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Epidemiologic and cross-sectional studies suggest that early life farming and animal exposures are associated with major health benefits, influencing immune development and modifying the subsequent risk of allergic diseases, including asthma. The Wisconsin Infant Study Cohort (WISC) study was established in central Wisconsin to test the hypothesis that early life animal farm exposures are associated with distinct innate immune cell maturation trajectories, decreased allergen sensitization and reduced respiratory viral illness burden during the first 2 years of life. Beginning in 2013, a total of 240 families have been enrolled, 16,522 biospecimens have been collected, and 4098 questionnaires have been administered and entered into a secure database. Study endpoints include nasal respiratory virus identification and respiratory illness burden score, allergic sensitization, expression of allergic disease, and anti-viral immune response maturation and profiles. The WISC study prospective design, broad biospecimen collections, and unique US rural community will provide insights into the role of environmental exposures on early life immune maturation profiles associated with protection from allergic sensitization and significant respiratory viral disease burden. The WISC study findings will ultimately inform development of new strategies to promote resistance to severe respiratory viral illnesses and design primary prevention approaches for allergic diseases for all infants.

Background: Biomarkers, preferably noninvasive, that predict asthma inception in children are lacking., Objective: Little is known about biomarkers of type 2 inflammation in early life in relation to asthma inception. We evaluated aeroallergen sensitization, peripheral blood eosinophils, and serum periostin as potential biomarkers of asthma in children., Methods: Children enrolled in the Childhood Origins of ASThma study were followed prospectively from birth. Blood samples were collected at ages 2, 4, 6, and 11 years, and serum-specific IgE levels, blood eosionophil counts, and periostin levels were measured in 244 children. Relationships among these biomarkers, age, and asthma were assessed., Results: Serum periostin levels were approximately 2- to 3-fold higher in children than previously observed adult levels. Levels were highest at 2 years (145 ng/mL), and did not change significantly between 4 and 11 years (128 and 130 ng/mL). Age 2 year periostin level of 150 ng/mL or more predicted asthma at age 6 years (odds ratio [OR], 2.3; 95% CI, 1.3-4.4). Eosinophil count of 300 cells/μL or more and aeroallergen sensitization at age 2 years were each associated with increased risk of asthma at age 6 years (OR, 3.1; 95% CI, 1.7-6.0 and OR, 3.3; 95% CI, 1.7-6.3). Children with any 2 of the biomarkers had a significantly increased risk of developing asthma by school age (≥2 biomarkers vs none: OR, 6.6; 95% CI, 2.7-16.0)., Conclusions: Serum periostin levels are significantly higher in children than in adults, likely due to bone turnover, which impairs clinical utility in children. Early life aeroallergen sensitization and elevated blood eosinophils are robust predictors of asthma development. Children with evidence of activation of multiple pathways of type 2 inflammation in early life are at greatest risk for asthma development., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Early life rhinovirus (RV) wheezing illnesses and aeroallergen sensitization increase the risk of asthma at school age. Whether these remain risk factors for the persistence of asthma out to adolescence is not established., Objective: We sought to define the relationships among specific viral illnesses and the type and timing of aeroallergen sensitization with the persistence of asthma into adolescence., Methods: A total of 217 children were followed prospectively from birth to age 13 years. The etiology and timing of viral wheezing illnesses during the first 3 years of life were assessed along with patterns of allergen sensitization. The associations between viral wheezing illnesses, presence and pattern of aeroallergen sensitization, and asthma diagnosis at age 13 years were evaluated., Results: When adjusted for all viral etiologies, wheezing with RV (odds ratio = 3.3; 95% CI, 1.5-7.1), but not respiratory syncytial virus (odds ratio = 1.0; 95% CI, 0.4-2.3), was associated with asthma at age 13 years. Age of aeroallergen sensitization also influenced asthma risk; 65% of children sensitized by age 1 year had asthma at age 13 years, compared with 40% of children not sensitized at age 1 year but sensitized by age 5 years, and 17% of children not sensitized at age 5 years. Early life aeroallergen sensitization and RV wheezing had additive effects on asthma risk at adolescence., Conclusions: In a high-risk birth cohort, the persistence of asthma at age 13 years was most strongly associated with outpatient wheezing illnesses with RV and aeroallergen sensitization in early life., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Viral respiratory infections can cause acute wheezing illnesses in children and exacerbations of asthma., Objective: We sought to identify variation in genes with known antiviral and pro-inflammatory functions to identify specific associations with more severe viral respiratory illnesses and the risk of virus-induced exacerbations during the peak fall season., Methods: The associations between genetic variation at 326 SNPs in 63 candidate genes and 10 phenotypes related to viral respiratory infection and asthma control were examined in 226 children enrolled in the RhinoGen study. Replication of asthma control phenotypes was performed in 2128 children in the Copenhagen Prospective Study on Asthma in Childhood (COPSAC). Significant associations in RhinoGen were further validated using virus-induced wheezing illness and asthma phenotypes in an independent sample of 122 children enrolled in the Childhood Origins of Asthma (COAST) birth cohort study., Results: A significant excess of P values smaller than 0.05 was observed in the analysis of the 10 RhinoGen phenotypes. Polymorphisms in 12 genes were significantly associated with variation in the four phenotypes showing a significant enrichment of small P values. Six of those genes (STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2) also showed significant associations with asthma exacerbations in the COPSAC study or with asthma or virus-induced wheezing phenotypes in the COAST study., Conclusions: We identified genetic factors contributing to individual differences in childhood viral respiratory illnesses and virus-induced exacerbations of asthma. Defining mechanisms of these associations may provide insight into the pathogenesis of viral respiratory infections and virus-induced exacerbations of asthma., (© 2015 John Wiley & Sons Ltd.)

Background: Sex influences the risk of wheezing illnesses and the prevalence of asthma throughout childhood., Objective: To better understand the mechanisms of these effects, we analyzed longitudinal relationships between sex, lung physiology, and asthma in the Childhood Origins of ASThma birth cohort study., Methods: Childhood Origins of ASThma birth cohort study children were followed prospectively from birth and assessed annually. Results of spirometry, fractional exhaled nitric oxide (Feno), mannitol provocation testing, and (3)He gas magnetic resonance imaging were assessed by sex using multivariate models including age, asthma diagnosis, and wheezing histories., Results: Girls had higher prebronchodilator forced expiratory volume in 0.5 seconds/forced vital capacity values than did boys (mean difference, 0.017; 95% CI, 0.000-0.034; P = .05) of equivalent age. Postbronchodilator findings were more pronounced, with boys demonstrating reduced forced expiratory volume in 0.5 seconds/forced vital capacity values than did girls of equivalent age (mean difference, 0.032; 95% CI, 0.014-0.049; P = .0005). Conversely, girls were noted to have higher ventilation defects on (3)He magnetic resonance imaging than did boys (P = .01). No differences were noted in the rate of positive responses to mannitol provocation or Feno measurements., Conclusions: Lower airflow values are present by spirometry for prepubertal boys than for age-matched girls; however, greater (3)He ventilation defects were noted in girls. This could represent a greater degree of subclinical air trapping in prepubertal girls because residual volumes are not detected on standard spirometric readings. No differences were noted between the 2 sexes with airway hyperresponsiveness (mannitol provocation testing) or inflammation (Feno). Prospective peripubertal follow-up will determine whether these differences persist or change with the de novo expression and remission of asthma based on sex and age., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Geographically distributed environmental factors influence the burden of diseases such as asthma. Our objective was to identify sparse environmental variables associated with asthma diagnosis gathered from a large electronic health record (EHR) dataset while controlling for spatial variation. An EHR dataset from the University of Wisconsin's Family Medicine, Internal Medicine and Pediatrics Departments was obtained for 199,220 patients aged 5-50years over a three-year period. Each patient's home address was geocoded to one of 3456 geographic census block groups. Over one thousand block group variables were obtained from a commercial database. We developed a Sparse Spatial Environmental Analysis (SASEA). Using this method, the environmental variables were first dimensionally reduced with sparse principal component analysis. Logistic thin plate regression spline modeling was then used to identify block group variables associated with asthma from sparse principal components. The addresses of patients from the EHR dataset were distributed throughout the majority of Wisconsin's geography. Logistic thin plate regression spline modeling captured spatial variation of asthma. Four sparse principal components identified via model selection consisted of food at home, dog ownership, household size, and disposable income variables. In rural areas, dog ownership and renter occupied housing units from significant sparse principal components were associated with asthma. Our main contribution is the incorporation of sparsity in spatial modeling. SASEA sequentially added sparse principal components to Logistic thin plate regression spline modeling. This method allowed association of geographically distributed environmental factors with asthma using EHR and environmental datasets. SASEA can be applied to other diseases with environmental risk factors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Asthmatics have unique characteristics that may influence cardiovascular morbidity. We tested the association of lower airway caliber, obstructive sleep apnea (OSA), and other asthma-related factors, with systemic hypertension (HTN)., Methods: Asthma individuals at specialty clinics completed the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ). Medical records were reviewed for diagnosed HTN, OSA and comorbidities, spirometry, and current medications. FEV1% predicted was categorized as ≥ 80 (reference), 70-79, 60-69, and < 60. SA-SDQ ≥ 36 for men and ≥ 32 for women defined high OSA risk., Results: Among 812 asthmatics (mean age ± standard deviation: 46 ± 14 years), HTN was diagnosed in 191 (24%), OSA in 65 (8%), and OSA or high OSA risk (combined OSA variable) in 239 (29%). HTN was more prevalent in lower FEV1% categories (p < 0.0001), in subjects with OSA, and those with combined OSA variable (55 vs. 21% and 46 vs. 14%, respectively, both p < 0.0001). With adjustment for covariates, associations with HTN remained significant for some FEV1% categories (70-79% odds ratio = 1.60 [95% CI 0.90-2.87]; 60-69% 2.73 [1.28-5.79]; < 60% 0.96 [0.43-2.14]), and for OSA (2.20 [1.16-4.19]). The combined OSA variable in comparison with OSA alone demonstrated a stronger association with HTN (3.17 [1.99-5.04]) in a reiteration of this model. Inhaled corticosteroids (ICS) at lowest doses, in comparison to no ICS use had an independent "protective" association with HTN (0.44 [0.22-0.90])., Conclusions: In this young population, worse lower airways obstruction and OSA were associated with HTN. In contrast, lower ICS doses attenuated likelihood for HTN. Adequate control of airway inflammation at appropriate ICS doses, and screening for OSA may reduce the burden of HTN in asthma.

Background: Detection of either viral or bacterial pathogens is associated with wheezing in children; however, the influence of both bacteria and viruses on illness symptoms has not been described., Objective: We evaluated bacterial detection during the peak rhinovirus season in children with and without asthma to determine whether an association exists between bacterial infection and the severity of rhinovirus-induced illnesses., Methods: Three hundred eight children (166 with asthma and 142 without asthma) aged 4 to 12 years provided 5 consecutive weekly nasal samples during September and scored cold and asthma symptoms daily. Viral diagnostics and quantitative PCR for Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis were performed on all nasal samples., Results: Detection rates were 53%, 17%, and 11% for H influenzae, S pneumoniae, and M catarrhalis, respectively, with detection of rhinovirus increasing the risk of detecting bacteria within the same sample (odds ratio [OR], 2.0; 95% CI, 1.4-2.7; P < .0001) or the following week (OR, 1.6; 95% CI, 1.1-2.4; P = .02). In the absence of rhinovirus, S pneumoniae was associated with increased cold symptoms (mean, 2.7 [95% CI, 2.0-3.5] vs 1.8 [95% CI, 1.5-2.2]; P = .006) and moderate asthma exacerbations (18% [95% CI, 12% to 27%] vs 9.2% [95% CI, 6.7% to 12%]; P = .006). In the presence of rhinovirus, S pneumoniae was associated with increased moderate asthma exacerbations (22% [95% CI, 16% to 29%] vs 15% [95% CI, 11% to 20%]; P = .01). Furthermore, M catarrhalis detected alongside rhinovirus increased the likelihood of experiencing cold symptoms, asthma symptoms, or both compared with isolated detection of rhinovirus (OR, 2.0 [95% CI, 1.0-4.1]; P = .04). Regardless of rhinovirus status, H influenzae was not associated with respiratory symptoms., Conclusion: Rhinovirus infection enhances detection of specific bacterial pathogens in children with and without asthma. Furthermore, these findings suggest that M catarrhalis and S pneumoniae contribute to the severity of respiratory tract illnesses, including asthma exacerbations., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility., Objective: To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials., Methods: A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial., Results: CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial)., Conclusions: In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Obesity is more prevalent in asthmatics. Sleep duration is a novel risk factor for obesity in general populations., Objective: We tested the association of sleep duration and asthma characteristics with obesity., Methods: Adults at tertiary clinics were surveyed on asthma symptoms and habitual sleep duration. Medical records were used to assess asthma severity step (1-4), extract height and weight, current medications and diagnosed comorbid conditions. BMI ≥30 kg/m(2) defined obesity. Habitual sleep was categorized as <6 (very short), 6 to <7 h (short), 7-8 h (normal), >8 to ≤9 h (long) and >9 h (very long). Inhaled corticosteroid doses were categorized as low, moderate and high., Results: Among 611 participants (mean BMI 30 ± 8), 249 (41%) were obese. After adjustment for covariates, obesity was associated with short and very long sleep: as compared to normal sleepers, the odds of being obese were on an average 66% higher ([95% CI: 1.07-2.57], p = 0.02) among short and 124% higher ([1.08-1.65], p = 0.03) among very long sleepers, and the association with very short sleep approached significance (1.74 [0.96-3.14], p = 0.06). Obesity was also significantly related to highest asthma step (1.87 [1.09-3.21], p = 0.02) and psychopathology (1.64 [1.08-2.48], p = 0.02), and a trend was seen with high-dose inhaled corticosteroids (1.82 [0.93-3.56], p = 0.08)., Conclusions: Obesity in asthmatics is associated with shorter and very long sleep duration, worse asthma severity, psychopathology and high-dose inhaled corticosteroids. Although this cross-sectional study cannot prove causality, we speculate that further investigation of sleep may provide new opportunities to reduce the rising prevalence of obesity among asthmatics.

Background: Prediction of subsequent school-age asthma during the preschool years has proven challenging., Objective: To confirm in a post hoc analysis the predictive ability of the modified Asthma Predictive Index (mAPI) ina high-risk cohort and a theoretical unselected population. We also tested a potential mAPI modification with a 2-wheezing episode requirement (m2API) in the same populations., Methods: Subjects (n [ 289) with a family history of allergy and/or asthma were used to predict asthma at age 6, 8, and 11 years with the use of characteristics collected during the first 3 years of life. The mAPI and the m2API were tested for predictive value., Results: For the mAPI and m2API, school-age asthma prediction improved from 1 to 3 years of age. The mAPI had high predictive value after a positive test (positive likelihood ratio ranging from 4.9 to 55) for asthma development at years 6,8, and 11. Lowering the number of wheezing episodes to 2(m2API) lowered the predictive value after a positive test(positive likelihood ratio ranging from 1.91 to 13.1) without meaningfully improving the predictive value of a negative test.Posttest probabilities for a positive mAPI reached 72% and 90%in unselected and high-risk populations, respectively., Conclusions: In a high-risk cohort, a positive mAPI greatly increased future asthma probability (eg, 30% pretest probability to 90% posttest probability) and is a preferred predictive test to them 2API. With its more favorable positive posttest probability,the mAPI can aid clinical decision making in assessing future asthma risk for preschool-age children.

Background: Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk., Objective: To define relationships among established sensitization to particular aeroallergens, quantitative analyses of allergen-specific IgE levels, pet exposure and sensitization, and asthma and rhinitis risk., Methods: Children at high-risk for the development of asthma and allergic diseases were enrolled at birth into the Childhood Origins of ASThma (COAST) study. Allergen-specific IgE was assessed at ages 1, 3, 6, and 9 years by fluoroenzyme immunoassay (Unicap(®) 100; Pharmacia Diagnostics). Current asthma and rhinitis were diagnosed at age 6 and 8 years., Results: Sensitization to dog was strongly associated with increased asthma risk (P < 0.0001). Sensitization to perennial compared with seasonal allergens was more strongly associated with asthma risk, while sensitization to seasonal allergens was more closely associated with rhinitis risk. Increased levels of specific IgE to perennial allergens were associated with an increased asthma risk (P = 0.05), while any detectable level of IgE to seasonal allergens was associated with increased rhinitis risk (P = 0.0009). While dog and cat sensitization were both independently associated with increased asthma and rhinitis risk, dog exposure at birth was associated with a reduced risk of asthma, regardless of dog sensitization status during the first 6 years of life (P = 0.05)., Conclusions and Clinical Relevance: Analysing specific patterns of an individual's allergic sensitization profile reveals additional relevant associations with asthma and rhinitis risk as opposed to the information gained from characterizing an individual as 'atopic' by the presence of any demonstrable sensitization alone. Furthermore, protective mechanisms of dog exposure with regards to asthma risk appear to be unrelated to the prevention of sensitization., (© 2012 Blackwell Publishing Ltd.)

Objective: Obstructive sleep apnea (OSA) worsens nocturnal asthma, but its potential impact on daytime asthma remains largely unassessed. We investigated whether the sleep disorder is associated with daytime, in addition to nighttime, asthma symptoms., Methods: Asthma patients at tertiary-care centers completed the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ), and an asthma control questionnaire. SA-SDQ scores ≥36 for males and ≥32 for females defined high OSA risk. Medical records were reviewed for established diagnosis of OSA and continuous positive airway pressure (CPAP) use., Results: Among 752 asthma patients, high OSA risk was associated similarly with persistent daytime and nighttime asthma symptoms (p < .0001 for each). A diagnosis of OSA was robustly associated with persistent daytime (p < .0001) in addition to nighttime (p = .0008) asthma symptoms. In regression models that included obesity and other known asthma aggravators, high OSA risk retained associations with persistent daytime (odds ratio [OR] = 1.96 [95% confidence interval [CI] = 1.31-2.94]) and nighttime (1.97 [1.32-2.94]) asthma symptoms. Diagnosed OSA retained an association with persistent daytime (2.08 [1.13-3.82]) but not with nighttime (1.48 [0.82-2.69]) asthma symptoms. CPAP use was associated with lower likelihood of persistent daytime symptoms (0.46 [0.23-0.94])., Conclusions: Questionnaire-defined OSA risk and historical diagnosis were each associated with persistent daytime asthma symptoms, to an extent that matched or exceeded associations with nighttime asthma symptoms. Unrecognized OSA may be a reason for persistent asthma symptoms during the day as well as the night.

Background: Children with allergic asthma have more frequent and severe human rhinovirus (HRV)-induced wheezing and asthma exacerbations through unclear mechanisms., Objective: We sought to determine whether increased high-affinity IgE receptor (FcεRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children., Methods: PBMCs were obtained from 44 children, and surface expression of FcεRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells, monocytes, and basophils was assessed by using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcεRI, followed by stimulation with HRV-16, and IFN-α and IFN-λ1 production was measured by Luminex. The relationships among FcεRI expression and cross-linking, HRV-induced IFN-α and IFN-λ1 production, and childhood allergy and asthma were subsequently analyzed., Results: FcεRIα expression on pDCs was inversely associated with HRV-induced IFN-α and IFN-λ1 production. Cross-linking FcεRI before HRV stimulation further reduced PBMC IFN-α (47% relative reduction; 95% CI, 32% to 62%; P< .0001) and IFN-λ1 (81% relative reduction; 95% CI, 69% to 93%; P< .0001) secretion. Allergic asthmatic children had higher surface expression of FcεRIα on pDCs and myeloid dendritic cells when compared with that seen in nonallergic nonasthmatic children. Furthermore, after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic nonasthmatic children (IFN-α, P= .004; IFN-λ1, P= .02) and nonallergic nonasthmatic children (IFN-α, P= .002; IFN-λ1, P= .01)., Conclusions: Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcεRI expression on pDCs and are reduced by FcεRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage caused by infection or allergen inhalation increases ATP levels in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X(7) can enhance airway leukocyte recruitment to the airways, and P2X(7) knockout mice display a reduced asthma-like phenotype., Objective: Based on the P2X(7) knockout mouse, we hypothesized that children with low P2X(7) function would have decreased rates of asthma., Methods: We used a functional assay to determine P2X(7) pore-producing capacity in whole-blood samples in a birth cohort at high risk for asthma development. The P2X(7) assay was validated with known loss-of-function alleles in human subjects. P2X(7) pore status categorization was used to assess asthma and allergy status in the cohort., Results: Attenuated P2X(7) function was associated with lower asthma rates at ages 6 and 8 years, and the greatest effects were observed in boys. Children with asthma at age 11 years who had low P2X(7) capacity had less severe disease in the previous year. Attenuated P2X(7) function was also associated with sensitization to fewer aeroallergens., Conclusion: P2X(7) functional capacity is associated with asthma risk or disease severity, and these relationships appear to be age related., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Rationale: The 2009 H1N1 flu appeared to cause more severe cold symptoms during the 2009-2010 flu season., Objectives: We evaluated H1N1 infections during peak viral season in children with and without asthma to determine whether the H1N1 infectivity rate and illness severity were greater in subjects with asthma., Methods: One hundred and eighty children, 4-12 years of age, provided eight consecutive weekly nasal mucus samples from September 5 through October 24, 2009, and scored cold and asthma symptoms daily. Viral diagnostics were performed for all nasal samples., Measurements and Main Results: One hundred and sixty-one children (95 with asthma, 66 without asthma) completed at least 6 of the 8 nasal samples. The incidence of H1N1 infection was significantly higher in children with asthma (41%) than in children without asthma (24%; odds ratio, 4; 95% confidence interval, 1.8-9; P < 0.001), but rates of human rhinovirus infection (90% each) and other viral infections (47 vs. 41%) were similar. In children with asthma, there was a nonsignificant trend for increased loss of asthma control during H1N1 infections compared with human rhinovirus infections (38 vs. 21%; odds ratio, 2.6; 95% confidence interval, 0.9-7.2; P = 0.07)., Conclusions: During peak 2009 H1N1 flu season, children with asthma were infected almost twice as often with H1N1 compared with other respiratory viruses. H1N1 infection also caused increased severity of cold symptoms compared with other viral infections. Given the increased susceptibility of children with asthma to infection, these findings reinforce the need for yearly influenza vaccination to prevent infection, and raise new questions about the mechanism for enhanced susceptibility to influenza infection in asthma.

Background: Asthma is a complex disease characterized by sex-specific differences in incidence, prevalence, and severity, but little is known about the molecular basis of these sex-based differences., Objective: To investigate the genetic architecture of sex differences in asthma risk, we evaluated (1) associations between polymorphisms in the IFNG gene and childhood-onset asthma in combined and sex-specific samples and (2) interactions between polymorphisms and sex on asthma risk., Methods: Main and sex-interaction effects of IFNG genetic diversity on asthma risk and IFN-γ levels were examined in a birth cohort of children at high risk for asthma and allergic diseases. Replication of the genetic association was assessed in an independent sample of asthma cases., Results: Significant genotype-sex interactions on asthma were observed for 2 IFNG single nucleotide polymorphisms, rs2069727 and rs2430561, which were in strong linkage disequilibrium with each other. In contrast, none of the 10 IFNG single nucleotide polymorphisms showed significant main effects on asthma. The observed genotype-sex interaction on asthma was characterized by nonadditivity; that is, heterozygous boys had the highest risk for asthma, and heterozygous girls had the lowest risk. The interaction effect was robust to other asthma risk factors but was limited to children who experienced wheezing illnesses with viral infections during the first 3 years of life. Genotype-sex interactions were also observed in the IFN-γ response to LPS in the first year of life. Finally, the sex-interaction effect was replicated in an independent population of childhood asthma cases., Conclusions: These results provide insight into the genetic basis of sex differences in asthma and highlight the potential importance of interactions among sex, genotype, and environmental factors in asthma pathogenesis., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Obesity has been proposed to be a risk factor for the development of childhood asthma., Objective: We sought to examine weight status from birth to age 5 years in relation to the occurrence of asthma at ages 6 and 8 years., Methods: Two hundred eighty-five full-term high-risk newborns with at least 1 asthmatic/atopic parent enrolled in the Childhood Origin of Asthma project were studied from birth to age 8 years. Overweight was defined by weight-for-length percentiles of greater than the 85th percentile before the age of 2 years and a body mass index percentile of greater than the 85th percentile at ages 2 to 5 years., Results: No significant concurrent association was found between overweight status and wheezing/asthma occurrence at each year of age. In contrast, longitudinal analyses revealed complex relationships between being overweight and asthma. Being overweight at age 1 year was associated with a decreased risk of asthma at age 6 (odds ratio [OR], 0.32; P = .02) and 8 (OR, 0.35; P = .04) years, as well as better lung function. However, being overweight beyond infancy was not associated with asthma occurrence. In fact, only children who were overweight at age 5 years but not at age 1 year had an increased risk of asthma at age 6 years (OR, 5.78; P = .05)., Conclusion: In children genetically at high risk of asthma, being overweight at age 1 year was associated with a decreased risk of asthma and better lung function at ages 6 and 8 years. However, being overweight beyond infancy did not have any protective effect and even could confer a higher risk for asthma., (Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Unrecognized obstructive sleep apnea (OSA) may lead to poor asthma control despite optimal therapy. Our objective was to evaluate the relationship between OSA risk and asthma control in adults., Methods: Patients with asthma seen routinely at tertiary-care clinic visits completed the validated Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ) and Asthma Control Questionnaire (ACQ). An ACQ score of >or= 1.5 defined not-well-controlled asthma, and an SA-SDQ score of >or= 36 for men and >or= 32 for women defined high OSA risk. Logistic regression was used to model associations of high OSA risk with not-well-controlled asthma (ACQ full version and short versions)., Results: Among 472 subjects with asthma, the mean +/- SD ACQ (full version) score was 0.87 +/- 0.90, and 80 (17%) subjects were not well controlled. Mean SA-SDQ score was 27 +/- 7, and 109 (23%) subjects met the definition of high OSA risk. High OSA risk was associated, on average, with 2.87-times higher odds for not-well-controlled asthma (ACQ full version) (95% CI, 1.54-5.32; P = .0009) after adjusting for obesity and other factors known to worsen asthma control. Similar independent associations were seen when using the short ACQ versions., Conclusions: High OSA risk is significantly associated with not-well-controlled asthma independent of known asthma aggravators and regardless of the ACQ version used. Patients who have difficulty achieving adequate asthma control should be screened for OSA.

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.

Rationale: Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood., Objectives: To define the relationship between specific viral illnesses and early childhood asthma development., Methods: A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed., Measurements and Main Results: Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age., Conclusions: Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

Rationale: Several studies have evaluated the associations between cord blood cellular responses and atopic diseases in children, but the results of these studies are inconsistent. Variations in blood processing factors and maternal and infant characteristics are typically not accounted for and may contribute to these inconsistencies., Methods: Cord blood samples were obtained from 287 subjects participating in the Childhood Origins of ASThma project, a prospective study of children at high risk for the development of asthma/allergies. Mononuclear cells were stimulated with phytohaemagglutinin (PHA), phorbal myristate acetate/ionomycin or a suspension of killed staphylococcus, and IFN-gamma, IL-10 and IL-13 were quantitated by ELISA. Cell yields and cytokine production were related to processing factors and maternal and infant characteristics., Results: The strongest relationships between independent variables and cell yield or cytokine responses occurred with the season of birth. The highest median cell yields were seen in fall, and the lowest in summer (difference of 47%, P=0.0027). Furthermore, PHA-induced IL-5 and IL-13 responses were approximately 50% higher in spring and summer than in fall or winter (P<0.0001). Clots in the cord blood samples were associated with a reduced median cell yield (42% reduction, P<0.0001), and an increased PHA-induced IL-10 secretion (27% increase, P=0.004)., Conclusions: These data suggest that season of collection, and to a lesser extent clotting in samples, affect cord blood mononuclear cell yield and cytokine responses. Careful documentation and analysis of processing and environmental variables are important in understanding biological relationships with cytokine responses, and also lead to greater comparability among studies using these techniques.

Background: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development., Methods: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated., Results: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-gamma responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-gamma responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma., Conclusions: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.

Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this "day care" effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with "day care" that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the "day care" effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses.