Advances in chronic obstructive pulmonary disease
- Funding: None.
- Conflict of interest: Christine McDonald has served on advisory boards for GlaxoSmithKline, Novartis, Pfizer; received conference support from Nycomed; has given presentations at educational meetings sponsored by Boehringer Ingelheim and Novartis.
Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation in the presence of identifiable risk factors. Inflammation is the central pathological feature in the pathogenesis of COPD. In addition to its pulmonary effects, COPD is associated with significant extrapulmonary manifestations, including ischaemic heart disease, osteoporosis, stroke and diabetes. Anxiety and depression are also common. Spirometry remains the gold standard diagnostic tool. Pharmacologic and non-pharmacologic therapy can improve symptoms, quality of life and exercise capacity and, through their effects on reducing exacerbations, have the potential to modify disease progression. Bronchodilators are the mainstay of pharmacotherapy, with guidelines recommending a stepwise escalating approach. Smoking cessation is paramount in managing COPD, with promotion of physical activity and pulmonary rehabilitation being other key factors in management. Comorbidities should be actively sought and managed in their own right. Given the chronicity and progressive nature of COPD, ongoing monitoring and support with timely discussion of advanced-care planning and end-of-life issues are recommended.
Background and epidemiology
Chronic obstructive pulmonary disease (COPD) represents a spectrum of lung diseases characterised by persistent airflow limitation due to varying combinations of small-airways disease (obstructive bronchiolitis) and emphysema. It is a major cause of morbidity and disability, having a prevalence of around 10% in those aged over 40 years.[1, 2] By 2030 COPD is predicted to have become the third-leading cause of death worldwide, with 90% of those deaths occurring in low- and middle-income countries. In Australia, COPD is responsible for 4% of all deaths in recent years and is the only major condition for which the burden of disease continues to increase as our population ages. Australian death rates from COPD per head of male population have declined substantially since their peak in the 1970s, reflecting changes in tobacco consumption. By contrast, female death rates peaked in the 1990s and have stabilised, reflecting the increased uptake of smoking by women over the last 3–4 decades.
Cigarette smoking is the most important risk factor for COPD. Although traditional teaching suggested 10–15% of smokers develop COPD, recent studies indicate some degree of airflow limitation is present in up to 50% of smokers, with clinically significant COPD being present in around 25%. It is increasingly recognised that a significant proportion of patients with COPD are non-smokers. This proportion is generally higher in developing countries where exposure to biomass smoke for heating and cooking is common (for example up to nearly 70% of people in India with COPD are non-smokers), but is still significant in the developed world, with just under 40% of people in a recent New Zealand study being never-smokers, and overall international figures ranging from 25% to 45%. Other risk factors include maternal smoking, long-standing asthma and respiratory symptoms, exposure to second-hand smoke and occupational exposures to dusts and fumes. Genetic susceptibility is an important factor in disease development, with the most well-established genetic factor, α1-antitrypsin deficiency, being present in 1–2% of individuals with COPD.
Spirometry is required to make a diagnosis of COPD. A medical history and clinical examination may suggest the diagnosis, but they are not reliable predictors of airflow obstruction. In the presence of symptoms such as shortness of breath, cough and/or sputum production and a history of relevant exposure(s), an individual with a post-bronchodilator forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio (FEV1/FVC) of less than 0.7 (indicating airflow limitation that is not fully reversible) is deemed to have COPD. This definition is widely accepted because of its practicality, although its use may lead to overdiagnosis in the elderly (as FEV1 declines more rapidly with age than does FVC) and underdiagnosis in younger adults. Consequently, some authors recommend that a lower limit of normal (fifth percentile of the normal distribution range of FEV1/FVC values) be applied. Unfortunately, by whatever definition airflow obstruction is measured, spirometry continues to be infrequently performed, even among those hospitalised for ‘exacerbation of COPD’ in Australia. Only 51% of a recently audited group of patients admitted to hospital with this diagnosis had undergone lung function testing in the 5 years prior to admission or during hospitalisation. This lack of confirmatory testing contributes to both under- and overtreatment of such patients.
COPD is a chronic inflammatory airway disease, but differs significantly from asthma in that the inflammation is relatively resistant to treatment with corticosteroids. Exposure to noxious injury triggers a predominantly neutrophilic infiltration with activation of the innate immune response. An inflammatory cascade ensues, with induction of type 1 and type 17 T helper cells and the subsequent development of transforming growth factor β-induced small-airway fibrosis and matrix metalloproteinase elastic tissue destruction. These responses appear to perpetuate even after removal of the initial stimulus and may be associated with ‘spillover’ of the inflammatory response from the lungs to the systemic circulation, leading to potential downstream effects, such as arterial stiffness and its consequences. Parenchymal destruction is associated with loss of lung tissue elasticity and small-airways collapse during exhalation, leading to so-called ‘gas trapping’, while goblet cell metaplasia and impaired mucociliary function contribute to excess mucus accumulation and worsening obstruction.
Overlap of COPD and asthma
The definition of COPD is quite broad and may include a variety of patients with distinct clinical and other features who may both present differently and respond differently to treatment (so-called ‘clinical phenotypes’). Many patients with COPD will report a history of asthma. This dual diagnosis or ‘overlap syndrome’ may be recognised through symptoms associated with variable airflow obstruction as well as incomplete reversibility of airflow obstruction on lung function testing. There is increasing evidence that patients with COPD and asthma experience more rapid disease progression than those with either disease alone. Airway hyperresponsiveness and an asthma diagnosis have been associated with a greater decline in FEV1 in both smokers and non-smokers. Patients with overlap syndrome have worse health-related quality of life and experience more frequent and severe respiratory exacerbations, despite younger age and reduced lifetime smoking exposure, when compared with those with COPD alone. The evidence base for management of this subgroup of patients is relatively limited, as they are commonly excluded from clinical trials.
Systemic effects and comorbidities
It has been proposed that the term ‘chronic systemic inflammatory syndrome’ be applied to COPD in order to highlight the underlying inflammatory response common to both COPD and many of its associated comorbidities, which are also commonly associated with smoking. Features include systemic oxidative stress, changes in vasomotor and endothelial function and enhanced circulating concentrations of procoagulant factors. Using a UK-wide validated primary care database, Feary et al. observed a fivefold increase in risk of cardiovascular disease, a threefold increase in risk of stroke and a twofold increase in risk of diabetes in patients with physician-diagnosed COPD. Suggested mechanisms, over and above smoking, that may be implicated in these interactions include increased aortic stiffness and associated left ventricular dysfunction, as well as increased platelet activation. Of note is the fact that having COPD increases the risk of lung cancer by up to 4.5-fold among long-term smokers. Considering lung- and non-lung-related manifestations of COPD as a ‘syndrome’ akin to the way in which we think of the metabolic syndrome, for example, may encourage investigation and appropriate management of some of the more common comorbidities described in association with COPD, including those mentioned as well as osteoporosis, hyperlipidaemia, hypertension, skeletal muscle abnormalities, anxiety and depression.
Acute exacerbations of COPD
An exacerbation of COPD is defined as an acute event characterised by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and necessitates a change in medication. COPD exacerbations are associated with considerable morbidity, mortality and healthcare costs. They are the second leading cause of hospitalisations in Australia. Exacerbations become more frequent as the severity of COPD worsens. Following hospitalisation for an exacerbation, quality of life and lung function decline, and patients are at risk for further serious exacerbations. A primary goal of treatment in COPD is therefore to reduce exacerbations. Triggers for acute exacerbations include viral and bacterial infections as well as environmental pollutants, heart failure, pulmonary embolism and other factors. Prompt treatment with short-acting bronchodilators, antibiotics as appropriate and corticosteroids has been demonstrated to hasten resolution and reduce need for hospitalisation. Non-invasive ventilatory support is indicated for hypercapnic respiratory failure and is effective in avoiding intubation and reducing risk of death. Mortality after hospitalisation for acute exacerbation may be as high as 22% at 12 months, although more recent data suggest a trend towards improved outcomes. An admission to hospital with an exacerbation of COPD is a sentinel event that should give pause for review of current management, including preventive therapies. Such episodes should act as a trigger for discussion about advanced-care planning and wishes concerning non-invasive and invasive ventilation should the need arise. Recent data suggest early pulmonary rehabilitation following exacerbation and hospitalisation may decrease readmission, and National Institute for Health and Care Excellence guidelines recommend this as standard of care.
Management of stable COPD
Although severity of airflow obstruction is classified according to FEV1 (as a percentage of the predicted normal value), and spirometry is essential in determining whether the probable cause of respiratory symptoms is COPD, clinical criteria, such as degree of breathlessness induced by daily activities and frequency of exacerbations, should also be used when evaluating overall disease severity.[26, 27] Validated tools, such as the modified Medical Research Council breathlessness scale and the COPD Assessment Test, may be helpful in assessing disease impact and treatment response.
The goals of management in stable COPD are to reduce symptoms, reduce the frequency and severity of exacerbations, improve exercise tolerance and health-related quality of life, slow disease progression and reduce mortality. Both pharmacologic and non-pharmacologic strategies may be employed. Guidelines for COPD management recommend a stepwise escalation of therapy based on disease severity. Two guidelines commonly used in Australia are the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Strategy Document and the locally developed COPD-X guideline. The recently updated (2011) GOLD Document has adopted a new stratification for disease severity, based on exacerbation rates and symptom scores in addition to degree of airflow obstruction. This is not significantly different from COPD-X, which determines severity based on clinical history and functional assessment as well as spirometry and emphasises consideration of the presence and treatment of complications and comorbidities in their own right.
Preventing or limiting lung damage through smoking cessation should be the foremost goal for all physicians managing COPD. Of course, all smokers should be encouraged to stop smoking, whether or not they have COPD. Smoking cessation reduces rate of decline of FEV1 as well as improving respiratory symptoms and health-related quality of life. To date, smoking cessation and home oxygen therapy (in severely hypoxaemic individuals) are the only strategies conclusively demonstrated to improve mortality in COPD. Even brief counselling can be effective. But additional strategies may be required for patients who continue to smoke despite having lung disease. All forms of nicotine replacement therapy (NRT) appear to assist smoking cessation in dependent smokers, and NRT is safe even in acute coronary syndromes. Agents such as the antidepressant and selective catecholamine reuptake inhibitor buproprion and the α4β2 nicotinic acetylcholine receptor partial agonist varenicline are also effective. All pharmacologic therapies must be combined with support and counselling for maximum efficacy.
The aims of pharmacotherapy in COPD are to relieve symptoms (notably, breathlessness) and to prevent deterioration, either by reducing exacerbations or by reducing decline in quality of life, or both. Bronchodilators remain the mainstay of therapy for COPD and include short- and long-acting β2 agonists (SABA and LABA) as well as short- and long-acting muscarinic antagonists (SAMA and LAMA).They can impact the gas trapping that is a feature of COPD, inducing improvements in inspiratory capacity and end-expiratory lung volume that may improve breathlessness and exercise capacity even in the absence of a demonstrable ‘bronchodilator response’ on simple spirometric testing. In addition to improving symptom control, both LAMA and LABA have been shown to reduce exacerbations and hospitalisations and to improve lung function. Despite the relative corticosteroid insensitivity of the inflammatory response in COPD, the addition of an inhaled corticosteroid is recommended in patients with moderate to severe COPD, especially in those with recurrent exacerbations, because of additional benefits in terms of reduced exacerbations as well as improved quality of life. These small additional benefits must be balanced against an increased risk for pneumonia and local side-effects of dysphonia and upper-airway candidiasis. Inhaler technique must be assessed regularly, and medications reviewed and either continued or discontinued based upon treatment response and tolerability. It is important that both patient and treating doctor are clear as to the expectations from treatment (for example, whether the treatment aims purely at symptom control or is aimed at longer-term outcomes such as prevention of exacerbations and/or hospitalisations, or both).
Indacaterol is a novel ‘ultra-LABA’ with 24-h bronchodilator efficacy allowing once-daily dosing. It may be superior to conventional LABA in patients with moderate to severe COPD and is comparable in efficacy with tiotropium. The combination of indacaterol plus tiotropium provides additional bronchodilation compared with each treatment alone. As understanding of COPD inflammatory pathways increases, newer therapies targeting inflammatory molecules have been developed. Roflumilast, a selective phosphodiesterase-4 inhibitor, has recently been approved for use in several countries for treatment of severe COPD (although not yet in Australia). It has been shown to be effective, with well-tolerated side effects, and may be suited for patients with severe COPD and frequent exacerbations. However, long-term data on efficacy and adverse events are not yet available, and its role in patients already receiving standard combination therapy is yet to be determined. Although standard-dose theophylline is considered a third- or fourth-line treatment in COPD, low-dose theophylline has recently been raised as a possible adjunct to current inhaled therapies, given experimental data demonstrating it enhances anti-inflammatory effects of inhaled corticosteroids in COPD airways through modification of histone deacetylase-2. Nonetheless, large-scale clinical trials investigating exacerbation reduction through this mechanism are awaited. Given the known anti-inflammatory and immunomodulatory effects of macrolide antibiotics, several studies have evaluated their effects on reducing COPD exacerbations. A recent study found a decreased rate of exacerbations in patients treated with daily azithromcyin. Adverse effects included ototoxicity and increased macrolide resistance. Azithromycin is also associated with cardiac toxicity. It remains to be seen what the treatment effect of chronic macrolide therapy is in COPD patients treated maximally with conventional therapies and whether benefits will outweigh risks to the individual and the community from their more widespread use.
Management of cardiac disease as a comorbidity
The importance of managing the common comorbidities in COPD, which may be considered either as ‘fellow travellers’ or as components of a chronic systemic inflammatory complex, is increasingly recognised. Many patients with COPD die from cardiovascular disease, and the prevalence of ventricular dysfunction in patients with COPD ranges from 9% to 52%. Diagnosing cardiac disease in COPD is made more difficult by similar presenting features, which, in both cases, may include breathlessness, fatigue and even chest discomfort. Beta-blockers have proven mortality benefits in cardiac disease, but their use remains low in patients with COPD because of their potential to provoke acute bronchospasm and worsen respiratory symptoms. Concerns have been allayed to some extent by a recent meta-analysis suggesting that cardioselective beta-blockers are safe and well tolerated even in patients with severe airflow obstruction. Nonetheless, the included studies were of short duration in small numbers of patients, thus providing little guidance about long-term safety and potential morbidity. Recent large observational database studies of patients with COPD added reassurance with the finding of beneficial effects of beta-blockers on overall mortality, without adverse effects on lung function.[38, 39] European Society of Cardiology guidelines assert that COPD is not a contraindication to the use of beta-blockers. Although low-dose initiation and gradual up-titration is recommended, and mild deterioration in pulmonary function and symptoms should not necessarily prompt discontinuation, prudence would dictate a cautious approach in the absence of long-term prospective data.
Other comorbidities should be managed according to appropriate guidelines.
Influenza vaccine reduces the number of acute exacerbations that occur in persons with COPD, but evidence regarding its effects on hospitalisations and mortality is inconclusive. Pneumococcal vaccine reduces the incidence of invasive pneumococcal disease, but there is a lack of evidence concerning its effect on morbidity or mortality in people with COPD. National Health and Medical Research Council guidelines recommend yearly influenza vaccinations and up-to-date pneumococcal vaccination for people with COPD.
Activity promotion, pulmonary rehabilitation and disease management
When patients with COPD begin to feel short of breath with activity, they typically reduce their activities and become more sedentary. COPD results in systemic functional limitations that lead to physical deconditioning and the development of the so-called ‘dyspnoea spiral’: progressive deconditioning and ever-worsening dyspnoea. Regular physical activity is recommended for all people with COPD and has been associated with reduced risk of hospital admissions.
In people with moderate to severe COPD, participation in outpatient pulmonary rehabilitation (generally around 6–8 weeks of graded exercises and education incorporating self-management education, provided by a multidisciplinary team) is associated with improved exercise capacity, less breathlessness and better quality of life and, in those who have been hospitalised, with reduced hospital admissions and mortality.
Action plans have been effective in asthma. They allow patients to develop coping skills, to anticipate early exacerbation symptoms, to self-initiate appropriate treatment and to seek medical advice prior to significant deterioration. COPD exacerbations are common in patients with moderate to severe COPD and may lead to hospitalisation. Trials assessing the effects of action plans in COPD management have shown conflicting results, with variable adjuncts to patient care in these trials likely contributors. Those with positive results, such as expedited exacerbation recovery and reduced hospital admissions, have included additional supports, such as intensive education and case management.[43-45] In contrast, action plans with limited or no self-management education and no case management have little beneficial effect. In view of the healthcare cost implications of COPD exacerbations, various models of self-management have been initiated in national healthcare systems, but the evidence for benefit has not been confirmed. Programmes may include self-management education about disease, optimisation of evidence-based medications, information and support from case managers and institution of self-management principles. A 2007 Cochrane meta-analysis concluded that self-management education in COPD was likely associated with reduced hospital admissions and no detrimental effects, but determined that larger randomised controlled trials were required before clear recommendations could be made. A recent UK study included a high-risk group of patients with COPD who had been recently hospitalised and reported no overall effect of a self-management programme on readmissions and death. However, only 42% of the patients were successful self-managers, and these individuals did have improved outcomes. A recent US study has raised concern. This multicentre trial of a comprehensive COPD care programme was discontinued prematurely by the data monitoring committee after only 44% of the planned 960 patients were enrolled, because of an excess of deaths in the intervention group (28 vs 10). The primary outcome of admission did not differ between the groups. It is not clear why so many deaths occurred in the intervention group. Although perhaps this was a chance occurrence, more studies are needed to determine the role of disease management in COPD.
The use of domiciliary oxygen is common at the more severe end of the COPD spectrum. In 2005 21 000 Australians were receiving domiciliary oxygen therapy, at an estimated annual cost of over A$32 million, with the major indication being COPD. Long-term continuous oxygen therapy has been proven to offer survival benefits in patients with COPD and severe hypoxaemia (PaO2 ≤ 55 mmHg or 55–59 mmHg with evidence of end-organ damage). However, the role of oxygen therapy in patients with exertional desaturation, nocturnal hypoxaemia or resting mild to moderate hypoxaemia is less clear. Recent studies suggest an absence of long-term effects on breathlessness or quality of life from the use of ambulatory oxygen therapy in normoxaemic or mildly hypoxaemic patients with COPD who desaturate with exertion, even though they may demonstrate small acute benefits during laboratory-based exercise tests.[51, 52] Nonetheless, occasional so-called ‘n-of-1 trials’ may be of use in some individuals. Isolated nocturnal hypoxaemia is not uncommon in COPD patients, particularly during rapid eye movement sleep. However, it has not been shown to lead to worse quality of life, daytime hypoxaemia or pulmonary hypertension. Limited studies have not consistently shown beneficial effects in sleep quality, pulmonary haemodynamics or survival over 2 years with nocturnal supplemental oxygen.[53-55] Similarly, patients with COPD and resting mild-to-moderate hypoxaemia have not shown a survival benefit with domiciliary oxygen therapy. The currently recruiting US Long-term Oxygen Treatment Trial (NCT00692198) may provide more data regarding the effects of domiciliary oxygen in the latter patient subgroup.
Non-invasive ventilation: acute versus stable
Non-invasive ventilation (NIV) is considered the standard of care for patients with acute exacerbations of COPD associated with hypercapnic respiratory failure and acidosis. It has been shown to reduce mortality, need for intubation, treatment failure, treatment complications and length of hospital stay. Patients who survive after an episode of acute hypercapnic respiratory failure treated with NIV are at high risk of readmission and life-threatening events during the following year. Although there are theoretical reasons why chronic NIV may benefit such patients, results from randomised controlled trials have been conflicting. A systematic review concluded there was no consistent clinically or statistically significant effect of domiciliary NIV on lung function, gas exchange, exercise tolerance, respiratory muscle strength or sleep efficiency. However, many included studies had small sample sizes, included patients without significant hypercapnia, were of limited duration and/or used low levels of inspiratory pressure support. An Australian study randomised 144 patients to receive home NIV plus long-term home oxygen therapy versus oxygen alone. Home NIV was associated with an improvement in survival up to 3.5 years, at the expense of worse quality of life. In summary, NIV may be a therapeutic option in stable COPD patients with chronic ventilatory failure, but further long-term randomised controlled trials are awaited.
Interventional therapy: surgery and devices
In patients with very severe COPD who remain incapacitated by dyspnoea despite maximal therapy, various surgical approaches have been trialled. Currently available surgical interventions include lung transplantation, lung volume reduction surgery and bullectomy. Since the first successful clinical lung transplant in 1983, transplantation has become a treatment option for selected patients with end-stage COPD, with improved survival. However, transplantation is limited by donor availability, the need for lifelong immunosuppression and its complications and the development of chronic allograft dysfunction in the form of bronchiolitis obliterans. In patients with emphysema, lung volume reduction surgery (LVRS) is aimed at relieving the hyperinflation and gas trapping associated with inadequate lung emptying and its associated mechanical disadvantage. LVRS and bullectomy in selected patients have been shown to improve lung function and exercise capacity in the long term, although perioperative morbidity (most commonly parenchymal air leaks) and mortality are significant. The majority of patients with end-stage COPD are not suitable surgical candidates because of their physiological fragility. Current selection guidelines for LVRS are largely based upon the results of the National Emphysema Treatment Trial inclusion criteria and outcome data and include bilateral, upper-lobe-predominant emphysema with significant hyperinflation and air trapping and a low maximal workload after pulmonary rehabilitation.
In order to obviate the need for surgery, there has been considerable recent interest in the development of bronchoscopic techniques for lung volume reduction. Modalities employed have included endobronchial valves or blockers, airway bypass, biologic sealants and airway implants. Endobronchial one-way valves block the airway leading to the targeted emphysematous lung. Apart from allowing air to be vented and preventing refilling, these valves also allow expulsion of mucus to minimise postobstructive infection. Modest improvements in lung function, exercise tolerance and symptoms have been demonstrated in selected patients with advanced heterogenous emphysema using endobronchial valves, although efficacy is variable and adverse effects include increased risk of COPD exacerbations, haemoptysis and pneumonia. Bronchoscopic thermal vapour ablation (BTVA) is a newer technique that utilises heated water vapour to induce thermal reaction and subsequent inflammatory response with permanent fibrosis and atelectasis, leading to reduction in volume of the targeted regions. Australia was involved in the first human study of BTVA for lung volume reduction in upper-lobe-predominant emphysema. Results indicate that BTVA significantly improves lung function, symptoms and exercise tolerance. The most common adverse effects of BTVA are lower respiratory events, pneumonia and haemoptysis. These complex procedures require careful patient selection and assessment by a multidisciplinary team at a specialised centre to ensure best outcomes.
Prognosis, palliative care and advanced-care planning
Lung function impairment is a strong predictor of mortality; however, use of lung function alone to classify disease severity does not capture the multidimensional nature of COPD. In patients with established COPD a variety of indices has been proposed that enhance the ability to predict mortality. Degree of hyperinflation as measured by inspiratory capacity/total lung capacity ratio is more closely associated with all cause and COPD mortality than FEV1. The BODE index, incorporating body mass index, degree of obstruction as measured by FEV1,dyspnoea score and exercise capacity as measured by 6 minutes' walk distance into a common index, enhances the ability to predict mortality. Further, the presence of comorbid disease increases the risk of both hospitalisation and mortality. The predominant causes of mortality in patients with mild disease are cardiac disease and malignancy, while as COPD severity increases, deaths due to respiratory disease are increasingly common.
Severe dyspnoea, cough, fatigue, social isolation, anxiety and depression are all features of late-stage COPD that adversely impact quality of life. The COPD disease course is often punctuated by recurrent exacerbations that may require hospitalisation and consideration of assisted ventilation. Hospitalisation for acute exacerbation increases subsequent mortality risk. As the disease progresses a more palliative approach to care may be appropriate. Determining prognosis in end-stage COPD is difficult; however, characteristics that should trigger discussions about a palliative approach to care, advanced-care planning and end-of-life issues include FEV1 < 25%, oxygen dependence, respiratory failure, heart failure or other comorbidities, weight loss or cachexia, decreased functional status, increasing dependence on others, and advancing age. Ideally, end-of-life discussions, including resuscitation and intubation wishes, and advanced-care planning, including consideration of the conferment of a medical enduring power of attorney, should occur in an outpatient setting when the patient's condition is relatively stable.
COPD is a common disease associated with significant morbidity and mortality. Spirometry is key to its diagnosis and is required in order to avoid under- and overtreatment. Smoking cessation and oxygen therapy in those who are hypoxaemic may reduce mortality. Pharmacologic and non-pharmacologic therapy can improve symptoms, quality of life and exercise capacity and, through their effects on reducing exacerbations, have the potential to modify disease progression. Comorbidities are common and require targeted treatment.