Chronic Obstructive Pulmonary Disease 

Chronic obstructive pulmonary disease (COPD) is estimated to affect 32 million persons in the United States and is the fourth leading cause of death in this country. Patients typically have symptoms of chronic bronchitis and emphysema, but the classic triad also includes asthma (as seen in the image below). (See Clinical Presentation.)

In Western Europe, Badham (1808) and Laennec (1827) made the classic descriptions of chronic bronchitis and emphysema in the early 19th century. A British medical textbook of the 1860s described the familiar clinical picture of chronic bronchitis as an advanced disease with repeated bronchial infections that ended in right-sided heart failure. Overall, this malady caused more than 5% of all deaths in the Middle Ages and earlier. The condition was most common among the poor; therefore, it was attributed to "bad" living.

Developments in the 20th century included the widespread use of spirometry (see Workup), recognition of airflow obstruction as a key factor in determining disability, and the improvement of pathologic methods to assess emphysema. Participants in the Ciba symposium of 1958 proposed definitions of chronic bronchitis and emphysema, incorporating the concept of airflow obstruction.

Chronic bronchitis is defined clinically as the presence of a chronic productive cough for 3 months during each of 2 consecutive years (other causes of cough being excluded). Emphysema, on the other hand, is defined pathologically as an abnormal, permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.

Airflow limitation in emphysema is due to loss of elastic recoil and decrease in airway tethering, whereas chronic bronchitis leads to narrowing of airway caliber and increase in airway resistance. Although some patients predominantly display signs of one of these diseases or the other, most fall somewhere in the middle of the spectrum between the 2 conditions.

Past definitions of COPD have been pessimistic at best, indicating that the disease process is irreversible and that therapy has little to offer. However, a more optimistic view has come to be widely accepted. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines define COPD as a disease state characterized by airflow limitation that is not fully reversible, is usually progressive, and is associated with an abnormal inflammatory response of the lungs to inhaled noxious particles or gases,^[1] (See Clinical Presentation.)

This GOLD characterization represents a paradigm shift—it suggests that the disease is treatable and preventable. (For a guideline summary, see Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.^[2] ) (See Treatment and Management.)

Oral and inhaled medications are used for patients with stable COPD to reduce dyspnea, improve exercise tolerance, and prevent complications. Most of the medications used in COPD treatment are directed at the potentially reversible mechanisms of airflow limitation. (See Medication.)

Pathologic changes in chronic obstructive pulmonary disease (COPD) occur in the large (central) airways, the small (peripheral) bronchioles, and the lung parenchyma. Most cases of COPD are the result of exposure to noxious stimuli, most often cigarette smoke. The normal inflammatory response is amplified in persons prone to COPD development. The pathogenic mechanisms are not clear but are most likely diverse. Increased numbers of activated polymorphonuclear leukocytes and macrophages release elastases in a manner that cannot be counteracted effectively by antiproteases, resulting in lung destruction.

The primary offender has been found to be human leukocyte elastase, with synergistic roles suggested for proteinase-3 and macrophage-derived matrix metalloproteinases (MMPs), cysteine proteinases, and a plasminogen activator. Additionally, increased oxidative stress caused by free radicals in cigarette smoke, the oxidants released by phagocytes, and polymorphonuclear leukocytes all may lead to apoptosis or necrosis of exposed cells. Accelerated aging and autoimmune mechanisms have also been proposed as having roles in the pathogenesis of COPD.^{[3, 4]}

Cigarette smoke causes neutrophil influx, which is required for the secretion of MMPs; this suggests, therefore, that neutrophils and macrophages are required for the development of emphysema.

Studies have also shown that in addition to macrophages, T lymphocytes, particularly CD8⁺, play an important role in the pathogenesis of smoking-induced airflow limitation.

To support the inflammation hypothesis further, a stepwise increase in alveolar inflammation has been found in surgical specimens from patients without COPD versus patients with mild or severe emphysema. Indeed, mounting evidence supports the concept that dysregulation of apoptosis and defective clearance of apoptotic cells by macrophages play a prominent role in airway inflammation, particularly in emphysema.^[5] Azithromycin (Zithromax) has been shown to improve this macrophage clearance function, providing a possible future treatment modality.^[6]

In patients with stable COPD without known cardiovascular disease, there is a high prevalence of microalbuminuria, which is associated with hypoxemia independent of other risk factors.^[7]

Chronic bronchitis

Mucous gland hyperplasia (as seen in the images below) is the histologic hallmark of chronic bronchitis. Airway structural changes include atrophy, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia, inflammation, and bronchial wall thickening.

Damage to the endothelium impairs the mucociliary response that clears bacteria and mucus. Inflammation and secretions provide the obstructive component of chronic bronchitis. Neutrophilia develops in the airway lumen, and neutrophilic infiltrates accumulate in the submucosa. The respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucus plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis. These changes, combined with loss of supporting alveolar attachments, cause airflow limitation by allowing airway walls to deform and narrow the airway lumen.

In contrast to emphysema, chronic bronchitis is associated with a relatively undamaged pulmonary capillary bed. The body responds by decreasing ventilation and increasing cardiac output. This V/Q mismatch results in rapid circulation in a poorly ventilated lung, leading to hypoxemia and polycythemia. Eventually, hypercapnia and respiratory acidosis develop, leading to pulmonary artery vasoconstriction and cor pulmonale. With the ensuing hypoxemia, polycythemia, and increased CO₂ retention, these patients have signs of right heart failure and are known as "blue bloaters."

Emphysema

Emphysema is a pathologic diagnosis defined by permanent enlargement of airspaces distal to the terminal bronchioles. This leads to a dramatic decline in the alveolar surface area available for gas exchange. Furthermore, loss of alveoli leads to airflow limitation by 2 mechanisms. First, loss of the alveolar walls results in a decrease in elastic recoil, which leads to airflow limitation. Second, loss of the alveolar supporting structure leads to airway narrowing, which further limits airflow.

Emphysema has 3 morphologic patterns:

• Centriacinar
• Panacinar
• Distal acinar, or paraseptal

Centriacinar emphysema is characterized by focal destruction limited to the respiratory bronchioles and the central portions of the acini. This form of emphysema is associated with cigarette smoking and is typically most severe in the upper lobes.

Panacinar emphysema involves the entire alveolus distal to the terminal bronchiole. The panacinar type is typically most severe in the lower lung zones and generally develops in patients with homozygous alpha1-antitrypsin (AAT) deficiency.

Distal acinar emphysema, or paraseptal emphysema, is the least common form and involves distal airway structures, alveolar ducts, and sacs. This form of emphysema is localized to fibrous septa or to the pleura and leads to formation of bullae (as seen in the images below). The apical bullae may cause pneumothorax. Paraseptal emphysema is not associated with airflow obstruction.

The gradual destruction of alveolar septae (shown in the image below) and of the pulmonary capillary bed in emphysema leads to a decreased ability to oxygenate blood. The body compensates with lowered cardiac output and hyperventilation. This V/Q mismatch results in relatively limited blood flow through a fairly well oxygenated lung with normal blood gases and pressures in the lung, in contrast to the situation in chronic bronchitis. Because of low cardiac output, the rest of the body suffers from tissue hypoxia and pulmonary cachexia. Eventually, these patients develop muscle wasting and weight loss and are identified as "pink puffers."

Emphysematous destruction and small airway inflammation

Emphysematous destruction and small airway inflammation often are found in combination in individual patients, leading to the spectrum that is known as COPD. When emphysema is moderate or severe, loss of elastic recoil, rather than bronchiolar disease, is the dominant mechanism of airflow limitation. By contrast, when emphysema is mild, bronchiolar abnormalities are most responsible for the majority of the deficit in lung function. Although airflow obstruction in emphysema is often irreversible, bronchoconstriction due to inflammation accounts for some reversibility. Airflow limitation is not the only pathophysiologic mechanism by which symptoms occur.

Dynamic hyperinflation

Lung volumes, particularly dynamic hyperinflation, have also been shown to play a crucial role in the development of dyspnea perceived during exercise. In fact, the improvement in exercise capacity brought about by several treatment modalities, including bronchodilators, oxygen therapy, lung volume reduction surgery (LVRS), and maneuvers learned in pulmonary rehabilitation, is more likely due to delaying dynamic hyperinflation rather than improving the degree of airflow obstruction.^{[8, 9, 10, 11, 12, 13, 14, 15]} Additionally, hyperinflation (defined as the ratio of inspiratory capacity to total lung capacity [IC/TLC]) has been shown to predict survival better than forced expiratory volume in 1 second (FEV₁).^[5]

Cigarette smoking

The primary cause of COPD is exposure to tobacco smoke. Overall, tobacco smoking accounts for as much as 90% of COPD risk.

Cigarette smoking induces macrophages to release neutrophil chemotactic factors and elastases, which lead to tissue destruction. Clinically significant COPD develops in 15% of cigarette smokers, although this number is believed to be an underestimate. Age of initiation of smoking, total pack-years, and current smoking status predict COPD mortality.

People who smoke have an increased annual decline in FEV₁: the physiologic normal decline in FEV₁ is estimated to be 20-30 ml/y, but the rate of decline in COPD patients is generally 60 ml/y or greater.

Secondhand smoke, or environmental tobacco smoke, increases the risk of respiratory infections, augments asthma symptoms, and causes a measurable reduction in pulmonary function.

A study by Nagelmann et al concluded that lung function deviation and lung structural changes are present in people who smoke cigarettes before the clinical signs of airway obstruction reveal them.^[16] These changes can be detected by body plethysmography and diffusing capacity measurement with routine spirometry.

Environmental factors

COPD does occur in individuals who have never smoked.^[17] Although the role of air pollution in the etiology of COPD is unclear, the effect is small when compared with that of cigarette smoking. In developing countries, the use of biomass fuels with indoor cooking and heating is likely to be a major contributor to the worldwide prevalence of COPD. Long-term exposure to traffic-related air pollution may be a factor in COPD in patients with diabetes and asthma.^[18]

Airway hyperresponsiveness

Airway hyperresponsiveness (ie, Dutch hypothesis) stipulates that patients who have nonspecific airway hyperreactivity and who smoke are at increased risk of developing COPD with an accelerated decline in lung function. Nonspecific airway hyperreactivity is inversely related to FEV₁ and may predict a decline in lung function.

The possible role of airway hyperresponsiveness as a risk factor for the development of COPD in people who smoke is unclear. Moreover, bronchial hyperreactivity may result from airway inflammation observed with the development of smoking-related chronic bronchitis. This may contribute to airway remodeling, leading to a more fixed obstruction, as is seen in persons with COPD.

Alpha1-antitrypsin deficiency

Alpha1-antitrypsin (AAT) is a glycoprotein member of the serine protease inhibitor family that is synthesized in the liver and is secreted into the bloodstream. The main purpose of this 394-amino-acid, single-chain protein is to neutralize neutrophil elastase in the lung interstitium and to protect the lung parenchyma from elastolytic breakdown. Severe AAT deficiency predisposes to unopposed elastolysis with the clinical sequela of an early onset of panacinar emphysema. To see complete information on Alpha1-Antitrypsin Deficiency, please go to the main article by clicking here.

AAT deficiency is the only known genetic risk factor for developing COPD and accounts for less than 1% of all cases in the United States. Severe AAT deficiency leads to premature emphysema at an average age of 53 years for nonsmokers and 40 years for smokers.

Nearly 24 variants of the AAT molecule have been identified, and all are inherited as codominant alleles. The common M allele (PiM) may be found in 90% of people, and homozygous (PiMM) phenotypes produce serum levels within the reference range. The homozygous PiZZ state is the most common deficiency state and accounts for 95% of people in the severely deficient category.

Intravenous drug use

Emphysema occurs in approximately 2% of persons who use intravenous (IV) drugs. This is attributed to pulmonary vascular damage that results from the insoluble filler (eg, cornstarch, cotton fibers, cellulose, talc) contained in methadone or methylphenidate.

The bullous cysts found in association with IV use of cocaine or heroin occur predominantly in the upper lobes. In contrast, methadone and methylphenidate injections are associated with basilar and panacinar emphysema.

Immunodeficiency syndromes

Human immunodeficiency virus (HIV) infection has been found to be an independent risk factor for COPD, even after controlling for confounding variables such as smoking, IV drug use, race, and age.^[19]

Apical and cortical bullous lung damage occurs in patients who have autoimmune deficiency syndrome and Pneumocystis carinii infection. Reversible pneumatoceles are observed in 10-20% of patients with this infection.

Vasculitis syndrome

Hypocomplementemic vasculitis urticaria syndrome (HVUS) may be associated with obstructive lung disease. Other manifestations include angioedema, nondeforming arthritis, sinusitis, conjunctivitis, and pericarditis.

Connective tissue disorders

Cutis laxa is a disorder of elastin that is characterized most prominently by the appearance of premature aging. The disease usually is congenital, with various forms of inheritance (ie, dominant, recessive). Precocious emphysema has been described in association with cutis laxa as early as the neonatal period or infancy. The pathogenesis of this disorder includes a defect in the synthesis of elastin or tropoelastin.

Marfan syndrome is an autosomal dominant inherited disease of type I collagen characterized by abnormal length of the extremities, subluxation of the lenses, and cardiovascular abnormality. Pulmonary abnormalities, including emphysema, have been described in approximately 10% of patients.

Ehlers-Danlos syndrome refers to a group of inherited connective tissue disorders with manifestations that include hyperextensibility of the skin and joints, easy bruisability, and pseudotumors; it has also been associated with a higher prevalence of COPD.

Salla disease

Salla disease is an autosomal recessive storage disorder described in Scandinavia; the disease is characterized by intralysosomal accumulation of sialic acid in various tissues. The most important clinical manifestations are severe mental retardation, ataxia, and nystagmus. Precocious emphysema has been described and likely is secondary to impaired inhibitory activity of serum trypsin.

The National Health Interview Survey reports the prevalence of emphysema at 18 cases per 1000 persons and chronic bronchitis at 34 cases per 1000 persons.^[20] While the rate of emphysema has stayed largely unchanged since 2000, the rate of chronic bronchitis has decreased. Another study estimates a prevalence of 10.1% in the United States.^[21] However, the exact prevalence of COPD in the United States is believed to be underestimated. This is largely due to the fact that it is an underdiagnosed (and undertreated) disease, because most patients do not present for medical care until the disease is in a late stage.

The exact prevalence of COPD worldwide is largely unknown, but estimates have varied from 7-19%. The Burden of Obstructive Lung Disease (BOLD) study found a global prevalence of 10.1%.^[22] Men were found to have a pooled prevalence of 11.8% and women 8.5%. The numbers vary in different regions of the world. Cape Town, South Africa, has the highest prevalence, affecting 22.2% of men and 16.7% of women.

Hannover, Germany, on the other hand, has the lowest prevalence, of 8.6% for men and 3.7% for women. The differences can be explained in part by site and sex differences in the prevalence of smoking. As noted above, these reports are widely believed to be underestimates because COPD is known to be underdiagnosed and undertreated. Additionally, the prevalence in women is believed to be increasing.

Although current rates of COPD in men are higher than the rates in women, the rates in women have been increasing. COPD occurs predominantly in individuals older than age 40 years.

Severe, early onset disease likely represents a distinct genotype and is more commonly seen in females, African Americans, and those with a maternal family history of COPD.^[23]

A study by Mintz et al estimated the prevalence of unidentified COPD.^[24] Using the Lung Function Questionnaire (LFQ) and spirometry results, the study determined that approximately 1 in 5 patients (21%) aged 30 years or older with a history of smoking for 10 years or longer seen in a primary care center is likely to have COPD.

In a study by Spitzer et al in Germany, airflow limitation as measured by spirometry was significantly more common in adults with posttraumatic stress disorder than in controls. Results were adjusted for lifestyle, clinical, and sociodemographic factors.^[25]

COPD is the fourth leading cause of death in the United States. In terms of COPD as the underlying cause of death, absolute mortality rates for US patients aged 25 years or older (2005) were 77.3 deaths per 100,000 males and 56.0 deaths per 100,000 females, or 64.3 persons per 100,000 overall. Internationally, overall mortality rates from COPD vary markedly, from more than 400 deaths per 100,000 males aged 65-74 years in Romania to fewer than 100 deaths per 100,000 population in Japan.

The FEV₁ was used to predict outcome in COPD until other factors were identified to play a role in determining the outcome of COPD patients. These discoveries resulted in the creation of the multidimensional BODE index (body mass index, obstruction [FEV₁], dyspnea [modified Medical Research Council dyspnea scale], and exercise capacity [6MWD]).^[26] This index was developed to assess an individual’s risk of death or hospitalization.

Prognosis is based on a point system, with all 4 factors used to determine the score, as follows:

• Body mass index: greater than 21 = 0 points; less than 21 = 1 point
• FEV₁ (postbronchodilator percent predicted): greater than 65% = 0 points; 50-64% = 1 point; 36-49% = 2 points; less than 35% = 3 points
• Modified Medical Research Council (MMRC) dyspnea scale: MMRC 0 = dyspneic on strenuous exercise (0 points); MMRC 1 = dyspneic on walking a slight hill (0 points); MMRC 2 = dyspneic on walking level ground, must stop occasionally due to breathlessness (1 point); MMRC 3 = dyspneic after walking 100 yards or a few minutes (2 points); MMRC 4 = cannot leave house; dyspneic doing activities of daily living (3 points)
• Six-minute walking distance: greater than 350 meters = 0 points; 250-349 meters = 1 point; 150-249 meters = 2 points; less than 149 meters = 3 points

The approximate 4-year survival based on the point system above is as follows:

• 0-2 points = 80%
• 3-4 points = 67%
• 5-6 points = 57%
• 7-10 points = 18%

The use of a clinical scoring system reinforces that determinants of prognosis in COPD remain multifactorial. Waschki et al argued that objective assessments of physical activity, including 6-minute walk test results, are best able to predict mortality.^[27] However, additional socioeconomic factors also likely play a role in COPD prognosis; for example, a retrospective cohort study highlighted the increased risk of COPD-related mortality in patients who reside in isolated rural areas.^[28]

A study by Sundh et al determined that the Clinical COPD Questionnaire (CCQ), which estimates quality of life in patients with COPD, is effective.^[29] The CCQ identified that heart disease, depression, and underweight status are independently associated with lower health-related quality of life in patients with COPD.

It is important to educate the patient with COPD about the disease and to encourage his or her active participation in therapy. The 2 most essential points for the patient to understand, as supported by the Institute for Clinical Systems Improvement (ICSI) 2011 Guidelines for the Diagnosis and Management of Chronic Obstructive Pulmonary Disease, are as follows^[30] :

• The dangers of smoking and the improvement in quality of life attainable with smoking cessation
• The need to seek medical care early during an exacerbation and to not wait until they are in distress

For more information, see Emphysema.