François Maltais

Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2007 update

Chronic obstructive pulmonary disease (COPD) is a major respiratory illness in Canada that is both preventable and treatable. Our understanding of the pathophysiology of this complex condition continues to grow and our ability to offer effective treatment to those who suffer from it has improved considerably. The purpose of the present educational initiative of the Canadian Thoracic Society (CTS) is to provide up to date information on new developments in the field so that patients with this condition will receive optimal care that is firmly based on scientific evidence. Since the previous CTS management recommendations were published in 2003, a wealth of new scientific information has become available. The implications of this new knowledge with respect to optimal clinical care have been carefully considered by the CTS Panel and the conclusions are presented in the current document. Highlights of this update include new epidemiological information on mortality and prevalence of COPD, which charts its emergence as a major health problem for women; a new section on common comorbidities in COPD; an increased emphasis on the meaningful benefits of combined pharmacological and nonpharmacological therapies; and a new discussion on the prevention of acute exacerbations. A revised stratification system for severity of airway obstruction is proposed, together with other suggestions on how best to clinically evaluate individual patients with this complex disease. The results of the largest randomized clinical trial ever undertaken in COPD have recently been published, enabling the Panel to make evidence-based recommendations on the role of modern pharmacotherapy. The Panel hopes that these new practice guidelines, which reflect a rigorous analysis of the recent literature, will assist caregivers in the diagnosis and management of this common condition.

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

BACKGROUND Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

The effect of obesity on chronic respiratory diseases: pathophysiology and therapeutic strategies

Sedentary lifestyles and increased pollution brought about by industrialization pose major challenges to the prevention of both obesity and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, obstructive sleep apnea and obesity hypoventilation syndrome. Obesity has emerged as an important risk factor for these respiratory diseases, and in many instances weight loss is associated with important symptomatic improvement. Moreover, obesity may influence the development and presentation of these diseases. In this article, we review the current understanding of the influence of obesity on chronic respiratory diseases and the clinical management of obesity concurrent with asthma, COPD, obstructive sleep apnea or obesity hypoventilation syndrome.

Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD

BACKGROUND Enzymatic and histochemical abnormalities of the peripheral muscle may play a role in exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to measure the mitochondrial enzyme activity of the vastus lateralis muscle in patients with COPD and to evaluate the relationship between enzyme activities and functional status. METHODS Fifty seven patients with COPD of mean (SD) age 66 (7) years with forced expiratory volume in one second (FEV1) 39 (15)% predicted and peak oxygen uptake (V˙o 2) of 14 (4) ml/min/kg and 15 normal subjects of similar age were included in the study. Each subject performed a stepwise exercise test up to maximal capacity during which five-breath averages of V˙o 2were measured. Muscle specimens were obtained by percutaneous needle biopsy of the vastus lateralis muscle and the activity of two mitochondrial enzymes (citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH)) was measured. The functional status of the patients was classified according to peakV˙o 2. RESULTS CS and HADH activities were markedly reduced in patients with COPD compared with normal subjects (22.3 (2.7) versus 29.5 (7.3) μmol/min/g muscle (p<0.0001) and 5.1 (2.0) versus 6.7 (1.9) μmol/min/g muscle (p<0.005), respectively). The activity of CS decreased progressively with the deterioration in the functional status while that of HADH was not related to functional status. Using a stepwise regression analysis, percentage predicted functional residual capacity (FRC), the activity of CS, oxygen desaturation during exercise, age, and inspiratory capacity (% pred) were found to be significant determinants of peakV˙o 2. The regression model explained 59% of the variance in peak V˙o 2 (p<0.0001). CONCLUSIONS The oxidative capacity of the vastus lateralis muscle is reduced in patients with moderate to severe COPD compared with normal subjects of similar age. In these individuals the activity of CS correlated significantly with peak exercise capacity and independently of lung function impairment.

Canadian Thoracic Society Recommendations for Management of Chronic Obstructive Pulmonary Disease – 2008 Update – Highlights for Primary Care

Chronic obstructive pulmonary disease (COPD) is a major respiratory illness in Canada that is preventable and treatable but unfortunately remains underdiagnosed. The purpose of the present article from the Canadian Thoracic Society is to provide up-to-date information so that patients with this condition receive optimal care that is firmly based on scientific evidence. Important summary messages for clinicians are derived from the more detailed Update publication and are highlighted throughout the document. Three key messages contained in the update are: use targeted screening spirometry to establish a diagnosis and initiate prompt management (including smoking cessation) of mild COPD; improve dyspnea and activity limitation in stable COPD using new evidence-based treatment algorithms; and understand the importance of preventing and managing acute exacerbations, particularly in moderate to severe disease.

Mechanical Ventilation–induced Diaphragm Disuse in Humans Triggers Autophagy

RATIONALE Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. OBJECTIVES To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. METHODS Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the α subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. MEASUREMENTS AND MAIN RESULTS Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. CONCLUSIONS We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.

Peripheral muscle endurance and the oxidative profile of the quadriceps in patients with COPD

Background: Based on previously reported changes in muscle metabolism that could increase susceptibility to fatigue, we speculated that patients with chronic obstructive pulmonary disease (COPD) have reduced quadriceps endurance and that this will be correlated with the proportion of type I muscle fibres and with the activity of oxidative enzymes. Methods: The endurance of the quadriceps was evaluated during an isometric contraction in 29 patients with COPD (mean (SE) age 65 (1) years; forced expiratory volume in 1 second 37 (3)% predicted) and 18 healthy subjects of similar age. The electrical activity of the quadriceps was recorded during muscle contraction as an objective index of fatigue. The time at which the isometric contraction at 60% of maximal voluntary capacity could no longer be sustained was used to define time to fatigue (Tf). Needle biopsies of the quadriceps were performed in 16 subjects in both groups to evaluate possible relationships between Tf and markers of muscle oxidative metabolism (type I fibre proportion and citrate synthase activity). Results: Tf was lower in patients with COPD than in controls (42 (3) v 80 (7) seconds; mean difference 38 seconds (95% CI 25 to 50), p<0.001). Subjects in both groups had evidence of electrical muscle fatigue at the end of the endurance test. In both groups significant correlations were found between Tf and the proportion of type I fibres and citrate synthase activity. Conclusion: Isometric endurance of the quadriceps muscle is reduced in patients with COPD and the muscle oxidative profile is significantly correlated with muscle endurance.

Self-management reduces both short- and long-term hospitalisation in COPD.

The aim of the present study was to assess the long-term impact on hospitalisation of a self-management programme for chronic obstructive pulmonary disease (COPD) patients. A multicentre, randomised clinical trial was carried out involving 191 COPD patients from seven hospitals. Patients who had one or more hospitalisations in the year preceding study enrolment were assigned to a self-management programme “Living Well with COPDTM” or to standard care. Hospitalisations from all causes were the primary outcome and were documented from the provincial hospitalisation database; emergency visits were recorded from the provincial health insurance database. Most patients were elderly, not highly educated, had advanced COPD (reflected by a mean forced expiratory volume in one second of 1 L), and almost half reported a dyspnoea score of 5/5 (modified Medical Research Council). At 2 years, there was a statistically significant and clinically relevant reduction in all-cause hospitalisations of 26.9% and in all-cause emergency visits of 21.1% in the intervention group as compared to the standard-care group. After adjustment for the self-management intervention effect, the predictive factors for reduced hospitalisations included younger age, sex (female), higher education, increased health status and exercise capacity. In conclusion, in this study, patients with chronic obstructive pulmonary disease who received educational intervention with supervision and support based on disease-specific self-management maintained a significant reduction in hospitalisations after a 2-year period.

The metabolic syndrome in patients with chronic obstructive pulmonary disease.

PURPOSE This study was undertaken to evaluate the presence of the metabolic syndrome in COPD patients who participated in a cardiopulmonary rehabilitation program. The metabolic syndrome is characterized by the presence of abdominal obesity, atherogenic dyslipidemia, raised blood pressure, presence of insulin resistance, and prothrombotic and inflammatory states that predispose to cardiovascular diseases. METHODS Thirty-eight COPD patients (age: 66 +/- 7 years, [mean +/- SD], FEV1: 43 +/- 16% predicted) and 34 control participants matched for age and gender are included in this study. The criteria for the identification of the metabolic syndrome include 3 or more of the following features: abdominal obesity (waist circumference: > 102 cm in men, > 88 cm in women), triglycerides levels (>or= 1.69 mmol/L), high-density lipoprotein cholesterol levels (< 1.0 mmol/L in men, < 1.3 mmol/L in women), blood pressure (>or= 130/ >or= 85 mm Hg), and fasting glucose levels (>or= 6.1 mmol/L). RESULTS Forty-seven percent of COPD patients and 21% of control participants presented 3 or more determinants of the metabolic syndrome. CONCLUSIONS The presence of metabolic syndrome is frequent in patients with COPD who participated in a cardiopulmonary program. Hence, this population should be considered for screening for the metabolic syndrome.

Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial

Background: Airway inflammation in chronic obstructive pulmonary disease (COPD) is characterised by infiltration of CD8+ T cells and CD68+ macrophages and an increased number of neutrophils, whereas few studies have described the presence of eosinophils. Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear, recent studies suggest that combination therapy could be beneficial. A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate (SFC) and fluticasone propionate (FP) alone on inflammatory cells in the airways of patients with COPD. Methods: Patients were treated in a randomised, double blind, parallel group, placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily (SFC, n = 19, 19 men, mean age 62 years), 500 µg FP twice daily (n = 20, 15 men, mean age 64 years) or placebo (n = 21, 17 men, mean age 66 years) for 3 months. At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8+ T lymphocytes, CD68+ macrophages, neutrophils and eosinophils were measured. Results: CD8+ cells were significantly reduced by SFC compared with placebo (difference −98.05 cells/mm2; 95% CI −143.14 to −52.9; p<0.001). Such a marked effect was not seen with FP alone (−44.67 cells/mm2; 95% CI −90.92 to 1.57; p = 0.06). CD68+ macrophages were also reduced by SFC compared with placebo (difference −31.68 cells/mm2; 95% CI −61.07 to −2.29; p = 0.03) but not by FP. SFC did not significantly change neutrophils and eosinophils compared with placebo. Conclusions: SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone.