Recently, chronic obstructive pulmonary disease (COPD) has gained interest as a major public health concern and 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 the year 2000 alone ¹ and currently ranks as the fourth leading cause of death in the United States, surpassed only by heart disease, cancer, and cerebrovascular disease. ^2,3 Furthermore, COPD is projected to have the fifth leading burden of disease worldwide by the year 2020. ⁴ COPD 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 overview of COPD. We address its definition, prevalence and epidemiology, pathology and pathophysiology, diagnosis, therapy, and outcomes. Also, because of recent insights regarding the relation between COPD and sleep disorders, we include a discussion on sleep and COPD.

Definitions

COPD is broadly defined and encompasses several clinical and pathologic entities, namely 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 individuals (∼60% to 70%) demonstrate a reversible component of airflow obstruction when tested repeatedly. ^5–8

Emphysema is specifically defined ^5–8 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 three months in each of two consecutive years in the absence of another identifiable cause of excessive sputum production.”

Whereas the American Thoracic Society (ATS), British Thoracic Society (BTS), and European Respiratory Society (ERS) definitions of COPD emphasize chronic bronchitis and emphysema, 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

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Prevalence and Epidemiology

The prevalence of COPD is increasing. In 1994, there were approximately 16.2 million men and women suffering from COPD in the United States and more than 52 million individuals around the world. ^1,2,8 The worldwide prevalence is likely to be underestimated for several reasons, including the delay in establishing the diagnosis, the variability in defining COPD, and the lack of age-adjusted estimates. Age adjustment is important because the prevalence of COPD in individuals younger than 45 years is low, whereas the prevalence is highest in patients older than 65 years. In 1995, 553,000 patients were treated for COPD in the United States and two thirds of those were older than 65 years. The prevalence in those older than 65 years was four times that in the 45- to 64-year-old group. ^9,10 The gender distribution of COPD is also changing, such that as of 2000, COPD deaths in women exceeded the number in men. ²

Because of its chronic and progressive nature, COPD represents a massive and growing burden, both 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. Because human capital constitutes an essential role in the economy of developing countries, the disability caused by COPD further magnifies the problem.

Although it has been difficult to estimate the costs associated with COPD, they include direct costs pertaining to outpatient and inpatient care expenses as well as the indirect costs resulting from the loss of productivity caused by premature death and disability, and the additional cost of disability. In the United States, for instance, hospitalization constitutes the bulk of all COPD-related health costs. In 1993, direct health costs of COPD were $14.7 billion, with the overall burden estimated at more than $30 billion. ^1,2,10

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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 individual to noxious particles and gases. Cigarette smoke remains the main causative agent, involved in more than 90% of cases; however, other gases and particles have been shown to play a role in pathogenesis, which is a result of an inflammatory process. In contrast to the eosinophilic inflammation seen in asthma, the predominant inflammatory cell 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

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 alpha-1 antitrypsin, has been shown to predispose to a panacinar form of emphysema. Individuals with severe deficiency of alpha-1 antitrypsin may develop emphysema at an early age (e.g., by the fourth decade), in contrast to the “usual” emphysema, which typically begins in the sixth decade.

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 frequent but not universal accompaniments. When COPD is complicated by hypoxemia, intimal and vascular smooth muscle thickening may cause pulmonary hypertension, which is a late and poor prognostic development in COPD. ^5–8,11,12

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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 (e.g., 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 FEV₁/forced vital capacity (FVC) ratio. ^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) may 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 suggests emphysema. Deficiency of α₁ antitrypsin is an uncommon cause of emphysema that continues to be under-recognized by practicing clinicians. ^13–15 The clinical recognition of patients with this condition is also based on clinical suspicion, but as outlined in the American Thoracic Society/European Respiratory Society (ATS/ERS) evidence-based standards document, specific circumstances should prompt suspicion of α₁-antitrypsin deficiency. They include emphysema occurring in a young individual (age 45 or younger) or without obvious risk factors (e.g., 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 PI*ZZ individuals. ¹³

The most common symptoms and signs 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 radiograph (CXR) is usually obtained to exclude other etiologies but may show hyperinflation and flattening of the diaphragms with increased retrosternal space on the lateral view, and hyperlucency reflecting oligemia. The chest radiograph is an insensitive test for diagnosing emphysema and is abnormal only when emphysema is relatively advanced. In contrast, high-resolution computed tomography (CT) scanning is far more sensitive and specific than CXR for diagnosing emphysema and readily identifies bullae and blebs that are the consequences of alveolar breakdown. However, save its role in selecting the proper candidate for lung volume reduction surgery (LVRS), the additional data from CT rarely alter therapy, making CT scanning not indicated for routine clinical use. ^5–8

Classification of Severity

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

More recently, in the context that one major purpose of staging systems is to establish prognosis, attention has focused on the additive value of assessing weight (i.e., body mass index), dyspnea, and exercise capacity (i.e., the 6-minute walk distance), to FEV₁ in staging COPD. ¹⁶ Indeed, the resultant index called BODE (for Body mass index, 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 four quartiles, which discriminate mortality risk better than FEV₁ alone.

Natural History and Prognosis of COPD

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, body mass index (BMI), airway responsiveness, hypoxemia, dyspnea, exercise capacity, and most importantly, the level of FEV₁, which remains the single best predictor of prognosis.

More fully discussed in the section on treatment, few interventions have been shown to change the natural history of COPD. Specifically, survival can be improved by use of supplemental oxygen by those hypoxemic on room air, ¹⁷ by allocation to smoking cessation, ^18,19 and—in selected individuals—by lung volume reduction surgery. ²⁰

Acute exacerbations of COPD (AECOPD) are a significant contributor to mortality. For example, in the SUPPORT study ²¹ of patients with AECOPD admitted to the hospital, of 1016 inpatients admitted 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. ²¹

Notably, in another study of individuals with AECOPD, the development of hypercapnia during an acute exacerbation of COPD appeared not to affect the risk of death with AECOPD. ²² 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 individuals. In contrast, patients with chronic hypercapnia demonstrated a much poorer outcome, with only an 11% 5-year survival rate. ²³ Notwithstanding these insights, well-designed studies and controlled trials are necessary to improve our ability to predict the outcomes for patients afflicted with this disease.

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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). ^24,25 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 may 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 REM sleep. REM-associated hypoxemia may 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 to worsening ventilation/perfusion (/ ) mismatch.

COPD and Obstructive Sleep Apnea Syndrome

The co-occurrence of COPD and obstructive sleep apnea syndrome (OSAS), also referred to as the “overlap syndrome,” involves a minority of COPD patients but identifying these individuals 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 their COPD and at the OSAS.

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Treatment

Treatment of Stable COPD

Once the diagnosis of COPD is established and the stage of the disease is determined, attention turns to patient education and risk factor modification, to pharmacologic and nonpharmacologic methods needed to ameliorate the signs and symptoms of COPD, and to optimizing patients' longevity and functional status. ^26,27

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. Discussing end-of-life issues and establishing advance directives are facilitated by the educational process, especially when applied in the setting of pulmonary rehabilitation. ^28,29

Smoking cessation is a cornerstone of patient education and confers many benefits, including slowing the accelerated 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 individuals were still abstinent at 11 years. ^18,19,26

Available strategies for smoking cessation include nicotine replacement, available in gum, patch, inhaler or nasal spray; bupropion (an antidepressant), smoking-cessation programs, varenicline, ³⁰ 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. ³¹ Use of the partial acetylcholine receptor agonist, varenicline, appears to allow higher rates of smoking cessation than does buproprion. ³⁰

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

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 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. As such, 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 (QOL) 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 methylxanthines and their potential for adverse drug-drug interactions, has hindered their widespread use. Long-acting formulations have allowed more consistent and stable plasma levels, thereby mitigating the problem.

Recently, newly-developed oral, highly selective phosphodiesterase-4 (PDE-4) inhibitors roflumilast ³² and cilomilast, ³³ 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 mg of roflumilast, 500 mg of roflumilast, or placebo over a period of 24 weeks. The primary end points were post-bronchodilator FEV₁ and health-related QOL. 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 < .0001). Similar findings were reported in the health-related QOL and rate of exacerbations with an acceptable safety profile. ³² Similarly, cilomilast was compared with placebo in a double-blind, placebo-controlled, parallel group trial. Here, patients were assigned to cilomilast 15 mg orally twice daily versus placebo, and followed for 24 weeks. Change from baseline FEV₁ and St. George's Respiratory Questionnaire (SGRQ) scores were the primary end points, with the rate of COPD exacerbations as the main secondary end point. Again, cilomilast was statistically superior to placebo in all study end points, with mild-to-moderate adverse events that were self limited. ³³ As promising as these studies seem, more studies are needed before these new PDE-4 inhibitors become part of the standard therapy of the stable COPD patient. ^5,33

In the early stages of COPD (e.g., stage I), a short-acting β-adrenergic agonist (e.g., albuterol, terbutaline, etc.) or an anticholinergic is used on an as-needed basis. As the disease progresses (e.g., stages II and III), regular use of one or more bronchodilators is frequently recommended. Some data suggest that a combination of albuterol and ipratropium bromide provides better bronchodilation than either agent alone. ^5,34–36 In 2004, the United States Food and Drug Administration 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. ³⁷ 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-M5 muscarinic receptors with a 6- to 20-fold greater affinity than ipratropium and for a more prolonged period of time ^38–40 and dissociates more rapidly from the M2 receptor associated with acetylcholine release, thereby conferring theoretical advantages over ipratropium. These advantages were shown in clinical trials comparing the two 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. ^39–42 Furthermore, when compared with long-acting β₂ agonists, tiotropium provided greater bronchodilation and 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. ⁴²

Corticosteroids

Although widely used, oral and inhaled corticosteroids have a limited role in managing patients with stable COPD. Several groups suggest brief trials of oral corticosteroids for patients with stable COPD. For example, the BTS suggests a course of oral prednisone (e.g., 30 mg daily) taken for 2 weeks, or a course of inhaled steroid (e.g., beclomethasone 500 mg twice daily or the equivalent) taken for 6 weeks. ⁷ Similarly, the ERS suggests a trial of corticosteroids (e.g., 0.4 to 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 At the same time, four randomized, placebo-controlled trials of inhaled corticosteroids in patients with COPD have shown no effect on the rate of FEV₁ decline, ^27,43–46 although one study suggested that steroid recipients experienced fewer COPD exacerbations than nonrecipients. ⁴⁵

A more recent trial was conducted comparing the effect of the salmeterol/fluticasone combination with either agent alone and with placebo, and 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. Specifically, the TRISTAN study, a 52-week, randomized, placebo-controlled study involving 1465 patients with moderate-to-severe COPD 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), ⁴⁷ 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 as well as a significant improvement in health status as defined by the St. George's Respiratory Questionnaire compared with the fluticasone, but not the salmeterol group. Finally, the rate of moderate and severe exacerbations was reduced by 25% in the combination group compared with placebo. ⁴⁷ This finding becomes all the more significant in the context that severe acute exacerbations have an independent negative impact on prognosis, with increased mortality associated with the frequency of severe exacerbations. ⁴⁸ Specifically, in a prospective cohort of 304 men with severe COPD (mean FEV₁, 46% predicted), older age, carbon dioxide (CO₂) tension, and acute exacerbation of COPD represented independent indicators of poor prognosis, with patients with three or more exacerbations showing the greatest mortality risk. ⁴⁸ Finally, whether the combination of an inhaled corticosteroid and long-term bronchodilator enhances survival in patients with COPD is the subject of ongoing research. ⁴⁹

Immunizations

Yearly prophylactic immunization with the influenza vaccine has been shown to reduce the incidence of influenza by 76% and is strongly recommended. ^50–52 Immunization once with the 23-polyvalent pneumococcal vaccine in individuals with COPD or, in the special case of individuals with immunodeficiency or those with splenectomy, every 5 years, is also recommended. ⁵²

Antibiotics

Prophylactic antibiotics have not shown benefit in the management of stable COPD and are not recommended. ^5–8

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 United States associates the long-term use (>2 months) of oral mucolytics with a reduction in acute COPD exacerbations and days of illness, and suggests the consideration of these agents in patients with recurrent, prolonged, severe COPD exacerbations. ⁵³ 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 contraindicated. ^5–8 In the specific case of alpha-1 antitrypsin deficiency, intravenous augmentation therapy with pooled human plasma antiprotease can raise serum levels of alpha-1 antitrypsin above a protective threshold value (11 micromolar). ¹³ Available evidence suggests that augmentation therapy can slow the rate of FEV₁ decline in individuals with severe deficiency of alpha-1 antitrypsin (e.g., with the PI*ZZ phenotype) and established airflow obstruction of moderate severity (e.g., FEV₁ 30% to 65% predicted). Currently available α₁-proteinase inhibitors in the United States include Prolastin (Talecris, Research Triangle, North Carolina), Aralast (Baxter Healthcare, Deerfield, Illinois), and Zemaira (ZLB Behring, King of Prussia, Pennsylvania).

Nonpharmacologic treatment of COPD includes pulmonary rehabilitation, long-term oxygen therapy (LTOT), ventilatory support, and lung volume reduction surgery (LVRS). Pulmonary rehabilitation is recommended at all stages by all available guidelines (see Table 2). ^5–8,54 Aerobic lower extremity training can improve exercise endurance, dyspnea, health care use, and overall quality of life. Upper extremity exercise and respiratory muscle training also appear helpful. ^5,54

Long-term oxygen therapy for patients with hypoxemia has been shown to improve survival in eligible patients with COPD. ¹⁷ Criteria for prescribing LTOT include a Pao₂ <55 mm Hg or Sao₂ <88% with or without increased Paco₂, or Pao₂ between 55 and 59 mm Hg or Sao₂ <89%, with right-sided failure reflected by evidence of pulmonary hypertension or polycythemia (e.g., hematocrit >55%).

Nocturnal noninvasive ventilatory support still has an unproven role in managing patients with stable COPD. Lung volume reduction surgery (LVRS) involves the resection of 20% to 35% of the emphysematous lung to improve lung mechanics. The procedure was first proposed by Brantigan and Mueller in the late 1940s, ⁵⁵ but was abandoned then because of unacceptably high associated mortality. More recently, available randomized, controlled trials show that LVRS is contraindicated in individuals with severely impaired lung function (e.g., FEV₁ <20% predicted, homogeneous emphysema or lung diffusing capacity, or both, for carbon monoxide <20% predicted), ^20–56 but that LVRS recipients with moderate degrees of airflow obstruction may experience an improved FEV₁, walking distance, and quality of life. ^20,56–58 In the recently published results of the National Emphysema Treatment Trial, a randomized controlled trial of LVRS versus medical therapy (including rehabilitation) in which 1218 individuals 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. ²⁰ On the other hand, the LVRS group had similar rates of survival as the medically managed group. In subsets defined by pre-specified exploration, a survival advantage was observed in the subgroup of patients with predominantly upper lobe emphysema and low baseline (i.e., post-rehabilitation) exercise capacity (defined as a maximal workload at <25 watts for women and 40 watts for men). ²⁰

Finally, lung transplantation is an option for patients with severe airflow obstruction and functional impairment. The five-year actuarial survival rate for patients undergoing single-lung transplantation for COPD is 43.2%. ^59–61 Selection criteria include an FEV₁ <25% predicted and/or a Paco₂ >55 mm Hg or cor pulmonale, or both.

Treatment of 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. ^5–8,62,63 Depending on the severity of baseline COPD, additional derangements may become manifest, such as hypoxemia, worsening hypercapnia, cor pulmonale with worsening lower extremity edema, or altered mental status. The main goals of treating AECOPD are to restore the individual to his or her previous stable baseline and to prevent or reduce the likelihood of recurrence. This requires identification of the precipitating factor or condition and its reversal or amelioration while optimizing gas exchange and improving the individual patient's symptoms. Treatment modalities similar to the ones used in stable COPD are used in managing acute exacerbations (Table 3). These include oxygen therapy, bronchodilators, antibiotics, corticosteroids, mechanical ventilation, and others.

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 65 mm 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 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, methylxanthines are used mostly 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. ^63–65 A narrow-spectrum antibiotic (e.g., amoxicillin, trimethoprim-sulfamethoxazole, doxycycline, etc.) 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 recorded in individuals 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. ⁶²

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. ^66–68

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. ^69–71 This mode is currently used in the treatment of acute respiratory failure of many causes, including COPD. Appropriate patient selection is critical to assure 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 adequate mask application, cardiovascular instability, or excessive secretions, or both. NIPPV improves symptomatic and physiologic variables, reduces the need for intuba-tion, hospital stay, and mortality, ⁷⁰ and does not use additional resources. ⁷¹

For patients who do not qualify for NIPPV and/or 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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Conclusion

Overall, COPD poses a common and significant clinical challenge for patients and clinicians alike. Clinicians' expert knowledge regarding diagnosis and management can enhance patients' longevity and quality of life.

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Summary

• Chronic obstructive pulmonary disease is emerging as a major cause of morbidity and mortality in the United States. COPD currently is the fourth leading cause of death among Americans.
• Chronic obstructive pulmonary disease is under-recognized overall, as is alpha-1 antitrypsin deficiency, a genetic predisposition to COPD.
• Among the available therapies for COPD, many can improve symptoms (e.g., bronchodilators, pulmonary rehabilitation). Three treatments—smoking cessation, supplemental oxygen used for 24 hours a day, and lung volume reduction surgery—have been shown to prolong life in appropriately selected COPD individuals.

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Suggested Readings

• AACP/AACVPR Pulmonary Rehabilitation Guidelines Panel . Pulmonary rehabilitation: Joint ACCP/AACVPR evidence-based guidelines. Chest. 112: 1997; 1363-1396.
• American Thoracic Society . Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease.
• American Thoracic Society/European Respiratory Society Statement . Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 168: 2003; 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. 166: 2002; 675-679.
• Maurer JR, Frost AE , Estenne M. 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. 66: 1998; 951-956.
• National Emphysema Treatment Trial Research Group . A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 348: 2003; 2059-2073.
• Pauwels RA, Buist AS , Calverley PM. 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. 163: 2001; 1256-1276.
• Pauwels RA, Lofdahl CG , Laitinen LA. 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. 340: 1999; 1948-1953.
• Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med. 350: 2004; 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. 343: 2000; 1902-1909.