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Asthma exacerbations in children are associated with respiratory viral infection and atopy, resulting in systemic immune activation and infiltration of immune cells into the airways. The gene networks driving the immune activation and subsequent migration of immune cells into the airways remains incompletely understood. Cellular and molecular profiling of PBMC was employed on paired samples obtained from atopic asthmatic children (n = 19) during acute virus-associated exacerbations and later during convalescence. Systems level analyses were employed to identify coexpression networks and infer the drivers of these networks, and validation was subsequently obtained via independent samples from asthmatic children. During exacerbations, PBMC exhibited significant changes in immune cell abundance and upregulation of complex interlinked networks of coexpressed genes. These were associated with priming of innate immunity, inflammatory and remodelling functions. We identified activation signatures downstream of bacterial LPS, glucocorticoids and TGFB1. We also confirmed that LPS binding protein was upregulated at the protein-level in plasma. Multiple gene networks known to be involved positively or negatively in asthma pathogenesis, are upregulated in circulating PBMC during acute exacerbations, supporting the hypothesis that systemic pre-programming of potentially pathogenic as well as protective functions of circulating immune cells preceeds migration into the airways. Enhanced sensitivity to LPS is likely to modulate the severity of acute asthma exacerbations through exposure to environmental LPS. [ABSTRACT FROM AUTHOR]

Background. The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence individuals' ability to detoxify environmental pollutants. Objective. To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. Methods. GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. Results. For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 ( p = .054) when assessed by genotype alone, which increased to 9.02 ( p = .050) when ETS was included, relative to individuals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold ( p = .002) increased risk of atopy ( p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile individuals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group; therefore, the odds for atopy were the same. Individuals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with individuals with at least one *C haplotype and not exposed to ETS ( p = .020). Conclusion. There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort. [ABSTRACT FROM AUTHOR]

Abstract: Cysteinyl leukotrienes (cysLTs) are pro-inflammatory mediators with increasing evidence for a role in childhood acute asthma. This study examined the influence of polymorphisms in cysLT pathway genes on urinary leukotriene E4 (uLTE4) levels and clinical status in acute asthmatic children. Children aged 2–16 years were recruited during an asthma attack (n=205). Where possible, asthma severity scores were assigned, ALOX5AP G-336A, ALOX5 G-1708A, LTC4S A-444C and G-1072A, GPX4 C718T, and CYSTLTR1 T927C genotypes were determined and uLTE4 was measured in acute and convalescent samples. uLTE4 levels were higher acutely compared with convalescence (acute GM: 115.7pg/mg creatinine; 95% CI 88.6–151.1, convalescence GM: 66.4pg/mg creatinine; 95% CI 51.5–85.6; n=50 paired samples, p=0.003) and paired sample analysis showed genotype-specific effects with significantly increased uLTE4 for LTC4S-444AA (acute GM: 127.9pg/mg creatinine; 95% CI 91.8–178.3, convalescence GM: 68.2pg/mg creatinine; 95% CI 50.5–92.0; n=32, p=0.002), LTC4S-1072 GG (acute GM: 126.7pg/mg creatinine; 95% CI 95.4–168.3, convalescence GM: 78.9pg/mg creatinine; 95% CI 59.7–104.1; n=39, p=0.019) and CYSLTR1 927 TT/T_ (acute GM: 96.8pg/mg creatinine; 95% CI 73.8–126.9, convalescence GM: 62.4pg/mg creatinine; 95% CI 46.8–83.3; n=28, p=0.036) but not AC/CC, GA/AA, or TC/CC/C_, respectively. When we compared the allele frequencies of the CYSLTR1 SNP between asthmatics and non-asthmatics, the 927C allele was found to be a risk allele for asthma (OR=2.13, 95% CI: 1.06–4.26, p=0.033). Genotypes were not associated with acute or convalescent uLTE4 levels alone and neither the SNPs nor uLTE4 correlated with acute asthma severity. Leukotriene pathway gene polymorphisms may influence the magnitude of cysLT production during an attack, yet their influence alone may not be substantial enough to alter the severity of exacerbations. [Copyright &y& Elsevier]

The aim of this study was to determine the influence of single nucleotide polymorphisms in the β2-adrenoceptor gene, on the response to inhaled β2-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to β2-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for β2Arg16Gly and β2Gln27Glu. For Gln27Glu, individuals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly β2-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1hourly: 2.6hr vs. 2.0 vs. 1.4, p = 0.02; 2 hourly: 10.6hr vs. 10.7 vs. 6.8, p = 0.07; 4 hourly: 29.8hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to β 2-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways. [ABSTRACT FROM AUTHOR]

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes. [ABSTRACT FROM AUTHOR]