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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.
La maladie pulmonaire obstructive chronique (MPOC) est une maladie respiratoire majeure au Canada, à la fois évitable et traitable. Notre compréhension de la physiopathologie de cette maladie complexe continue d’évoluer, et notre capacité d ’offrir un traitement efficace aux personnes atteintes s’est améliorée considérablement. La présente initiative en matière d’éducation de la Société canadienne de thoracologie (SCT) vise à fournir de l’information à jour au sujet des progrès dans le domaine, afin que les patients atteints de cette maladie reçoivent des soins optimaux fondés sur des données probantes solides. Depuis la publication des dernières recommandations de prise en charge de la SCT en 2003, on a mis au jour une pléthore de nouvelles données scientifiques. Le groupe de travail de la SCT a évalué consciencieusement les conséquences de ces nouvelles connaissances en matière de soins cliniques optimaux, et le présent document contient les conclusions tirées de cet examen. Les faits saillants de cette mise à jour sont de nouvelles données épidémiologiques sur la mortalité et la prévalence de la MPOC, qui en révèlent l’émergence comme trouble de santé d’importance pour les femmes, une nouvelle rubrique sur les comorbidités de la MPOC, une plus grande attention accordée aux bienfaits significatifs de l’association des thérapies pharmacologiques et non pharmacologiques et un nouvel exposé sur la prévention des exacerbations aiguës. On propose un système révisé de stratification pour établir la gravité de l’obstruction des voies aériennes, de même que d’autres suggestions sur le meilleur moyen de procéder à l’évaluation clinique de chaque patient atteint de cette maladie complexe. Les résultats du plus grand essai clinique aléatoire jamais entrepris dans le domaine de la MPOC ont récemment été publiés, ce qui a permis au groupe de travail de présenter des recommandations probantes sur le rôle de la pharmacothérapie moderne. Le groupe de travail espère que ces nouvelles lignes de pratique, qui reflètent une analyse rigoureuse des publications récentes, aideront les dispensateurs de soins dans le diagnostic et la prise en charge de cette maladie courante.
The Canadian Thoracic Society (CTS) Review Panel evaluated all peer-reviewed papers published in the area of chronic obstructive pulmonary disease (COPD) from 2003 to the present. Fifteen content experts undertook responsibility to review their designated topics and each submitted his or her analysis and recommendations to the Panel for discussion during two separate conference meetings. Evidence weighting for each recommendation was assigned based on criteria listed in Table 1 (1). A working document summarizing the scientific review together with consensus recommendations (draft i) was circulated to the Panel for feedback and final approval. The revised draft (ii) was then widely circulated for feedback from external experts from affiliated societies (family physicians, nursing, physical therapy, respiratory therapy, pharmacists). The final draft incorporated revisions from these numerous experts and was submitted for publication.
COPD is a respiratory disorder largely caused by smoking, and is characterized by progressive, partially reversible airway obstruction and lung hyperinflation, systemic manifestations, and increasing frequency and severity of exacerbations.
COPD is usually suspected in patients with a significant smoking history who present with progressive exertional dyspnea, cough and/or sputum production, and frequent respiratory tract infections. All patients with suspected COPD should have their lung function assessed by spirometry (2). The forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC) is the most important measurement for the identification of an obstructive impairment (2). A post bronchodilator FEV1/FVC ratio of less than 0.7 defines airflow obstruction that is not fully reversible, and is necessary to establish a diagnosis of COPD.
In 2004, COPD was the fourth leading cause of death in both men and women in Canada (3), a significant increase from 1999 when it was the fifth leading cause of death (4). In 2004, 5152 men and 4455 women died of COPD, a mortality increase of more than 12% in women from 1999 (3,4). The number of COPD deaths in women increased by 117% from 1988 to 2003 and will likely surpass the number of deaths in men in the near future (3,4) (Figure 1). The number of deaths among men decreased by 7% within this time frame, although it still remains high. Age-standardized mortality rates increase sharply for those over 75 years of age. The change in age composition of the population with an increasing number of people older than 65 years of age will result in continued increases in mortality rates for COPD (particularly in women) in the foreseeable future. Furthermore, the estimated mortality rate is a significant underestimation because the primary cause of death is often coded as another diagnosis, such as congestive heart failure or pneumonia (5).
Currently available prevalence estimates based on self-reporting or physician diagnosis likely significantly underestimate the true prevalence of COPD (6,7). According to the 2005 Canadian Community Health Survey, 4.4% of Canadians aged 35 years or older (over 700,000 adults) have probable COPD based on self-reporting of diagnoses made by health care professionals (4). For the same age group, the prevalence among men is 3.9% and the prevalence for women now stands at 4.8%. The overall prevalence of probable COPD has been similar since 1994/1995, although the questions used to elicit the information have differed somewhat over the years. In 2000/2001, the prevalence of probable COPD increased with age for both men and women (Figure 2). Women have a higher prevalence of COPD in all age groups except for the 75 year and older age group, in which the male prevalence is higher (men 11.8%, women 7.5%).
In Canada, cigarette smoke is the main inflammatory trigger in COPD. COPD develops in some smokers but not others due to a complex interaction between the susceptible host and its changing environment. Some host factors have been well studied, including alpha1-antitrypsin (AAT) deficiency, a history of childhood viral infections and bronchial hyper-responsiveness. Environmental risk factors other than exposure to tobacco smoke include occupational exposures and air pollution (3,8,9).
COPD is characterized by complex and diverse pathophysiological manifestations. Persistent inflammation of the small and large airways, as well as the lung parenchyma and its vasculature, occurs in a highly variable combination that differs from patient to patient.
Understanding of this inflammatory process continues to grow (10–22). Evidence of airway inflammation is present even in early disease where spirometric abnormalities are minor (23). The inflammatory process in COPD persists long after the inciting stimulus (cigarette smoke) is withdrawn (22). It is clear that the inflammatory process in COPD is different in many important respects from that in asthma (18,24).
Expiratory flow limitation is the pathophysiological hallmark of COPD. This arises because of intrinsic airway factors that increase resistance (eg, mucosal inflammation and edema, airway remodelling and fibrosis, and secretions) and extrinsic airway factors (eg, reduced airway tethering from emphysema and regional extraluminal compression by adjacent overinflated alveolar units) (19,20,23). Emphysematous destruction also reduces elastic lung recoil and, thus, the driving pressure for expiratory flow, further compounding flow limitation. Further modulation of airway calibre in COPD is provided by the autonomic nervous system, which can be pharmacologically manipulated.
Expiratory flow limitation with dynamic collapse of the small airways compromises the ability of patients to expel air during forced and quiet expiration; thus, air trapping and lung overinflation occurs (Figure 3). The volume of air in the lungs at the end of quiet expiration (ie, end-expiratory lung volume) is increased and is a continuous dynamic variable in COPD. When the breathing rate acutely increases (and expiratory time diminishes) as, for example, during exercise in COPD, there is further dynamic lung overinflation as a result of air trapping, which contributes to dyspnea (25). Acute-on-chronic hyperinflation has been shown to be an important determinant of shortness of breath during exercise and with exacerbations in COPD (25–29).
Oxygen uptake and carbon dioxide elimination by the lungs are compromised because of regional inequalities of ventilation and perfusion throughout the lungs, leading ultimately to hypoxemia and hypercapnia.
Destruction of the vascular bed due to emphysema, together with the vasoconstrictor effects of chronic hypoxia, lead to pulmonary hypertension and right heart failure (30). New evidence suggests that pulmonary hypertension is due to direct toxic effects of tobacco smoke on the pulmonary vasculature, resulting in the production of endothelial-derived vasoactive mediators and vascular remodelling. Changes seen are similar to those found in idiopathic pulmonary arterial hypertension (31,32). The presence of pulmonary hypertension in COPD indicates a poor prognosis (33,34). Significant pulmonary hypertension at rest is rarely a problem in COPD and it affects only a minority of patients. When severe pulmonary hypertension occurs in less advanced COPD, the presence of another disease should be considered (35).
In the recent Towards a Revolution in COPD Health (TORCH) trial (36), which followed more than 6000 patients with COPD over a three-year period, 35% of deaths were adjudicated to be due to pulmonary causes, 27% to cardiovascular disease, 21% to cancer and in 7% the primary cause of death was not known. Comorbidity has been defined as a recognized and distinct disease entity coexisting with the primary disease of interest. COPD is associated with many comorbid conditions, particularly those related to the cardiovascular system. Other comorbidities frequently associated with COPD include osteopenia and osteoporosis (37), glaucoma and cataracts (38), cachexia and malnutrition (39), peripheral muscle dysfunction (40), cancer (41) and the metabolic syndrome (42). Rates of recognized depression in COPD vary from 20% to 50% and increase with disease severity (43,44).
Soriano et al (38) found that compared with controls, COPD patients had increased risk of angina (a 1.67-fold increase) and myocardial infarction (a 1.75-fold increase). They also had increased risk for fractures (a 1.58-fold increase) and glaucoma (a 1.29-fold increase). Sidney et al (45) found that compared with age- and sex-matched control subjects, COPD patients were 2.7 times more likely be hospitalized for ventricular arrhythmias, 2.1 times more likely to be hospitalized for atrial fibrillation, two times more likely to be hospitalized for angina, 1.9 times more likely to be hospitalized for myocardial infarction and 3.9 times more likely to be hospitalized for congestive heart failure. Overall, COPD patients were 1.8 times more likely to die from cardiovascular causes of mortality and two times more likely to be hospitalized for cardiovascular diseases than were age- and sex-matched control subjects (45).
The main causes of mortality in mild or moderate COPD are lung cancer and cardiovascular diseases, while in more advanced COPD (less than 60% FEV1), respiratory failure becomes the predominant cause. However, even in patients with advanced COPD, cardiovascular events account for approximately 20% of all deaths (42). Cardiovascular disease also leads to hospitalization of COPD patients. For example, in the Lung Health Study (46), cardiovascular causes accounted for 42% of first hospitalizations and 44% of second hospitalizations of patients with relatively mild COPD. In comparison, respiratory causes accounted for only 14% of hospitalizations.
Not only do comorbidities increase the risk of certain causes of mortality, they also increase all-cause mortality risk in COPD. Antonelli Incalzi et al (47) found that five-year mortality risk was significantly predicted by an FEV1 less than 0.59 L (hazard ratio [HR]=1.49) and age (HR=1.04), as well as electrocardiogram signs of right ventricular hypertrophy (HR=1.76), chronic renal failure (HR=1.79), and myocardial infarction or ischemia (HR=1.42), with an overall sensitivity of 63% and a specificity of 77%.
Skeletal muscle dysfunction is also a significant comorbidity. In more advanced COPD, when patients become immobilized with dyspnea, there are measurable metabolic and structural abnormalities of peripheral locomotor muscles. The prevalence of peripheral muscle wasting is estimated at 30% and increases with disease severity (48). These peripheral muscle abnormalities contribute to exercise intolerance (49), and result from the combined effects of immobility, altered nutritional status, prolonged hypoxia and, possibly, sustained systemic inflammation (50,51). Loss of muscle mass is a predictor of mortality, independent of lung function (52,53).
The mechanistic link between COPD and comorbidities is uncertain. COPD and many of the comorbidities share a common risk factor, namely, cigarette smoking. Recently, some evidence has implicated systemic and pulmonary inflammation as the common link between COPD and certain comorbid conditions, such as lung cancer, cardiovascular disease and cachexia (54–61).
Underdiagnosis of COPD remains a significant problem and many patients already have advanced pulmonary impairment at the time of diagnosis (62). Early diagnosis, when coupled with successful smoking cessation interventions, will provide substantial long-term health benefits (63). Smoking cessation in patients with mild COPD has been shown to slow the progression of decline in FEV1 and, thus, alter the natural history of the disease (63,64). Earlier diagnosis and management may also be important given the availability of effective modern pharmacotherapy, which improves symptoms and health status in patients with COPD. In a recent study (65), approximately 50% of individuals diagnosed with COPD through screening received new treatment as a result of the diagnosis.
Mass screening of asymptomatic individuals for COPD is not supported by the current evidence and therefore is not recommended. Targeted spirometric testing to establish early diagnosis in individuals at risk for COPD is recommended (8,9,66–69). A postbronchodilator FEV1/FVC ratio less than 0.7 confirms the presence of airway obstruction that is not fully reversible and is currently widely accepted as the diagnostic criterion for COPD. However, this fixed ratio can lead to false positive diagnosis in the elderly (70). Comparison of the FEV1/FVC ratio to the lower limits of normal adjusted for age and height (ie, below the 5th percentile of predicted normal) may be preferable (71). If the diagnosis is uncertain, referral to a specialist for further assessment is appropriate.
No clinical, evidence-based criteria currently exist to help guide the caregiver in selecting individuals who are at risk for COPD for diagnostic spirometry. The Canadian Lung Assocation has suggested that patients who are older than 40 years of age and who are current or ex-smokers should undertake spirometry if they answer yes to any one of the following questions:
Acute exacerbation is a common initial clinical presentation of COPD. Therefore, it is recommended that long-term smokers (current or past) who seek medical attention for treatment of respiratory tract infection should be offered elective diagnostic spirometry when the acute symptoms subside and the patient’s condition has stabilized.
Objective indices of airway obstruction often fluctuate over time but must persist and not fully normalize if a diagnosis of COPD is to be made. Accordingly, it is possible that the diagnosis of COPD cannot be established at the first evaluation.
Clinical assessment begins with a thorough history which should include the following:
Physical examination of patients with COPD, although important, is not usually diagnostic and even careful physical examination can underestimate the presence of significant airflow limitation. With more advanced disease, signs of lung hyperinflation, right heart failure and generalized muscle wasting may be evident (74). Physical examination should be undertaken to assess for possible comorbidities.
Postbronchodilator spirometry is required to assist in the evaluation of the severity of airway obstruction to establish the diagnosis of COPD.
More extensive pulmonary function testing may be undertaken in selected patients for a more complete clinical characterization of the COPD phenotype. These additional tests may include other tests of airway function (small airway function), inspiratory capacity, static lung volumes, diffusing capacity and tests of respiratory muscle function.
The 6 minute walking test is a useful test of functional disability and provides prognostic information (75,76). Arterial oxygen desaturation during walking can be measured accurately with a pulse oximeter. Cardiopulmonary exercise testing (77) provides excellent objective measurement of pulmonary impairment, and the peak symptom-limited oxygen uptake during incremental cycle exercise is an independent prognostic factor in COPD (78). Cardiopulmonary exercise testing also has an established role in presurgical evaluation, particularly in patients with more advanced disease. Constant work rate cycle endurance tests can be used to evaluate the impact of therapeutic interventions (79,80).
Arterial blood gas measurements should be considered for patients with an FEV1 less than 40% predicted if they have low arterial oxygen saturation (less than 92% on oximetry) (81), or for patients in whom respiratory failure is suspected (77). Venous blood tests may be obtained to assess polycythemia, anemia, AAT level and protease inhibitor type (77).
Assessment of nutritional status (eg, body mass index, lean body mass) and peripheral muscle function (eg, strength and endurance testing, dual energy x-ray absorptiometry scans and computed tomography imaging) can be undertaken in selected patients.
Chest x-rays are not diagnostic for COPD, but are often required to rule out comorbidities. High-resolution computed tomography scanning can be used to identify the extent and distribution of the airspace dilation that characterizes emphysema, but is currently not routinely required (77).
Echocardiography, including echo-Doppler estimation of peak right ventricular systolic pressure, can be used to assess pulmonary hypertension in selected patients (77).
Although the validation of airflow limitation is best made by spirometry, the validation of airway inflammation may be made by quantitative cell counts in induced or spontaneously expectorated sputum, because bronchitis is an important component of the characteristics of airway disease and difficult to recognize without measurement (82). Sputum differential cell counts may be useful in deciding if inhaled corticosteroids (ICSs) are needed, or to detect an infection that may require treatment with an antibiotic (83,84). Currently, there is no evidence to identify whether the detection of steroid-responsive eosinophilic bronchitis in COPD or asthma indicates the need for long-term corticosteroids. However, a treatment strategy that uses sputum cell counts to guide therapy decreases exacerbations in patients with COPD (85).
Biomarkers such as C-reactive protein and sputum cytology are being used to investigate the underlying cellular and molecular pathophysiology of COPD. They may be useful in predicting disease progression, disease instability, response to therapy (new and current) and mortality (41,86,87). Genetic factors are known to influence susceptibility to the development of COPD. There is an increasing body of literature supporting the measurement of candidate genes and markers but to date no clinically useful screening gene or marker has been developed to identify susceptible smokers (88–90).
Additional investigations to identify comorbidities are often required in patients with more advanced COPD (see above).
No consensus exists as to which parameters should be routinely used in charting the course of the disease in individual patients. Traditionally, the rate of decline of FEV1 has been used to assess disease progression. Faster rates of decline often occur in active smokers (64) and appear to be greater in patients with frequent exacerbations (91). Other important outcomes which provide prognostic information include the number and severity of exacerbations and hospitalizations (92–97), age (78,98–101), nutritional status (body weight , fat-free mass , body mass index [53,78,99,102]), the presence of gas exchange abnormalities (diffusing capacity [78,101,103], arterial blood gases [99,100,103], use of long-term oxygen therapy ), MRC dyspnea scale (73,78,105), the ratio of inspiratory capacity to total lung capacity (105), exercise tolerance (6 minute walking distance [75,105], peak oxygen uptake , maximal work rate ), use of oral corticosteroids (100,101), the presence of comorbidities (42,47) and the presence of pulmonary hypertension (33,34).
Most existing paradigms for the stratification of disease severity use the FEV1 (106,107). However, there is a relatively poor correlation between the FEV1 and the risk of mortality, and there is no consensus as to which risk stratification system should be used. Some patients with relatively minor abnormalities in spirometry may have significant exertional symptoms and require further investigation. The ideal system would use a composite index with evaluation in the domains of impairment (function), disability (activity) and handicap (participation). The BODE index (body mass index, airflow obstruction, dyspnea and exercise capacity) is a recently published comprehensive grading system of disease severity that better predicts survival than FEV1 alone (108). FEV1 measurement by itself, while necessary for diagnostic purposes and for follow-up of the disease, correlates less well with symptom intensity, exercise capacity and quality of life (26,109). The MRC dyspnea scale represents an easy and useful clinical measure which better reflects overall disease impact among COPD patients (Table 3).
A simple stratification system of severity based on both spirometry and the MRC dyspnea grade is provided in Table 3, with the recognition that measures of impairment and subjective symptoms may be poorly correlated in individual patients. This stratification system requires formal validation but nonetheless provides important clinical information to guide treatment decisions.
In most instances, physicians can readily differentiate between COPD and asthma (Table 4). However, in a small proportion of patients, diagnostic differentiation can be challenging and may require additional investigation. COPD patients generally have a later age of onset of symptoms and have a significant smoking history. In COPD, symptoms are chronic and slowly progressive over years, whereas in asthma, symptoms of shortness of breath are more intermittent and less likely to be associated with progressive disability. When patients exhibit the clinical features outlined above, together with a demonstration of persistent airway obstruction (ie, postbronchodilator FEV1/FVC ratio less than 0.7) in response to a trial of acute bronchodilator therapy, this strongly suggests the diagnosis of COPD. Importantly, it should be stressed that a significant bronchodilator response does not exclude the diagnosis of COPD.
It is important to identify patients with mixed asthma and COPD (eg, asthmatic patients with a significant smoking history). In practice, the relative contribution of each disease to airway obstruction is often difficult to ascertain. Patients with a large improvement in FEV1 (eg, greater than 0.4 L) following an inhaled short-acting bronchodilator likely have underlying asthma (110). Marked diurnal variability of peak expiratory flow rates or significant fluctuations over time in any measure of airway obstruction is also suggestive of asthma. Large spirometric improvements following treatment with inhaled or oral steroids also suggest asthma. Only the baseline eosinophil count in induced sputum has been shown to significantly correlate with reversibility of airway obstruction following treatment with oral corticosteroids (level of evidence: 3B) (111–113). The potential utility of this test in clinical practice needs further assessment. Patients with combined asthma and COPD may benefit from combination therapy with both beta2-agonist and anticholinergic bronchodilators, and if the asthma component is prominent, earlier introduction of ICS may be justified. Moreover, education and self-management plans for mixed disease need to be individualized, and will reflect different goals and treatment expectations than for patients with either disease alone.
Other conditions included in the differential diagnosis of older patients presenting with progressive breathlessness include cardiovascular conditions, pulmonary vascular disease (eg, pulmonary emboli), severe deconditioning, obesity, anemia, interstitial lung disease and, rarely, neuromuscular disease. Patients with advanced COPD often have several comorbidities (see above).
Referral to a specialist may be appropriate when there is uncertainty over the diagnosis; symptoms are severe or disproportionate to the level of obstruction; there is an accelerated decline of function (FEV1 decline of 80 mL or more per year over a two-year period); and the onset of symptoms occurs at a young age. Specialists can also assist in the assessment and management of patients who fail to respond to bronchodilator therapy, or those who require pulmonary rehabilitation or an assessment for oxygen therapy. Specialist assistance may also be needed for the management of patients with severe or recurrent exacerbations of COPD, for patients with complex comorbidities, and for those requiring assessment for surgical intervention (ie, bullectomy, lung volume reduction surgery [LVRS], lung transplantation).
The goals of management of COPD are as follows:
Therapy would be expected to escalate from MRC grade 2 through to grade 5. Patients with an MRC grade of 3 to 5 are disabled and require a more intensive comprehensive management strategy to optimize outcomes, including combined pharmacotherapeutic and nonpharmacological interventions from the outset (Figure 4). A management approach for patients with symptomatically milder COPD (MRC dyspnea score of 2) is outlined in Table 5.
Components of COPD education should be individualized because they will vary with disease severity. Important educational components are outlined in Table 6. Education alone is not associated with improved lung function or exercise performance (114). Specific educational interventions, such as self-management programs with the support of a case manager and smoking cessation, have been shown to be effective in reducing health resource utilization, both related and unrelated to management of acute exacerbations of COPD (AECOPD) (63,115).
In 2005, 22% of Canadians aged 12 years and older still smoked, with the highest percentage of smokers (ie, 28%) in the 20- to 34-year-old cohort (116) (Figure 5). The relationship between smoking status and the development of clinically significant COPD is complex and depends on age, sex and the spirometric definition used for COPD (117). Like the Global Initiative for Chronic Obstructive Lung Disease, the CTS requires an FEV1/FVC ratio less than 0.70 to support the diagnosis of COPD; using that criterion, it has been shown that 25% of current smokers older than 45 years have COPD (117). In this same observational study, the prevalence of COPD in male and female smokers aged 61 to 62 years was 39% and 46%, respectively. Many other smokers will have objective evidence of damage to smaller airways. Quitting smoking produces only a small improvement of the FEV1. However, the subsequent rate may return toward that of a nonsmoker, thus helping to delay the onset of disability due to COPD. Smoking cessation is the single most effective intervention to reduce the risk of developing COPD and to slow its progression (level of evidence: 1A). Quitting will result in symptomatic relief of chronic cough, sputum expectoration, shortness of breath and wheezing, and reduce the risk of cardiovascular disease and cancer of the lung and other organs. Although approximately 41% of smokers try to quit smoking each year, only approximately 10% achieve and maintain abstinence (118).
At least 70% of smokers visit a physician each year and smoking cessation advice is quoted as an important motivator to quit (119). Quitting advice given to all smokers, regardless of whether they have chronic disease, by physicians (level of evidence: 1A), nonphysician health professionals (level of evidence: 2A), and individual and group counselling (levels of evidence: 1A), increases cessation (119).
The use of medication, including nicotine replacement therapy and the antidepressant bupropion, approximately doubles cessation rates and is recommended unless there are contraindications (119,120) (level of evidence: 1A) (Table 7). Nicotine replacement therapy in conjunction with bupropion may have additive effects (121). A new nicotinic acetylcholine partial agonist, varenicline, has been shown to be more efficacious than bupropion or placebo (level of evidence: 1A). Varenicline has been shown to have superior short- and long-term efficacy compared with placebo (122–126), as well as superior short-term efficacy compared with bupropion (122,123). However, results showing varenicline’s long-term benefit over bupropion are inconsistent after one year of follow-up (122,123,125).
Bronchodilators currently form the mainstay of pharmacological therapy for COPD (Figure 6). Bronchodilators work by decreasing airway smooth muscle tone, thus improving expiratory flow and lung emptying and reducing hyperinflation. Little information exists concerning the efficacy of pharmacotherapy in patients with milder COPD (ie, FEV1 greater than 65% predicted), making evidence-based guidelines for this subpopulation impossible. Evidence supporting the use of three classes of bronchodilators in COPD, as well as the combination products, is summarized below.
The Optimal Therapy study (156) was a randomized, double-blind, placebo-controlled trial that studied the effectiveness of adding SALM or SALM/FP to therapy with tiotropium for the treatment of patients with moderate and severe COPD (FEV1 less than 65% of the predicted value). Although the study did not show that the addition of SALM/FP to tiotropium significantly improved overall exacerbation rates (primary outcome), significant benefits were demonstrated on secondary outcomes (lung function, quality of life and hospitalization rates).
Another recent study (178) demonstrated that combination therapy with SALM/FP compared with SALM monotherapy reduces the frequency of moderate to severe exacerbations in patients with severe COPD.
Inhaled anticholinergic drugs are generally well tolerated. A bitter taste is reported by some using ipratropium. Occasional prostatic symptoms with urinary retention have been reported. The use of wet nebulizer solutions with a face mask can precipitate glaucoma if the drug gets directly into the eye. In clinical trials, tiotropium has been associated with a dry mouth in 12% to 16% of patients; however, less than 1% of patients withdrew from the trial due to this side effect. Urinary retention occurred in 0.73% of patients taking tiotropium; urinary tract infection occurred in 7.3% of patients taking tiotropium, compared with 5.1% of patients taking placebo (146,147). Supraventricular tachy-arrhythmias are reported at a rate of between 0.1% and 1% greater with tiotropium than placebo (tiotropium bromide product monograph). Available information on the pharmacokinetics of the LAAC tiotropium suggest that the addition of short-acting anticholinergics (ipratropium bromide, combination ipratropium bromide and salbutamol) should not result in additional benefits in terms of increased bronchodilation but may instead predispose patients to significant adverse effects (179).
Inhaled beta2-agonists are generally well tolerated. The most common adverse effects involve the cardiovascular system and the central nervous system. Cardiovascular effects include tachycardia, palpitation and flushing. Extrasystoles and atrial fibrillation may also be seen. In patients with coronary artery disease, beta2-agonists may induce angina. Central nervous system effects include irritability, sleepiness and tremor. Other adverse effects of beta2-agonists may include gastrointestinal upset, nausea, diarrhea, muscle cramps and hypokalemia (143). The TORCH study (36) confirmed the safety of SALM therapy in patients with moderate to severe COPD over the three-year period of the study.
Adverse effects of ICS include dysphonia and oral candidiasis (180–182). ICS in doses greater than 1.5 mg/day of beclomethasone equivalent may be associated with a reduction in bone density (183,184). Long-term high doses of ICS are associated with posterior subcapsular cataracts, and, rarely, ocular hypertension and glaucoma (185–187). Skin bruising is also common with high-dose exposure (169,170,172). In the TORCH study, the probability of having pneumonia was significantly higher among patients receiving ICS compared with placebo (19.6% in the SALM/FP group, 18.3% in the FP group and 12.3% in the placebo group) (36). In a recent large cohort study, a dose-related increase in the risk of pneumonia requiring hospitalization was also found among patients using ICS (188).
Case 1 is a 57-year-old woman with COPD. She complains of dyspnea only with heavier exertion such as climbing stairs or dancing. She is not short of breath walking on level ground. Her FEV1 is 80% predicted post bronchodilator.
This patient has MRC grade 2 dyspnea (mild exertional limitation) and mild airflow obstruction.
The initiation of a rapid-onset, short-acting bronchodilator to be used as needed is suggested. The patient should be prescribed a short-acting beta2-agonist (eg, salbutamol) or a short-acting anticholinergic (eg, ipratropium bromide), two to three puffs every 4 h as needed, or both, for dyspnea relief. With persistent symptoms requiring frequent use of short-acting bronchodilators, a long-acting bronchodilator could be added.
Case 2 is a 67-year-old man with COPD. He complains of dyspnea when walking 50 m to 75 m on level ground at a slow pace. He has no history of COPD exacerbations during the past two years. His FEV1 is 55% of predicted.
This patient has MRC grade 4 dyspnea (moderate exertional limitation) and moderate airflow obstruction.
Initiation of a long-acting anticholinergic (eg, tiotropium) or a long-acting beta2-agonist (eg, salmeterol or formoterol). Short-acting beta2-agonists should be used as needed for immediate symptom relief.
If patient is still dyspneic after initiation of the above, then a combination of two long-acting bronchodilators is recommended to maximize symptom relief. In the event that symptoms persist despite combining inhaled long-acting bronchodilators, consideration should be given to replacing the LABA with lower dose LABA/ICS combination (eg, SALM/FP or FM/BUD).
Case 3 is a 62-year-old woman with COPD. She complains of dyspnea when combing her hair or getting dressed. She is unable to walk more than 25 m because of dyspnea. She has had three COPD exacerbations in the past two years that have required treatment with antibiotics and/or systemic corticosteroids. Her FEV1 is 35% of predicted.
This patient has MRC grade 5 dyspnea (severe exertional limitation) and severe airflow obstruction.
Initiation of long-acting anticholinergic (eg, tiotropium once daily), plus a combination LABA/ICS product (eg, SALM/FP or FM/BUD)twice daily. Short-acting beta2-agonists should be used as needed for immediate symptom relief.
If the patient is still dyspneic after initiation of the above, then consider adding a long-acting theophylline preparation, with monitoring of blood levels, side effects and potential drug interactions.
Several short-term trials have been reported over the past 50 years. A meta-analysis (189) based on 15 studies meeting pre-established quality criteria was performed in 1991. Improvement of at least 20% of the FEV1 from baseline was set as the clinically meaningful difference. It was estimated that only 10% of patients with stable COPD benefit from oral corticosteroids in the short term based on this operational definition (95% CI 18%) (190).
The benefits of maintenance oral corticosteroid therapy must be weighed against the risk of adverse events. Adverse events are numerous and include adrenal suppression, osteoporosis, cataract formation, dermal thinning, muscle weakness, hypertension, diabetes, psychosis and hyperadrenocorticism (191–195).
AECOPD is defined as a sustained worsening of dyspnea, cough or sputum production leading to an increase in the use of maintenance medications and/or supplementation with additional medications (level of evidence: 3). The term ‘sustained’ implies a change from baseline lasting 48 h or more. In addition, exacerbations should be defined as either purulent or nonpurulent because this is helpful in predicting the need for antibiotic therapy (level of evidence: 2A).
Acute exacerbations are the most frequent cause of medical visits, hospital admissions and death among patients with COPD (196). In addition, frequent exacerbations are an important determinant of quality of life in this group of patients (197,198) and contribute to accelerated rates of decline in lung function (199). AECOPD are often under-recognized and under-reported by patients, leading to prolonged periods of symptoms and marked impairment in quality of life (200).
The average COPD patient experiences approximately two exacerbations per year but this is highly variable and as many as 40% of individuals with COPD may not have any exacerbations. Exacerbations are related to the severity of underlying airflow obstruction: patients with a lower FEV1 have more frequent and more severe exacerbations (201). Patients with mild to moderate disease have a 4% short-term mortality rate if admitted to hospital (199,202), but mortality rates can be as high as 24% if patients are admitted to an intensive care unit (ICU) with respiratory failure (203–206). In addition, this group of patients requiring ICU admission has a one-year mortality rate as high as 46%. A significant percentage of patients requiring hospitalization for AECOPD require subsequent readmissions because of persistent symptoms, and experience at least a temporary decrease in their functional abilities following discharge (203,207,208).
At least one-half of AECOPD are thought to be infectious in nature. Many of these are initially viral in origin and the remainder are due to bacterial infection. Other triggering factors for exacerbations include congestive heart failure, exposure to allergens and irritants (ie, cigarette smoke, dust, cold air or pollutants) and pulmonary embolism (209).
A complete history and physical examination should be performed to rule out other causes for worsening cough and dyspnea. In one recent study (236), pulmonary embolism was found in up to 25% of patients hospitalized with unexplained exacerbation and should therefore be considered in this setting.
Inhaled bronchodilators should be used to improve airway function and reduce lung hyperinflation, thus relieving dyspnea in AECOPD (level of evidence: 2A). Combined short-acting beta2-agonist and anticholinergic inhaled therapy is recommended in the acute situation (239–242) (level of evidence: 3C). A role for initiation of therapy with long-acting bronchodilators appears promising but there is insufficient evidence to allow for firm recommendations at this time (243).
There is good evidence to support the use of oral or parenteral corticosteroids in most patients with moderate to severe AECOPD (level of evidence: 1A) (229,244–248). The exact dose and duration of therapy should be individualized, but treatment periods of between 10 and 14 days are recommended (level of evidence: 1A). Dosages of 30 mg to 40 mg of prednisone equivalent per day are suggested (level of evidence: 1A). Hyperglycemia is associated with poorer outcomes in patients admitted with AECOPD (249), so the risks and benefits of corticosteroid therapy must be considered in individual patients.
Several randomized, placebo-controlled trials of antibiotic therapy have been performed in AECOPD (250–258). Based on the results of these studies, it is recognized that antibiotics are beneficial in the treatment of more severe purulent AECOPD (259) (level of evidence: 1A). In the smaller subset of patients who produce only mucoid (white or clear) sputum during AECOPD, recovery usually occurs without antibiotics (260). Novel indicators of bacterial infection, such as serum procalcitonin, may soon help guide decisions regarding the need for antibiotic therapy (261).
Patients can be divided into two groups – simple or complicated exacerbations – based on the presence of risk factors that either increase the likelihood of treatment failure or are more likely to be associated with more virulent or resistant microbial pathogens (level of evidence: 3C) (Table 9). This approach to management of AECOPD has not been formally evaluated in clinical studies but nevertheless was considered to be a useful practical management guide by the Panel.
Pulmonary rehabilitation is the most effective therapeutic strategy for improving dyspnea, exercise endurance (Figure 7) and quality of life compared with standard care (262,263). These improvements in dyspnea and exercise performance are largely attributable to the exercise training component of the rehabilitation program (264,265), because education alone has no effect on these parameters (114,266). Psychosocial support in the rehabilitation setting is also a key contributor to the success of such programs. No clinical trials have been designed and powered to study the impact of pulmonary rehabilitation on mortality. However, participation in a pulmonary rehabilitation program incorporating exercise training is associated with a trend toward reduced mortality rate compared with standard care alone (114,232).
Evidence from several randomized, controlled trials is available to support the use of a lower extremity aerobic exercise training regimen for patients with COPD to improve exercise capacity, dyspnea and quality of life (263) (level of evidence: 1A). Incorporating strengthening exercises into the training regimen is also recommended. Compared with placebo, greater improvement in peripheral muscle strength and endurance, submaximal exercise capacity and quality of life have been shown with strength exercises in patients with COPD and a wide range of disease severity (267–269) (level of evidence: 1A). These benefits of strength training can be obtained in a safe and well-accepted manner by the participants (267–269). The gains in muscle strength are greater with muscle training than with endurance training (270–272), while the gain in endurance to constant workrate exercise are greater with endurance training compared with strength training alone (271,273). Based on this, combining aerobic and strength training would appear to be an optimal rehabilitation strategy in patients with COPD (270–272). Whether the addition of strength training to endurance training translates into further improvement in exercise tolerance or quality of life has not been confirmed (270–272).
The development of innovative ways to improve tolerance to high-intensity training is the subject of intense research. Different techniques such as interval training (274,275), non-invasive ventilation (276,277), oxygen (278,279), heliox (280), and anabolic supplementation (281) have been used. Neuromuscular electrostimulation training has also been introduced as a possible rehabilitative strategy in patients with COPD (282–285). High-intensity training is associated with better physiological outcomes (278,286,287). However, these greater physiological benefits do not automatically translate into larger gains in quality of life and other relevant clinical outcomes (278,287). Further research is necessary to determine the optimal training intensity in patients with COPD.
Recent randomized controlled trials with long-term follow-up of patients after rehabilitation have shown a trend toward decreased hospital days, fewer exacerbations and more efficient primary care use (114,230–232). A recent meta-analysis (288) showed evidence from six RCTs that pulmonary rehabilitation is effective in COPD patients after acute exacerbations: risk for hospital admissions and mortality were reduced; and HRQL and exercise capacity were improved.
The benefits of pulmonary rehabilitation (improved dyspnea, activity level and quality of life) are usually sustained for several months after the end of an exercise program (114,230,289–292). However, initial improvement in these parameters is progressively lost after stopping exercise, highlighting the importance of incorporating a carefully supervised maintenance exercise program. AECOPD are recognized as having a negative influence on exercise maintenance programs in this population.
Despite the proven benefits of pulmonary rehabilitation, a recent national survey revealed that only 98 programs exist in Canada. These programs combined have a capacity to serve only approximately 1.2% of the COPD population in Canada. Regional disparity in access to pulmonary rehabilitation was also highlighted in the survey: most programs were located in Ontario and Quebec, whereas some provinces (eg, Newfoundland, Prince Edward Island) had none (293). Strategies should be developed to improve availability of pulmonary rehabilitation at a lower cost. In this regard, self-monitored home-based rehabilitation is a promising approach (294).
Criteria for referral to a pulmonary rehabilitation program include: clinically stable, symptomatic COPD; reduced activity levels and increased dyspnea despite pharmacological treatment; no evidence of active ischemic, musculoskeletal, psychiatric or other systemic disease; and sufficient motivation for participation. In North America, most patients enter rehabilitation at this late stage of their disease. Exercise training is too often considered as a last resort therapeutic modality; to minimize the consequences of COPD, it would be advisable to consider pulmonary rehabilitation as early as possible in the natural evolution of the disease.
The cost-effectiveness of pulmonary rehabilitation added to standard care has been compared with that of standard care alone in two large controlled, randomized clinical trials (295,296). The direct and indirect costs related to health-care delivery (including the cost related to the rehabilitation program) were compared in the two treatment arms. The general conclusion of these studies is that: the extra expenses associated with pulmonary rehabilitation are completely offset by the reduction in health care utilization costs; the cost-effectiveness profile is better for outpatient than inpatient pulmonary rehabilitation; and pulmonary rehabilitation is highly cost-effective compared with many other interventions incorporated into routine clinical practice, such as hip replacement, coronary artery bypass graft and hemodialysis. This important information should spur the implementation of pulmonary rehabilitation in a broader basis across the country.
The survival benefit of domiciliary oxygen has been documented by two large, randomized, controlled trials: the MRC and the Nocturnal Oxygen Therapy study groups (297,298). Both studies were conducted in hypoxemic COPD patients (with a partial pressure of arterial oxygen [PaO2] 60 mmHg or less), most of whom were male. Taken together, these trials demonstrated that the benefits from long-term oxygen therapy (LTOT) are dose-dependent: the longer the exposure to supplemental oxygen, the larger the benefits in terms of survival.
Nocturnal oxygen desaturation in COPD has been suggested to increase mortality (299,300). It has also been associated with poor sleep quality as indicated by reduced sleep time, increased sleep stage changes and increased arousal frequency (301). In two clinical trials (299,300) and in a subsequent meta-analysis (302), nocturnal oxygen therapy was not shown to increase survival in COPD patients with ‘isolated’ nocturnal oxygen desaturation. It also has not been shown to be consistently effective in improving sleep quality in these patients (300,303,304). Moreover, because obstructive sleep apnea is common, there is a high likelihood that a few patients will have both conditions.
Moderate hyperoxia during submaximal exercise testing increases exercise time, reduces exercise minute ventilation and dynamic lung hyperinflation, and may delay respiratory muscle dysfunction in patients with moderate to severe COPD (305–307). A number of recent short-term mechanistic studies have demonstrated that hyperoxia, either alone or combined with helium or bronchodilators, is associated with large improvements in exercise endurance and exertional dyspnea in patients without significant arterial oxygen desaturation (308–311). The acute improvements with hyperoxia are approximately double those achieved with bronchodilators alone; bronchodilators and hyperoxia have additive effects on dyspnea and exercise endurance (308). However, most patients do not benefit from ambulatory oxygen despite the acute benefits of oxygen therapy on exercise tolerance. Ambulatory oxygen has been used in patients with COPD with isolated exercise-induced oxygen desaturation and in patients with COPD with resting hypoxemia qualifying for LTOT. Studies performed in the former subset of patients demonstrate that the impact of ambulatory oxygen on quality of life and exercise is modest and not clinically important (312–314). Similar conclusions have been reached in patients qualifying for LTOT (315,316). Occasional responders to ambulatory oxygen have been reported (313,314). However, identification of these patients is a challenge because the long-term response to ambulatory oxygen cannot be predicted from the acute exercise response to oxygen (313,316).
Numerous randomized controlled trials and a recent systematic review support the benefit of noninvasive positive pressure ventilation (NPPV) in the setting of AECOPD (317–327). However, not all patients with COPD exacerbations benefit from NPPV (320,328–330) (Table 10). A combined nasal/oral (full face) mask is preferable and has been shown to be more comfortable (331).
Patients with advanced COPD who have been designated as Do Not Rescuscitate or Do Not Intubate can still be considered for NPPV: three studies suggest that hospital survival rates range from 50% to 60% in these patients (332–334). However, one-year survival of these patients may be as low as 30%, and one-third of these patients are likely to require rehospitalization.
A large RCT on the use of NPPV in patients with AECOPD treated on a respiratory ward rather than the ICU reported a reduction in mortality for the group treated with NPPV for both those with severe (pH less than 7.3) or less severe exacerbations (326). However, the mortality rate of the severe subgroup of patients treated on the ward with NPPV was higher than that reported in the literature for apparently similar patients treated in the ICU. As such, in patients with severe COPD exacerbations, NPPV should be initiated in a setting that provides adequate cardiopulmonary monitoring and personnel skilled at endotracheal intubation and invasive mechanical ventilation, should the patient fail NPPV (level of evidence: 2B).
A recent paper (335) concluded that there was insufficient evidence to recommend the use of NPPV in hypercapnic patients with stable COPD (ie, patients who are not currently exacerbating).
Six randomized clinical trials have all reported better outcomes in the surgical arms three to 12 months after surgery (336–341). However, these trials did not include large numbers of patients (n=37 to n=60). The results of larger trials with longer duration of follow-up are now available: the National Emphysema Treatment Trial (NETT) (342), the Overholt Blue-Cross Emphysema Surgery Trial (OBEST) (343) and the Canadian Lung Volume Reduction Trial (CLVRT) (344). The NETT initially established a subgroup of patients with emphysema who are harmed by LVRS (345) (level of evidence: 1E). Patients with an FEV1 less than 20% predicted and either homogeneous distribution emphysema or a diffusing capacity of no more than 20% predicted have higher mortality rates if they undergo LVRS.
Recent larger trials have reported improved FEV1 and reduced lung volumes, improved HRQL and increased exercise capacity after two years in patients randomized to LVRS. Long-term (median 4.3 years) follow-up is now available from the NETT (346). The surgical arm showed a survival advantage with a five-year risk ratio for death of 0.86 (P=0.02) relative to medically treated patients. Improvements in maximal exercise and HRQL were maintained for three and four years, respectively. As in the two-year results, patients with upper lobe-predominant emphysema and low exercise capacity (less than 40 W) had the best results, with a five-year risk ratio for death of 0.67 (P=0.003). Upper lobe-predominant emphysema with high exercise capacity had no survival advantage but did show sustained improvements in exercise capacity and HRQL.
The Panel considers this new information to be supportive of LVRS as a potentially effective option for management of advanced COPD (level of evidence: 1A) in patients who meet the carefully designed criteria defined by these studies (Table 11). However, the procedure is expensive, with estimates of $120,000 per quality-adjusted life year gained (343,347), and its adoption should be balanced against the available resources. Recent innovations that use the knowledge gained from LVRS, such as bronchial lung volume reduction (348), may well be more cost-effective but an RCT is required before any recommendation can be made.
Lung transplantation is an excellent option for certain carefully selected patients with advanced COPD (level of evidence: 3A). Over 12,000 lung transplants have been performed to date, with COPD accounting for 60% and 30% of the single and bilateral procedures, respectively (349). Anticipated survival rates following lung transplantation for all disease states are in the range of 75% at one year and 50% at five years (349). However, recipients with COPD appear to have better outcomes than those with other conditions (level of evidence: 3B). Chronic graft dysfunction associated with obliterative bronchiolitis, thought to be a manifestation of chronic rejection, is the major complication affecting long-term morbidity and mortality, and is present in at least one-half of long-term survivors (350). The latest guidelines from the International Society for Heart and Lung Transplantation suggest that patients with COPD should be referred when they have a BODE score of five (351).
The CTS has published detailed guidelines on the assessment and management of AAT deficiency (352).
The Panel believes that we need to improve our understanding of patients’ experiences and needs through well-timed, honest, informative and empathetic, yet realistic, conversations that can form the basis of effective advanced care planning. Discussions about end-of-life issues often occur too late, are held in inappropriate settings (such as the ICU) and do not meet the expectations of patients (354). Patients with features of advanced disease that increase the likelihood of death from an episode of acute exacerbation should be targeted for discussions regarding end-of-life care preferences during outpatient visits. These features of advanced disease can be summarized in a global score (eg, the BODE index ) or identified individually as severe airflow obstruction (eg, FEV1 less than 40% predicted), poor functional status (eg, MRC 4 to 5), poor nutritional status (eg, body mass index less than 19 kg/m2) and recurrent severe acute exacerbations requiring hospitalization (355,356).
The quality of life of patients with advanced COPD is often poor. Many patients with advanced COPD rate their quality of life as worse than that of patients who have survived cardiopulmonary resuscitation or living with inoperable lung cancer (357,358). The emotional consequences of severe COPD include anxiety, fear, panic and depression. These psychological factors can impose an additional barrier to effective symptom control (359,360), further reduce quality of life and require pharmacological and nonpharmacological treatment strategies for effective management.
Caregiver burden is a major concern to patients with advanced COPD (361). Few studies have adequately evaluated this aspect of the disease, partly due to a lack of validated instruments to measure caregiver burden in COPD.
For information on the CTS COPD Guidelines Dissemination and Implementation Committee, or to request COPD Guideline Implementation tools, please visit our Web site at <www.COPDguidelines.ca>.
The authors wish to thank Canadian Lung Association administrative staff Laura Monette and Virginia Fobert for their assistance with the manuscript. Reviewers of the manuscript include: Michelle Bishop (Centre for Chronic Disease Prevention and Control, Public Health Agency of Canada), Elaine Chong (Canadian Pharmacists Association), Gordon Dyck (Family Physician), Darrel Melvin (Respiratory Health Services), Pat Steele (Canadian Respiratory Health Professionals), Cheryl Winger (Canadian Respiratory Health Professionals), Susan Deveau, Brad Donoff, Jennifer Haddon, Martin Holroyde, Nicholas Makris, Renata Rea, Carle Rykman, Kevin Schultz, Michael Shaw and Katherine Webb.
SPONSORING ORGANIZATIONS: Canadian College of Family Physicians, The Lung Association, Canadian Respiratory Health Professionals.
COMPETING INTERESTS: Collectively, the physicians on the Scientific Review Panel have on at least one occasion 1) acted as consultants for; 2) received research funds from; 3) received speaker’s fees from; and 4) received travel assistance from the various pharmaceutical companies listed below.
FUNDING: These guidelines were developed under the auspices of the Scientific Review Panel of the Canadian Thoracic Society. This process was facilitated by funding from Abbot Laboratories Inc, ALTANA Pharma Inc, AstraZeneca Canada Inc, Bayer Canada Inc, Boehringer Ingelheim (Canada) Inc, GlaxoSmithKline Inc and Pfizer Canada. None of the pharmaceutical sponsors played a role in the collection, review, analysis or interpretation of the scientific data or in any decisions regarding recommendations.