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 currently ranks as the fourth leading cause of death in the United States, surpassed only by heart disease, cancer, and cerebrovascular disease.^1,2 Furthermore, COPD is projected to become the fifth leading burden of disease worldwide by the year 2020.³ 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.

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.^4-7

Emphysema is specifically defined4 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 defined⁴ 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."

While 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.^4-7 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."⁷

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.^1,7 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 under 45 years old is low, while the prevalence is highest in patients over 65 years old. In 1995, 553,000 patients were treated for COPD in the United States and two thirds of those were more than 65 years old. The prevalence in those over 65 was fourfold that in the 45- to 64-year-old group.^8,9

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, $14.7 billion were spent on direct health costs of COPD, with the overall burden estimated at more than $30 billion.^1,9

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 over 90% of cases; however, other gases and particles have been shown to play a role in pathogenesis, which is due to 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.¹⁰

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 alpha1-antitrypsin, has been shown to predispose to a panacinar form of emphysema. Individuals with severe deficiency of alpha1-antitrypsin may develop emphysema at an early age (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 the excessive mucus secretion. Airflow obstruction and emphysematous change is a frequent but not universal accompaniment. Finally, 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.^4-7,10,11

The diagnosis of COPD is suggested by findings on history and/or physical examination and is confirmed by laboratory tests, usually with a supportive risk factor (eg, of familial COPD and/or of cigarette exposure). 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.^4-7 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. Alpha 1-antitrypsin deficiency is an uncommon cause of emphysema that continues to be underrecognized by practicing clinicians. The clinical recognition of patients with this condition is also based on clinical suspicion, but as outlined in the recently released American Thoracic Society/European Respiratory Society (ATS/ERS) evidence-based standards document, specific circumstances should prompt suspicion of alpha 1-antitrypsin deficiency. They include emphysema occuring in a young individual (age 45 or less) or without obvious risk factors (eg, smoking or occupational exposure) or with prominent basilar emphysema on imaging, necrotizing panniculitis, anti-neutrophil cytoplasmic antibody (C-ANCA)-postive 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.¹²

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 is usually done to exclude other etiologies but may show hyperinflation and flattening of the diaphragms. Although not indicated for routine clinical care, high-resolution computed tomography (CT) imaging can image the bullae and blebs that are the consequence of alveolar breakdown.^4-7

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, 4 groups—the ATS, the ERS, the BTS, and the GOLD—have developed staging systems for COPD based on the value of FEV₁ % predicted. All systems propose 3-stage classifications of COPD, though the FEV₁ criteria vary among systems.^4-7

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, airway responsiveness, hypoxemia, and most importantly, the level of FEV₁, which remains the single best predictor of prognosis. The use of long-term oxygen therapy in hypoxemic patients has been shown to improve survival,¹³ and smoking cessation slows the rate of FEV₁ decline.¹⁴ The natural history of patients with COPD following an acute exacerbation has been closely examined in the SUPPORT study.¹⁵ Here, of 1,016 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 flow 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.¹⁵

Notwithstanding these insights, well-designed studies and controlled trials are necessary to improve our ability to predict the outcome for patients afflicted with this disease.

Treatment of Stable COPD:

Once the diagnosis is established and the stage of the disease is determined, attention turns to patient education and risk factor modification as well as pharmacologic and nonpharmacologic modalities needed to ameliorate the signs and symptoms of COPD and to optimize patients' longevity and functional status.¹⁶

Patient education is an essential component 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, therapeutic modalities 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.^17,18

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 non-smokers over the 11-year study, the rate of FEV₁ decline slowed to 30 ml/year in men and 22 ml/year in women compared to the 66 ml/year and 54 ml/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 to 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.^14,19

Available strategies for smoking cessation including nicotine replacement, available as gum, patch, or nasal spray; bupropion (an antidepressant), smoking-cessation programs, 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 alone.²⁰

Beyond education and smoking cessation, the goals of pharmacologic and non-pharmacologic treatment 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.

Bronchodilators
Bronchodilators are a mainstay of COPD treatment, and include ß-adrenergic agonists, anticholinergics, and methylxanthines. Beta-adrenergic agonists are effective in alleviating symptoms and improving exercise capacity, and can produce significant increases in FEV₁. Oral theophylline has been shown to lessen dyspnea despite lack of significant rises in FEV₁.²¹ In the early stages of COPD (eg, stage 1), a short-acting ß-adrenergic agonist (eg, albuterol, terbutaline, etc) or anticholinergic is used on an as-needed basis. As the disease progresses (eg, stages 2 and 3), 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.^22,23 Recently, 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.²⁴ 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 6-20 fold greater affinity than ipratropium and for a more prolonged period of time²⁵; 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.^26-28 Furthermore, when compared with long-acting ß2-agonists, tiotropium provided greater bronchodilation and reduced dyspnea than salmeterol. Specifically, a large double-blind, placebo-controlled trial revealed a significant reduction in yearly incidence as well as delay to first COPD exacerbation than either salmeterol or placebo.²⁹

Corticosteroids
Though widely used, oral and inhaled corticosteroids have a very 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 (eg, 30 mg daily) taken for 2 weeks, or a course of inhaled steroid (eg, beclomethasone 500 mcg twice daily or equivalent) taken for 6 weeks.⁶ Similarly, the ERS suggests a trial of corticosteroids (eg, 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.⁵ At the same time, 4 randomized, placebo-controlled trials of inhaled corticosteroids in patients with COPD have shown no effect on the rate of FEV₁ decline,^23,31-33 although one study suggested that steroid recipients experienced fewer COPD exacerbations than nonrecipients.³³

Immunizations
Prophylactic immunization with the influenza vaccine yearly and with the 23-polyvalent pneumococcal vaccine every 5-10 years is recommended.^34,35

Antibiotics
Prophylactic antibiotics have not shown benefit in the management of stable COPD and are not recommended.^4-7

Mucokinetics
Mucokinetic drugs (eg, ambroxol, erdosteine, carbocysteine, iodinated glycerol, etc) are not beneficial and are not recommended.^4-7

Other
Antitussives containing narcotics and other therapies, such as inhaled nitric oxide, may be harmful. Their use is contraindicated.^4-7

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 (of 11 micromolar). Available evidence suggests that augmentation therapy can slow the rate of FEV₁ decline in individuals with severe deficiency of alpha 1-antitrypsin (eg, PI*ZZ phenotypes) and established airflow obstruction of moderate severity (eg, FEV₁ 30-65% predicted). Currently available alpha 1 proteinase inhibitors in the United States include Prolastin, Aralast, and Zemaira.

Non-pharmacologic treatments include 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 (Table 2).^4-7 Aerobic lower extremity training can improve exercise endurance, dyspnea, health care utilization, and overall quality of life, whereas the role of upper extremity exercise and respiratory muscle training remains unclear.³⁶ Long-term oxygen therapy for patients with hypoxemia has been shown to improve survival in eligible patients with COPD.¹³ 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 (eg, hematocrit > 55%).

Nocturnal non-invasive ventilatory support still has an unproven role in managing patients with stable COPD. LVRS involves the resection of 20% to 35% of the emphysematous lung in order to allow improved lung mechanics. The procedure was first proposed by Brantigan and Mueller in the late 1940s,³⁷ but was abandoned then because of unacceptably high mortality. More recently, as surgical mortality rates have decreased to 3% to 5%, the role of LVRS is being actively investigated.³⁸ Available randomized, controlled trials to date show that LVRS is contraindicated in individuals with severely impaired lung function (eg, FEV₁ < 20% predicted, homogeneous emphysema, and/or lung diffusing capacity for carbon monoxide < 20% predicted),³⁹ but that LVRS recipients with moderate degrees of airflow obstruction may experience an improved FEV₁, walking distance, and quality of life.⁴⁰ In the recently published results of the National Emphysema Treatment Trial, a randomized controlled trial of LVRS vs. 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 to the medically managed group. 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 both predominantly upper lobe emphysema and low baseline (ie, post-rehabilitation) exercise capacity (defined as a maximal workload at <25 W for women and 40 W for men).^41,42

Finally, lung transplantation is an option for patients with severe airflow obstruction and functional impairment. Five-year actuarial survival rates for patients undergoing single-lung transplantation for COPD are 43.2%.⁴³ Selection criteria include an FEV₁ < 25% predicted and/or a PaCO₂ > 55 mm Hg and/or cor pulmonale.⁴⁴

Treatment of Acute Exacerbations of COPD:

Acute exacerbation of COPD (AECOPD) represents an acute worsening of the baseline COPD, generally characterized by worsened dyspnea and increased volume and purulence of sputum.^4-7,45,46 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 patient to his or her previous stable baseline and to take measures that 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 utilized in managing acute exacerbations (Table 3). They include oxygen therapy, bronchodilators, antibiotics, corticosteroids, and 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 around 60 to 65 mm Hg, thereby assuring near-maximal hemoglobin saturation while minimizing the potential for deleterious hypercapnia. Hypercapnia complicating supplemental oxygen is best ascribed to ventilation-perfusion mismatch rather than to depression of the respiratory drive or the Haldane effect.

Bronchodilators
Bronchodilators are widely used in AECOPD, and ß-adrenergic agonists and anticholinergics are first-line therapy. As in stable COPD, both can improve airflow in AECOPD, and although recommendations vary, combined therapy is often recommended. Beta-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. The use of sustained-release preparations seems to lessen the potential for side effects.^4-7,45

Antibiotics
Antibiotics play a favorable role in treating AECOPD, especially in the setting of increased volume and purulence of phlegm.^47,48 A narrow-spectrum antibiotic (eg, amoxicillin, trimethoprim-sulfamethoxazole, doxycycline, etc.) is the recommended first-line therapy by all available guidelines. The optimal duration of treatment is still unclear, although most guidelines recommend treating for between 7 and 14 days.⁴⁵

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 as the likeliest optimal duration.^49-51

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. 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, and/or excessive secretions.⁵² NIPPV improves symptomatic and physiologic variables, reduces the need for intubation, hospital stay, and mortality,^52-54 and does not use additional resources.⁵⁵

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 is 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 deployed 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.^44,45

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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