but the contribution of allergen exposure to the increase in FENO levels is unknown., Objective: We evaluated (1) whether FENO levels were increased in children with allergic sensitization or asthma; (2) whether specific allergen exposure increased FENO levels in sensitized, but not unsensitized, children; and (3) whether sedentary behavior increased FENO levels independent of allergen exposures., Methods: At age 12 years, in a birth cohort of children with a parental history of allergy or asthma, we measured bed dust allergen (dust mite, cat, and cockroach) by means of ELISA, specific allergic sensitization primarily based on specific IgE levels, and respiratory disease (current asthma, rhinitis, and wheeze) and hours of television viewing/video game playing by means of questionnaire. Children performed spirometric maneuvers before and after bronchodilator responses and had FENO levels measured by using electrochemical detection methods (NIOX MINO)., Results: FENO levels were increased in children with current asthma (32.2 ppb), wheeze (27.0 ppb), or rhinitis (23.2 ppb) compared with subjects without these respective symptoms/diagnoses (16.4-16.6 ppb, P < .005 for all comparisons). Allergic sensitization to indoor allergens (cat, dog, and dust mite) predicted higher FENO levels and explained one third of the variability in FENO levels. FENO levels were highest in children both sensitized and exposed to dust mite. Greater than 10 hours of weekday television viewing was associated with a 0.64-log increase in FENO levels after controlling for indoor allergen exposure, body mass index, and allergic sensitization., Conclusion: Allergen exposures and sedentary behavior (television viewing/video game playing) might increase airway inflammation, which was measured as the FENO., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

T(H)2 immune responses are required for the 2 fundamental pathological processes characteristic of allergic disease: IgE-mediated hypersensitivity and eosinophilic inflammation. The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology. The recent explosion of T(H) subpopulations combined with the wide availability of polychromatic cytokine staining has facilitated the discovery of T(H)2 lineage heterogeneity. In this article we review T(H)2 heterogeneity and ask the following question: At what point do these subpopulations graduate from in vitro curiosities to immunologically robust therapeutic targets? We propose criteria to establish a T-cell subset as a biologically relevant entity and address the evidence to support these T(H)2 subpopulations having a unique function or specific contribution to allergic pathology or host defense., (Published by Mosby, Inc.)

Background: The identification of the disease-causing insect in venom allergy is often difficult., Objective: To establish recombinant allergen-based IgE tests to diagnose bee and yellow jacket wasp allergy., Methods: Sera from patients with bee and/or wasp allergy (n = 43) and patients with pollen allergy with false-positive IgE serology to venom extracts were tested for IgE reactivity in allergen extract-based tests or with purified allergens, including nonglycosylated Escherichia coli-expressed recombinant (r) Api m 1, rApi m 2, rVes v 5, and insect cell-expressed, glycosylated rApi m 2 as well as 2 natural plant glycoproteins (Phl p 4, bromelain)., Results: The patients with venom allergy could be diagnosed with a combination of E coli-expressed rApi m 1, rApi m 2, and rVes v 5 whereas patients with pollen allergy remained negative. For a group of 29 patients for whom the sensitizing venom could not be identified with natural allergen extracts, testing with nonglycosylated allergens allowed identification of the sensitizing venom. Recombinant nonglycosylated allergens also allowed definition of the sensitizing venom for those 14 patients who had reacted either with bee or wasp venom extracts. By IgE inhibition studies, it is shown that glycosylated Api m 2 contains carbohydrate epitopes that cross-react with natural Api m 1, Ves v 2, natural Phl p 4, and bromelain, thus identifying cross-reactive structures responsible for serologic false-positive test results or double-positivity to bee and wasp extracts., Conclusion: Nonglycosylated recombinant bee and wasp venom allergens allow the identification of patients with bee and wasp allergy and should facilitate accurate prescription of venom immunotherapy., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

IgE, mast cells, basophils, and eosinophils are essential components of allergic inflammation. Antigen-specific IgE production, with subsequent fixation of IgE to FcepsilonRI receptors on mast cells and basophils, is central to the initiation and propagation of immediate hypersensitivity reactions. Mast cells, basophils, and eosinophils are central effector cells in allergic inflammation, as well as in innate and adaptive immunity. This review highlights what is known about these components and their roles in disease pathogenesis., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Clinical laboratory analyses aid in the diagnosis and management of human allergic (IgE-dependent) diseases. Diagnosis of immediate-type hypersensitivity begins with a thorough clinical history and physical examination. Once symptoms compatible with an allergic disorder have been identified, a skin test, blood test, or both for allergen-specific IgE antibodies provide confirmation of sensitization, which strengthens the diagnosis. Skin testing provides a biologically relevant immediate-type hypersensitivity response with resultant wheal-and-flare reactions within 15 minutes of allergen application. Allergen-specific IgE antibody in serum is quantified by using 3 laboratory-based autoanalyzers (ImmunoCAP, Immulite, and HYTEC-288) and novel microarray and lateral-flow immunoassays. Technologic advances in serologic allergen-specific IgE measurements have involved increased automation, with enhanced reproducibility, greater quantification, lower analytic sensitivity, and component-supplemented extract-based allergen use. In vivo provocation tests involving inhalation, ingestion, or injection of allergens serve to clarify discordant history and skin- or blood-based measures of sensitization. Other diagnostic allergy laboratory analyses include total and free serum IgE measurement, precipitating IgG antibodies specific for organic dusts, mast cell tryptase, and indicator allergen analyses to assess indoor environments to promote patient-targeted allergen avoidance programs. A critique is provided on the predictive utility of serologic measures of specific IgE for food allergy and asthma. Reasons for the lack of clinical utility for food-specific IgG/IgG4 measurements in allergy diagnosis are examined. When the specific IgE measures are inconsistent with the clinical history, they should be confirmed by means of repeat and alternative method analysis. Ultimately, the patient's clinical history remains the principal arbiter that determines the final diagnosis of allergic disease., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Adverse immune responses to foods affect approximately 5% of young children and 3% to 4% of adults in westernized countries and appear to have increased in prevalence. Food-induced allergic reactions are responsible for a variety of symptoms and disorders involving the skin and gastrointestinal and respiratory tracts and can be attributed to IgE-mediated and non-IgE-mediated (cellular) mechanisms. Genetic disposition and environmental factors might abrogate oral tolerance, leading to food allergy. Disease outcomes are influenced by the characteristics of the immune response and of the triggering allergen. Diagnosis is complicated by the observation that detection of food-specific IgE (sensitization) does not necessarily indicate clinical allergy. Therefore diagnosis requires a careful medical history, laboratory studies, and, in many cases, an oral food challenge to confirm a diagnosis. Novel diagnostic methods, including ones that focus on immune responses to specific food proteins or epitopes of specific proteins, are under study. Currently, management of food allergies consists of educating the patient to avoid ingesting the responsible allergen and to initiate therapy (eg, with injected epinephrine for anaphylaxis) in case of an unintended ingestion. Improved therapeutic strategies under study include oral and sublingual immunotherapy, Chinese herbal medicine, anti-IgE antibodies, and modified vaccines., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: We reported an increased risk of serious pneumococcal disease (SPD) among patients with asthma. It is not known whether this is true for patients with other atopic conditions., Objective: To determine the relationship between atopic conditions other than asthma and SPD., Methods: The study subjects were residents of Rochester, Minn, who developed SPD between 1964 and 1983 and their 2 sex-matched and age-matched controls. We used a population-based computer-linked medical diagnosis system to identify all individuals with potential SPD. All records were reviewed by using explicit predetermined criteria for SPD. All individuals with atopic conditions were identified by the physician diagnoses including atopic dermatitis or eczema, allergic rhinitis, and hay fever documented in medical records. The associations between these atopic conditions and SPD were assessed by using conditional logistic regression., Results: A total of 3941 records were reviewed, and we identified 174 SPD cases. Of these 174 cases, 50.6% were male, and 94.3% were Caucasian. Twenty-six (14.9%) of the SPD cases and 29 (8.3%) of the controls had atopy. Atopic conditions other than asthma were associated with an increased risk of SPD (odds ratio, 2.13; 95% CI, 1.04-4.35; P = .04) after adjusting for smoking status, previous high-risk conditions for SPD, educational status, and ethnicity., Conclusion: Like asthma, other atopic conditions, particularly atopic dermatitis, are associated with an increased risk of SPD. There may be a common immunogenetic mechanism underlying increased risk of SPD among individuals with either asthma or other atopic conditions. Our study findings need to be studied further., (Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood., Objective: To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children., Methods: Children at high risk of asthma and other allergic diseases because of parental history were enrolled at birth and followed prospectively. FeNO was measured by an online technique at ages 6 and 8 years. Relationships among FeNO, various atopic characteristics, and asthma were evaluated., Results: Reproducible FeNO measurements were obtained in 64% (135/210) of 6-year-old and 93% (180/194) of 8-year-old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at ages 6 and 8 years had increased levels of FeNO compared with those not sensitized (geometric mean; 6 years, 10.9 vs 6.7 parts per billion [ppb], P < .0001; 8 years, 14.6 vs 7.1 ppb, P < .0001). FeNO was higher in children with asthma than in those without asthma at 8 years but not 6 years of age (6 years, 9.2 vs 8.3 ppb, P = .48; 8 years, 11.5 vs 9.2 ppb, P = .03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallergen sensitization (P = .33). There were no correlations between FeNO and spirometric indices at 6 or 8 years of age., Conclusion: These findings underscore the importance of evaluating allergen sensitization status when FeNO is used as a potential biomarker in the diagnosis and/or monitoring of atopic diseases, particularly asthma.

Background: Null mutations within the filaggrin gene (FLG) are associated with moderate-to-severe atopic eczema; their role in mild-to-moderate eczema in the general population is unknown., Objective: We sought to investigate the significance of 5 common FLG null mutations in childhood atopic eczema in an unselected population cohort., Methods: Eight hundred eleven English children aged 7 to 9 years were screened for FLG mutations. Eczema cases were defined by using United Kingdom diagnostic criteria and skin examination. Asthma and seasonal rhinitis cases were defined by parental questionnaire. Association between phenotype and genotype was investigated using Fisher exact test and logistic regression analysis., Results: The 12-month period prevalence of atopic eczema was 24.2% (95% CI, 21.2% to 27.2%), with 96% (115/120) of cases having mild-to-moderate disease. The combined null genotype (carriage of > or = 1 FLG mutations) was significantly associated with atopic eczema (P = 1.2 x 10(-4)). The odds ratio (OR) for individuals carrying 2 null mutations was 26.9 (95% CI, 3.3-217.1), but heterozygote carriers showed no significant increase in risk (OR, 1.2; 95% CI, 0.7-1.9). Eight of 190 eczema cases (4.2%) carried 2 FLG null mutations and thus might be attributed to filaggrin deficiency. Asthma in the context of eczema showed significant association with the FLG null mutations (P = 7.1 x 10(-4)). There was no association of FLG with asthma independent of eczema (P = .15) and no association with seasonal rhinitis (P = .66)., Conclusion: FLG null mutations are significantly associated with mild-to-moderate atopic eczema in childhood, with a recessive pattern of inheritance.

Background: Atopic disease is a major health problem. Mutations in the filaggrin gene (FLG) confer major susceptibility to eczema and related asthma., Objective: We sought to determine the natural history and burden of atopic disease conferred by the 2 most common FLG mutations in a large, population-based birth cohort study., Methods: We analyzed the effect of the most common null alleles (R501X and 2282del4) on several atopic phenotypes in a cohort of approximately 7000 English children born in 1990-1991., Results: FLG null alleles associated strongly with eczema; eczema associated with these mutations presents in early life and is more persistent (hazard ratio for eczema resolution for those with FLG mutations to FLG wild type, 0.67; 95% CI, 0.58-0.77; P = 5 x 10(-8)). FLG mutations conferred a population asthma risk of 1.80 (95% CI, 1.34-2.41; P = .00019); asthma risk was especially high in the context of eczema (odds ratio, 3.16; 95% CI, 2.25-4.43; P = 1.4 x 10(-11)). Strong associations were identified with sensitization to grass, house dust mite, and cat dander and sensitization to multiple allergens (odds ratio, 2.12; 95% CI, 1.03-4.37; P = 5.42 x 10(-27))., Conclusion: FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. They confer risk of a particular trajectory for eczema, with increased duration of disease and greater risk of asthma and multiple allergic sensitizations. FLG alleles help define the risk profile of children with eczema and help define the "eczema plus early wheeze" and "eczema plus asthma" phenotypes.

Background: GATA3 activates transcription of the T(H)2 cytokines, including IL13, an important step in the allergic inflammatory pathway., Objective: We sought to identify associations of single nucleotide polymorphisms of the genes GATA3 and IL13 and their interactions with rhinitis and allergic sensitization during childhood., Methods: We performed genetic association studies in a cohort of children (n = 923) who have been evaluated for the development of rhinitis and allergic sensitization by means of skin prick tests (SPTs) at age 10 years. Pyrosequencing was used to genotype 7 polymorphisms from GATA3 and 5 from IL13. A novel model-selection procedure combining logistic regression models and classification was used to study the contributions of the polymorphisms and their interactions., Results: Combinations of polymorphisms and their interactions increase the risk for rhinitis and allergic sensitization at age 10 years. A model with rs1058240, rs379568, and rs4143094 (GATA3) and rs1800925 (IL13) and their interactions was selected to predict rhinitis and positive SPT responses. rs1058240 was associated with rhinitis and allergic rhinitis (P < .05), and the gene-gene interaction rs1058240:rs1800925 was associated with rhinitis (P = .043). The odds ratios for 4 genotype combinations were significant for rhinitis or SPTs (P < .044)., Conclusion: Gene-gene interaction between GATA3 and IL13 polymorphisms can influence the risk of childhood rhinitis. Our study suggests that set associations of polymorphisms are important in studying genetic associations for complex phenotypes, such as rhinitis and atopy.

Background: Cigarette smoke has immunosuppressant effects, but its effect on allergic sensitization is unclear., Objective: To investigate associations between parental and personal smoking and skin prick tests (SPTs) for atopy in a population-based birth cohort of 1037 participants followed to adulthood., Methods: Parental history of atopic disease, parental smoking, and personal smoking were obtained at multiple assessments between birth and age 32 years. Atopy was assessed by SPTs for 11 common inhaled allergens at ages 13 and 32 years., Results: Children of atopic parents were less likely to have positive SPTs at age 13 years if either parent smoked (odds ratio, 0.55; P = .009). This association was not significant after adjusting for breast-feeding history, number of siblings, and childhood socioeconomic status. Subjects with atopic parents were also less likely to develop positive results to SPTs between ages 13 and 32 years if they smoked themselves (odds ratio, 0.18; P < .001). This reduction in risk remained significant after adjusting for multiple potential confounding factors. Neither parental nor personal smoking was significantly associated with allergic sensitization among subjects whose parents did not have a history of atopic disease. Few of those with positive SPT results at age 13 years had negative tests at age 32 years, and there was no evidence that this was influenced by smoking., Conclusion: Personal and parental smoking is associated with a reduced risk of allergic sensitization in people with a family history of atopy.

Background: Maternal history of asthma or atopy is among the most consistently reported risk factors for asthma and atopy in children, yet the molecular basis for this observation remains unclear. Mitochondria are inherited exclusively through the maternal line, raising the possibility that sequence variation in the mitochondrial genome contributes to the pathogenesis of asthma and atopy., Objective: We set out to determine whether common European mitochondrial haplogroups are associated with asthma-related atopic phenotypes., Methods: We studied 654 self-reported white children age 5 to 12 years with mild to moderate asthma participating in the Childhood Asthma Management Program. Eight haplogroup-tagging polymorphisms were genotyped with TaqMan probe hybridization assays, and mitochondrial haplogroup tests of association with asthma-related and atopy-related phenotypes were performed with haplo.stats., Results: We found significant evidence of mitochondrial haplogroup association with total serum IgE levels (global significance, P = .04), with carriers of European haplogroup U (frequency 11%) having higher total serum IgE levels (median level, 684 IU/L) compared with noncarriers (389 IU/L; P = .001). Haplogroup U carriers also had trends of greater skin prick test reactivity (P = .03) and higher frequency of atopic dermatitis (P = .07), although global haplogroup tests for these later 2 phenotypes were not significant at an alpha level of 0.05., Conclusion: These data are the first to suggest that common mitochondrial haplogroups influence the atopic diathesis., Clinical Implications: These findings may provide a molecular explanation for the prominent influence of maternal history of atopy on the development of atopy in offspring.