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Environmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain.We sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children.We examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7 years of age among 442 children.Higher house dust concentrations of cockroach, mouse, and cat allergens in the first 3 years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P .01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate 0.05) more or less abundant, respectively, in the homes of children with asthma. A majority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P = .048) and maternal stress and depression scores.Among high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.

Background Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. Objective We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). Results We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively ( P −6 for differentially methylated regions and P −10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. Conclusions Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

Background Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches. Objective We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Methods Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Results Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm 3 ), and allergen sensitizations (15 of 22 tested). Conclusions Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified.

Background Treatment levels required to control asthma vary greatly across a population with asthma. The factors that contribute to variability in treatment requirements of inner-city children have not been fully elucidated. Objective We sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma. Methods Asthmatic children aged 6 to 17 years underwent baseline assessment and bimonthly guideline-based management visits over 1 year. Difficult-to-control and easy-to-control asthma were defined as daily therapy with 500 μg of fluticasone or greater with or without a long-acting β-agonist versus 100 μg or less assigned on at least 4 visits. Forty-four baseline variables were used to compare the 2 groups by using univariate analyses and to identify the most relevant features of difficult-to-control asthma by using a variable selection algorithm. Nonlinear seasonal variation in longitudinal measures (symptoms, pulmonary physiology, and exacerbations) was examined by using generalized additive mixed-effects models. Results Among 619 recruited participants, 40.9% had difficult-to-control asthma, 37.5% had easy-to-control asthma, and 21.6% fell into neither group. At baseline, FEV 1 bronchodilator responsiveness was the most important characteristic distinguishing difficult-to-control asthma from easy-to-control asthma. Markers of rhinitis severity and atopy were among the other major discriminating features. Over time, difficult-to-control asthma was characterized by high exacerbation rates, particularly in spring and fall; greater daytime and nighttime symptoms, especially in fall and winter; and compromised pulmonary physiology despite ongoing high-dose controller therapy. Conclusions Despite good adherence, difficult-to-control asthma showed little improvement in symptoms, exacerbations, or pulmonary physiology over the year. In addition to pulmonary physiology measures, rhinitis severity and atopy were associated with high-dose asthma controller therapy requirement.

Background Pathway analyses can be used to determine how host and environmental factors contribute to asthma severity. Objective To investigate pathways explaining asthma severity in inner-city children. Methods On the basis of medical evidence in the published literature, we developed a conceptual model to describe how 8 risk-factor domains (allergen sensitization, allergic inflammation, pulmonary physiology, stress, obesity, vitamin D, environmental tobacco smoke [ETS] exposure, and rhinitis severity) are linked to asthma severity. To estimate the relative magnitude and significance of hypothesized relationships among these domains and asthma severity, we applied a causal network analysis to test our model in an Inner-City Asthma Consortium study. Participants comprised 6- to 17-year-old children (n = 561) with asthma and rhinitis from 9 US inner cities who were evaluated every 2 months for 1 year. Asthma severity was measured by a longitudinal composite assessment of day and night symptoms, exacerbations, and controller usage. Results Our conceptual model explained 53.4% of the variance in asthma severity. An allergy pathway (linking allergen sensitization, allergic inflammation, pulmonary physiology, and rhinitis severity domains to asthma severity) and the ETS exposure pathway (linking ETS exposure and pulmonary physiology domains to asthma severity) exerted significant effects on asthma severity. Among the domains, pulmonary physiology and rhinitis severity had the largest significant standardized total effects on asthma severity (−0.51 and 0.48, respectively), followed by ETS exposure (0.30) and allergic inflammation (0.22). Although vitamin D had modest but significant indirect effects on asthma severity, its total effect was insignificant (0.01). Conclusions The standardized effect sizes generated by a causal network analysis quantify the relative contributions of different domains and can be used to prioritize interventions to address asthma severity.

Asthma definitions vary widely across research studies and feature a trade-off between inclusivity and precision. Harmonizing definitions across multiple asthma birth cohort studies highlights these challenges.

Background Variability in response to inhaled corticosteroids (ICSs) can result in less than optimal asthma control. Development of biomarkers assessing the therapeutic efficacy of corticosteroids is important. Objective We sought to examine whether in vitro PBMC responses to corticosteroids relate to the clinical ICS response. Methods PBMCs were collected from 125 children with asthma (6-17 years) at enrollment (visit 0 [V0]) and after 1 year of bimonthly guidelines-based management visits (visit 6 [V6]). Difficult-to-control and easy-to-control asthma were defined as requiring daily therapy with 500 μg or more of fluticasone propionate (FLU) with or without a long-acting β-agonist versus 100 μg or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor α and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-α) were measured by using RT-PCR in freshly isolated cells and in response to 10−8 mol/L FLU. Results Compared with PBMCs from patients with easy-to-control asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor α levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-α suppression by FLU between V0 and V6 (P = .07) were observed in patients with easy-to-control asthma. In contrast, no changes between V0 and V6 in IL-8 and TNF-α suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroid-mediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-to-control and easy-to-control asthma between V0 and V6 (P = .05 and P = .03, respectively). Conclusions PBMCs of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high-dose ICSs had reduced in vitro responsiveness to corticosteroids.

Background Studies have demonstrated that IgE-binding cross-reactive epitopes between shrimp, cockroach, and house dust mite tropomyosins can account for the presence of detectable IgE to shrimp in patients with cockroach and dust mite allergies. Objective We investigated the correlation between IgE-mediated sensitization to shrimp, cockroach, and dust mite in relation to allergen exposure in inner-city children. Methods Five hundred four serum samples from the National Cooperative Inner-City Asthma Study were evaluated for specific IgE to shrimp, and the results were compared with specific IgE to cockroach (Blattella germanica) and dust mite (Dermatophagoides farinae). Associations between IgE sensitization to these allergens and environmental exposures were determined. Results There was a strong positive correlation between shrimp, cockroach, and dust mite IgE levels. High exposure to cockroach (B germanica) in the home, particularly in the bedroom and television room, was significantly correlated with higher shrimp and cockroach IgE levels. In contrast, high exposure to dust mite in the home was highly correlated with IgE levels to D farinae but not with shrimp IgE levels. There is a synergistic relationship between cockroach IgE levels and exposure in predicting shrimp IgE levels. Conclusions For children with evidence of IgE-mediated sensitization to cockroach and shrimp, having high exposure to cockroach in the home can contribute to higher shrimp IgE levels, which might not correlate with clinical reactivity. Further patient evaluations with clinical histories of shrimp exposure and reactions, as well as oral food challenges, would have to be performed to confirm these findings.

Background Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy; however, the influences of parental characteristics and prenatal factors on neonatal immune responses are incompletely understood. Objective This study investigates potential correlations between urban parental, prenatal, and perinatal factors on innate and adaptive stimuli-induced cytokine responses. Methods Five hundred sixty and 49 children of parents with and without allergic disease or asthma, respectively, were enrolled into a prospective birth cohort study (Urban Environment and Childhood Asthma). Cord blood mononuclear cells were incubated with innate and adaptive immune stimuli, and cytokine responses (ELISA) were compared with season of birth, parental characteristics, in utero stressors, and fetal growth. Results Many cytokine responses varied by season of birth, including 2-fold to 3-fold fluctuations with specific IFN-α and IFN-γ responses. Birth weight was inversely associated with IFN-γ responses to respiratory syncytial virus ( R = −0.16), but positively associated with IL-8 responses to a variety of innate stimuli ( R = 0.08-0.12). Respiratory syncytial virus–induced cytokine responses were 21% to 54% lower in children of mothers with asthma. Cytokine responses were generally lower in babies born to parents with allergy/asthma. Conclusions Innate cytokine responses are associated with parental allergic or airway disease, somatic fetal growth, ethnicity, and season of birth. Collectively, these findings suggest that urban prenatal exposures and familial factors affect the development of the fetal immune system.

Background Exposure to indoor allergens contributes to increased asthma morbidity. The Inner-City Asthma Study, a randomized trial involving home environmental allergen and irritant remediation among children aged 6 through 11 years with moderate-to-severe asthma, successfully reduced asthma symptoms. A cost-effectiveness analysis can help stakeholders to evaluate the potential costs and benefits of adopting such a program. Objective We sought to assess the cost-effectiveness of the environmental intervention of the Inner-City Asthma Study. Methods Incremental cost-effectiveness ratios for a 2-year study period were calculated. Health outcome was measured as symptom-free days. Resource use measures included ambulatory visits, hospitalizations, and pharmaceutical use. CIs were obtained by using bootstrapping. Results The intervention, which cost $1469 per family, led to statistically significant reductions in symptom days, unscheduled clinic visits, and use of β-agonist inhalers. Over the year of the intervention and a year of follow-up, the intervention cost was $27.57 per additional symptom-free day (95% CI, $7.46-$67.42). Subgroup analysis showed that targeting the intervention to selected high-risk subgroups did not reduce the incremental cost-effectiveness ratio. Conclusions A targeted home-based environmental intervention improved health and reduced service use in inner-city children with moderate-to-severe asthma. The intervention is cost-effective when the aim is to reduce asthma symptom days and the associated costs.

Background Asthma continues to be an increasing cause of morbidity in the pediatric population, and studies have shown an association between food sensitivity and asthma. Objective We investigated the degree of food allergen sensitization in inner-city patients with asthma. Methods Five hundred four random serum samples from the National Cooperative Inner City Asthma Study were evaluated for specific IgE (UniCap) to 6 common food allergens (egg, milk, soy, peanut, wheat, and fish). Statistical analyses were performed to determine food sensitization prevalence and its association with asthma morbidity. Results Forty-five percent of patients had evidence of sensitization (food-specific IgE ≥0.35 kU/L) to at least 1 food. Nineteen percent had IgE levels at ≥50% positive predictive value for clinical reactivity to at least 1 food, with 4% of patients having levels >95% positive predictive value for food allergy. Children sensitized to foods had higher rates of asthma hospitalization ( P P =.025). Sensitization to foods also correlated with sensitization to more indoor and outdoor aeroallergens ( P Conclusion Food allergen sensitization is highly prevalent in the inner-city population with asthma, and it is associated with increased asthma healthcare and medication use. Therefore, food allergen sensitivity may be a marker for increased asthma severity.

Our purpose was to estimate the annual risk of death in the United States from cardiovascular disease attributable to low-dose combination oral contraceptives.Estimates of the risk of death from cardiovascular disease attributable to low-dose oral contraceptives were modeled on data from studies published through 1997 and from age-specific mortality rates in the United States for 1993 and 1994.Attributable risk of death from cardiovascular disease resulting from oral contraceptive use is 0.06 and 3.0 per 100,000 nonsmokers 15 to 34 years of age and 35 to 44 years of age, respectively. In smokers this risk increases, respectively, to 1.73 and 19.4 per 100,000 users in these 2 age groups; however, 97% and 85% of this risk is due to the combined effects of smoking and using oral contraceptives. The attributable risk of death from cardiovascular disease in nonsmoking oral contraceptive users is lower than the risk of death from pregnancy in nonusers of oral contraceptives at all ages; however, among smoking oral contraceptive users more than 35 years of age, the excess risk of death from oral contraceptives is higher than the risk of death from pregnancy.There is virtually no excess attributable risk of death from cardiovascular disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive.The annual risk of death in the US from cardiovascular disease attributable to low-dose combination oral contraceptives (OCs) was estimated through use of data from studies published in 1980-1997 and from age-specific mortality rates for 1993 and 1994. Four cardiovascular disease categories were included: myocardial infarction, venous thromboembolism and pulmonary embolism, ischemic stroke, and hemorrhagic stroke. The overall risk of death from cardiovascular disease among nonsmoking users of low-dose OCs is 0.06/100,000 women in the 15-34 year age group and 3.03/100,000 women in the 35-44 year age group. For young nonsmokers, the excess mortality risk associated with OC use is smaller than the risk of death from pregnancy, whether terminated by abortion or carried to term. Among OC users who smoke, the risk of cardiovascular mortality is 1.73/100,000 in 15-34 year olds and 19.4/100,000 in women 35-44 years old; however, 97% and 85% of this risk, respectively, is composed of the combined OC-smoking risk. Among smoking OC users over 35 years of age, the excess risk of death from OCs exceeds the risk of death from pregnancy. Young nonsmokers raise their risk of death from cardiovascular disease by less than 10% (0.60-0.65/100,000) by using OCs, while young women who do not use OCs increase their risk of death by 260% (0.60-1.57/100,000) by smoking cigarettes. For older women, the corresponding increases are 95% among nonsmoking OC users and 315% among smoking nonusers. These estimates indicate that women over 35 years of age who smoke should not be permitted to use either low- or high-dose OCs because of the excess attributable risk of death from cardiovascular disease.

To determine the efficacy of the lactational amenorrhea method of family planning (amenorrhea during full or nearly full breastfeeding for 6 months postpartum).Prospective noncomparative study.Normal breastfeeding women in Karachi and Multan, Pakistan, most delivered at home by a midwife.Three hundred ninety-nine newly delivered mothers who successfully had breastfed a previous child and chose the lactational amenorrhea method to prevent a subsequent pregnancy, 391 of whom were followed for a full year.Mothers were taught, before or shortly after delivery, to use the method and were interviewed in their homes each month by a Lady Health Visitor.Life-table pregnancy rates. Periods of postpartum or lactational abstinence were excluded in the calculation of the pregnancy rates.During full or nearly full breastfeeding, while the women were amenorrheic and not otherwise contracepting, the rate of pregnancy was 0.6%. The pregnancy rate during lactational amenorrhea alone was 1.1% at 1 year postpartum.The lactational amenorrhea method was found to be highly effective for 6 months. A high degree of contraceptive protection endures for a full year during lactational amenorrhea, but not after the return of menses during breastfeeding.399 mother-infant pairs were admitted into the study, 99 in the rural areas around Multan and 300 in Karachi. 378 remained in the follow-up for the full year. The mean age of the volunteers was 27.2. 25% were from the rural areas, and 37.6% were able to read and write. The women reported an average of 4.4 pregnancies and had 3.9 living children. Only 6% ever had used a family planning method in the past, and this included withdrawal as well as modern contraceptive methods. 26.4% of the women returned to menses during the first 6 months postpartum, and 40.7% of the infants were given regular supplements by this time. Considering both factors together, 47.9% of women were still protected by the lactational amenorrhea method (LAM) by the end of the 6th month postpartum. By the end of the 8th month, virtually all infants were receiving regular supplements, although only 7.4% had been weaned by the end of follow-up at 1 year postpartum. By the end of 12 months there were 29 pregnancies, including two miscarriages. Of the two pregnancies that occurred during amenorrhea, one occurred after 5 months postpartum (single LAM failure) and the other occurred at 9 months postpartum, 3.5 months after regular supplementation began. The single LAM failure, which occurred during the 6th postpartum month, resulted in a life-table pregnancy rate of 0.58% (95% confidence interval [CI], 0.00-1.58%). The rate of pregnancy during the first 6 months postpartum during breastfeeding in the absence of the use of another contraceptive constituted the failure rate of the LAM during correct plus incorrect use. During use of the LAM so defined, 0.96% were pregnant by the end of 5 months postpartum (95% CI, 0.00-2.15%) and 1.65% were pregnant by 6 months (95% CI, 0.12-3.18%). Two pregnancies occurred by the end of a year, for a 12-month life-table pregnancy rate of 1.12% (95% CI, 0.00-2.59%).

Background: Wheezing illnesses cause major morbidity in infants and are frequent precursors to asthma. Objective: We sought to examine environmental factors associated with recurrent wheezing in inner-city environments. Methods: The Urban Environment and Childhood Asthma study examined a birth cohort at high risk for asthma (n 5 560) in Baltimore, Boston, New York, and St Louis. Environmental assessments included allergen exposure and, in a nested case-control study of 104 children, the bacterial content of house dust collected in the first year of life. Associations were determined among environmental factors, aeroallergen sensitization, and recurrent wheezing at age 3 years. Results: Cumulative allergen exposure over the first 3 years was associated with allergic sensitization, and sensitization at age 3 years was related to recurrent wheeze. In contrast, first-year exposure to cockroach, mouse, and cat allergens was negatively associated with recurrent wheeze (odds ratio, 0.60, 0.65, and 0.75, respectively; P < .01). Differences in house dust bacterial content in the first year, especially reduced exposure to specific Firmicutes and Bacteriodetes, was associated with atopy and atopic wheeze. Exposure to high levels of both allergens and this subset of bacteria in the first year of life was most common among children without atopy or wheeze. Conclusions: In inner-city environments children with the highest exposure to specific allergens and bacteria during their first year were least likely to have recurrent wheeze and allergic sensitization. These findings suggest that concomitant exposure to high levels of certain allergens and bacteria in early life might be beneficial and suggest new preventive strategies for wheezing and allergic diseases. (J Allergy Clin Immunol 2014;nnn:nnn-nnn.)

Background Cockroach allergy is a key contributor to asthma morbidity in children living in urban environments. Objective We sought to document immune responses to cockroach allergen and provide direction for the development of immunotherapy for cockroach allergy. Methods Four pilot studies were conducted: (1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults. Results The adult SLIT trial (n = 54; age, 18-54 years) found a significantly greater increase in cockroach-specific IgE levels between the active and placebo groups (geometric mean ratio, 1.92; P 4 levels in actively treated subjects ( P = .09) but no evidence of functional blocking antibody response. The pediatric SLIT trial (n = 99; age, 5-17 years) found significant differences in IgE, IgG, and IgG 4 responses between both active groups and the placebo group but no consistent differences between the high- and low-dose groups. In the SCIT study the treatment resulted in significant changes from baseline in cockroach IgE, IgG 4 , and blocking antibody levels. The safety profile of cockroach immunotherapy was reassuring in all studies. Conclusions The administration of cockroach allergen by means of SCIT is immunologically more active than SLIT, especially with regard to IgG 4 levels and blocking antibody responses. No safety concerns were raised in any age group. These pilot studies suggest that immunotherapy with cockroach allergen is more likely to be effective with SCIT.

M O N D A Y 750 Cysteine Proteases Induce Production and Extracellular Release of IL-33 in Airway Epithelial Cells S. Seno, K. Iijima, S. M. O’Grady, H. Kita; Mayo Clinic, Rochester, MN, Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, JAPAN, Departments of Integrated Biology and Physiology and Animal Science, University of Minnesota, St. Paul, MN. RATIONALE: Interleukin (IL)-33 plays a pivotal role in T helper (Th) 2-type immune responses. IL-33 is constitutively expressed and stored in the nucleus of airway epithelial cells and is considered an ‘‘alarmin’’, which is released extracellularly when cells are damaged. Little is known regarding the mechanisms involved in production and secretion of IL-33. METHODS: Normal human bronchial epithelial (NHBE) cells were cultured with cysteine proteases (bromelain, papain) or extracts of house dust mite (HDM) in vitro. Na€ive non-sensitized mice were exposed to cysteine proteases in vivo. The mechanisms were studied by pharmacologic inhibitors and small interfering RNA (siRNA). RESULTS: NHBE cells constitutively expressed mRNA and produced protein for IL-33; IL-33 was localized mainly in the nucleus of resting cells. Cysteine proteases at low concentrations (e.g. 0.1 mg/ml) did not affect production but induced extracellular release of IL-33 within 2 h. In contrast, these cysteine proteases at high concentrations (e.g. 50 mg/ ml) enhanced IL-33 production. Similarly, HDM extracts induced IL-33 release, which is dependent on extracts’ cysteine protease activities. Pharmacologic inhibitors and siRNAs for a protease receptor (PAR2) and a purinergic receptor (P2Y2) attenuated both IL-33 production and release induced by cysteine proteases. Airway exposure of mice to cysteine proteases enhanced production of IL-33 in vivo. CONCLUSIONS: Production and extracellular release of IL-33 by airway epithelial cells is upregulated by exposure to cysteine proteases through receptors sensing protease activities and cellular stress. Cysteine protease activities in allergens may play important roles in promoting Th2-type immune responses in the airway.

Background The Urban Environment and Childhood Asthma study was established to investigate the immunologic and environmental causes of asthma in inner-city children. Objective We sought to evaluate potential atopic outcomes in the first 12 months and their relationships to environmental exposures and immune development. Methods A birth cohort of 560 children with at least 1 parent with allergy or asthma was established in Baltimore, Boston, New York, and St Louis. Wheezing is assessed every 3 months, allergen-specific IgE yearly, and mononuclear cell cytokine responses at birth and yearly; environmental assessments include dust allergen and endotoxin, maternal stress, and indoor nicotine and nitrogen dioxide levels. Results Key outcomes in the first year include wheeze in 49%, 2 or more episodes of wheeze in 23%, eczema in 30%, and detectable IgE to milk, egg, and/or peanut in 32% and to cockroach in 4%. Household dust revealed levels of greater than 2 μg/g to cockroach in 40%, mite in 19%, cat in 25%, and mouse in 29%, and 66% of homes housed at least 1 smoker. Positive associations were detected between multiple wheeze and cotinine levels, maternal stress, and maternal depression, whereas cytokine responses to a variety of innate, adaptive, and mitogenic stimuli were inversely related to eczema. Conclusions This high-risk cohort of inner-city infants is exhibiting high rates of wheeze, eczema, and allergic sensitization. Low cytokine responses at birth might be a risk factor for eczema, whereas a variety of adverse environmental exposures contribute to the risk of wheezing in infancy. These findings provide evidence of specificity in the interactions between immune development, environmental exposures, and the development of early features that might predict future asthma.

Background The prevalence of both obesity and allergic disease has increased among children over the last several decades. Previous literature on the relationship between obesity and allergic disease has been inconsistent. It is not known whether systemic inflammation could be a factor in this relationship. Objective We sought to examine the association of obesity with total and allergen-specific IgE levels and allergy symptoms in US children and adolescents and to assess the role of C-reactive protein. Methods National Health and Nutrition Examination Survey data from 2005-2006 included measurement of total and allergen-specific IgE levels and allergy questions. Overweight was defined as the 85th or greater to less than the 95th percentile of body mass index for age, and obesity was defined as the 95th percentile or greater. Linear and logistic regression models were used to examine the association of weight categories with total IgE levels, atopy, allergen-specific IgE levels, and allergy symptoms among youth aged 2 to 19 years. Results Geometric mean total IgE levels were higher among obese (geometric mean ratio, 1.31; 95% CI, 1.10-1.57) and overweight (ratio, 1.25; 95% CI, 1.02-1.54) children than among normal-weight children. The odds ratio (OR) for atopy (any positive specific IgE measurement) was increased in the obese children compared with that seen in those of normal weight; this association was driven largely by allergic sensitization to foods (OR for atopy, 1.26 [95% CI, 1.03-1.55]; OR for food sensitization, 1.59 [95% CI, 1.28-1.98]). C-reactive protein levels were associated with total IgE levels, atopy, and food sensitization. Conclusions Obesity might be a contributor to the increased prevalence of allergic disease in children, particularly food allergy. Systemic inflammation might play a role in the development of allergic disease.