Julie Milot

Six-Minute Walking Versus Shuttle Walking: Responsiveness to Bronchodilation in Chronic Obstructive Pulmonary Disease

Background: The responsiveness of the endurance shuttle walk to functional changes following bronchodilation has recently been reported. The current literature suggests that the 6 min walking test (6MWT) is less responsive to bronchodilation than the endurance shuttle walk. Aim: To compare bronchodilator-induced changes in exercise performance with the 6MWT and the endurance shuttle walk. Methods: In a randomised, double-blind, placebo-controlled, crossover trial, 14 patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 s (FEV1) 50 (8)% predicted) completed two 6MWTs and two endurance shuttle walks, each preceded by nebulised placebo or 500 μg ipratropium bromide. Cardiorespiratory parameters were monitored during each walking test with a portable telemetric gas analyser. Quadriceps twitch force was measured by magnetic stimulation of the femoral nerve before and after each walking test. Results: The 6 min walking distance did not change significantly after bronchodilation despite a significant increase in FEV1 of 0.18 (0.09) litres (p<0.001). A similar change in FEV1 (0.18 (0.12) litres, p<0.001) was associated with a significant improvement in the distance walked on the endurance shuttle walk (Δdistance ipratropium bromide – placebo  =  144 (219) m, p = 0.03). Quadriceps muscle fatigue was infrequent (<15% of patients) after both walking tests. Conclusion: The endurance shuttle walk is more responsive than the 6MWT for detecting changes in exercise performance following bronchodilation.

Impact of preinduced quadriceps fatigue on exercise response in chronic obstructive pulmonary disease and healthy subjects

Exercise intolerance in chronic obstructive pulmonary disease (COPD) results from a complex interaction between central (ventilatory) and peripheral (limb muscles) components of exercise limitation. The purpose of this study was to evaluate the influence of quadriceps muscle fatigue on exercise tolerance and ventilatory response during constant-workrate cycling exercise testing (CWT) in patients with COPD and healthy subjects. Fifteen patients with COPD and nine age-matched healthy subjects performed, 7 days apart, two CWTs up to exhaustion at 80% of their predetermined maximal work capacity. In a randomized order, one test was performed with preinduced quadriceps fatigue and the other in a fresh state. Quadriceps fatigue was produced by electrostimulation-induced contractions and quantified by maximal voluntary contraction and potentiated twitch force (TwQ(pot)). Endurance time and ventilatory response during CWT were compared between fatigued and fresh state. Endurance time significantly decreased in the fatigued state compared with the fresh condition in COPD (356 +/- 69 s vs. 294 +/- 45 s, P < 0.05) and controls (450 +/- 74 s vs. 340 +/- 45 s, P < 0.05). Controls showed significantly higher ventilation and end-exercise dyspnea scores in the fatigued condition, whereas, in COPD, fatigue did not influence ventilation or dyspnea during exercise. The degree of ventilatory limitation, as expressed by the Ve/maximum voluntary ventilation ratio, was similar in both conditions in patients with COPD. We conclude that it is possible to induce quadriceps fatigue by local electrostimulation-induced contractions. Our findings demonstrate that peripheral muscle fatigue is an additional important factor, besides intense dyspnea, that limits exercise tolerance in COPD.

Clinical utilization of genomics data produced by the international Pseudomonas aeruginosa consortium

The International Pseudomonas aeruginosa Consortium is sequencing over 1000 genomes and building an analysis pipeline for the study of Pseudomonas genome evolution, antibiotic resistance and virulence genes. Metadata, including genomic and phenotypic data for each isolate of the collection, are available through the International Pseudomonas Consortium Database (http://ipcd.ibis.ulaval.ca/). Here, we present our strategy and the results that emerged from the analysis of the first 389 genomes. With as yet unmatched resolution, our results confirm that P. aeruginosa strains can be divided into three major groups that are further divided into subgroups, some not previously reported in the literature. We also provide the first snapshot of P. aeruginosa strain diversity with respect to antibiotic resistance. Our approach will allow us to draw potential links between environmental strains and those implicated in human and animal infections, understand how patients become infected and how the infection evolves over time as well as identify prognostic markers for better evidence-based decisions on patient care.

Combined effect of dietary supplementation with pressurized whey and exercise training in chronic obstructive pulmonary disease: a randomized, controlled, double-blind pilot study.

Pressurized whey supplementation, by its antioxidant and nutritional properties, may improve exercise tolerance and potentiate the effects of exercise training in patients with chronic obstructive pulmonary disease (COPD). In this randomized, double-blind, placebo-controlled study, 22 patients with COPD were allocated to receive active pressurized whey or placebo (casein) dietary supplementation for a 16-week period. Patients continued their usual physical activities for the first 8 weeks, whereas they were subjected to an exercise training program for the remaining 8 weeks of the study. Patients were evaluated at baseline, after 8 weeks of supplementation alone (time point, 8 weeks), and after 8 weeks of its combination with exercise training (time point, 16 weeks). The constant workrate cycle endurance test (CET), potentiated quadriceps twitch force, mid-thigh cross-sectional area, and Chronic Respiratory Questionnaire (CRQ) were used to evaluate the effects of treatments. The inflammatory (C-reactive protein and interleukin-6) and oxidant/antioxidant (protein oxidation and glutathione) blood profiles were also characterized. At week 8, there was no increase in CET time in either group. At week 16, there was a statistically significant increase in CET time in the whey-only group (P < .05). Further, at week 16, there was clinically significant improvement in the Dyspnea and the Mastery scales of the CRQ in both groups. Also, the Fatigue and Emotional Control scales of the CRQ showed clinically significant improvement in the whey-only group. Study interventions did not modify significantly the systemic inflammatory and oxidative stress markers that were assessed. Thus dietary supplementation with pressurized whey may potentiate the effects of exercise training on exercise tolerance and quality of life in patients with COPD.

Relationship between changes in diurnal variation of expiratory flows, lung volumes and respiratory symptoms after acute asthma

We looked at the comparative recovery of asthma symptoms and changes in airflow obstruction after an acute exacerbation of asthma in 26 asthmatics, aged 18-69 years (mean = 43). In the 4 weeks following the acute episode, they recorded their respiratory symptoms and twice-daily peak expiratory flow rates (PEFR). In 14 subjects, lung volumes were also measured on days 1, 7 and 30. Mean initial FVC and FEV1 [+/- SEM (% predicted)] were 2.30 +/- 0.16 (61%) and 1.18 +/- 0.08 (39%). The rate of improvement of airflow obstruction initially paralleled that of asthma symptoms in subjects with mild or with a recent onset of asthma. On the first study day, diurnal variation of PEFR was minimal, increased rapidly during the first week of treatment and stabilized thereafter. Mean daily delta PEFR was significantly higher in the first than at the fourth week (P = 0.005). Recovery of asthma symptoms was associated with an overall reduction in FRC and RV but there was no significant correlation between FRC or RV and dyspnea score or PEFR. Perception of airflow obstruction was generally lower, improvement of symptoms slower and of smaller amplitude in those with long-standing asthma. In conclusion, during recovery from acute asthma: (1) diurnal variation of PEFR is initially minimal, increases rapidly after beginning steroids and stabilize in the two following weeks; (2) in patients with more than mild or long-standing asthma, and magnitude and range of perception of asthma symptoms is reduced and correlates less with PEFR; and (3) no significant correlation could be found between FRC or RV and dyspnea score or PEFR.

Effect of Bisoprolol on Respiratory Function and Exercise Capacity in Chronic Obstructive Pulmonary Disease

Cardioselective β blockers are considered to have little impact on lung function at rest in patients with chronic obstructive pulmonary disease (COPD). However, their effects on dynamic hyperinflation, an important mechanism contributing to symptoms and exercise tolerance in patients with COPD, have not been evaluated. Twenty-seven patients with moderate to severe COPD (forced expiratory volume in 1 second 52 ± 13% predicted) completed pulmonary function tests, echocardiography, maximal exercise tests, and cycle endurance tests at baseline. Inspiratory capacity was measured at 2-minute intervals during the cycle endurance test to quantify dynamic hyperinflation. Pulmonary function and cycle endurance testing were repeated after 14 days of bisoprolol 10 mg/day and 14 days of placebo in a randomized, double-blind, placebo-controlled, crossover trial. The extent of dynamic hyperinflation at peak isotime exercise with bisoprolol and placebo was compared. Peak isotime was defined as the latest time point that was reached during the 2 cycle endurance tests. Changes in inspiratory capacity from rest to peak isotime were different with bisoprolol compared to placebo (-0.50 ± 0.35 vs -0.41 ± 0.33 L, p = 0.01). Exercise duration tended to be lower with bisoprolol compared to placebo (305 ± 125 vs 353 ± 172 seconds, p = 0.11). The magnitude of change in exercise duration between the bisoprolol and placebo conditions was correlated with the magnitude of change in inspiratory capacity (r = 0.57, p <0.01). In conclusion, bisoprolol was associated with modest worsening dynamic hyperinflation, whereas exercise duration remained unchanged in patients with moderate to severe COPD. The magnitude of these effects was small and should not contraindicate the use of bisoprolol in patients with COPD.

The potential for aclidinium bromide, a new anticholinergic, in the management of chronic obstructive pulmonary disease

Long-acting muscarinic antagonists (LAMAs) play a central role in the management of chronic obstructive pulmonary disease (COPD). Previously, only one LAMA (tiotropium) was available for the treatment of COPD, necessitating the development of other therapeutic options due to the heterogeneity of COPD and patient responses to treatment. This article reviews the COPD management potential of aclidinium bromide, a LAMA administered twice daily (BID) by a multidose dry powder inhaler that is indicated for maintenance treatment of COPD. Aclidinium possesses kinetic selectivity for the M3 versus M2 receptor and is rapidly hydrolyzed in plasma to two major inactive metabolites, resulting in a low and transient systemic exposure and minimizing the potential for systemic side effects. A pharmacokinetic study with multiple doses of twice-daily aclidinium demonstrated the short half-life of aclidinium in plasma, suggesting that a steady state may be reached as early as the second day postdose. In a phase II study, twice-daily aclidinium 400 µg provided 24-hour bronchodilation, with significant improvements versus tiotropium during the second half of the day. In two phase III studies (ACCORD I and ATTAIN), both aclidinium 200 µg and 400 µg BID provided statistically significant improvements in trough forced expiratory volume in 1 second (FEV1) and other related lung function measurements. Improvements in peak FEV1 on day 1 were comparable to those at study end, demonstrating that aclidinium provides maximal bronchodilation after the first dose that is maintained over time. Health status was significantly improved and dyspnea, nighttime and morning symptoms of COPD were likewise significantly reduced with aclidinium. Numerically greater improvements in efficacy were observed with the 400 µg dose compared with the lower dose, with similar safety profiles between the two doses and a low incidence of anticholinergic side effects. The approved therapeutic dose of aclidinium 400 µg BID is thus an effective new treatment option for patients with COPD.

Cluster Analysis in Patients with GOLD 1 Chronic Obstructive Pulmonary Disease

Background We hypothesized that heterogeneity exists within the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 spirometric category and that different subgroups could be identified within this GOLD category. Methods Pre-randomization study participants from two clinical trials were symptomatic/asymptomatic GOLD 1 chronic obstructive pulmonary disease (COPD) patients and healthy controls. A hierarchical cluster analysis used pre-randomization demographics, symptom scores, lung function, peak exercise response and daily physical activity levels to derive population subgroups. Results Considerable heterogeneity existed for clinical variables among patients with GOLD 1 COPD. All parameters, except forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), had considerable overlap between GOLD 1 COPD and controls. Three-clusters were identified: cluster I (18 [15%] COPD patients; 105 [85%] controls); cluster II (45 [80%] COPD patients; 11 [20%] controls); and cluster III (22 [92%] COPD patients; 2 [8%] controls). Apart from reduced diffusion capacity and lower baseline dyspnea index versus controls, cluster I COPD patients had otherwise preserved lung volumes, exercise capacity and physical activity levels. Cluster II COPD patients had a higher smoking history and greater hyperinflation versus cluster I COPD patients. Cluster III COPD patients had reduced physical activity versus controls and clusters I and II COPD patients, and lower FEV1/FVC versus clusters I and II COPD patients. Conclusions The results emphasize heterogeneity within GOLD 1 COPD, supporting an individualized therapeutic approach to patients. Trial registration www.clinicaltrials.gov. NCT01360788 and NCT01072396.

Exacerbation induces a microbiota shift in sputa of COPD patients

Little is known about the microbiota shift induced by exacerbation in chronic obstructive pulmonary disease (COPD) patients. The sputa microbiota of COPD patients was evaluated when clinically stable and during acute exacerbations of the disease. Sputa microbiota was analyzed using 16S ribosomal RNA gene pyrosequencing and quantitative polymerase chain reaction-based pathogen detection. Nine COPD patients were enrolled. Pyrosequencing of 16S rRNA genes identified 2,267 unique bacterial operational taxonomic units. Principal microbiota shifts during exacerbation were in either Proteobacteria, Firmicutes or Bacteroidetes. Streptococcus and Moraxella levels were detected during exacerbation in severe (Global Initiative for Chronic Obstructive Lung Disease 3) COPD patients. Most of the clinically-important genera found in the sputum with the pyrosequencing of 16S rRNA gene correlated with specific quantitative polymerase chain reactions for bacteria while respiratory viruses were nearly absent. Sputum microbiotas of exacerbated COPD patients are complex. This pilot study shows a clear shift in the microbiota of patients during exacerbation. The nature of this shift varies from patient to patient in such a way that the treatment should be patient-specific. Further studies are needed to establish the impact of microbial exacerbations on the pulmonary microbiota.