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Background Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology. Objective The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation. Methods We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into the highest and lowest bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high ( N  = 277) vs. low ( N  = 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed. Results We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR = 2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways. Conclusion MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients. Trial registration LOCCS cohort [ClinicalTrials.gov number NCT00156819, Registration date 20050912], GACRS cohort [ClinicalTrials.gov number NCT00021840].

Environmental tobacco smoke (ETS) has adverse effects on the health of asthmatics, however the harmful consequences of ETS in relation to asthma severity are unknown. In a multicenter study of severe asthma, we assessed the impact of ETS exposure on morbidity, health care utilization and lung functions; and activity of systemic superoxide dismutase (SOD), a potential oxidative target of ETS that is negatively associated with asthma severity. From 2002-2006, 654 asthmatics (non-severe 366, severe 288) were enrolled, among whom 109 non-severe and 67 severe asthmatics were routinely exposed to ETS as ascertained by history and validated by urine cotinine levels. ETS-exposure was associated with lower quality of life scores; greater rescue inhaler use; lower lung function; greater bronchodilator responsiveness; and greater risk for emergency room visits, hospitalization and intensive care unit admission. ETS-exposure was associated with lower levels of serum SOD activity, particularly in asthmatic women of African heritage. ETS-exposure of asthmatic individuals is associated with worse lung function, higher acuity of exacerbations, more health care utilization, and greater bronchial hyperreactivity. The association of diminished systemic SOD activity to ETS exposure provides for the first time a specific oxidant mechanism by which ETS may adversely affect patients with asthma.

Dry powder inhalers (DPIs) are prescribed after hospitalization for acute exacerbation of COPD (AECOPD). Peak inspiratory flow (PIF) affects DPI delivery. To study the impact of PIF on readmission after hospitalization for AECOPD. A retrospective analysis of hospitalized patients, enrolled in an AECOPD care plan, was performed. Data analyzed included PIF, age, sex, length of stay, Charlson Comorbidity Index, COPD Assessment Test score, modified Medical Research Council score, percent predicted FEV , FVC, and inspiratory capacity. A PIF equal to and less than 60 L/min was defined as suboptimal (sPIF). Outcome measures included 30- and 90-day COPD and all-cause readmissions, and days to next COPD and all-cause readmissions. Of the 123 subjects, 52% (n = 64) had sPIF. They had greater COPD Assessment Test scores (29.1 ± 5.9 vs. 25.3 ± 8.7; P = 0.0073), rates of 90-day COPD readmissions (28.1 vs. 13.6%; P = 0.048), fewer median days to COPD (63.5 [interquartile range (IQR), 21-89.8] vs. 144 [IQR, 66-218]; P = 0.002) and all-cause readmissions (65.5 [IQR, 24.3-107.3] vs. 101 [IQR, 54.5-205.5]; P = 0.009). PIF was the only variable (P = 0.041) that predicted days to COPD readmission in a multivariate model incorporating age, sex, percent predicted FEV , Charlson Comorbidity Index, and inspiratory flow group. In a group of patients with sPIF (n = 22), all-cause and COPD 30- and 90-day readmission rates were significantly lower for those discharged with nebulizer compared with DPI therapy. sPIF is common during AECOPD and predicts all-cause and COPD readmissions. Patients with sPIF may benefit from nebulized therapies. We recommend checking PIF in patients hospitalized for AECOPD for selection of delivery devices.

Chronic obstructive pulmonary disease (COPD) is a disease with marked metabolic disturbance. Previous studies have shown the association between single metabolites and lung function for COPD, but whether a combination of metabolites could predict phenotype is unknown. We developed metabolomic severity scores using plasma metabolomics from the Metabolon platform from two US cohorts of ever-smokers: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) (n = 648; training/testing cohort; 72% non-Hispanic, white; average age 63 years) and the COPDGene Study (n = 1120; validation cohort; 92% non-Hispanic, white; average age 67 years). Separate adaptive LASSO (adaLASSO) models were used to model forced expiratory volume at one second (FEV1) and MESA-adjusted lung density using 762 metabolites common between studies. Metabolite coefficients selected by the adaLASSO procedure were used to create a metabolomic severity score (metSS) for each outcome. A total of 132 metabolites were selected to create a metSS for FEV1. The metSS-only models explained 64.8% and 31.7% of the variability in FEV1 in the training and validation cohorts, respectively. For MESA-adjusted lung density, 129 metabolites were selected, and metSS-only models explained 59.0% of the variability in the training cohort and 17.4% in the validation cohort. Regression models including both clinical covariates and the metSS explained more variability than either the clinical covariate or metSS-only models (53.4% vs. 46.4% and 31.6%) in the validation dataset. The metabolomic pathways for arginine biosynthesis; aminoacyl-tRNA biosynthesis; and glycine, serine, and threonine pathway were enriched by adaLASSO metabolites for FEV1. This is the first demonstration of a respiratory metabolomic severity score, which shows how a metSS can add explanation of variance to clinical predictors of FEV1 and MESA-adjusted lung density. The advantage of a comprehensive metSS is that it explains more disease than individual metabolites and can account for substantial collinearity among classes of metabolites. Future studies should be performed to determine whether metSSs are similar in younger, and more racially and ethnically diverse populations as well as whether a metabolomic severity score can predict disease development in individuals who do not yet have COPD.

Abstract Rationale As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation. Objectives We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity. Methods Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (FeNO), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated. Measurements and Main Results Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of FeNO and serum arginase activity. However, Arg bioavailability was positively associated with FeNO only in healthy control subjects; Arg bioavailability was unrelated to FeNO or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma. Conclusions Unlike FeNO, Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.

In adolescents and adults with moderate-to-severe asthma, the addition of formoterol to inhaled glucocorticoids was associated with a lower risk of asthma exacerbations than that with glucocorticoids alone and with a similar risk of serious asthma-related events. Current guidelines for the management of asthma suggest that inhaled glucocorticoids should be used as initial controller therapy, with a long-acting beta-agonist (LABA) then added if symptoms remain uncontrolled or increase in severity. 1 Although LABAs have been an available treatment option for asthma since 1990, 2 questions remain regarding the safety of this drug class. 3 These concerns originate mainly from the results of two large studies in which the effects of adding the LABA salmeterol to existing asthma treatment were reviewed. 4 , 5 These studies showed higher rates of asthma-related death and other serious outcomes related to asthma among patients receiving salmeterol . . .

Patients with asthma vary markedly in their clinical response to inhaled glucocorticoids. These investigators used a novel approach to identify a common variant in the glucocorticoid-induced transcript 1 gene associated with a decreased response to glucocorticoids. Asthma is a complex genetic syndrome that affects 300 million persons worldwide. 1 The response to treatment is also genetically complex and is characterized by high intraindividual repeatability 2 and high interindividual variability, 3 with up to 40% of patients with asthma having no response to therapy. Inhaled glucocorticoids are the most widely prescribed medications for controlling asthma. Levels of endogenous glucocorticoids are heritable and vary, both at baseline and in response to environmental perturbation. 4 – 6 Moreover, studies in families with conditions other than asthma have shown both familial segregation and heritability in responses to glucocorticoid medications. 7 , 8 Given the heritability within the . . .