In the United States, chronic obstructive pulmonary disease (COPD) affects nearly 16 million people and was the third leading cause of death in 2014.1 Globally, COPD is the fourth leading cause of death, though it is expected to be third by the year 2020.2
COPD, which is usually caused by significant exposure to noxious stimuli, is characterized by limited airflow, accompanied by dyspnea, cough, mucus production, inflammation, and periods of worsening symptoms, called exacerbations, which trap gas in the lungs.2 The chronic inflammation of COPD destroys tissue in the lung parenchyma (resulting in emphysema), constricts the small airways (causing obstructive bronchiolitis), and reduces lung elastic recoil (see Figure 1).2 Patients with COPD may have chronic bronchitis according to some definitions of the disease, but the majority do not have cough and sputum production that persists for at least three months in each of two consecutive years, as the term chronic bronchitis is often clinically defined.2
Although COPD, like asthma, is an obstructive lung disease, the pathophysiology underlying the two conditions differs significantly. In COPD, cytotoxic CD8+ T cells and inflammatory cells, such as neutrophils, macrophages, and eosinophils, are predominant.3 By contrast, in asthma, mast cells and their mediators play a primary role.
To increase awareness of COPD, encourage related research, and improve care by disseminating evidence-based COPD prevention and management strategies, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was launched in 1998 as a collaboration between the National Heart, Lung, and Blood Institute, National Institutes of Health, and World Health Organization.2 The first report was issued in 2001, with revisions published in 2006 and 2011; since 2011, the report has been revised annually. The fourth and most recent major revision was released in 2017, and included significant changes related to COPD classification, as well as to pharmacologic, nonpharmacologic, and comorbidity management (see Table 12, 4, 5). Minor revisions appear in the 2018 report.
This article describes COPD risk factors and clinical manifestations, diagnostic testing, and the refined GOLD assessment tool used to classify COPD. It explains how COPD classification guides pharmacologic and nonpharmacologic management, and illustrates, using a patient scenario, how the revised GOLD recommendations can be put into practice. This article focuses on managing stable COPD, rather than COPD exacerbations.
COPD RISK FACTORS AND CLINICAL MANIFESTATIONS
A variety of risk factors are associated with COPD, though tobacco smoking is the most common. Additional risk factors include exposure to noxious particles or gases, including biomass fuels; occupational exposure to dust, chemicals, and fumes; female sex; and advanced age.2, 6-8 A genetic risk factor, alpha-1 antitrypsin deficiency (AATD), which is associated with the inability to adequately synthesize the protein alpha-1 antitrypsin, is more prevalent among white patients. Patients with AATD tend to have an atypical risk profile in that they are often nonsmokers.9 Other important risk factors for COPD include airway hyperresponsiveness, family history of asthma, and frequent childhood respiratory infections.2, 10 Low socioeconomic status has been identified as a risk factor as well, but that may be related to pollutant exposure, poor nutrition, residential crowding, or other factors associated with poverty.2
Clinical manifestations of COPD include the following2:
- progressive dyspnea that becomes worse with exercise
- chronic cough, which may be intermittent or nonproductive
- recurrent wheeze
- chronic sputum production
DIAGNOSTIC TESTING AND COPD CLASSIFICATIONS
COPD may be suspected if a patient has any known COPD risk factors and clinical manifestations. Peak expiratory flow measures have weak specificity and cannot be used to diagnose COPD; rather, diagnosis requires a thorough medical history of risk factors and symptoms, as well as spirometric testing.2
Spirometric classification. Spirometry measures the forced expiratory volume in the first second (FEV1) of exhalation and the forced vital capacity (FVC)—the total volume exhaled. Spirometry measures are obtained both before and after a bronchodilator is administered. If the postbronchodilator ratio of FEV1 to FVC is less than 70%, it is consistent with irreversible obstructive lung disease and indicative of COPD, though patients whose FEV1/FVC falls between 60% and 80% should be retested for confirmation on a separate occasion.2 If a patient meets the diagnostic criteria for COPD, the World Health Organization recommends ordering an AATD screening, and the GOLD report supports that recommendation.2 AATD screens below 20% of predicted normal value suggest that the COPD has a genetic component and that all family members should be screened.2
The GOLD report creates four classifications of COPD based on the percentage of FEV1 of predicted normal value2:
- GOLD 1 is a FEV1 at or above 80% of predicted normal value
- GOLD 2 is a FEV1 of 50% to 79% of predicted normal value
- GOLD 3 is a FEV1 of 30% to 49% of predicted normal value
- GOLD 4 is a FEV1 below 30% of predicted normal value
Exacerbation risk and symptoms. A further classification based on exacerbation risk and symptoms is used to determine optimal management strategies after COPD diagnosis.2 Patients who within the past year have had two or more exacerbations, or one exacerbation requiring hospital admission, are at high risk for further exacerbations.2 Patients who within the past year have had no exacerbations, or only one that did not require hospital admission, are at low risk for exacerbation.2
Symptoms and symptom burden can be assessed with either the COPD Assessment Test (CAT)11 or the modified British Medical Research Council Questionnaire (mMRC).12 The GOLD report, however, supports the CAT as a more robust assessment.2 The CAT measures symptom burden on a Likert-type scale, with scores ranging from 0 to 40. The higher the score, the more symptoms the patient has. For classification purposes, a CAT score of less than 10 is considered a low symptom burden and a score of 10 or higher a high symptom burden.2 The mMRC measures the patient's level of dyspnea using grades 0 to 4, with higher grades indicating a greater level.12 For classification purposes, an mMRC score of 0 to 1 is interpreted as a low symptom burden and an mMRC score of 2 or higher as a high symptom burden.2 The GOLD report suggests that either test can be used along with the patient's exacerbation history to classify a patient into Group A, B, C, or D (see Figure 2) and that patients should be reclassified during annual examinations and with any change in lung function.2
Smoking cessation is the most influential factor in slowing COPD progression.2 Providers can use the “5 A's” model as a framework to empower patients to quit smoking.2, 13, 14 This model identifies the five major interventional steps as follows:
- ask—identify tobacco users and document status
- advise—urge the patient to quit
- assess—determine the patient's desire to quit
- assist—provide resources, such as cessation programs and information about pharmacologic aids
- arrange—schedule follow-up contact
A systematic review of 42 randomized trials that assessed the effect of smoking cessation advice from health care providers on a total of more than 31,000 smokers found that such advice increased a patient's likelihood of both quitting smoking and remaining a nonsmoker 12 months later, with intensive advice (involving longer initial counseling periods, adjunctive aids, and follow-up support) resulting in slightly higher rates of cessation.15 Nicotine replacement products or medications to reduce tobacco dependence, or combination therapy with both, may further increase the likelihood of successful smoking cessation.14
Vaccinations. Influenza and pneumococcal vaccinations may help prevent exacerbations by reducing the likelihood of lower respiratory tract infections. In six trials that specifically included patients with COPD, inactivated influenza vaccine significantly reduced the total number of COPD exacerbations per vaccinated patient.16 Pneumococcal vaccinations are recommended for anyone over age 65 and for those under age 65 who have chronic heart disease, lung disease, liver disease, diabetes, or alcoholism, as well as for cigarette smokers.17 The GOLD report recommends that patients with COPD who are under age 65 should receive the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and that patients with COPD who are over age 65 should receive the 13-valent pneumococcal conjugate vaccine (PCV13).2
MEDICATIONS USED IN STABLE COPD
Providers need to be familiar with both the medications used to treat COPD and the various means of delivery. COPD medications are commonly administered through inhalation directly to pulmonary tissue, which reduces the potential for adverse systemic effects. With inhaled medications, it's important to verify that the patient understands and can demonstrate proper delivery technique.
All types of inhalers are frequently misused.18 A systematic review of studies evaluating the use of dry powder inhalers by patients with asthma or COPD found that most patients did not use their inhalers appropriately, frequently failing to exhale before inhalation, position or load the inhaler correctly, inhale deeply, or hold their breath after inhalation; however, proper training in technique seemed to improve efficient use, especially when training sessions were repeated and technique was evaluated at regular intervals.19 (The website of Use-inhalers, an independent health care organization unaffiliated with any pharmaceutical company, provides free training videos and patient instruction handouts in multiple languages: https://use-inhalers.com/professional-home.)
A prospective study of 14 healthy volunteers who did not use an inhaler regularly sought to identify the effects of the most common inhalation delivery errors during use of a dry powder salbutamol (also called albuterol) inhaler.20 Investigators found that exhalation into the device before inhalation, insufficient inspiratory flow, and missed doses caused the greatest reduction in drug delivery.
COPD management goals. COPD medications are not curative, but rather pursue the two broad management goals of (1) reducing symptoms, thereby increasing exercise tolerance and improving health status, and (2) reducing risk of exacerbations, disease progression, and death.2 Medications that reduce COPD symptoms and risk of exacerbation include bronchodilators (β-2 agonists, antimuscarinics), antiinflammatories (inhaled glucocorticoids, oral glucocorticoids, phosphodiesterase-4 inhibitors), antibiotics, mucolytics, and alpha-1 antitrypsin augmentation therapy. (See Table 2 for a selected list of medications.)
β-2agonists relax smooth muscle airways by stimulating β-2 adrenergic receptors, thereby increasing cyclic adenosine monophosphate and inhibiting bronchoconstriction. There are short-acting and long-acting β-2 agonists. Short-acting β-2 agonists (SABAs) have a typical duration of four to six hours, and in inhaled form may be used as a rescue medication. Long-acting β-2 agonists (LABAs), which typically have a duration of 12 hours, increase lung function, reduce exacerbations, and improve quality of life, though they do not significantly reduce mortality or adverse events.21 A systematic review of 13 randomized controlled trials that compared the once-daily LABA indacaterol with placebo or twice-daily LABAs and included a total of 9,961 participants with stable COPD found that once-daily indacaterol was as effective as twice-daily LABAs in reducing the perception of dyspnea and improving lung function.22 With respect to quality of life, as well, no measurable differences between indacaterol and twice-daily LABAs were noted. Adverse effects associated with β-2 agonists include resting sinus tachycardia, cardiac rhythm disruptions, and exaggerated somatic tremor, which occurs primarily in older patients taking higher doses and is more pronounced when the drugs are taken orally rather than by inhalation.
Antimuscarinic drugs block bronchoconstriction by inhibiting acetylcholine on muscarinic receptors, thereby relaxing smooth muscle airways. Short-acting muscarinic antagonists (SAMAs), such as ipratropium (Atrovent), have a duration of four to six hours. SAMAs block the inhibitory muscarinic 2 (M2) neuronal receptor, which causes vagally induced bronchoconstriction. A systematic review of 11 randomized controlled trials that compared the antimuscarinic ipratropium, alone or in combination with a SABA, with a SABA alone (delivered by inhaler or nebulizer) found that ipratropium provided small benefits over SABAs in nonasthmatic adults with COPD in terms of lung function and the need for oral steroids.23 Long-acting muscarinic antagonists (LAMAs), such as tiotropium (Spiriva, Spiriva Respimat), bind to M1, M2, and M3 receptors, binding for far longer periods to M3 receptors, and producing prolonged bronchodilation compared with SAMAs. While LAMAs may do little to improve FEV1, they can improve lung function and health-related quality of life.24 They have also demonstrated superiority in reducing exacerbation rates when compared with LABA treatment.25, 26
Antimuscarinics are associated with fewer systemic adverse effects; dry mouth (xerostomia) is the most common adverse effect. The following strategies can help patients manage xerostomia:
- Take frequent, small sips of water to promote hydration.
- Use sugar-free lozenges, gum, or mints to increase saliva production.
- Avoid foods high in salt, such as nuts and crackers.
- Do not use mouthwashes that contain alcohol.
- Limit the intake of caffeinated drinks because caffeine is dehydrating.
- Use a lip moisturizer.
- Stop smoking.
Methylxanthines, such as theophylline (Elixophyllin, Theo-24), have a modest bronchodilatory effect and may improve lung function when added to the LABA salmeterol.27, 28 This medication, however, has a narrow therapeutic window and requires close monitoring of the patient's serum levels.
Combination SABA–SAMA inhalation therapy may increase bronchodilation by acting on different mechanisms while limiting dose-related adverse effects. Together, these therapies have been shown to improve FEV1 response compared with either medication alone.29
Combination LABA–ICS vs. LABA–LAMA inhalation therapy. Inhaled corticosteroids (ICSs) should not be used as stand-alone therapy in patients with stable COPD, and may have such adverse effects as oral candidiasis, hoarse voice, skin bruising, and pneumonia. An ICS combined with a LABA, however, is more effective at lower doses than either therapy is alone.30 A systematic review of 15 randomized, double-blind studies involving 7,814 participants that compared LABA–ICS combination therapy with ICS therapy alone found that the number of exacerbations per study participant and the probability of death were reduced with combination treatment, and lung function and quality of life also improved.30 However, another systematic review of 11 studies involving 9,839 participants found that a twice-daily regimen of a LABA–LAMA combination produced a greater improvement in FEV1 and reduced exacerbations and risk of pneumonia, while increasing quality of life measures, when compared with a LABA–ICS.31 LABA–LAMA therapy is, therefore, preferred over LABA–ICS.
Inhaled triple therapy consisting of a LABA, a LAMA, and an ICS may improve lung function and patient outcomes.32 Adding a LAMA to existing LABA–ICS therapy has been shown to improve lung function in patients at high risk for exacerbation.33 Providers should consult the refined GOLD ABCD assessment tool and pharmacologic treatment algorithm before initiating triple therapy (see Figure 3).2 An analysis of prescribing practices in the United Kingdom suggests there may be a tendency toward premature use of triple therapy in patients assigned to GOLD Groups A, B, or C.34
Short-term oral glucocorticoids play a role in managing COPD exacerbations though they have numerous adverse effects, including bone fracture, epigastric disturbance, psychiatric symptoms, skin conditions, and hyperglycemia.35
Phosphodiesterase-4 inhibitors should be used only in patients determined to be in GOLD Group D with a FEV1 below 50% of predicted normal value and chronic bronchitis.2 Common adverse effects associated with these medications include nausea, vomiting, diarrhea, sleep disturbance, and headache.36
Continuous macrolide antibiotic therapy has been shown in some studies to reduce exacerbation rates in patients with COPD of moderate severity.37 Studies of pulsed macrolide antibiotic therapy, on the other hand, have produced mixed results.37, 38 Continuous antibiotic therapy may lead to bacterial resistance and should be used with caution.
Mucolytic therapy may reduce COPD exacerbation risk and modestly improve health status.39
Alpha-1 antitrypsin augmentation therapy, which is administered only by IV infusion, may help with the subset of COPD patients who have AATD.9
USING COPD CLASSIFICATION TO GUIDE TREATMENT
The refined GOLD ABCD assessment tool and pharmacologic treatment algorithm assist clinicians in adhering to evidence-based pharmacologic management strategies.
In Group A, patients may use a short-acting bronchodilator, such as a SABA or SAMA. However, regular use of short-acting bronchodilators is not recommended. The GOLD report advocates monitoring outcomes in patients using a short-acting bronchodilator, and if symptoms are not under control or patients experience adverse effects, bronchodilator treatment may need to stop or another class of bronchodilators may need to be prescribed.2 For example, if a patient is using a short-acting bronchodilator too frequently or with poor symptom control, consider prescribing a LAMA.
In Group B, patients can start therapy with a long-acting bronchodilator, either a LAMA or a LABA. If symptoms persist, the provider may add another long-acting bronchodilator to the regimen, prescribing a LABA–LAMA combination. If symptoms decrease with LABA–LAMA combination therapy, the provider may consider returning the patient to a single bronchodilator.2
In Group C, patients may start with a LAMA, but if symptoms persist, a second long-acting bronchodilator, such as a LABA, may need to be added, or a LABA–ICS combination substituted. (Since ICSs elevate the risk of pneumonia, LABA–LAMA combination therapy is preferred.2)
In Group D, the GOLD report recommends starting with LABA–LAMA combination therapy, because this group of patients has had better results with that combination than with single bronchodilator therapy, and LABA–LAMA combinations have proven superior to LABA–ICS combinations in preventing exacerbations. In addition, Group D patients are at elevated risk for pneumonia when treated with an ICS. However, in patients with a history of asthma–COPD overlap, the provider should ensure that combination therapy includes an ICS and then adjust the medication regimen to that which produces the fewest adverse effects with the greatest reduction in dyspnea. If the patient's symptoms persist without relief or the patient has more exacerbations, triple therapy with a LAMA, a LABA, and an ICS may be prescribed to control symptoms. For patients who continue to have exacerbations and a FEV1 less than 50% of predicted normal value with chronic bronchitis, recommendations include adding the phosphodiesterase-4 inhibitor roflumilast (Daliresp) or a macrolide antibiotic to the regimen.2
Providers may consider escalating or deescalating a patient's COPD medication regimen as patient symptoms and exacerbation risk intensifies or abates.2 See How to Put the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Recommendations into Practice: A Patient Scenario.2, 40
A growing body of evidence supports nonpharmacologic management strategies to improve quality of life in patients with COPD.
Pulmonary rehabilitation and exercise. Pulmonary rehabilitation, defined as “exercise training for at least four weeks” that may or may not include related education or psychological support, has been shown to have multiple benefits, such as improved health-related quality of life, decreased dyspnea, and increased exercise capacity.2, 41 The American Thoracic Society and the European Respiratory Society issued a policy statement that advocated pulmonary rehabilitation programs that include exercise training, education designed to promote physical and psychological health, smoking cessation, and self-management.2 The GOLD report recommends that patients in Groups B through D be enrolled in a pulmonary rehabilitation program.2
Education and self-management. The GOLD investigators found that the benefits of stand-alone education were unclear.2 However, they emphasize that, while education by itself may neither change behavior nor motivate patients, it can improve self-care skills and impart information about COPD, specific therapies, strategies for minimizing dyspnea, and when to seek help.2 The GOLD report suggests that personalized self-management design plans may be created based on COPD group classification (see Table 32).
Nutritional support. Some patients with COPD are prone to pulmonary cachexia, a loss of lean muscle mass associated with adverse outcomes. Patients with a low body mass index tend to have worse outcomes. Nutritional supplementation has been shown to increase lean body mass and skinfold thickness, improve respiratory muscle strength, and increase health-related quality of life.42
Oxygen therapy delivered for at least 15 hours per day has been shown to improve survival rates among patients with chronic respiratory failure and severe resting hypoxemia.40 It has not, however, been shown to increase survival or time to first hospitalization among patients with stable COPD who have mild to moderate resting, nocturnal, or exercise-induced arterial desaturation.43, 44
Noninvasive positive-pressure ventilation (NPPV) is a self-administered respiratory support system that uses positive pressure to support spontaneous breathing. Among patients with COPD, NPPV has been shown to lower risks of in-hospital mortality and hospital-acquired pneumonia, reduce lengths of stay, and lower costs of hospital treatment, though patients with multiple comorbidities and those who are admitted with pneumonia may require invasive mechanical ventilation.45 NPPV may also be beneficial at discharge. A randomized controlled trial of 166 patients who used bilevel NPPV during hospitalization showed a statistically and clinically significant reduction in hospitalization readmission rates among those who were discharged with NPPV compared with those who were not (39.7% versus 75% at 180 days).46 Furthermore, patients who were discharged with NPPV and readmitted were less likely to be admitted to the ICU (8% versus 32% at 180 days) and less likely to be intubated (6% versus 18% at 180 days).
Continuous positive airway pressure (CPAP). Patients who have both COPD and obstructive sleep apnea, known as “overlap syndrome,” benefit from using CPAP during sleep. An analysis of outcomes among 228 patients with overlap syndrome who were treated with CPAP, 213 with overlap syndrome who were not treated with CPAP, and 210 who had COPD only, found that patients with overlap syndrome who were not treated with CPAP had a higher rate of exacerbation-related hospitalization and death from any cause over a median follow-up period of 9.4 years than patients who had COPD only. Patients with overlap syndrome who were treated with CPAP had no increased risk of either outcome.47
Interventional therapy. For selected patients with severe COPD, extensive parenchymal damage, hyperinflation, and no contraindications, there are a variety of interventional therapies—including bullectomy, lung volume reduction surgery, bronchoscopic lung volume reduction, endobronchial valve therapy, and lung volume reduction coil—that can decrease lung volume, increase recoil, and reduce hyperinflation.2 The choice of intervention depends on the presence and size of bullae, the extent and pattern of emphysema, and the presence or absence of interlobar collateral ventilation. In patients with severe COPD and no contraindications, a lung transplant may be an option.2 A Cochrane review found that patients who had lung volume reduction surgery were at increased risk for death three months after the procedure.48
MANAGING COMORBID DISEASES
Patients with COPD often have multiple comorbidities and chronic, systemic inflammation. Divo and colleagues found that the 12 comorbidities most strongly associated with increased risk of death in COPD were lung cancer, pulmonary fibrosis, congestive heart failure, coronary artery disease, atrial fibrillation or flutter, esophageal cancer, liver cirrhosis, gastric or duodenal ulcer, diabetes with neuropathy, pancreatic cancer, breast cancer, and anxiety.49 Comorbid conditions do not alter the treatment of COPD, and a COPD diagnosis does not alter the treatment of other comorbid conditions, though the GOLD report does recommend limiting polypharmacy whenever possible.2
Patients may benefit from palliative care even when receiving optimal pharmacologic therapy, as it may reduce dyspnea, fatigue, depression, and anxiety.2 Research supports the use of opioids, neuromuscular electrical stimulation, oxygen therapy, and a fan blowing in the patient's face to decrease the sensation of breathlessness.2 Benzodiazepines have not been shown to have any beneficial effect, and there is insufficient evidence to recommend distractive auditory stimulation (music), relaxation, counseling, breathing relaxation training, or psychotherapy at this point.2
Palliative treatment is not restricted to end-of-life care, but hospice provides a framework for delivering increasing palliative care, and providers may consider discussing hospice with patients to determine interest in this service. Family members of patients with COPD also need support and information in order to make decisions consistent with the patient's desires.
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