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Background Exhaled nitric oxide (eNO) is a biomarker of airway inflammation and seems to precede respiratory symptoms, such as asthma, in childhood. Identifying genetic determinants of postnatal eNO levels might aid in unraveling the role of eNO in epithelial function or airway inflammation and disease. Objective We sought to identify genetic determinants of early postnatal eNO levels and subsequent respiratory symptoms during the first year of life. Methods Within a population-based birth cohort, eNO levels were measured in healthy term infants aged 5 weeks during quiet tidal breathing in unsedated sleep. We assessed associations of single nucleotide polymorphisms with eNO levels in a genome-wide association study and subsequent symptoms of lower respiratory tract infections during the first year of life and asked whether this was modified by prenatal and early-life environmental factors. Results We identified thus far unknown determinants of infant eNO levels: rs208515 ( P = 3.3 × 10 −8 ), which is located at 6q12, probably acting in “ trans ” and explaining 10.3% of eNO level variance, and rs1441519 ( P = 1.6 × 10 −6 ), which is located at 11p14, potentially affecting nitric oxide synthase 3 (NOS3) expression, as shown by means of in vitro functional analyses. Moreover, the 6q12 locus was inversely associated with subsequent respiratory symptoms ( P < .05) and time to recovery after first respiratory symptoms during the first year of life ( P < .05). Conclusion The identification of novel genetic determinants of infant eNO levels might implicate that postnatal eNO metabolism in healthy infants before first viral infections and sensitization is related to mechanisms other than those associated with asthma, atopy, or increased risk thereof later in life. [ABSTRACT FROM AUTHOR]

Background: Globally, the number of children born by cesarean delivery is constantly increasing. However, hormonal and physiological changes associated with labor and vaginal delivery are considered necessary for lung maturation.Objective: We aimed to assess whether the mode of delivery is associated with changes in respiratory and atopic outcomes during infancy and at school age.Study Design: We included 578 children, born at ≥37 weeks of gestation, from a prospective birth cohort study. We compared weekly respiratory symptoms throughout the first year of life and infant lung function (tidal breathing and multiple-breath washout) at 5 weeks of age between children born by cesarean delivery (N=114) and those born by vaginal delivery (N=464) after term pregnancy in healthy women. At a follow-up visit conducted at 6 years of age (N=371, of which 65 were delivered by cesarean delivery), we assessed respiratory, atopic, and lung function outcomes (spirometry, body plethysmography, and multiple-breath washout). We performed adjusted regression analyses to examine the association between cesarean delivery and respiratory and atopic outcomes. To account for multiple testing, we used the Bonferroni correction, which led to an adapted significance level of P<.002.Results: During infancy, children born by cesarean delivery did not have more respiratory symptoms than those born by vaginal delivery (median, 4 weeks; interquartile range, 7 weeks vs median, 5 weeks; interquartile range, 7 weeks; adjusted incidence rate ratio, 0.8; 95% confidence interval, 0.6-1.0; P=.02). Infant lung function was similar between the groups. Children born by cesarean delivery did not have a higher incidence of "ever wheezing" (adjusted odds ratio, 0.9; 95% confidence interval, 0.5-1.8; P=.78) or current asthma (adjusted odds ratio, 0.4; 95% confidence interval, 0.0-3.5; P=.42) at school age than those born by vaginal delivery. There was no difference in the lung function parameters between the groups.Conclusion: Cesarean delivery was not associated with respiratory symptoms in the first year of life, nor with different respiratory or atopic outcomes at school age, when compared with vaginal delivery. Our results indicate that there are no long-term consequences on the respiratory health of the child associated with cesarean delivery. [ABSTRACT FROM AUTHOR]

Background Phenotypes of childhood-onset asthma are characterized by distinct trajectories and functional features. For atopy, definition of phenotypes during childhood is less clear. Objective We sought to define phenotypes of atopic sensitization over the first 6 years of life using a latent class analysis (LCA) integrating 3 dimensions of atopy: allergen specificity, time course, and levels of specific IgE (sIgE). Methods Phenotypes were defined by means of LCA in 680 children of the Multizentrische Allergiestudie (MAS) and 766 children of the Protection against allergy: Study in Rural Environments (PASTURE) birth cohorts and compared with classical nondisjunctive definitions of seasonal, perennial, and food sensitization with respect to atopic diseases and lung function. Cytokine levels were measured in the PASTURE cohort. Results The LCA classified predominantly by type and multiplicity of sensitization (food vs inhalant), allergen combinations, and sIgE levels. Latent classes were related to atopic disease manifestations with higher sensitivity and specificity than the classical definitions. LCA detected consistently in both cohorts a distinct group of children with severe atopy characterized by high seasonal sIgE levels and a strong propensity for asthma; hay fever; eczema; and impaired lung function, also in children without an established asthma diagnosis. Severe atopy was associated with an increased IL-5/IFN-γ ratio. A path analysis among sensitized children revealed that among all features of severe atopy, only excessive sIgE production early in life affected asthma risk. Conclusions LCA revealed a set of benign, symptomatic, and severe atopy phenotypes. The severe phenotype emerged as a latent condition with signs of a dysbalanced immune response. It determined high asthma risk through excessive sIgE production and directly affected impaired lung function. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that children raised on farms are protected from asthma and allergies. It is unknown whether the farming effect is solely mediated by atopy or also affects nonatopic wheeze phenotypes. Objective: We sought to study the farm effect on wheeze phenotypes and objective markers, such as lung function and exhaled nitric oxide, and their interrelation with atopy in children. Methods: The GABRIEL Advanced Studies are cross-sectional, multiphase, population-based surveys of the farm effect on asthma and allergic disease in children aged 6 to 12 years. Detailed data on wheeze, farming exposure, and IgE levels were collected from a random sample of 8023 children stratified for farm exposure. Of those, another random subsample of 858 children was invited for spirometry, including bronchodilator tests and exhaled nitric oxide measurements. Results: We found effects of exposure to farming environments on the prevalence and degree of atopy, on the prevalence of transient wheeze (adjusted odds ratio, 0.78; 95% CI, 0.64-0.96), and on the prevalence of current wheeze among nonatopic subjects (adjusted odds ratio, 0.45; 95% CI, 0.32-0.63). There was no farm effect on lung function and exhaled nitric oxide levels in the general study population. Conclusions: Children living on farms are protected against wheeze independently of atopy. This farm effect is not attributable to improved airway size and lung mechanics. These findings imply as yet unknown protective mechanisms. They might include alterations of immune response and susceptibility to triggers of wheeze, such as viral infections. [ABSTRACT FROM AUTHOR]

Abstract: Within the EU project “Health Effects of Particles from Motor Engine Exhaust and Ambient Pollution” (HEPMEAP), ambient particulate matter (PM) was collected at sites, with varying traffic density and sources of PM emissions, in the Netherlands and Munich, Germany. In the Netherlands, measurements were conducted close to four schools which had participated 4 years earlier in a study on respiratory health of children attending schools near motorways. In Munich, measurements were conducted at a high traffic inner city and a suburban background (low traffic) site. Measurements were spaced over a period of approximately 1 year. Collection of PM was conducted using both high volume and low volume impaction methods. In addition to PM mass, PM-absorbance (‘soot’) and NO2 were measured as indicators of fossil fuel combustion. PM2.5 and PM10 concentrations calculated from the high volume collections were highly correlated with PM2.5 and PM10 concentrations measured simultaneously by low volume samplers (R 2 0.87–0.94). Both high and low volume measurements showed little difference in semi annual average PM mass concentrations between sites within each country, with PM concentrations at the highest exposed sites being only about 10–30% higher compared to the lowest exposed sites. Contrasts for PM-absorbance and NO2 were significantly higher than for PM mass (70–90% in the Netherlands and 90–167% in Germany). This demonstrates a higher impact of traffic on these components compared to PM mass. [Copyright &y& Elsevier]

Abstract Background Adverse effects of higher air pollution levels before and after birth on subsequent lung function are often reported in the literature. We assessed whether low-to-moderate levels of air pollution during preschool-age impact upon lung function at school-age. Methods In a prospective birth cohort of 304 healthy term-born infants, 232 (79%) completed lung function at follow-up at six years. Using spatial-temporal models, levels of individual air pollution (nitrogen dioxide (NO 2) and ozone (O 3), particulate matter with a diameter <10 μm (PM 10)) were estimated for the time windows pregnancy, first up to the sixth year of life separately, and birth until follow-up at six years. Time window means were compared to World Health Organization (WHO) guideline limits. Associations of exposure windows with spirometry and body plethysmography indices were analyzed using regression models, adjusting for potential confounders. For subgroup analysis, air pollution exposure was categorized into quartiles (four groups of 52 children). Results Mean NO 2 level from birth until follow-up was [mean (range)] [11.8 (4.9 to 35.9 μg/m3)], which is almost 4-times lower than the WHO suggested limit of 40 μg/m3. In the whole population, increased air pollution levels from birth until follow-up were associated with reduced lung function at six years. In the subgroup analysis, the 52 children exposed to NO 2 levels from the highest quartile during pregnancy, the first and second years of life and from birth until follow-up, had a significant decrease in forced expiratory volume in 1 s (FEV 1). Per interquartile range increase of NO 2 , FEV 1 decreased by [z-score change (95% confidence interval)] [−1.07 (−1.67 to −0.47)], [−1.02 (−1.66 to −0.39)], [−0.51 (−0.86 to −0.17)] and [−0.80 (−1.33 to −0.27)], respectively. Air pollution exposure during pregnancy and childhood resulted in a non-significant decrease in lung volume at six years, as assessed by functional residual capacity measured by body plethysmography (FRC pleth). Conclusion Our results suggest that exposure to higher NO 2 levels, which are still much lower than WHO guideline limits, especially during the sensitive period of early lung development, may be associated with reduced lung function at school-age. These findings support the concept of age and dose-dependent pollution effects on lung function in healthy school-aged children and underline the importance of pollution reduction measures. Highlights • Low-level early life NO 2 exposure associates with impaired school-age lung function. • These effects occurred at annual NO 2 <20 μg/m3, thus below recommended WHO threshold. • These dose dependent effects were mainly found for NO 2 exposure in infancy. • Thus, infancy seems to be a susceptible window for air pollution effects. [ABSTRACT FROM AUTHOR]