Search

Background: Extracellular DNA (e-DNA) and neutrophil extracellular traps (NETs) are linked to asthmatics airway inflammation. However, data demonstrating the characterization of airway inflammation associated with excessive e-DNA production and its impact on asthma outcomes are limited., Objective: To characterize the airway inflammation associated with excessive e-DNA production and its association with asthma control, severe exacerbations and pulmonary function, particularly, air trapping and small airway dysfunction., Methods: We measured e-DNA concentrations in induced sputum from 134 asthma patients and 28 healthy controls. We studied the correlation of e-DNA concentrations with sputum neutrophils, eosinophils and macrophages and the fractional exhaled nitric oxide (FeNO). Lung function was evaluated using spirometry, body plethysmography, impulse oscillometry and inert gas multiple breath washout. We stratified patients with asthma into low-DNA and high-DNA to compare lung function impairments and asthma outcomes., Results: Patients with severe asthma had higher e-DNA concentration (54.2 ± 42.4 ng/µl) than patients with mild-moderate asthma (41.0 ± 44.1 ng/µl) or healthy controls (26.1 ± 16.5 ng/µl), (all p values < 0.05). E-DNA concentrations correlated directly with sputum neutrophils (R = 0.49, p < 0.0001) and negatively with sputum macrophages (R = - 0.36, p < 0.0001), but neither with sputum eosinophils (R = 0.10, p = 0.26), nor with FeNO (R = - 0.10, p = 0.22). We found that 29% of asthma patients (n = 39) had high e-DNA concentrations above the upper 95th percentile value in healthy controls (55.6 ng /μl). High-DNA was associated with broad lung function impairments including: airflow obstruction of the large (FEV 1 ) and small airways (FEF50%, FEF25-75), increased air trapping (RV, RV/TLC), increased small airway resistance (R5-20, sReff), decreased lung elasticity (X5Hz) and increased ventilation heterogeneity (LCI), (all P values < 0.05). We also found that high e-DNA was associated with nearly three-fold greater risk of severe exacerbations (OR 2·93 [95% CI 1.2-7.5]; p = 0·012), worse asthma control test (p = 0.03), worse asthma control questionnaire scores (p = 0.01) and higher doses of inhaled corticosteroids (p = 0.026)., Conclusion: Increased production of extracellular DNA in the airway characterizes a subset of neutrophilic asthma patients who have broad lung function impairments, poor symptom control and increased risk of severe exacerbations.

The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference -0.357, 95% CI -0.661- -0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation., Competing Interests: Conflict of interest: F. Maltais reports research support from Boehringer Ingelheim, GSK, AstraZeneca, Grifols and Novartis, advisory board participation for Boehringer Ingelheim and GSK, and speaking engagements for Boehringer Ingelheim, Grifols and Novartis. Conflict of interest: J-L. Aumann has nothing to disclose. Conflict of interest: A-M. Kirsten reports institutional compensation for clinical trials from Boehringer Ingelheim, during the conduct of the study; has lectured for Boehringer Ingelheim, AstraZeneca and Berlin-Chemie, and reports institutional compensation for clinical trials from AstraZeneca, Boehringer Ingelheim, Roche, GSK, Novartis, Chiesi, Bayer Healthcare and Sanofi, outside the submitted work. Conflict of interest: É. Nadreau has nothing to disclose. Conflict of interest: H. Macesic is an employee of Boehringer Ingelheim. Conflict of interest: X. Jin is an employee of Boehringer Ingelheim. Conflict of interest: A. Hamilton is an employee of Boehringer Ingelheim. Conflict of interest: D.E. O'Donnell reports grants from AstraZeneca, Boehringer Ingelheim and GSK, during the conduct of the study; and personal fees for serving on speaker bureaus, consultation panels and advisory boards from Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Novartis and Pfizer, outside the submitted work., (Copyright ©ERS 2019.)

Background and Purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV 1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use., Materials and Methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313)., Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV 1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL ( P <0.001). In addition, IND/MF (QMF149) treatment significantly improved COPD exacerbation-related parameters during the 12-week period. Other significant improvements with IND/MF (QMF 149) vs Sal/Flu were noted for dyspnea at week 12 and other COPD symptoms and COPD rescue medication use over the 12 weeks. The safety and tolerability profiles of both the treatments were similar., Conclusion: IND/MF (QMF149) (150/160 µg once daily) offered superior lung function and symptom efficacy and a favorable safety profile compared with Sal/Flu (50/500 µg twice daily) in patients with moderate-to-very severe COPD., Competing Interests: Disclosure AMT, BH and AR are employees of Novartis Pharma AG. WC is an employee of Novartis Pharmaceuticals Corporation. KMB declares that no personal payments were received from any pharmaceutical entity in the past 5 years. KMB and JB are full-time employees of Insaf Respiratory Research Institute. AMK is an employee of the Pulmonary Research Institute at LungClinic Grosshansdorf. AMK received speaking honoraria, honoraria for participation in advisory board meetings, and travel support for attending congresses in respiratory medicine from Boehringer Ingelheim, AstraZeneca, and Novartis. RNVZS has received honoraria for academic work from Novartis, AZ, CIPLA, ASPEN, Pfizer, GSK, and MSD. The authors report no other conflicts of interest in this work.

Background: The TORRACTO ® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment., Methods: The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients., Results: A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo., Conclusion: Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].

Background: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study., Methods: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed., Results: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV 1 ) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV 1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P <0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P <0.05). Aclidinium improved trough FEV 1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P <0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P <0.05). Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks. Tolerability showed similar incidence of AEs in each arm., Conclusion: In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity., Competing Interests: Disclosure JB has received consulting fees, speaker’s fees, and travel expenses from AstraZeneca and has also received compensation for organizing or participating in advisory boards for Cytos, Boehringer Ingelheim, Almirall, AstraZeneca, Novartis, and Revotar Biopharmaceuticals. The institution where JB is currently employed has received compensation for the design, performance, or participation in single or multicenter clinical trials in the past 5 years from several companies including Almirall, Altana, AstraZeneca, Boehringer Ingelheim, Cytos, GSK, Meda Pharmaceuticals, Merck Sharp & Dohme, Mundipharma, Novartis, Pfizer, and Revotar Biopharmaceuticals. RM has received consulting fees, speaker’s fees, and travel expenses from Boehringer Ingelheim and has also received compensation for participating in advisory boards for Boehringer Ingelheim, Almirall, AstraZeneca, and Novartis. Furthermore, RM has received compensation for participation in multicenter clinical trials in the past 5 years from several companies including Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Merck Sharp & Dohme, Mundipharma, Novartis, Pearl, Roche, and Takeda. A-MK is a current employee of Pulmonary Research Institute at LungenClinic Grosshansdorf; the institution received compensation for the design of and/or participation in clinical trials from Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Pfizer, Infinity Pharmaceuticals, TEVA, Sterna Biologicals, Chiesi, Bayer, and Takeda. Furthermore, A-MK has received consulting fees, and speaker’s fees from AstraZeneca, Boehringer Ingelheim, and Roche. FC and EGG are employees of AstraZeneca PLC, Barcelona, Spain, and former employees of Almirall S.A., Barcelona, Spain.

Background: Two replicate, double-blind, placebo-controlled, 6-week crossover studies assessed the effect of the once-daily long-acting β2-agonist olodaterol 5 μg and 10 μg on constant work-rate cycle endurance in patients with moderate to very severe chronic obstructive pulmonary disease., Methods: Patients received placebo, olodaterol 5 μg once daily (QD) and olodaterol 10 μg QD in a randomised order for 6 weeks each, with a 2-week washout period in between. The primary end point was change in endurance time during constant work-rate cycle ergometry to symptom limitation at 75 % maximal work capacity after 6 weeks of treatment (2 h post-dose), based on log10-transformed data. Key secondary end points were inspiratory capacity at isotime and intensity of breathing discomfort at isotime., Results: 151 and 157 patients were randomised and treated in Studies 1222.37 and 1222.38, respectively, with 147 and 154 being included in the full analysis sets. Mean endurance time at week 6 was increased compared to placebo by 14.0 % (Study 1222.37; p < 0.001) and 11.8 % (Study 1222.38; p < 0.01) with olodaterol 5 μg, and by 13.8 % (Study 1222.37; p < 0.001) and 10.5 % (Study 1222.38; p < 0.01) with olodaterol 10 μg. Inspiratory capacity at isotime increased with olodaterol 5 μg (Study 1222.37, 0.182 L, p < 0.0001; Study 1222.38, 0.084 L, p < 0.05) and 10 μg (Study 1222.37, 0.174 L; Study 1222.38, 0.166 L; both studies, p < 0.0001), and breathing discomfort was significantly reduced in Study 1222.37 (olodaterol 5 μg, 0.77 Borg units, p < 0.001; olodaterol 10 μg, 0.63 Borg units, p < 0.01) but not Study 1222.38., Conclusions: These studies provide further characterisation of the efficacy of olodaterol, showing that improvements in airflow (forced expiratory volume in 1 s) are associated with increases in inspiratory capacity and improvements in exercise endurance time., Trial Registrations: NCT01040130 (1222.37) and NCT01040793 (1222.38).

Background: Little is known about the consequences of idiopathic pulmonary fibrosis (IPF) for physical activity (PA)., Objectives: We aimed to investigate levels of PA in IPF and to study associations of PA with lung function, exercise capacity, symptoms, and quality of life., Methods: In stable patients with IPF we measured PA (steps per day, SPD; physical activity level, PAL; minutes of moderate activity, MMA) by accelerometry (SenseWear Armband) for 1 week. We also assessed lung function (forced vital capacity, FVC; diffusing capacity for carbon monoxide, DLCO); exercise capacity (6-minute walking distance, 6MWD); dyspnea (modified Medical Research Council, mMRC); fatigue (Multidimensional Fatigue Inventory, MFI-20), and generic (12-Item Short Form Survey, SF-12) and health-related quality of life (St. George's Respiratory Questionnaire) as further clinical variables., Results: We investigated 48 patients with IPF in two centers (mean age, 67 years; 75% male; 23% on long-term oxygen therapy; mean FVC 75%pred.; mean DLCO 43%pred.; mean 6MWD 355 ± 140 m; mean SPD 5,017 ± 3,360). On a bivariate level, all clinical variables were significantly associated with SPD (p < 0.05). The associations of mMRC, MFI-20, SF-12 (physical health), and 6MWD with SPD were independent of impaired lung function (p < 0.05). At multivariate analyses, either 6MWD (total explained variance of the model, total R2: 42%) or MFI-20 (total R2: 39%) were the strongest independent predictors of SPD., Conclusion: Fatigue and exercise capacity are strong and independent predictors of PA in patients with IPF, which suggests that both measures should be assessed when the consequences of IPF for PA in daily life are studied., (© 2016 S. Karger AG, Basel.)