Chronic Obstructive Pulmonary Disease
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 2000 alone,1 and it currently ranks as the fourth leading cause of death in the United States, surpassed only by heart disease, cancer, and cerebrovascular disease.2,3 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.
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 persons (∼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 three months in each of two 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
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 persons 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 persons younger than 45 years is low, and 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, and as of 2000, COPD deaths in women exceeded the number in men.2
Although it has been difficult to estimate the costs associated with COPD, they include direct costs pertaining to outpatient and inpatient care expenses, 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, and the overall burden was estimated at more than $30 billion.1,2,10
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, 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
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.5–8,11,12
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 a decreased FEV1/FVC (forced vital capacity) 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) 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 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 person (age ≤45 years) 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 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 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 chest x-ray for diagnosing emphysema and readily identifies bullae and blebs that are the consequences of alveolar breakdown. However, save for its role in selecting the proper candidate for lung volume reduction surgery, the additional data from CT rarely alter therapy, making CT scanning not currently 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 British Thoracic Society (BTS), and GOLD—have developed staging systems for COPD based on the value of FEV1 percent predicted. All systems propose three- or four-stage classifications of COPD, although the FEV1 criteria vary among systems.5–8
In the context that one major purpose of staging systems is to establish prognosis, attention has focused on the value of including weight (i.e., body mass index [BMI]), dyspnea, and exercise capacity (i.e., the 6-minute walk distance), with FEV1 in staging COPD.16 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 four quartiles, which discriminate mortality risk better than FEV1 alone.
Natural History and Prognosis
Few interventions have been shown to change the natural history of COPD. For persons hypoxemic in room air, survival can be improved by use of supplemental oxygen.17 Smoking cessation can improve survival in smokers,18,19 and lung volume reduction surgery can improve survival in selected patients.20
Acute exacerbations of COPD (AECOPD) are a significant contributor to mortality. For example, in the SUPPORT study21 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 patients 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 persons. 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 with this disease.
SLEEP AND COPD
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 can occur as tidal volume falls.
) mismatch.TREATMENT
Stable COPD
Once the diagnosis of COPD is established and the stage of the disease is determined, attention turns to patient education and modification of risk factors, 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 less than 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.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 bronchodilators, 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 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 methylxanthines and their potential for adverse drug-drug interactions have hindered their widespread use. Long-acting formulations have allowed more-consistent and stable plasma levels, thereby mitigating the problem.
Phosphodiesterase Inhibitors
Newly developed oral, highly selective phosphodiesterase 4 (PDE4) inhibitors roflumilast32 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 µg of roflumilast, 500 µg 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 < .0001). Similar findings were reported in the health-related quality of life 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 PDE4 inhibitors become part of standard therapy for the stable COPD patient.5,33
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