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Published: October 2012

Chronic Obstructive Pulmonary Disease

Georges Juvelekian

James K. Stoller

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Recently, chronic obstructive pulmonary disease (COPD) has gained interest as a major public health concern. It is currently the focus of intense research because of its persistently increasing prevalence, mortality, and disease burden. COPD was responsible for more than 2.5 million deaths worldwide in 2000 alone.1 It currently ranks as the third leading cause of death in the United States (U.S.).2-3 COPD is projected to have the fifth leading burden of disease worldwide by the year 2020.4 It is one of the leading causes of disability worldwide and is the only disease for which the prevalence and mortality rates continue to rise.

This chapter presents a concise review of COPD. We address its definition, prevalence and epidemiology, pathology and pathophysiology, diagnosis, therapy, and outcomes. Also, because of recent developments, we have included a discussion of the relationship between COPD and sleep disorders.

Definitions

COPD is broadly defined and encompasses several clinical and pathologic entities, primarily emphysema and chronic bronchitis. Evidence of airflow obstruction that is chronic, progressive, and for the most part fixed, characterizes COPD. Notwithstanding the presence of irreversible airflow obstruction in COPD, most people with the disease (~60%-70%) demonstrate a reversible component of airflow obstruction when tested repeatedly.5-8

Emphysema is specifically defined5-8 in pathologic terms as "alveolar wall destruction with irreversible enlargement of the air spaces distal to the terminal bronchioles and without evidence of fibrosis." Chronic bronchitis is defined as "productive cough that is present for a period of 3 months in each of 2 consecutive years in the absence of another identifiable cause of excessive sputum production."

The American Thoracic Society (ATS), British Thoracic Society (BTS), and European Respiratory Society (ERS) definitions of COPD emphasize chronic bronchitis and emphysema, but the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposes a definition of COPD that focuses on the progressive nature of airflow limitation and its association with abnormal inflammatory response of the lungs to various noxious particles or gases.5-8 According to the GOLD document, COPD is defined as "a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases."8 The current definition also emphasizes the importance of exacerbations and of systemic comorbidities (eg, cardiovascular disease) in framing the clinical course of COPD.

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Prevalence and Epidemiology

The prevalence of COPD is increasing. Recent estimates suggest that there are approximately 23.6 million men and women with COPD in the U.S. and more than 52 million sufferers around the world.1,2,8 The worldwide prevalence is likely to be underestimated for several reasons, including delays in establishing the diagnosis, the variability in defining COPD, and the lack of age-adjusted estimates. The BOLD study, a recent multinational population-based study, placed the worldwide overall prevalence of stage-II or higher COPD at 10.1% with a higher prevalence rate for men (11.8%) than for women (8.5 %). The rates and severity of spirometrically confirmed COPD were higher than those previously reported.9 Age adjustment is important because the prevalence of COPD in people aged <45 years is low and the prevalence is highest in patients aged >65 years. In 1995, 553,000 patients were treated for COPD in the U.S., two-thirds of them were aged >65 years. The prevalence of COPD in those aged >65 years was 4 times that among those aged 45-64 years.10-11 The gender distribution of COPD is also changing and, since 2000, the number of COPD deaths in women has exceeded those in men.2

Because of its chronic and progressive nature, COPD represents a massive and growing burden in direct and indirect costs. In developing countries where smoking continues to be extremely prevalent, the health and economic burdens are higher than in developed nations. The disability caused by COPD in such countries further magnifies the problem.

Although it has been difficult to estimate the costs associated with COPD, they include direct costs relating to outpatient and inpatient care expenses, the indirect costs resulting from the loss of productivity caused by premature disability and death, and the additional cost of disability. In the U.S., hospitalization accounts for the bulk of all COPD-related health costs. In 2007, direct health costs of COPD were $23.6 billion, and the overall cost burden was estimated at more than $42 billion.1,2,11

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Pathogenesis and Pathology

As indicated in the definition of emphysema, the pathologic hallmark is elastin breakdown with resultant loss of alveolar wall integrity. This process is triggered by the exposure of a susceptible person to noxious particles and gases. Cigarette smoke remains the main causative agent, implicated in >90% of cases. However, other gases and particles have been shown to play a role in causing COPD,12 which results from an inflammatory process. In contrast to the eosinophilic inflammation seen in asthma, the predominant inflammatory cell in COPD is the neutrophil. Macrophages and CD8+ T lymphocytes are increased in the various parts of the lungs, and several mediators, including leukotriene B4, interleukin 8, and tumor necrosis factor, contribute to the inflammatory process.6

Recent observations by McDonough et al have challenged the traditional understanding of the pathogenesis of emphysema. Whereas the accepted wisdom has placed the initial insult at alveolar wall destruction, a more recent study by this group suggests that the narrowing and disappearance of terminal bronchioles precede and lead to the alveolar destruction that occurs in centrilobular and panlobular emphysema. Specifically, the authors applied microcomputer tomography to assess the terminal bronchioles of 78 patients with various stages of COPD in addition to lungs explanted from COPD transplant patients and control normal lungs. Comparing the numbers and dimensions of terminal bronchioles in the different groups led the authors to postulate that narrowing and loss of terminal bronchioles precede the emphysematous destruction observed in patients with COPD.13

Oxidative stress is regarded as another important process in the pathogenesis of COPD, and altered protease-antiprotease balance, at least in individuals with severe deficiency of α1-antitrypsin, has been shown to predispose to panacinar emphysema. Individuals with severe deficiency of α1-antitrypsin can develop emphysema at an early age (eg, by the fourth or fifth decade) in contrast to the “usual” emphysema, which typically begins in the sixth to seventh decades of life.

The pathologic hallmark of chronic bronchitis is an increase in goblet cell size and number that leads to excessive mucus secretion. Airflow obstruction and emphysematous change are common but not universal accompaniments. When COPD is complicated by hypoxemia, intimal and vascular smooth muscle thickening can cause pulmonary hypertension, which is a late and poor prognostic development in COPD.5-8,14,15

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Diagnosis

The diagnosis of COPD is suggested by findings on history or physical examination, or both, and is confirmed by laboratory tests, usually with a supportive risk factor (eg, familial COPD or cigarette exposure, or both). Spirometry is indispensable in establishing the diagnosis because it is a standardized and reproducible test that objectively confirms the presence of airflow obstruction. Characteristically, spirometry shows a decreased forced expiratory volume in 1 second (FEV1) and a decreased FEV1/FVC (forced vital capacity) ratio, the latter defined as being abnormal if below 0.70 or the fifth predicted percentile.5-8 Evidence of reversible airflow obstruction, defined as a post-bronchodilator rise of FEV1 and/or FVC by 12% and 200 mL, is present in up to two-thirds of patients with serial testing. Measurement of the diffusing capacity for carbon monoxide (DLCO) can help differentiate between emphysema and chronic bronchitis. Specifically, in the context of fixed airflow obstruction, a decreased diffusing capacity indicates a loss of alveolar-capillary units, which is consistent with (but does not establish) emphysema.

Deficiency of α1-antitrypsin is an uncommon cause of emphysema that continues to be under-recognized by practicing clinicians.16-18 Guidelines from the American Thoracic Society/European Respiratory Society (ATS/ERS) suggest testing all symptomatic adults with fixed airflow obstruction for α1-antitrypsin deficiency. These guidelines also call for heightened suspicion under specific clinical circumstances. These include: emphysema occurring in a young person (aged ≤45 years) or without obvious risk factors (eg, smoking or occupational exposure) or with prominent basilar emphysema on imaging, necrotizing panniculitis, antineutrophil cytoplasmic antibody (C-ANCA)-positive vasculitis, bronchiectasis of undetermined etiology, otherwise unexplained liver disease, or a family history of any one of these conditions, especially siblings of individuals who are positive for theα1-antitrypsin variant (Pi-ZZ).16

The most common symptoms and signs of COPD include cough, dyspnea on exertion, and increased phlegm production. Additional signs and symptoms include wheezing, prolonged expiration with pursed-lip breathing, barrel chest, use of accessory muscles of breathing and, in advanced cases, cyanosis, evidence of right heart failure, and peripheral edema. A chest x-ray is usually obtained to exclude other etiologies but might show hyperinflation and flattening of the diaphragm with increased retrosternal space on the lateral view and hyperlucency reflecting oligemia. The chest x-ray is an insensitive test for diagnosing emphysema and is abnormal only when the disease is relatively advanced. In contrast, high-resolution computed tomography (CT) scanning is far more sensitive and specific than chest x-ray for diagnosing emphysema and readily identifies bullae and blebs that are the consequences of alveolar breakdown. Chest CT is essential for identifying proper candidates for lung volume reduction surgery, though its role in clinical management of COPD otherwise is still evolving.5-8

Classification of Severity

Because the degree of FEV1 reduction carries prognostic implications and correlates with mortality and morbidity, a staging system based on the degree of airflow obstruction has been proposed by different societal guidelines. As reviewed in Table 1, 4 groups — the ATS, the ERS, the British Thoracic Society (BTS), and GOLD — have developed staging systems for COPD based on the value of FEV1 percent predicted. All systems propose 3- or 4-stage classifications of COPD, although the FEV1 criteria vary among systems.5-8

Table 1: Staging of Disease Severity
Disease Severity FEV1 Predicted ATS ERS BTS GOLD
Stage 0: at risk Normal;
Chronic symptoms (cough, sputum production)
Stage I: mild ≥50% ≥70% >80% ≥80% with or without chronic symptoms
Stage II: moderate 35%-49% 50%-69% 31%-80% 50%-79% with or without chronic symptoms
Stage III: severe <35% <50% ≤30 30%-49% with or without chronic symptoms
Stage IV: very severe <30%

ATS, American Thoracic Society; BTS, British Thoracic Society; ERS, European Respiratory Society; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

In the context that one major purpose of a staging system is to establish prognosis, attention has focused on the value of including weight (ie, body mass index [BMI]), dyspnea, and exercise capacity (ie, the 6-minute walk distance), with FEV1 in staging COPD.19 Indeed, the resultant index, called BODE (for BMI, obstruction, dyspnea, and exercise capacity) has been shown to better predict survival in COPD than FEV1 alone. BODE scores of 0 to 10 (most impaired) are stratified into 4 quartiles, which discriminate mortality risk better than FEV1 alone. Other multifactorial prognostic systems (eg, ADO [for age, dyspnea, and obstruction] and DOSE [for dyspnea, obstruction, smoking, and exercise capacity]) have also been proposed.20,21

In the most recent revision of the GOLD strategy document, the concept of spirometric stages has been replaced by spirometric grades because the level of FEV1 alone has been found to incompletely predict disease status. A composite measure of level of symptoms and frequency of exacerbations has been added to FEV1 to categorize patients into 4 groups:

In the context that one major purpose of a staging system is to establish prognosis, attention has focused on the value of including weight (ie, body mass index [BMI]), dyspnea, and exercise capacity (ie, the 6-minute walk distance), with FEV1 in staging COPD.19 Indeed, the resultant index, called BODE (for BMI, obstruction, dyspnea, and exercise capacity) has been shown to better predict survival in COPD than FEV1 alone. BODE scores of 0 to 10 (most impaired) are stratified into 4 quartiles, which discriminate mortality risk better than FEV1 alone. Other multifactorial prognostic systems (eg, ADO [for age, dyspnea, and obstruction] and DOSE [for dyspnea, obstruction, smoking, and exercise capacity]) have also been proposed.20,21

In the most recent revision of the GOLD strategy document, the concept of spirometric stages has been replaced by spirometric grades because the level of FEV1 alone has been found to incompletely predict disease status. A composite measure of level of symptoms and frequency of exacerbations has been added to FEV1 to categorize patients into 4 groups:

  • Group A: (low risk, fewer symptoms) includes patients with an FEV1 >50% (grade 1 or 2) and low level of symptoms as judged by a COPD Assessment Test (CAT) score <10, or a modified Medical Research Council Dyspnea Scale (mMRC) score <2 and 0-1 exacerbations in the previous year
  • Group B: (low risk, more symptoms) includes patients with an FEV1 >50% and 0-1 exacerbations in the previous year but symptomatic with CAT score >10, or mMRC score >2
  • Group C: (high risk, fewer symptoms) includes patients with an FEV1 <50% and CAT score <10, or mMRC score <2 but with ≥2 exacerbations in the previous year
  • Group D: (high risk, more symptoms) includes patients with an FEV1 <50%, CAT score >10, or mMRC >2 and ≥2 exacerbations in the previous year.8

The CAT and the mMRC are validated tools that assess symptoms and correlate well with the Saint George’s Respiratory Questionnaire (SGRQ), a widely used quality of life instrument in COPD research. The CAT is an 8-item questionnaire with scores ranging from 0-5 for each question (total range 0-40) with a score >10 being abnormal.22 This test is easier to administer and correlates more strongly with outcome measures in COPD patients than does FEV1. These characteristics have led to its adoption in the new GOLD strategy approach to assessing severity and grading patients with COPD.23

Natural History and Prognosis

Several factors influence the natural history and affect survival in patients with COPD. These factors include age, smoking status, pulmonary artery pressure, resting heart rate, BMI, airway responsiveness, hypoxemia, dyspnea, exercise capacity, exacerbation frequency, and most importantly, the level of FEV1, which remains the single best indicator of prognosis.

Few interventions have been shown to change the natural history of COPD. For patients who are hypoxemic on room air, survival can be improved by use of supplemental oxygen.24 Smoking cessation can improve survival in smokers,25,26 and lung volume reduction surgery can improve survival in selected patients.27

Acute exacerbations of COPD (AECOPD) are a significant contributor to mortality. For example, in the SUPPORT study28 of 1,016 patients with AECOPD admitted to the hospital with hypercapnic respiratory failure, 89% survived the acute hospitalization, but only 51% were alive at 2 years. Patient characteristics associated with mortality at 6 months included increased severity of illness, lower body mass index, older age, poor prior functional status, lower PaO2/Fio2 (inspired fraction of oxygen), and lower serum albumin. However, congestive heart failure and cor pulmonale were associated with longer survival time at 6 months, and this was attributed to the effective therapy available for the management of these conditions. The overall severity of illness on the third day of hospitalization, as measured by the APACHE III score, was the most important independent predictor of survival at 6 months.28

Notably, in another study of patients with AECOPD, the development of hypercapnia during an acute exacerbation of COPD appeared not to affect the risk of death with AECOPD.29  Specifically, in a prospective study involving 85 patients admitted with acute exacerbation and followed for 5 years, the mortality rate was not significantly different between hypercapnic and eucapnic patients. In contrast, patients with chronic hypercapnia demonstrated a much poorer outcome, with only an 11% rate of 5-year survival.30

To better understand the impact of exacerbations on the natural history of COPD, a large 3-year observational cohort study has been performed (the ECLIPSE study). Results from ECLIPSE showed that the rate and severity of exacerbations increased with disease severity. More importantly, ECLIPSE showed that the best single predictor of future exacerbations, a major factor influencing outcome, was a history of exacerbations, suggesting a distinct phenotype for patients with frequent exacerbations. Furthermore, patients with frequent exacerbations demonstrated a poorer outcome over the study period.31

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Sleep and COPD

In the context of a growing understanding of sleep and the interactions between disorders of sleep and COPD, this section reviews the mechanism of hypoxemia in sleep and the overlap between COPD and obstructive sleep apnea syndrome (OSAS).

Hypoxemia During Sleep in COPD

Under normal circumstances, sleep results in a decrease in ventilation and in chemo-responsiveness to the arterial partial pressure of carbon dioxide (PaCO2).32,33 The decreased ventilation appears to be almost entirely related to a drop in tidal volume. Normally, this decrease in tidal volume does not result in hypoxemia, because the drop in the arterial partial pressure of oxygen (PaO2) occurs on the flat portion of the oxyhemoglobin dissociation curve, thereby preserving the oxygen saturation (SaO2). However, in patients with COPD whose oxygenation during wakefulness may already be on the steep portion of the oxyhemoglobin dissociation curve, hypoxemia during sleep can occur as tidal volume falls.

The most pronounced hypoxemia occurs during the rapid eye movement (REM) stage of sleep because of the generalized muscle hypotonia that accompanies this stage. REM-associated hypoxemia can reach critically low levels, especially in patients with already borderline waking oxygenation, with potentially deleterious clinical consequences such as cardiac dysrhythmias, pulmonary hypertension, and polycythemia.

Hypoxemia during sleep in COPD is primarily a result of hypoventilation, but it is also caused by a decrease in functional residual capacity (FRC) and a worsening ventilation/perfusion (V/Q) mismatch.

COPD and Obstructive Sleep Apnea Syndrome

The co-occurrence of COPD and OSAS, also referred to as the overlap syndrome, involves a minority of COPD patients, but identifying these patients is important because their nocturnal hypoxemia tends to be more pronounced, leading to a greater likelihood of adverse clinical events. It follows that in patients with the overlap syndrome, therapy must be directed at both the COPD and the OSAS.

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Treatment

Stable COPD

Once the diagnosis of COPD is established and the stage of the disease is determined, attention should turn to patient education and modification of risk factors, to pharmacologic and non-pharmacologic methods needed to ameliorate the signs and symptoms of COPD, and to optimizing patients’ longevity and functional status.34,35

Patient education is an essential component of treatment because it facilitates reduction of risk factors and improves the individual patient’s ability to cope with the disease. Education requires a team approach that includes, in addition to the physician and the patient, home health nurses, social workers, physical therapists, occupational therapists, and others. In addition to risk factor reduction, education should provide a basic, simple-to-understand overview of COPD, its pathophysiology, medications and their proper use, and instructions on when to seek help. The educational process, especially when applied in the setting of pulmonary rehabilitation, facilitates discussing end-of-life issues and establishing advance directives.36,37 Several randomized trials have demonstrated the value of an education and management program for patients with COPD, including development of a home action plan for the patient to initiate an antibiotic and course of systemic corticosteroids in the event of an exacerbation.38-40 However, results of a recent trial suggest the need for additional study of self-management strategies in COPD.41

Smoking cessation is a cornerstone of patient education and confers many benefits, including slowing the rate of FEV1 decline among smokers, improvements in symptoms, and lessening the risk of lung cancer. For example, data from the Lung Health Study (LHS) show that in the sustained nonsmokers over that 11-year study, the rate of FEV1 decline slowed to 30 mL per year in men and 22 mL per year in women compared with the 66 mL per year and 54 mL per year decline in continuing male and female smokers, respectively. The result was that 38% of continuing smokers had an FEV1 <60% of predicted normal at 11 years compared with only 10% of sustained quitters. Aggressive smoking cessation intervention with counseling and nicotine patch allowed 22% of LHS participants to achieve sustained smoking cessation over 5 years, and 93% of these participants were still abstinent at 11 years.25,26,34

Available strategies for smoking cessation include nicotine replacement (available in gum, patch, lozenge, inhaler and nasal spray), bupropion (an antidepressant), smoking-cessation programs, varenicline,42 counseling, and combinations of these. Randomized, controlled trials suggest that the combination of nicotine replacement and bupropion confers greater likelihood of achieving smoke-free status than either therapy alone.43 Use of the partial acetylcholine receptor agonist varenicline appears to allow higher rates of smoking cessation than does buproprion.42

Beyond education and smoking cessation, the goals of pharmacologic and non-pharmacologic treatments are to enhance survival, quality of life, and functional status, and to lessen mortality. As reviewed in Table 2, available treatments include bronchodilators, corticosteroids, immunizations, antibiotics, mucokinetics, and others.

Table 2: Recommendations by Professional Societies for Management of Stable COPD
American Thoracic Society 1995 Consensus European Respiratory Society 1995 Consensus British Thoracic Society 1997 Consensus Global Initiative for Chronic Obstructive Lung Disease 2011 Evidence-Based Review
Diagnostic Testing
Recommended: Recommended: Recommended: Recommended:
Spirometry Spirometry Spirometry Spirometry
Pre- and post-BD Pre- and post-BD Pre- and post-BD Pre- and post-BD
Pre- and post-corticosteroids only if inadequate response to treatment Pre- and post-corticosteroids in stages 2 and 3 Pre- and post-corticosteroids in stages 2 and 3 Pre- and post-corticosteroids in stages 2 and 3
CXR CXR CXR in moderate or severe disease CXR to exclude alternative Dx and establish presence of significant comorbidities
CT: not routinely, but helpful in predicting the benefit of pulmonary resection for giant bullous disease CT assessment of bullae Restricted to assessment of bullous emphysema CT when Dx is in doubt or if LVRS is contemplated
ABG in stages 2 and 3 ABG in stages 2 and 3 or SaO2 <92% ABG in severe disease ABG if pulse oximetry <92%
α1-AT deficiency in early, severe disease α1-AT deficiency in early, severe disease Not discussed α1-AT deficiency in early COPD (age <45) or strong family history
Bronchodilator Therapy
β2 Agonist first line PRN use; anticholinergic first line for regular use; theophylline and/or sustained release albuterol for persistent symptoms β2 Agonist or anticholinergic as needed; combination if needed; theophylline if no response to other BD; long-acting inhaled β2-agonist or oral if needed Short-acting β2 agonist or inhaled anticholinergic as needed; regular β2 agonist and/or anticholinergics and/or combination for advanced stages; long-acting β2 agonist if evidence of improvement; theophylline is of limited value Short-acting BD as needed
Regular treatment with one or more BD in advanced stages; long-acting inhaled BD more convenient; combination BD and anticholinergics is better than either agent alone
PDE-4 inhibitor may be useful in properly selected patients
Corticosteroids
If corticosteroid response established: If corticosteroid response established: If corticosteroid response established: If corticosteroid response established:
  • Lowest effective oral dose used
  • Insufficient data to support use of aerosolized steroid
  • Inhaled steroids
  • Inhaled steroids in patients with mild disease but “fast decline” of FEV1 (>50 mL per yr)
  • Inhaled steroids
  • Inhaled steroids
  • Inhaled steroids in stages 2 and 3
  • Long-term monotherapy with oral or inhaled steroids not recommended
Antibiotics
Not recommended Not recommended Not recommended Not recommended
Mucokinetics
Not recommended Not recommended Not recommended Not recommended
α-1 Antitrypsin Augmentation Therapy
In appropriate patients Not recommended Not discussed In appropriate patients
Vaccinations
Influenza recommended; pneumococcal recommended Influenza recommended; pneumococcal, insufficient data Influenza and pneumococcal recommended Influenza and pneumococcal recommended
Smoking Cessation
Recommended; smoking cessation protocol Recommended Recommended Recommended
Lung Volume Reduction Surgery
In appropriately selected patients In appropriately selected patients In appropriately selected patients Not recommended, insufficient data
Lung Transplantation
In appropriately selected patients In appropriately selected patients In appropriately selected patients In appropriately selected patients
Home Mechanical Ventilation
Non-elective ventilation supported; elective ventilation not supported No recommendation provided Elective and non-elective ventilation modestly supported Not supported
Long-Term Oxygen Therapy
Recommended in patients with chronic hypoxemia Recommended in patients with chronic hypoxemia Recommended in patients with chronic hypoxemia Recommended in patients with chronic hypoxemia
Pulmonary Rehabilitation
Recommended; upper extremity training and breathing retraining supported Recommended Recommended Recommended along with nutritional counseling, and education

ABG, arterial blood gas; α1-AT, Alpha-1 antitrypsin; BD, bronchodilator; COPD, chronic obstructive pulmonary disease; CXR, chest x-ray; CT, computed tomography; Dx, diagnosis; FEV1, forced expiratory volume in 1 second; LVRS, lung volume reduction surgery; RHF, right heart failure. ©2002 The Cleveland Clinic Foundation.

Bronchodilators

Bronchodilators are a mainstay of COPD treatment and include β-adrenergic agonists, anticholinergics, and methylxanthines. β-adrenergic agonists are effective in alleviating symptoms and improving exercise capacity, and they can produce significant increases in FEV1.5,6 Their effect is achieved through smooth-muscle relaxation, resulting in improved lung emptying, reduced thoracic gas volume and residual volume, and lessened dynamic hyperinflation. It is believed that the increase in exercise tolerance and reduction in symptoms of breathlessness are primarily a result of an improvement in inspiratory capacity rather than an increase in FEV1. Oral theophylline has been shown to lessen dyspnea and improve the health-related quality of life despite lack of significant rise in FEV1, with improvements believed to be a result of increased respiratory muscle performance. However, the narrow therapeutic index of older methylxanthines (which are phosphodiesterase inhibitors) and their potential for adverse drug-drug interactions have hindered their widespread use. The more specific phosphodiesterase-4 inhibitor, roflumilast (see below), has been approved on the strength of evidence that it confers some bronchodilation and can avert exacerbations in patients with advanced COPD who have had frequent exacerbations.44

Phosphodiesterase-4 Inhibitors

Newly developed oral, highly selective phosphodiesterase-4 (PDE-4) inhibitors roflumilast45 and cilomilast,46 have shown promise in the management of stable COPD. Specifically, a randomized, double-blind study involving more than 1400 patients with moderate-to-severe COPD compared patients assigned to receive 250 mcg of roflumilast, 500 mcg of roflumilast, or placebo over a period of 24 weeks. The primary end points were post-bronchodilator FEV1 and health-related quality of life. Secondary end points included the rate of COPD exacerbations. Although there was no significant difference in the post-bronchodilator FEV1 in the treatment arms, both were superior to placebo (P < 0.0001). Similar findings were reported in the health-related quality of life and rate of exacerbations with an acceptable safety profile.45 In 2011, the U.S. Food and Drug Administration (FDA) approved roflumilast for the treatment of stable COPD in patients with frequent exacerbations.44 In the most recent GOLD strategy document, roflumilast is listed as an alternative treatment option in group D patients.8

β-Adrenergic Agonists and Antimuscarinic Agents

In the early stages of COPD (eg, stage I), a short-acting β-adrenergic agonist (eg, albuterol, terbutaline) or an anticholinergic is used on an as-needed basis. As the disease progresses (eg, stages II and III), regular use of one or more bronchodilators is often recommended. Some data suggest that a combination of albuterol and ipratropium bromide provides better bronchodilation than does either agent alone.5,47-49

In 2004, the FDA approved a new anticholinergic agent, tiotropium, for the long-term, once daily, maintenance treatment of bronchospasm associated with stable COPD, including chronic bronchitis and emphysema.50 Although this is the same indication granted to ipratropium, tiotropium has shown significant advantages over ipratropium, both pharmacologically and clinically. Specifically, tiotropium blocks the M1 to M5 muscarinic receptors with a 6- to 20-fold greater affinity than ipratropium and for a longer period51-53 and dissociates more rapidly from the M2 receptor associated with acetylcholine release, thereby conferring theoretical mechanistic advantages over ipratropium.

These advantages were shown in clinical trials comparing the 2 agents. Specifically, tiotropium demonstrated significantly greater bronchodilation than ipratropium, and users experienced less dyspnea, fewer acute exacerbations, reduced albuterol use, and improved nocturnal oxygen saturation.52-55 When compared with long-acting β2-agonists, tiotropium provided greater bronchodilation and more-reduced dyspnea than salmeterol. A large double-blind, placebo-controlled trial showed a significantly greater reduction in yearly incidence as well as delay to first COPD exacerbation compared with either salmeterol or placebo.55 With the approval in the U.S. of a once-daily β-agonist (indacaterol) and early comparisons with tiotropium,56 it is likely that further clarification of the relative roles of these long-acting agents, especially in concert with other agents, will be the subject of ongoing study and forthcoming recommendations. Other long-acting agents (eg, vilanterol57) are also currently under investigation.

Results of a large randomized, controlled trial (called UPLIFT) assessing the efficacy of tiotropium (compared with placebo) have shown that tiotropium conferred benefits of a lower exacerbation frequency but neither slowed the rate of FEV1 decline nor lowered the mortality rate.58

In the 2011 GOLD document, β-adrenergic agonists are recommended in all 4 COPD groups (A-D). In group A, short-acting beta-agonist (SABA) agents or short-acting muscarinic agents (SAMA) are first-line therapies with long-acting beta agonists) (LABA) or long-acting muscarinic agents (LAMA) as alternatives. In groups B, C, and D, LABA, LAMA, or a combination are deemed either first- or second-line therapies.8

Corticosteroids

Inhaled corticosteroids play an important role in managing patients with stable COPD though systemic steroids should generally be reserved for managing acute exacerbations. Several groups suggest brief trials of oral corticosteroids for patients with stable COPD. For example, the BTS suggests a course of oral prednisone (eg, 30 mg daily) taken for 2 weeks or a course of inhaled steroid (eg, beclomethasone 500 mcg twice daily or the equivalent) taken for 6 weeks.7 Similarly, the ERS suggests a trial of corticosteroids (eg, 0.4-0.6 mg/kg/day) taken for 2 to 4 weeks. Patients with significant FEV1 responses are considered candidates for long-term inhaled corticosteroids.6 The weight of evidence from randomized, placebo-controlled trials of inhaled corticosteroids in patients with COPD shows no effect on the rate of FEV1 decline,35,59-62 although one study (TORCH) did show a slowed rate of FEV1 decline in patients who received inhaled steroids.63 Several other randomized, controlled clinical trials have also assessed the role of inhaled corticosteroids (eg, called Euroscop [European Respiratory Society study on chronic obstructive pulmonary disease], ISOLDE, Copenhagen City, Lung Health Study, and OPTIMAL) and of inhaled steroids combined with LABAs regarding exacerbation frequency, quality of life, rate of change of FEV1, and, in one study (TORCH), mortality.63 The weight of evidence, including from meta-analyses,64,65 suggested that inhaled corticosteroids can lessen the frequency of acute exacerbations of COPD, but (with the exception of the TORCH trial) inhaled corticosteroids do not appear to affect the rate of FEV1 decline. The combination of inhaled fluticasone and salmeterol appears better than placebo in enhancing health-related quality of life and lessening exacerbation frequency. The one trial (TORCH) that examined mortality as a primary outcome measure showed that the combination of inhaled fluticasone and salmeterol (500 mcg/50 mcg, respectively, twice daily) conferred a 2.6% absolute reduction in mortality (15.2%-12.6%; 17.5% relative reduction), although this difference missed statistical significance (P = 0.052).

Regarding the effects of combined LABA-inhaled steroid, the TORCH trial was conducted to compare the effect of the salmeterol-fluticasone combination with either agent alone and with placebo. The trial found that the combination therapy was significantly more effective than sole therapy with the long-acting bronchodilator, or fluticasone, or placebo in patients with COPD.63 Another similar trial, the so-called TRISTAN study, was a 52-week, randomized, placebo-controlled study involving 1,465 patients with moderate-to-severe COPD. This trial showed significant improvement in FEV1 in the salmeterol-fluticasone combination versus salmeterol (treatment difference of 73 mL, P < 0.0001), fluticasone (treatment difference of 95 mL, P < 0.0001),64 and placebo (treatment difference of 133 mL, P < 0.0001). Other benefits included a decrease in the use of rescue medications in the combination group and a significant improvement in health status as defined by the St. George's Respiratory Questionnaire compared with the fluticasone group but not the salmeterol group. The rate of moderate and severe exacerbations was reduced by 25% in the combination group compared with placebo.64

This finding becomes all the more significant in the context that severe acute exacerbations have an independent adverse impact on prognosis, with increased mortality associated with the frequency of severe exacerbations.65 In a prospective cohort of 304 men with severe COPD (mean FEV1, 46% of predicted), older age, PCO2, and acute exacerbation of COPD represented independent indicators of poor prognosis, and patients with 3 or more exacerbations showed the greatest mortality risk.65 In the ECLIPSE study, the "frequent exacerbator" phenotype was associated with a poorer quality of life, higher frequency of gastroesophageal reflux, and a higher white blood cell count, suggesting ongoing inflammation in addition to the worsened disease severity.31 Currently, inhaled corticosteroids are widely used, especially for patients with frequent exacerbations of COPD, although recent concerns about excess pneumonia risk in users of inhaled steroids have spurred some controversy and will certainly receive prospective scrutiny.

Immunizations

Yearly prophylactic immunization with the influenza vaccine has been shown to reduce the incidence of influenza by 76% and is strongly recommended.66-68 Immunization once with the 23- polyvalent pneumococcal vaccine in patients with COPD or, in the special case of patients with immunodeficiency or those with splenectomy, every 5 years, is also recommended.67

Antibiotics

Although many studies of prophylactic antibiotics have not shown benefit in the management of stable COPD, recent studies of regular macrolide use (ie, azithromycin and erythromycin) have shown benefit, with fewer exacerbations and/or longer times to a first exacerbation.69,70 The precise role of long-term use macrolides in the face of existing drugs to decrease exacerbation frequency (eg, inhaled corticosteroids, roflumilast, etc.) warrants further study.

Mucokinetic Agents

Mucoactive agents are varied and include ambroxol, erdosteine, carbocysteine, iodinated glycerol, N-acetylcysteine, surfactant, and others, all of which have been studied with conflicting results. However, a Cochrane systematic review of 23 randomized, controlled trials in Europe and the U.S. associates the long-term use (>2 months) of oral mucolytics with a reduction in acute COPD exacerbations and days of illness and suggests considering these agents in patients with recurrent, prolonged, severe COPD exacerbations.71 Still, the latest guidelines by the ATS and BTS do not recommend the routine use of mucoactive agents in the management of chronic COPD.5-8

Others

Antitussives containing narcotics and other therapies, such as inhaled nitric oxide, may be harmful. Their use in COPD is relatively contraindicated.5-8 In the specific case of α1-antitrypsin deficiency, intravenous augmentation therapy with pooled human plasma antiprotease can raise serum levels of α1-antitrypsin above a serum protective threshold value (11 micro molar or ~57 mg/dL using nephelometry).16 Available observational studies show that augmentation therapy can slow the rate of FEV1 decline in patients with severe deficiency of α1-antitrypsin (eg, with the Pi-ZZ phenotype) and established airflow obstruction of moderate severity (eg, FEV1 30%-65% of predicted). Also, 2 randomized controlled trials of augmentation therapy have shown trends toward slower rates of lung density loss in augmentation therapy recipients.72 Currently, 4 preparations of pooled human plasma antiprotease have received FDA approval and appear generally similar in effect, with some variation in product formulation.72

Non-pharmacologic treatment of COPD includes pulmonary rehabilitation, long-term oxygen therapy, ventilatory support, and lung volume reduction procedures, both surgical (LVRS) and bronchoscopic. Pulmonary rehabilitation is recommended at all stages by all available guidelines (see Table 2).5-8,73-74 Aerobic lower extremity training can improve exercise endurance, dyspnea, use of health care, and overall quality of life. Upper extremity-exercise and respiratory muscle training also appear helpful.5,73

Long-term oxygen therapy for patients with hypoxemia has been shown to improve survival in eligible patients with COPD.24 Criteria for prescribing long-term oxygen therapy include a PaO2 <55mm Hg or SaO2 <88% with or without increased PaCO2, or PaO2 between 55 and 59mm Hg or SaO2 <89%, with right-sided failure reflected by evidence of pulmonary hypertension or polycythemia (eg, hematocrit >55%). Because the evidence of benefit of supplemental oxygen is scant in COPD patients with moderate resting hypoxemia (ie, SpO2 between 89% to 92%) or desaturation solely with exercise, a large multicenter controlled trial of oxygen versus no oxygen sponsored by the National Institutes of Health (Long-term Oxygen Treatment Trial [LOTT]) is currently examining the survival benefits of supplemental oxygen for patients with COPD with these specific characteristics, ie, moderate hypoxemia (pulse oximetry saturation of 89%-92% on room air at rest) and/or desaturation only with activity.74

Nocturnal noninvasive ventilatory support still has an unproven role in managing patients with stable COPD. Lung volume reduction surgery (LVRS) involves resecting 20% to 35% of the emphysematous lung to improve lung mechanics. The procedure was first proposed by Brantigan and Mueller in the late 1940s,75 but it was abandoned then because of unacceptably high associated mortality. More recently, randomized, controlled trials show that LVRS is contraindicated in patients with severely impaired lung function (eg, FEV1 <20% predicted, homogeneous emphysema and/or lung diffusing capacity for carbon monoxide <20% predicted)27,76-80 but that patients with moderate degrees of airflow obstruction who undergo LVRS might experience an improved FEV1, walking distance, and quality of life.27,76-80 In the results of the National Emphysema Treatment Trial (NETT), a randomized, controlled trial of LVRS versus medical therapy (including rehabilitation) in which 1218 subjects with moderate COPD (FEV1 <45% predicted) were enrolled, the LVRS group overall experienced improved disease-specific quality of life and exercise capacity compared with the medically managed group.27,79 On the other hand, the LVRS group had rates of survival similar to those of the medically managed group. In prespecified subsets, a survival advantage was observed in the subgroup of patients with predominantly upper lobe emphysema and low baseline (ie, post-rehabilitation) exercise capacity (defined as a maximal workload at <25 watts for women and 40 watts for men).27,79 A longer-term overall survival benefit was demonstrated in those allocated to LVRS.

The high short-term mortality (5%) and more importantly the increased morbidity from LVRS coupled with the strict selection criteria of LVRS candidates has led to several innovative bronchoscopic techniques targeting outcomes similar to LVRS.81,82 These novel approaches include endobronchial blockers, airway bypass, endobronchial valves, thermal vapor ablation, biological sealants, and airway implants. To date, the clinical benefit of these options remains incompletely characterized with a few available studies. For example, the VENT study randomly assigned 220 patients with heterogeneous emphysema to receive an endobronchial valve and 101 controls to receive standard medical care and demonstrated a 6%-7% increase in FEV1 and a significant improvement in 6-minute walk test (6MWT) at 6 months. However, the benefit was offset by an increased incidence of hemoptysis and COPD exacerbations.82 Further studies are awaited to better identify subsets of COPD patients who can benefit from these promising techniques.

Lung transplantation is an option for patients with severe airflow obstruction and functional impairment. The 5-year actuarial survival rate for patients undergoing single-lung transplantation for COPD is 43.2%.83-85 Selection criteria include an FEV1 <25% predicted or a PaCO2 >55 mm Hg or cor pulmonale, or both.

Acute Exacerbations of COPD

Acute exacerbation of COPD (AECOPD) represents an acute worsening of the patient's baseline condition, generally characterized by worsened dyspnea and increased volume and purulence of sputum.5-8,86-88 Depending on the severity of baseline COPD, additional derangements can occur, including hypoxemia, worsening hypercapnia, cor pulmonale with worsening lower extremity edema, or altered mental status.

The main goals of treating AECOPD are to restore the patient to his or her previous stable baseline and to prevent or reduce the likelihood of recurrence. This requires identifying the precipitating factor or condition and reversing or ameliorating it while optimizing gas exchange and improving the patient’s symptoms. Treatment modalities similar to the ones used in stable COPD are used in managing acute exacerbations (Table 3), with the notable exception that systemic corticosteroids may play a role in managing patients with AECOPD. Other treatments for AECOPD include oxygen therapy, bronchodilators, antibiotics, mechanical ventilation, and others.

Table 3: Recommendations by Professional Societies for Management of Acute Exacerbations of COPD
American Thoracic Society European Respiratory Society British Thoracic Society Global Initiative for Chronic Obstructive Lung Disease
Bronchodilators
Recommended: β2 agonists ± anticholinergics; IV aminophylline if inadequate response Recommended: β2 agonists ± anticholinergics; methylxanthines if needed as second-line therapy in severe exacerbations Recommended: β2 agonists ± anticholinergics; IV aminophylline if inadequate response Recommended: β2 agonist dose increase ± anticholinergics ± IV aminophylline depending on disease severity
Corticosteroids
Oral or systemic Oral or systemic empirically 7-14 days of systemic steroids Systemic steroids
Antibiotics
Narrow-spectrum antibiotic; broad spectrum if no response Inexpensive antibiotic empirically for 7-14 days; if ineffective, choice guided by sputum culture Common oral antibiotics usually adequate; Broader spectrum if no response or if more severe exacerbation Empirically with increased sputum volume and purulence based on local sensitivity patterns to usual pathogens
Oxygen Therapy
Raise PaO2 > 60mm Hg Keep SaO2 ≥90% and/or PaO2 ≥60mm Hg. Avoid PaCO2 rise by >10mm Hg or pH drop to <7.25 Raise PaO2 to ≥50mm Hg while avoiding pH <7.26 Keep SaO2 between 88%-92%
Ventilatory Support
NIPPV or invasive mechanical ventilation based on criteria NIPPV in appropriate patients NIPPV or invasive mechanical ventilation if pH <7.26 with rising PaCO2 despite controlled oxygen therapy NIPPV or invasive mechanical ventilation based on selection and exclusion criteria.
Chest Physiotherapy
Only if sputum volume is >25 mL/day Help in clearance of secretions Not recommended May be beneficial in certain circumstances

COPD, chronic obstructive pulmonary disease; NIPPV, noninvasive positive pressure ventilation. ©2002 The Cleveland Clinic Foundation.

Oxygen Therapy

The role of oxygen therapy is to correct the hypoxemia that usually accompanies the AECOPD. The end point is to maintain oxygen tension at approximately 60 to 65mm Hg, thereby assuring near-maximal hemoglobin saturation while minimizing the potential for deleterious hypercapnia. Hypercapnia complicating supplemental oxygen is mainly a result of ventilation-perfusion mismatch, with generally smaller contributions of depression of the respiratory drive and the Haldane effect.

Bronchodilators

Bronchodilators are widely used in AECOPD, and β-adrenergic agonists and anticholinergics are first-line therapies. As in stable COPD, both can improve airflow in AECOPD, and although recommendations vary, combined therapy is often recommended. β-Adrenergic agonists generally have a quicker onset of action, whereas anticholinergics have a more favorable side-effect profile. Because of their potential side effects, as well as their limited benefit, older methylxanthines have been reserved as second-line therapy.5-8

Antibiotics

Antibiotics play a favorable role in treating AECOPD, especially in the setting of increased volume and purulence of phlegm.87-89 A narrow-spectrum antibiotic (eg, amoxicillin, trimethoprim-sulfamethoxazole, doxycycline) is often recommended as first-line therapy, although use of a beta-lactam/beta-lactamase combination has been recommended in patients with severe AECOPD, and fluoroquinolones have been used in patients suspected to be colonized with Pseudomonas aeruginosa.8 The optimal duration of treatment is still unclear, although most guidelines recommend treating for between 7 and 14 days.85,86

Corticosteroids

Randomized clinical trials generally support the use of systemic corticosteroids to enhance airflow and to lessen treatment failure in AECOPD. Prolonged therapy beyond 2 weeks confers no additional benefits, with 5 to 10 days being the likeliest optimal duration.93-95

Noninvasive Positive Pressure Ventilation and Mechanical Ventilation

Noninvasive positive pressure ventilation (NIPPV) is emerging as a preferred method of ventilation in adequately selected patients with acute respiratory acidemia.90-93 This mode is used in the treatment of acute respiratory failure of many causes, including COPD. Appropriate patient selection is critical to ensure the success of NIPPV. Poor candidates are those with acute respiratory arrest, altered mental status with agitation or lack of cooperation, distorted facial anatomy preventing proper application of the mask, cardiovascular instability, or excessive secretions. NIPPV improves symptomatic and physiologic variables; reduces the need for intubation, hospital stay, and mortality; and does not use additional resources.93-95

For patients who do not qualify for NIPPV or who show evidence of worsening respiratory failure and life-threatening acidemia despite NIPPV, intubation and mechanical ventilation are indicated. This method of ventilation carries numerous risks and complications, including ventilator-acquired pneumonia and barotrauma. Adequate ventilator management is necessary, and every effort should be undertaken to minimize the duration of mechanical ventilation.

Others

Mucolytics, expectorants, and chest physiotherapy have not been shown to improve the outcome and are not recommended.5-8

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Conclusions

Overall, COPD poses a common, growing, and significant clinical challenge for patients and clinicians alike. Clinicians' expert knowledge regarding diagnosis and management can enhance patients' longevity and quality of life. Results of emerging studies will likely lead to enhancements in current management and new paradigms in managing patients with COPD.

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Summary

  • COPD is emerging as a major cause of morbidity and mortality in the U.S. and is currently is the third leading cause of death among Americans.
  • COPD is under-recognized overall, as is α1-antitrypsin deficiency, a genetic predisposition to COPD.
  • The frequency of exacerbations and the presence of co-morbidities (eg, cardiovascular disease, musculoskeletal disease, etc.) affect the clinical course of COPD.
  • Among the available therapies for COPD, many can improve symptoms (eg, bronchodilators, pulmonary rehabilitation). Three treatments—smoking cessation, supplemental oxygen used 24 hours a day, and lung volume reduction surgery—have been shown to prolong life in appropriately selected COPD patients.

Suggested Readings

  • AACP/AACVPR Pulmonary Rehabilitation Guidelines Panel. Pulmonary rehabilitation: Joint ACCP/AACVPR evidence-based guidelines. Chest 1997;112:1363-1396.
  • American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. thoracic.org, accessed May 30, 2008.
  • Qaseem A, MD, PhD, MHA, Wilt TJ, MD, MPH et al: Diagnosis and Management of Stable Chronic Obstructive Pulmonary Disease: A Clinical Practice Guideline Update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155:179-191.
  • American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with α1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818-900.
  • Anthonisen NR, Connett JE, Murray RP: Smoking and lung function of Lung Health Study participants after 11 years. The Lung Health Study Research Group. Am J Respir Crit Care Med 2002;166:675-679.
  • Maurer JR, Frost AE, Estenne M, et al: International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society. Transplantation 1998;66:951-956.
  • Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775-789.
  • Aaron SD, Vandemheen KL, Ferguson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2007; 146: 545-555.
  • National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348:2059-2073.
  • Pauwels RA, Buist AS, Calverley PM, et al: GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256-1276. goldcopd.com
  • Pauwels RA, Lofdahl CG, Laitinen LA, et al: Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999;340:1948-1953.
  • Sutherland ER, Cherniack RM: Management of chronic obstructive pulmonary disease. N Engl J Med 2004;350:2689-2697.
  • The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343:1902-1909.

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