Jean Bourbeau

An Official American Thoracic Society Statement: Update on the Mechanisms, Assessment, and Management of Dyspnea

BACKGROUND Dyspnea is a common, distressing symptom of cardiopulmonary and neuromuscular diseases. Since the ATS published a consensus statement on dyspnea in 1999, there has been enormous growth in knowledge about the neurophysiology of dyspnea and increasing interest in dyspnea as a patient-reported outcome. PURPOSE The purpose of this document is to update the 1999 ATS Consensus Statement on dyspnea. METHODS An interdisciplinary committee of experts representing ATS assemblies on Nursing, Clinical Problems, Sleep and Respiratory Neurobiology, Pulmonary Rehabilitation, and Behavioral Science determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant expertise. The final content of this statement was agreed upon by all members. RESULTS Progress has been made in clarifying mechanisms underlying several qualitatively and mechanistically distinct breathing sensations. Brain imaging studies have consistently shown dyspnea stimuli to be correlated with activation of cortico-limbic areas involved with interoception and nociception. Endogenous and exogenous opioids may modulate perception of dyspnea. Instruments for measuring dyspnea are often poorly characterized; a framework is proposed for more consistent identification of measurement domains. CONCLUSIONS Progress in treatment of dyspnea has not matched progress in elucidating underlying mechanisms. There is a critical need for interdisciplinary translational research to connect dyspnea mechanisms with clinical treatment and to validate dyspnea measures as patient-reported outcomes for clinical trials.

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.

Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial

Context Physicians use multiple medications to treat chronic obstructive pulmonary disease (COPD). Contribution In this multicenter trial, 449 adults with moderate or severe COPD were randomly assigned to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium and fluticasonesalmeterol for 1 year. About 63%, 65%, and 60% of patients, respectively, had exacerbations. The third group, but not the second group, had better lung function and fewer hospitalizations than the first group. Caution Many patients discontinued assigned medications. Implications Adding fluticasonesalmeterol to tiotropium may improve lung function and decrease hospitalizations, but it does not affect reduce exacerbations in patients with moderate or severe COPD. The Editors Most patients with moderate or severe chronic obstructive pulmonary disease (COPD) experience chronic progressive dyspnea that is not alleviated by short-acting bronchodilators. It is therefore not surprising that many patients are treated with multiple inhaled medications to optimize their lung function and minimize symptoms (1). Published guidelines on COPD state that the goals of pharmacologic therapy should be to control symptoms, improve health status, and reduce the frequency of COPD exacerbations (2, 3), and many published guidelines advocate combining different classes of long-acting bronchodilators or inhaled steroids to achieve these goals (2, 3). In the past several years, several studies have shown that treatment of COPD with the long-acting anticholinergic tiotropium (47); the long-acting 2-agonist salmeterol (810); or products that combine inhaled steroids and long-acting 2-agonists, such as fluticasonesalmeterol or budesonideformoterol (1114), improve dyspnea and quality of life and decrease exacerbation rates compared with placebo. However, no studies have assessed whether therapy with a combination of these products provides greater clinical benefit than does therapy with these agents used alone. 2-Agonists and anticholinergics work by different mechanisms to cause bronchodilation (15), and inhaled corticosteroids may have an anti-inflammatory effect in COPD (16). Thus, it makes theoretical and intuitive sense that combining these therapies might be more beneficial than therapy with 1 agent alone. However, safety concerns, such as side effects associated with long-term use of long-acting 2-agonists and inhaled corticosteroids, and economic issues related to the additional costs of these medications may argue against routine use of inhaled medication polypharmacy without evidence of efficacy. We therefore conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether combining tiotropium with salmeterol or fluticasonesalmeterol produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium therapy alone. Methods Design We designed a parallel-group, 3-group, randomized, double-blind, placebo-controlled trial in patients with moderate or severe COPD that was conducted from October 2003 to January 2006. The study protocol has been published elsewhere (17). The research ethics boards of all participating centers approved the study, and all trial participants provided written informed consent. Setting and Participants We enrolled patients with diagnosed moderate or severe COPD from 27 Canadian medical centers. Twenty centers were academic hospitalbased pulmonary clinics, 5 were community-based pulmonary clinics, and 2 were community-based primary care clinics. Eligible patients had to have had at least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before randomization. Additional inclusion criteria were age older than 35 years; a history of 10 pack-years or more of cigarette smoking; and documented chronic airflow obstruction, with an FEV1FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65% of the predicted value. We excluded patients with a history of physician-diagnosed asthma before 40 years of age; those with a history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction; those receiving oral prednisone; those with a known hypersensitivity or intolerance to tiotropium, salmeterol, or fluticasonesalmeterol; those with a history of severe glaucoma or severe urinary tract obstruction, previous lung transplantation or lung volume reduction surgery, or diffuse bilateral bronchiectasis; and those who were pregnant or were breastfeeding. Persons with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study. Randomization and Interventions We randomly assigned patients to 1 of 3 treatment groups for 52 weeks: tiotropium (Spiriva [Boehringer Ingelheim Pharma, Ingelheim, Germany]), 18 g once daily, plus placebo inhaler, 2 puffs twice daily; tiotropium, 18 g once daily, plus salmeterol (Serevent [GlaxoSmithKline, Research Triangle Park, North Carolina]), 25 g/puff, 2 puffs twice daily; or tiotropium, 18 g once daily, plus fluticasonesalmeterol (Advair [GlaxoSmithKline]), 250/25 g/puff, 2 puffs twice daily. Randomization was done through central allocation of a randomization schedule that was prepared from a computer-generated random listing of the 3 treatment allocations, blocked in variable blocks of 9 or 12 and stratified by site. Neither research staff nor patients were aware of the treatment assignment before or after randomization. All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms. Any treatment with inhaled corticosteroids, long-acting 2-agonists, and anticholinergics that the patient may have been using before entry was discontinued on entry into the study. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines, was continued in all patient groups. Tiotropium was administered by using a Handihaler device (Boehringer Ingelheim). Study drugs were administered through a pressurized metered-dose inhaler using a spacer device (Aerochamber Plus, Trudell Medical, London, Ontario, Canada), and patients were taught the correct inhalation technique to ensure adequate drug delivery. The metered-dose inhalers containing placebo, salmeterol, and fluticasonesalmeterol were identical in taste and appearance, and they were enclosed in identical tamper-proof blinding devices. The medication canisters within the blinding devices were stripped of any identifying labeling. Adherence to therapy was assessed by weighing the returned inhaler canisters. Measurements and Outcomes The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation within 52 weeks of randomization. Respiratory exacerbations were defined, according to the 2000 Aspen Lung Conference Consensus definition, as a sustained worsening of the patients respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD (18). An acute change in regular COPD medications was defined as physician-directed, short-term use of oral or intravenous steroids, oral or intravenous antibiotics, or both therapies. Secondary outcomes were the mean number of COPD exacerbations per patient-year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalizations for COPD; the total number of hospitalizations for all causes; and changes in health-related quality of life, dyspnea, and lung function. Health-related quality of life was assessed by using the St. Georges Respiratory Questionnaire (19), dyspnea was assessed by using the Transitional Dyspnea Index (20) and the dyspnea domain of the Chronic Respiratory Disease Questionnaire (21), and lung function was assessed by measuring the FEV1 according to established criteria of the American Thoracic Society. Follow-up Procedures Patients were monitored for exacerbations by monthly telephone calls. Exacerbations and all secondary outcomes were also assessed through patient visits at baseline and at 4, 20, 36, and 52 weeks after randomization. For every suspected exacerbation, we contacted both the patient and the patients treating physician to ensure that the medical encounter had been prompted by acute respiratory symptoms and a full report, including physician, emergency department, and hospital records that described the circumstances of each suspected exacerbation, was prepared. The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review, and the committee confirmed whether the encounter met the study definition of COPD exacerbation. For the purposes of the trial, we considered that a patient had experienced a new COPD exacerbation if he or she had not been receiving oral steroids and antibiotics for at least 14 days after the previous exacerbation. Patients were followed for the full 52-week duration of the trial, and primary and secondary outcomes were recorded throughout the 1-year period regardless of whether patients had experienced an exacerbation or discontinued treatment with study medications. We did not break the study blinding for patients who prematurely discontinued treatment with study medications. Adverse events were captured by the research coordinators through monthly patient telephone interviews and at scheduled patient visits by using checklists of potential side effects. Physicians rated events as expected or unexpected, and they were asked to rate event severity and attribute causality of adverse events to the study drugs. Statistical Analysis We designed the study to detect an 18% absolute d

The burden of COPD in Italy: results from the confronting COPD survey

Chronic obstructive pulmonary disease is a smoking-related condition of progressive airflow obstruction, with disabling symptoms of chronic dyspnoea, cough and sputum production. In Spain, as in other countries worldwide, only a limited number of studies have attempted to quantify the impact of COPD on the patient, healthcare system and society. To obtain comprehensive information about the burden of this disease, an economic analysis of a large international survey, Confronting COPD in North America and Europe, was conducted. The results of the economic analysis of data from the Spanish survey sample estimated that the annual cost of COPD to the healthcare system was Euro 3238 per patient, with indirect costs amounting to Euro 300 per patient bringing the total societal cost of the disease to Euro 3538 per patient per year. A significant proportion of the economic burden of COPD on the Spanish healthcare system was associated with inpatient hospitalization (Euro 2708), which accounted for almost 84% of the total direct cost of the disease. As the major cause of inpatient hospitalization for COPD is acute exacerbations, these results highlight the need for interventions in the outpatient setting to prevent exacerbations in Spain. The impact of COPD on the healthcare system may also be due to the underdiagnosis and treatment of COPD, suggesting that costs may be reduced by improving the diagnosis and treatment of the disease in primary care. The sub-analysis of costs from the survey showed that patients with severe COPD were associated with considerably higher total societal costs than patients with mild disease (Euro 9850 versus Euro 1316 per patient). Therefore, introducing interventions to reduce the progression to severe COPD could also reduce the impact of the disease.

Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis

Background: A systematic review was undertaken to evaluate the efficacy of tiotropium, a long acting anticholinergic drug, on clinical events, symptom scales, pulmonary function, and adverse events in stable chronic obstructive pulmonary disease (COPD). Methods: A systematic search was made of the Cochrane trials database, MEDLINE, EMBASE, CINAHL, and a hand search of 20 respiratory journals. Missing data were obtained from authors and the manufacturer. Randomised controlled trials of ⩾12 weeks’ duration comparing tiotropium with placebo, ipratropium bromide, or long acting β2 agonists (LABA) were reviewed. Studies were pooled to yield odds ratios (OR) or weighted mean differences with 95% confidence intervals (CI). Results: Nine trials (8002 patients) met the inclusion criteria. Tiotropium reduced the odds of a COPD exacerbation (OR 0.73; 95% CI 0.66 to 0.81) and related hospitalisation (OR 0.68; 95% CI 0.54 to 0.84) but not pulmonary (OR 0.50; 95% CI 0.19 to 1.29) or all-cause (OR 0.96; 95% CI 0.63 to 1.47) mortality compared with placebo and ipratropium. Reductions in exacerbations and hospitalisations compared with LABA were not statistically significant. Similar patterns were evident for quality of life and symptom scales. Tiotropium yielded greater increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from baseline to 6–12 months than did placebo, ipratropium, and LABA. Decline in FEV1 over 1 year was 30 ml (95% CI 7 to 53) slower with tiotropium than with placebo and ipratropium (data were not available for LABA). Reports of dry mouth and urinary tract infections were increased with tiotropium. Conclusions: Tiotropium reduced COPD exacerbations and related hospitalisations, improved quality of life and symptoms, and may have slowed the decline in FEV1. Long term trials are warranted to evaluate the effects of tiotropium on decline in FEV1 and to clarify its role compared with LABA.

Independent Effect of Depression and Anxiety on Chronic Obstructive Pulmonary Disease Exacerbations and Hospitalizations

RATIONALE Depression and anxiety are significant comorbid and potentially modifiable conditions in chronic obstructive pulmonary disease (COPD), but their effects on exacerbations are not clear. OBJECTIVES To investigate the independent effect of depression and anxiety on the risk of COPD exacerbations and hospitalizations. METHODS A multicenter prospective cohort study in 491 patients with stable COPD in China. Multivariate Poisson and linear regression analyses were used, respectively, to estimate adjusted incidence rate ratios (IRRs) and adjusted effects on duration of events. MEASUREMENTS AND MAIN RESULTS Depression and anxiety were measured using the Hospital Anxiety and Depression Scale (HADS) at baseline. Other measurements included sociodemographic, clinical, psychosocial, and treatment characteristics. Patients were then monitored monthly for 12 months to document the occurrence and characteristics of COPD exacerbations and hospitalizations. Exacerbation was determined using both symptom-based (worsening of > or =1 key symptom) and event-based definitions (> or =1 symptom worsening plus > or =1 change in regular medications). A total of 876 symptom-based and 450 event-based exacerbations were recorded, among which 183 led to hospitalization. Probable depression (HADS depression score > or = 11) was associated with an increased risk of symptom-based exacerbations (adjusted IRR, 1.51; 95% confidence interval [CI], 1.01-2.24), event-based exacerbations (adjusted IRR, 1.56; 95% CI, 1.02-2.40), and hospitalization (adjusted IRR, 1.72; 95% CI, 1.04-2.85) compared with nondepression (score < or = 7). The duration of event-based exacerbations was 1.92 (1.04-3.54) times longer for patients with probable anxiety (HADS anxiety score > or = 11) than those with no anxiety (score < or = 7). CONCLUSIONS This study suggests a possible causal effect of depression on COPD exacerbations and hospitalizations. Further studies are warranted to confirm this finding and to test the effectiveness of antidepressants and psychotherapies on reducing exacerbations and improving health resource utilizations.

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.

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary.

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed. Read the executive summary of the new @GOLD_COPD 2017 report in the European Respiratory Journal http://ow.ly/XxfD308BDfc

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.

Managing Dyspnea in Patients with Advanced Chronic Obstructive Pulmonary Disease: A Canadian Thoracic Society Clinical Practice Guideline

Dyspnea is a cardinal symptom of chronic obstructive pulmonary disease (COPD), and its severity and magnitude increases as the disease progresses, leading to significant disability and a negative effect on quality of life. Refractory dyspnea is a common and difficult symptom to treat in patients with advanced COPD. There are many questions concerning optimal management and, specifically, whether various therapies are effective in this setting. The present document was compiled to address these important clinical issues using an evidence-based systematic review process led by a representative interprofessional panel of experts. The evidence supports the benefits of oral opioids, neuromuscular electrical stimulation, chest wall vibration, walking aids and pursed-lip breathing in the management of dyspnea in the individual patient with advanced COPD. Oxygen is recommended for COPD patients with resting hypoxemia, but its use for the targeted management of dyspnea in this setting should be reserved for patients who receive symptomatic benefit. There is insufficient evidence to support the routine use of anxiolytic medications, nebulized opioids, acupuncture, acupressure, distractive auditory stimuli (music), relaxation, handheld fans, counselling programs or psychotherapy. There is also no evidence to support the use of supplemental oxygen to reduce dyspnea in nonhypoxemic patients with advanced COPD. Recognizing the current unfamiliarity with prescribing and dosing of opioid therapy in this setting, a potential approach for their use is illustrated. The role of opioid and other effective therapies in the comprehensive management of refractory dyspnea in patients with advanced COPD is discussed.