Chronic Bronchitis

Mucus is produced by mucous glands present in the larger airways and by goblet cells in the airway epithelium. Chronic bronchitis is characterized by hypertrophy of the mucous glands (Figure 41-1). Goblet cells that occur predominantly in the surface epithelium of the larger airways increase in number and change in distribution, extending more peripherally. Bronchial biopsy studies confirm findings in resected lungs and show bronchial wall inflammation in chronic bronchitis. Activated T lymphocytes are prominent in the proximal airway walls, with a predominance of the CD8 suppressor T lymphocyte subset, rather than the CD4 subset, as seen in asthma. Macrophages are also prominent. Sputum volume correlates with the degree of inflammation in the airway wall. Neutrophils are present, particularly in the bronchial mucus-secreting glands (Figure 41-1), and become more prominent as the disease progresses. In stable chronic bronchitis, the high percentage of intraluminal neutrophils is associated with the presence of neutrophil chemotactic factors, including interleukin-8 (IL-8) and leukotriene B₄ (LTB₄). Elastase released from these cells is a potent stimulant for the secretion of mucus. Macrophages and CD8⁺ T cells also accumulate in the mucous glands.

Figure 41-1 A, Central bronchus from lung of cigarette smoker with normal lung function. Only small amounts of muscle are present, and epithelial glands are small. This contrasts sharply with B, bronchus from patient with chronic bronchitis, where the muscle appears as a thick bundle and the glands are enlarged. C, Enlarged glands at higher magnification, showing evidence of chronic inflammation in glands involving polymorphonuclear leukocytes (arrowhead) and mononuclear cells, including plasma cells (arrow).

(Courtesy Dr. J. C. Hogg.)

Evidence indicates that the airway inflammation in patients with chronic bronchitis persists after smoking cessation, particularly if the production of sputum persists, although cough and sputum improve in most smokers who quit. Airway wall changes include squamous metaplasia of the airway epithelium, loss of cilia and ciliary function, and increased smooth muscle and connective tissue.

Small Airways Disease and Bronchiolitis

The smaller bronchioles (<2 mm in internal diameter) normally contribute relatively little to the total airway resistance, because there are so many airways of this size in parallel. Considerable narrowing of these airways can occur before pulmonary function becomes impaired and symptoms develop. Small airways inflammation is one of the earliest changes in asymptomatic cigarette smokers. The inflammatory cell profiles in the small airways are similar to those in larger airways, including the predominance of CD8⁺ lymphocytes, increase in CD8/CD4 ratio, and increased macrophages. Mucosal ulceration, goblet cell hyperplasia, and squamous cell metaplasia may be present, as well as mesenchymal cell accumulation and fibrosis. With progression of the condition, structural remodeling may occur, characterized by increased collagen content and scar tissue formation that narrows the airways and produces fixed airway obstruction (Figure 41-2).

Figure 41-2 Histologic sections of peripheral airways. A, Section from cigarette smoker with normal lung function, showing near-normal airway. B, Section from patient with small airways disease, showing inflammation in wall and inflammatory exudate in airway lumen. C, More advanced case of small airways disease, with reduced lumen, structural reorganization of airway wall, increased smooth muscle, and deposition of peribronchiolar connective tissue.

(Courtesy Dr. J. C. Hogg.)

Emphysema

Pulmonary emphysema is defined as abnormal permanent enlargement of air spaces distal to the terminal bronchioles, accompanied by destruction of bronchiolar walls. The major types of emphysema are recognized according to the distribution of enlarged air spaces within the acinar unit, the part of lung parenchyma supplied by a single terminal bronchiole, as follows:

Figure 41-3 Diagrammatic representation and CT scans of distribution of abnormal air spaces within acinar unit in two major types of emphysema. A, Acinar unit in normal lung (left top) and in centrilobular emphysema, showing focal enlargement of air spaces around respiratory bronchiole. CT scans show patchy centrilobular emphysema. B, Panlobular (panacinar) emphysema, showing confluent, even involvement of acinar unit. CT scans show diffuse, low-attenuation areas of panlobular emphysema.

Air space enlargement can be identified macroscopically when the enlarged space reaches 1 mm. A bulla is a localized area of emphysema, conventionally defined as greater than 1 cm in size.

Centrilobular and panlobular emphysema can occur alone or in combination. The association with cigarette smoking is clearer for centrilobular than panlobular emphysema, although smokers can develop both types. Those with centrilobular emphysema appear to have more abnormalities in the small airways than those with panlobular emphysema. Panacinar emphysema appears more severe in the lower lobes, in contrast to centriacinar emphysema, which usually concentrates in the upper lobes. Panlobular emphysema is associated with α₁-antitrypsin deficiency, but can also be found in patients with no identified genetic abnormality.

Other types include paraseptal (periacinar or distal acinar) emphysema, in which enlarged air spaces occur along the edge of the acinar unit, but only where it abuts against a fixed structure such as the pleura or a vessel. Mixed types of emphysema occur in COPD patients.

The bronchioles and small bronchi are supported by attachment to the outer aspect of adjacent alveolar walls. This arrangement maintains the tubular integrity of the airways. Loss of these attachments and consequent loss of lung elastic recoil may lead to distortion or irregularities of the airways, which contributes to the airflow limitation. The inflammatory cell profile in the alveolar walls is similar to that described in the airways and persists throughout the disease.

Pulmonary Vasculature

Changes in the pulmonary vasculature occur early in the course of COPD; thickening of the intima is followed by increase in smooth muscle and infiltration of the vessel wall with inflammatory cells, including macrophages and CD8⁺ T lymphocytes. As the disease progresses, greater amounts of smooth muscle, proteoglycans, and collagen accumulate, thickening the arterial wall. The development of chronic alveolar hypoxia in patients with COPD results in hypoxic vasoconstriction and subsequently leads to structural changes in the pulmonary vasculature, pulmonary hypertension, and right ventricular hypertrophy and dilation (cor pulmonale).

Risk Factors

Cigarette Smoking

Cigarette smoking is the single most important identifiable etiologic factor in COPD. The cause-and-effect relationship between cigarette smoking and COPD derives from several well-controlled population studies over the last four decades.

Maternal smoking is associated with low birth weight and decreased lung function at birth, which may lead to decreased level of function in early adulthood, increasing the risk of developing COPD depending on lifestyle, particularly smoking history. Further, smoking by either parent is associated with an increase in respiratory illness in the first 3 years of life, which may contribute to airflow limitation in later life.

Mild airflow limitation and a reduced increase in lung function occur in smoking adolescents. In addition, the plateau FEV₁ in the third decade of life is also shortened considerably by cigarette smoking, which results in the initiation of FEV₁ decline years earlier than in those who do not smoke.

In adulthood the effect of smoking on FEV₁ decline is well known. In general there is a significant dose-response effect, with smokers having lower lung function the more and the longer they smoke. There is, however, considerable variation. Most longitudinal studies indicate that the decline in FEV₁ in smokers ranges from 45 to 90 mL per year, in contrast to the normal 30 mL/yr (Figure 41-4). However, values vary considerably among individuals, and some experience significantly greater decline, at least temporarily, which may explain why COPD may seem to surface over a short period in the fifth and sixth decades of life. Some nonsmokers have impaired lung function, and 15% to 20% of COPD patients are lifelong nonsmokers. Conversely, some heavy smokers are able to maintain normal lung function, although the frequently quoted “15% to 20%” of smokers who are thought to develop clinically significant COPD is probably an underestimate. About 35% of smokers with normal lung function initially developed COPD during a 25-year follow-up in the Copenhagen City Heart Study.

Figure 41-4 Decline in forced expiratory volume in 1 second (FEV₁) in smokers and nonsmokers. Horizontal dashed lines represent level of FEV₁ consistent with disability or death; curved dashed lines represent change in FEV₁ decline with smoking cessation.

Pipe and cigar smokers have significantly greater morbidity and mortality from COPD than nonsmokers, although the risk is less than that from cigarettes. There is a trend to an increased relative risk of chronic airflow limitation from passive smoking, but the effect is not powerful enough to demonstrate clinical significance. Epidemiologic studies have associated cessation of smoking with a decrease in the prevalence of respiratory symptoms and improvement in the subsequent decline in FEV₁ (Figure 41-4). The first effect on lung function after smoking cessation is a small increase of 50 to 100 mL in FEV₁. There is some debate on whether decline in FEV₁ after smoking cessation completely normalizes, although in general those who quit smoking continue to have an FEV₁ decline slightly larger than in those who never smoked.

Host Factors

Other Factors

An association between COPD patients’ economic status, education, and lung function and COPD hospitalization has been shown in a Danish study, despite relatively small differences among social classes. However, social risk factors are likely multifactorial and may relate to intrauterine exposure, childhood infections, childhood environment, diet, housing conditions, and occupational factors.

The role of gender as a risk factor for COPD remains unclear. Previous studies typically showed greater COPD mortality in men than women, but more recent studies show that COPD now has almost equal prevalence in men and women, probably reflecting the change in tobacco smoking. Women may be more susceptible to the effects of tobacco smoke than men, but this is still debated.

Prevalence

In the past, imprecise definitions of COPD and underdiagnosis have resulted in underreporting of the condition. Prevalence studies of COPD vary depending on the survey method employed, including self-report of physician diagnosis of COPD, prebronchodilator or postbronchodilator spirometry, and respiratory symptom questionnaires. The lowest prevalence figures come from physician self-reporting; most national surveys indicate that about 6% of the general population has been diagnosed with COPD. This figure probably reflects the underrecognition of COPD, particularly in the early stages, when symptoms are not recognized as representing a disease.

Studies based on standardized spirometry suggest that 25% of subjects over age 40 have airflow limitation (FEV₁/FVC <0.7). However, prevalence data vary depending on the spirometric criteria used to define COPD. The use of a postbronchodilator, fixed FEV₁/FVC (<0.7) leads to potential underdiagnosis in younger adults and overdiagnosis in older adults (>50). Other prevalence studies are based on percent predicted FEV₁. In a UK population survey, 10% of men and 11% of women age 18 to 64 years had an FEV₁ greater than 2 standard deviations (SD) below their predicted values; the numbers increased with age, particularly in smokers. In current smokers 40 to 65 years old, 18% of men and 14% of women had an FEV₁ greater than 2 SD below normal, compared with 7% and 6% of male and female nonsmokers, respectively.

Approximately 14 million people in the United States have COPD, increasing by 42% since 1982. The best data available come from the 1988-1994 NHANES-III study. Prevalence of mild COPD (defined as FEV₁/FVC <0.7 and FEV₁ >80% predicted) was 6.9% and prevalence of moderate COPD (defined as FEV₁/FVC <0.7 and FEV₁ ≤80% predicted) was 6% for those age 25 to 75. The prevalence of both mild and moderate COPD was higher in males than females, in whites than in blacks, and increased steeply with age. Airflow limitation affected an estimated 14.2% of current white male smokers, 6.9% of ex-smokers, and 3.3% of never-smokers. Airflow limitation occurred in 13.6% of white female smokers, 6.8% of ex-smokers, and 3.1% of never-smokers. Less than 50% of COPD patients, based on the presence of airflow limitation, had a physician diagnosis of COPD.

Data from five Latin American cities in five different countries showed the presence of COPD (FEV₁/FEC ratio <0.7) increased sharply with age. The highest prevalence was in the over-60 age-group and ranged from 18.4% in Mexico City to 31.1% in Montevideo, Uruguay. In 12 Asian-Pacific countries, prevalence of moderate to severe COPD in those over age 30 was 6.3%. However, prevalence rates ranged from 3.5% to 6.7% across the Asia-Pacific region.

The UK national study reported abnormally low FEV₁ in 10% of males and 11% of females age 60 to 65 years. In England and Wales, an estimated 900,000 people have a diagnosis of COPD, although because of underdiagnosis, the true number is likely closer to 1.5 million. The mean age at diagnosis in the UK was 67 years, and prevalence increased with age. COPD was more common in men than in women and was associated with socioeconomic deprivation. The prevalence of diagnosed COPD has increased in the UK in women from 0.8% in 1990 to 1.4% in 1997, but did not change over the same period in men. Similar trends are found in the United States, again probably reflecting differences in smoking habits. National surveys of consultations in British general practices found a modest decline in the number of middle-aged men with symptoms of COPD and a slight increase in middle-aged women. These trends are confounded by changes over the years in the application of the diagnostic labels for this condition, particularly the overlap between COPD and asthma.

Morbidity and Socioeconomic Impact

Morbidity data in patients with COPD are less available and less reliable than mortality data, but the number of physician visits, emergency department (ED) visits, and hospitalizations in COPD patients increases with age, is greater in men than women, and is likely to increase with the aging population.

The ERS White Book provides data on the mean number of consultations for major respiratory diseases across 19 European countries. In most, consultations for COPD equal the number for asthma, pneumonia, lung cancer, and tuberculosis combined. In the United States in 2000, there were 8 million physician office/hospital outpatient visits for COPD, 1.5 million ED visits, and 673,000 hospitalizations.

The disability-adjusted life years (DALYs) for a condition is the sum of years lost because of premature mortality and years of life lived with disability, adjusted for the severity of the disability. In 1990, COPD was the 12th leading cause of DALYs in the world, about 2.1% of the total. COPD is projected to be the fifth leading cause of DALYs worldwide in 2020.

In the UK, emergency admissions for exacerbations of COPD increased from 0.5% of all hospital admissions in 1991 to 1% in 2000. Morbidity from COPD increases with age and is greater in men than women. COPD morbidity also may be affected by comorbidities (e.g., ischemic heart disease, diabetes mellitus) and may impact health status. Airway diseases (chronic bronchitis and emphysema, COPD, and asthma) account for a calculated 24.4 million lost working days per year in the UK, which represents 9% of all certified sickness absence among men, and 3.5% of the total in women. Respiratory diseases in the UK rank as the third most common cause of days of certified incapacity, with COPD accounting for 56% of these days lost in men and 24% in women. Most admissions are in the over-65 age-group and patients with advanced disease, although admissions recur at all stages. About 25% of patients diagnosed with COPD are admitted to the hospital, and 15% of all outpatients are admitted each year. In 2002-2003, there were 110,000 hospital admissions for COPD exacerbations in England, representing 8% of all emergency admissions. The burden in primary care is even greater, providing 86% of COPD care. Patients with COPD average six or seven visits annually to their general practitioner.

Mortality

Chronic obstructive pulmonary disease is the fourth leading cause of death in the United States and Europe and is projected to be the third leading cause of death (now fifth) worldwide by 2020, a result of the increase in smoking in the developing world and the changing demographics in those countries with increasing longevity of their populations. Large international variations in mortality for COPD cannot be entirely explained by differences in diagnostic patterns, diagnostic labels, or smoking habits. Death certification figures underestimate mortality because as previously stated, COPD is often cited as a contributory factor to the cause of death. COPD death rates are low under age 45 and increase steeply with age. Although mortality from COPD in men has been falling slightly, mortality in women has increased. U.S. data (2000-2005) indicate that COPD accounts for 5% of all deaths, with age-standardized mortality rate stable at approximately 64 deaths per 100,000 population; however, mortality in males fell from 83.8 in 2000 to 77.3 per 100,000 in 2005 and increased in females from 54.4 to 56.0 per 100,000.

In the UK in 2003, an estimated 26,000 persons (14,000 men, 12,000 women) died from COPD, 4.9% of all deaths, 5.4% of all male deaths, and 4.2% of all female deaths. Mortality from COPD in the UK has fallen in men but risen in women over the last 25 years, except in the over-75 age-group. In American women the decline in mortality which was recorded until 1975 has reversed and has increased substantially between 1980 and 2000, from 20.1 to 56.7 per 100,000, whereas the increase in men has been more modest, from 73.0 to 82.6 per 100,000. These trends presumably relate to the later peak prevalence of cigarette smoking in women compared with men. In the UK, age-adjusted death rates from chronic respiratory diseases vary by a factor of 5 to 10 in different geographic locations. Mortality rates tend to be higher in urban areas than in rural areas.

In the UK, COPD reduces life expectancy by an average of 1.8 years (76.5 vs. 78.3). The reduction in life expectancy increases with age, from 1.1 year in mild disease to 1.7 years in moderate disease and 4.1 years in patients with severe disease.

Air Space Inflammation

Inflammation is present in the lungs, particularly in the small airways, of all smokers. This inflammatory response is thought to be a normal, protective, innate immune response to inhaled toxins. This response is amplified in patients who develop COPD, through mechanisms not fully understood. COPD does develop in some patients who do not smoke, but the inflammatory response in these patients is not well characterized. The abnormal inflammatory response in COPD leads to tissue destruction, impairment of defense mechanisms that limit such destruction, and defective repair mechanisms. In general, the inflammatory and structural changes in the airways increase with disease severity and persist even after smoking cessation.

The innate inflammatory immune system provides primary protection against the continuing insult from inhalation of toxic gases and particles. The first line of defense consists of the mucociliary clearance apparatus and macrophages that clear foreign material from the lower respiratory tract; both are impaired in COPD. The second line of defense of the innate immune system is the exudation of plasma and circulating cells into both large and small conducting airways and the alveoli. This process is controlled by an array of proinflammatory chemokines and cytokines (Box 41-3). COPD is characterized by increased neutrophils, macrophages, T lymphocytes (CD8 > CD4), and dendritic cells in various parts of the lungs (see Box 41-2). Generally, the extent of inflammation is related to degree of airflow limitation. These inflammatory cells are capable of releasing a variety of cytokines and mediators that participate in the disease process. This inflammatory cell pattern is greatly different from that found in asthma.

An adaptive immune response is also present in the lungs of patients with COPD, as shown by the presence of mature lymphoid follicles, which increase in number in the airways according to disease severity. Their presence has been attributed to the large antigen load associated with bacterial colonization or frequent low respiratory tract infections, or possibly an autoimmune response. Dendritic cells are major antigen-presenting cells, are increased in the small airways, and provide a link between the innate and adaptive immune responses.

Both central airways and peripheral airways are inflamed in smokers with COPD. Smokers with chronic bronchitis have greater inflammation in bronchial glands. Recent studies characterizing the inflammation show increased infiltration of mast cells, macrophages, and neutrophils in smokers with chronic bronchitis (see Box 41-1). An increase in T lymphocytes, mainly in the CD8⁺ subset, occurs, in contrast to the predominance of the CD4 T cell subset in asthma. CD8 lymphocytes may have a role in apoptosis and destruction of alveolar wall epithelial cells, through the release of perforins and tumor necrosis factor alpha (TNF-α). Excessive recruitment of CD8 T lymphocytes may occur in response to repeated viral infections, damaging the lungs in susceptible smokers.

Proteinase/Antiproteinase Imbalance

Important for understanding the pathogenesis of COPD, an association was seen between α₁-antitrypsin deficiency and development of early-onset emphysema. Alpha₁-antitrypsin is a potent inhibitor of serine proteases and has greatest affinity for the enzyme neutrophil elastase. It is synthesized in the liver and increases from its usual plasma concentration as part of the acute-phase response. The activity of this protein is critically dependent on the methionine-serine sequence at its active site. Table 41-1 provides the average α₁-antitrypsin plasma levels for the more common phenotypes.

A deficiency in alpha₁-antitrypsin levels, particularly the inability to increase levels in the acute response, results in unrestrained proteolytic damage to lung tissue, leading to emphysema, which develops at an earlier age than in the patient with the more common emphysema in COPD. Cigarette smoking is a cofactor in the development of emphysema in alpha₁-antitrypsin–deficient patients, probably as a result of oxidation and thus inactivation of the remaining functional α₁-antitrypsin by oxidants in cigarette smoke. Hypothetically, under normal circumstances, the release of proteolytic enzymes from inflammatory cells, which migrate to the lungs to fight infection or after cigarette smoke inhalation, does not cause damage because of inactivation of these proteolytic enzymes by an excess of inhibitors. In conditions of excessive enzyme load or with absolute or functional deficiency of antiproteinases, however, an imbalance develops between proteinases and antiproteinases that favors proteinases, leading to uncontrolled enzyme activity and degradation of lung connective tissue in alveolar walls, resulting in emphysema. Cigarette smoke and inflammation produce oxidative stress, which primes several inflammatory cells to release a combination of proteases and to inactivate several antiproteases by oxidation.

This simplified protease/antiprotease theory is complicated by the presence of other antiproteases (e.g., antileukoprotease) and other proteases (e.g., metalloproteases) released from macrophages (Table 41-2).

Table 41-2 Proteinases and Antiproteinases in COPD

COPD, chronic obstructive pulmonary disease.

Elastase Synthesis and Repair

An abnormality of elastin synthesis and repair may be involved in the pathogenesis of emphysema. Severe starvation has been reported to cause COPD in both humans and animals; in addition, starvation can exacerbate proteinase-induced emphysema in animal models. Whether the milder malnutrition that occurs in emphysematous patients has a role in the pathogenesis is unknown.

Certain disorders of connective tissues, including Ehlers-Danlos syndrome and cutis laxa (generalized elastolysis), have been associated with the development of emphysema. Emphysema also develops in some animal models with genetic defects in tissue metabolism.

Oxidant/Antioxidant Imbalance

Considerable evidence supports the presence of an imbalance between oxidants and antioxidants that favors the oxidants (oxidative stress) in patients with COPD. Cigarette smoke itself produces a huge oxidant burden in the air spaces, and oxidants are released in increased amounts from the activated inflammatory cells that migrate into the air spaces in response to smoking, as noted earlier. Important antioxidants such as glutathione may also be affected by inhalation of cigarette smoke. Smoking initially depletes glutathione, but a subsequent rebound of levels occurs, presumably as a protective mechanism against the effects of cigarette smoking.

Studies have measured increased markers of oxidative stress, such as products of lipid peroxidation reactions, in biologic fluids of patients with COPD as indirect measurements of reactive oxygen species activity. Evidence shows increased markers of oxidative stress in bronchoalveolar lavage (BAL) fluid, sputum, exhaled breath, and breath condensate as well as systemically in the blood and skeletal muscle in patients with COPD, supporting a role for oxidative stress in its pathogenesis. Oxidative stress can directly damage cells, increase air space epithelial permeability, inactivate antiproteases, and importantly, trigger an enhanced inflammatory response by activating redox-sensitive transcription factors (e.g., NF-κB, AP-1). Also, oxidative modification of target molecules occurs more in the lungs in patients with COPD than in smokers without COPD.

Histone deacetylase-2 (HDAC2) is modified by oxidative stress in COPD, resulting in decreased level and activity. Decrease in HDAC2 results in acetylation of the lysine residues and DNA, resulting in uncoiling of DNA and increasing the accessibility of transcription factors and RNA polymerase to the transcriptional machinery, thus increasing gene transcription. Studies of resected lungs indicate that HDAC2 protein and activity is reduced in lung tissue in COPD as a result of oxidative modification of the molecule and is associated with an increase in histone-4 acetylation at the IL-8 promoter and increased IL-8 mRNA expression. This mechanism may be responsible for perpetuating inflammation in COPD.

The transcription factor nuclear erythroid-related factor 2 (Nrf2) controls the expression of several of the most important antioxidant enzymes. COPD lungs have decreased expression of Nrf2 transcriptional activity, which may result in reduced protection against oxidative stress.

Other Mechanisms

Autoimmunity, apoptosis, and cell senescence also may be involved in the pathogenesis of emphysema (Figure 41-6). Studies show that apoptosis occurs in emphysematous lungs, predominantly involving endothelial cells in the alveolar walls and resulting from a decrease in vascular endothelial growth factor (VEGF) or VEGF signaling, also shown to occur in association with emphysema in human lungs. These data led to the concept of an “alveolar maintenance program” required for the structural preservation of the lungs. Cigarette smoke is thought to cause disruption of this maintenance program, resulting in emphysema. The lung destruction or tissue destruction of emphysema is therefore caused by the mutual interaction of alveolar cell apoptosis, oxidative stress, and protease/antiprotease imbalance.

Similar features between pulmonary emphysema and lung aging led to the hypothesis that both conditions share underlying mechanisms, including oxidative stress, inflammation, and apoptosis. The cellular equivalent of aging is senescence, which is characterized by a nonproliferative stage in which cells are metabolically active and apoptosis resistant. Mechanisms associated with cell senescence include accumulation of DNA damage, impairment of DNA repair, epigenetic modifications in nuclear DNA, protein damage, oxidative stress, and telomere attrition. Telomere length is decreased in cells from emphysematous lungs, as are antiaging molecules such as sirtuins, suggesting a role for accelerated aging and cell senescence in the pathogenesis of emphysema.

Considerable evidence supports the role of the adaptive immune response in the progression of COPD. The presence of autoantibodies to lung structural cells and elastase suggests involvement of autoimmune mechanisms in pathogenesis of COPD.

Both oxidants and proteases such as elastase are important secretagogues for mucus and thus may be involved in the hypersecretion of mucus that occurs in chronic bronchitis. Airway mucus synthesis is regulated by the epidermal growth factor receptor (EGFR) system. Cigarette smoke upregulates EGFR expression and activates EGFR tyrosine phosphorylation, causing mucus synthesis in epithelial cells by a mechanism that probably involves oxidative stress.

Airflow Limitation and Hyperinflation

The characteristic physiologic abnormality in COPD is a decrease in maximum expiratory flow, which results from (1) loss of lung elasticity and (2) increase in airway resistance in small airways.

The main site of airflow limitation in COPD occurs in the small conducting airways (<2 mm in diameter) and results from inflammation, narrowing (airway remodeling), and inflammatory exudates in the small airways, features that correlate with the reduction in FEV₁. Other factors contributing to the airflow limitation include loss of the lung elastic recoil (caused by destruction of alveolar walls) and destruction of alveolar support (from alveolar attachments). The resultant airway obstruction causes progressive trapping of the air during expiration, resulting in hyperinflation at rest and dynamic hyperinflation during exercise. Lung hyperinflation reduces the inspiratory capacity, and thus functional residual capacity (FRC) increases, particularly during exercise (Figure 41-7). These features are thought to occur early in the course of the disease and result in the breathlessness and limited exercise capacity typical of COPD. Bronchodilators reduce air trapping and thus decrease lung volumes, improving symptoms and exercise capacity. Tests of overall lung mechanics (e.g., FEV₁, airway resistance) are usually abnormal in patients with COPD when breathlessness develops.

Figure 41-7 In health, the body meets the increased oxygen demand produced by exercise by using some of the inspiratory reserve volume of the lungs to increase tidal volume. COPD, chronic obstructive pulmonary disease. EELV, end-expiratory lung volume; EILV, end-inspiratory lung volume; IC, inspiratory capacity; IRV, inspiratory reserve volume; TLC, total lung capacity.

(Data from O’Donnell DE et al: Am J Respir Crit Care Med 164:770, 1999.)

Residual volume, FRC, and (in some cases) total lung capacity (TLC) increase. Maximum expiratory flow-volume curves show a characteristic convexity toward the volume axis, with preservation of peak expiratory flow initially. The uneven distribution of ventilation in advanced COPD causes a reduction in “ventilated” lung volume, and thus the carbon monoxide transfer factor (TLCO) is almost always reduced, although the lung diffusing capacity for carbon monoxide (DLCO), normalized to ventilated alveolar volume (DLCO/VA/KCO), may remain relatively well preserved in patients without emphysema.

The ability to draw air through the conducting airways during inspiration depends on the strength of the respiratory muscles, which in turn depends on their resting length; the compliance of the respiratory system (lung and chest wall); and the resistance of the airways. Exhalation is normally passive and results from the elastic recoil of the lungs. The characteristic changes in the static pressure-volume curve of the lungs in COPD are an increase in static compliance and a reduction in static transpulmonary pressure at any given lung volume. These changes are generally thought to indicate emphysema.

The resistance to airflow depends on the length and diameter of the airways and the physical properties of the respirable gas. At a constant airway diameter, airflow on inhalation is proportional to the difference between atmospheric gas pressure and alveolar pressure. During exhalation, airflow depends on the difference between alveolar and atmospheric pressures. Throughout inhalation and during the initial portion of exhalation, this relationship is constant. However, at a certain point during exhalation, flow cannot increase despite further increases in alveolar pressure. This is a result of dynamic compression of the airways, which limits flow, as illustrated by the flow-volume loop (Figure 41-8). During exhalation from TLC, flow increases to a point beyond which additional expiratory effort has no effect. During tidal breathing, expiratory flow is well below that attainable during maximum expiration. In COPD, however, the flow-volume loop is different. The major site of the fixed airway narrowing in COPD is in peripheral airways of diameter less than 2 mm. Loss of lung elastic recoil pressure is also an important mechanism of airway obstruction, resulting from a reduction in the distending force applied to the intrathoracic airways. Dynamic expiratory compression of the airways is enhanced by loss of lung recoil and by atrophic changes in the airways and loss of support from the surrounding alveolar walls, allowing flow limitation at lower driving pressure and flow.

Figure 41-8 Flow-volume loop over normal individual and patient with chronic obstructive pulmonary disease (COPD). Patients who have COPD may reach airflow limitation even during tidal breathing.

(From Celli B. In Albert R, Spiro SG, Jett JR, editors: Comprehensive respiratory medicine, St Louis, 1999, Mosby.)

In addition to a decrease in peak expiratory flow, the later expiratory portion of the flow-volume curve is concave relative to the volume axis in patients with COPD. In severe disease the flow generated during tidal breathing may actually reach the maximum possible flow (Figure 41-8). Such patients, in response to the increased metabolic demands of exercise, for example, are unable to increase ventilation. Increased respiratory rate results in gas trapping from incomplete alveolar emptying, so-called dynamic overinflation. This increased lung volume increases the elastic recoil and is associated with an increase in the end-expiratory alveolar pressure. The result is an increase in the work of breathing because pleural pressure must drop below alveolar pressure before inspiration of air can occur.

Pulmonary Gas Exchange

Ventilation-perfusion (V/Q) mismatching (as a result of decreased alveolar ventilation without a corresponding reduction in perfusion) is the most important cause of impaired pulmonary gas exchange in COPD. Other causes, such as impaired alveolar-capillary diffusion of oxygen and increased shunt, are much less important. In general, gas exchange worsens as the disease progresses. The distribution of ventilation is uneven in patients with COPD. Mechanisms that reduce blood flow include local destruction of vessels in alveolar walls as a result of emphysema, hypoxic vasoconstriction in areas of severe alveolar hypoxemia, and passive vascular obstruction from increased alveolar pressure and distention.

Respiratory Muscles

In patients with severe COPD, a combination of lung overinflation and malnutrition results in muscle weakness, reducing the capacity of the respiratory muscles to generate pressure over the range of tidal breathing. In addition, the load against which the respiratory muscles need to act is increased because of the increase in airway resistance. Overinflation of the lungs leads to shortening and flattening of the diaphragm, impairing its ability to generate force to lower pleural pressure. During quiet tidal breathing in normal subjects, expiration is largely passive and depends on the elastic recoil of lungs and chest wall. Patients with COPD increasingly need to use their rib cage muscles and inspiratory accessory (e.g., sternocleidomastoid) muscles, even during quiet breathing. During exercise, this pattern may be even more distorted and may result in paradoxical motion of the rib cage.

Patients with COPD have impaired values of global function of the respiratory muscles, such as maximum inspiratory mouth pressure (PE_max), although these measurements are effort-dependent. Diaphragmatic function can be assessed during inspiration by measurement of transdiaphragmatic pressure (Pdi), using balloon-tipped catheters with small transducers in the esophagus and stomach. Pdi values are reduced in patients with COPD.

Pulmonary Hypertension

Pulmonary hypertension complicating COPD is generally defined by a mean pulmonary artery pressure (Ppa) greater than 20 mm Hg. This is different from the definition of idiopathic hypertension (Ppa >25 mm Hg). In the natural history of COPD, pulmonary hypertension is often preceded by an abnormally large increase in Ppa (>30 mm Hg) during exercise.

The term cor pulmonale is often used synonymously with pulmonary hypertension in COPD. However, cor pulmonale is defined as right ventricular (RV) hypertrophy (enlargement) resulting from disease that affects the structure or function of the lungs. This is a pathologic definition and thus of limited value in clinical practice, because the diagnosis of RV hypertrophy is difficult to make. Pulmonary hypertension is the cause of cor pulmonale, so it is best to use the term pulmonary hypertension in COPD rather than cor pulmonale.

There are few data on the prevalence of pulmonary hypertension resulting from COPD, because large studies of right-sided heart catheterization or Doppler echocardiography have not been undertaken. An estimate of the prevalence of pulmonary hypertension in COPD can be obtained from calculating the number of subjects with significant hypoxemia who require long-term oxygen therapy. Significant hypoxemia (PaO₂ <55 mm Hg, FEV₁ <50% of predicted) occurs in 0.3% of the UK population 45 or older. Extrapolation from this figure suggests that in England and Wales, 60,000 patients may be at risk of pulmonary hypertension and eligible for long-term oxygen therapy. Extrapolating these figures to the United States, 300,000 COPD patients are at risk of pulmonary hypertension. Box 41-4 lists the factors leading to pulmonary hypertension in patients with COPD.

Pulmonary artery hypertension occurs late in the course of COPD, concurrent with the development of hypoxemia. Alveolar hypoxia is the most important functional factor in the development of pulmonary hypertension in COPD. Acute hypoxia causes pulmonary vasoconstriction, and chronic hypoxia induces structural changes or remodeling of the pulmonary vasculature, leading to sustained pulmonary hypertension.

The pulmonary hypertension in COPD is precapillary, because of an increased pressure difference between Ppa and pulmonary capillary wedge pressure, reflecting the increased pulmonary vascular resistance. Pulmonary hypertension in COPD is mild to moderate, with a resting Ppa in the stable stage of the disease ranging between 20 and 35 mm Hg. Ppa of 40 mm Hg or greater is unusual in COPD patients, except when measured during an acute exacerbation or during exercise; approximately 1% of patients exhibit severe pulmonary hypertension (Ppa >40 mm Hg). These patients are characterized by less severe airflow limitation but profound hypoxemia and hypocapnia. These patients may have an increased reactivity of the pulmonary arteries to hypoxia or coexisting idiopathic pulmonary hypertension. COPD patients with severe pulmonary hypertension in COPD have a poorer prognosis.

The progression of pulmonary hypertension is slow in COPD patients, and Ppa may remain stable for several years. The mean change in Ppa in a cohort of COPD patients is small (0.5 mm Hg/yr). Also, symptoms and physical signs are of little help in the diagnosis of pulmonary hypertension in COPD patients. The sensitivity of electrocardiography in diagnosing pulmonary hypertension is poor as well. Doppler echocardiography is the best method for the noninvasive diagnosis of pulmonary hypertension. However, right-sided heart catheterization remains the “gold standard” for diagnosing pulmonary hypertension.

The Ppa value is a good indicator of prognosis in patients with COPD. Five-year survival in a group of patients with initial Ppa less than 25 mm Hg was 66%, whereas in those with initial Ppa greater than 25 mm Hg, survival was only 36%.

The development of structural changes in the pulmonary arteries results in persistent pulmonary hypertension and RV hypertrophy/enlargement and dysfunction. Cor pulmonale is the major cardiovascular complication of COPD and is associated with a poor prognosis. Peripheral edema results from a combination of increased venous pressure and renal hormonal changes, leading to increased salt and water retention.

Skeletal Muscle Dysfunction/Wasting and Weight Loss

Peripheral muscle dysfunction is a prominent contributor to exercise limitation, increases health care utilization, and is an independent indicator of morbidity and mortality in COPD.

Weight loss is common in patients with COPD. A decreased body weight is reported in 49% of patients referred to a UK center for pulmonary rehabilitation. The prevalence of muscle wasting in COPD is probably underestimated, as extrapolated from body weight measurements, because fat-free mass (FFM) may be reduced despite preservation of body weight. Independent of body mass index (BMI) and disease severity, FFM index can predict mortality in COPD patients. The prevalence of FFM depletion was about 30% in patients with an FEV₁ of 30% to 70% of predicted and is associated with impaired peripheral muscle strength. Weight loss and loss of muscle mass result from the effects of systemic inflammation, an imbalance between muscle protein synthesis and breakdown, muscle apoptosis, and muscle disuse. Increased systemic inflammatory mediators (e.g., TNF-α, IL-6, O₂ free radicals) may mediate some systemic effects.

Osteoporosis is recognized as one of the systemic effects of COPD. In the TORCH study (Towards a Revolution in COPD Health), 18% of men and 30% of women had osteoporosis, and 42% of men and 41% of women had osteopenia, based on bone mineral density (BMD) assessments. The etiology of osteoporosis in COPD is complex. Several risk factors for osteoporosis are common features in COPD patients, including aging, limited physical activity, vitamin D deficiency, cigarette smoking, hypogonadism, and systemic corticosteroid use. A consequence of osteoporosis is that prevalence of vertebral fractures in COPD patients is 20% to 30%. This can result in increased kyphosis, compromising pulmonary function.

Osteoporosis is related to emphysema and to arterial wall stiffness. Moreover, the osteoprotegerin (OPG)/receptor activator of nuclear factor κB (RANK)/RANK ligand (RANKL) system has been identified as a possible mediator of arterial calcification, suggesting common links between osteoporosis and vascular diseases.

Cardiovascular Disease

Cardiovascular disease is one of the most important comorbidities related to COPD. A study that included 11,943 COPD patients reported a two-fold to four-fold increase in mortality risk from cardiovascular disease over a 3-year follow-up compared with an age-matched and gender-matched control group without COPD. In a cohort of patients with mild COPD in the Lung Health Study, cardiovascular complications accounted for 22% of all deaths during follow-up and for 42% of first hospitalizations. In this study, for every 10% increase in FEV₁, cardiovascular mortality increased by 28%, and nonfatal cardiovascular events increased by almost 20%, after adjustments for relevant confounders such as age, gender, smoking status, and treatment. There is strong epidemiologic evidence that reduced FEV₁ is a marker of cardiovascular mortality. A systematic review and meta-analysis included more than 80,000 patients identified and almost a twofold risk of cardiovascular mortality in patients with the lowest versus the highest lung function quintiles. COPD is an important risk factor for atherosclerosis, ischemic heart disease, cerebrovascular accident (stroke), and sudden cardiac death. Underlying mechanisms that contribute to the increased risk of atherosclerosis in COPD patients are not well understood and probably multifactorial, including low-grade systemic inflammation, endothelial dysfunction, and arterial stiffness.

Anemia

Although hypoxemia in COPD can be associated with secondary polycythemia, as a compensatory mechanism to improve oxygen transport to the tissues, polycythemia is present in only 6% of COPD patients, whereas anemia is present in 13% to 33%. The anemia in COPD is normochromic, normocytic, and is likely mediated by shortened red blood cell survival, decreased erythropoietin, and dysregulation of iron homeostasis. Anemia contributes to impaired oxygen transport to the tissues and exercise intolerance and has been associated with increased mortality in COPD patients.

Depression

Depression has been reported in 10% to 80% of patients with COPD, 2% to 5% higher than in the normal age-matched population. Depression is part of a vicious cycle involving poor health status, isolation, sedentary lifestyle, and worsening health status, resulting in the development of a reactive depression. Depression may also precede the development of COPD. Systemic inflammation may also contribute to development of depression.

Lung Cancer

Lung cancer is three to four times more common in COPD patients than in the general population and constitutes an important mortality risk in COPD patients. Patients with COPD have a higher incidence of lung cancer independent of the history of cigarette smoking. COPD is associated with the risk of developing small cell and squamous cell carcinoma, although no relationship seems to exist between COPD and the risk of developing adenocarcinoma.

Diabetes

The prevalence of diabetes in COPD patients has ranged from 1% to 16% of patients in different studies. Smoking is also a risk factor, and quitting smoking reduces the risk of diabetes. A reduction in lung function has also been associated with diabetes. Inflammatory markers such as TNF-α, IL-6, and C-reactive protein (CRP) have been associated with diabetes, and these inflammatory markers are elevated in COPD and may mediate insulin resistance by blocking signaling through the insulin receptor. The metabolic syndrome also appears to be more common in COPD patients, reflecting concomitant diabetes and cardiovascular disease with airway obstruction.

Gastroesophageal Reflux

An increase in gastroesophageal reflux disease (GERD) has been identified in COPD patients, being more common in those patients with an FEV₁ less than 50% predicted. GERD also appears to be a precipitant of exacerbations of COPD.

Symptoms

Patients with COPD characteristically complain of the symptoms of breathlessness on exertion, chest tightness, wheeze, chronic cough, and lower respiratory tract infections. The cough is often, but not invariably, productive. Breathlessness is the symptom that usually causes the patient to seek medical attention and is the most disabling symptom.

Patients often date the onset of their illness to an acute exacerbation of cough with sputum production, which leaves them with a degree of chronic breathlessness. Close questioning, however, usually reveals a cough with small amounts of mucoid sputum (usually <60 mL/day), often in the morning for many years. A productive cough occurs in up to 50% of cigarette smokers and may precede the onset of breathlessness. Many patients may dismiss this as simply “smoker’s cough.” The frequency of nocturnal cough does not appear to be increased in stable COPD. Paroxysms of coughing in the presence of severe airflow limitation generate high intrathoracic pressures, which can produce syncope and “cough fractures” of the ribs.

Breathlessness is usually first noticed on climbing hills or stairs, or hurrying on level ground, which later becomes progressive and persistent. It usually heralds at least moderate impairment of expiratory flow. Patients may adapt their breathing pattern and their behavior to minimize the sensation of breathlessness. The perception of breathlessness varies greatly among patients with the same impairment of ventilatory capacity. However, when the FEV₁ has fallen to 35% or less of the predicted value, breathlessness is usually present on minimal exertion. Severe breathlessness is often affected by changes in environmental temperature or occupational exposure to dust and fumes. Some patients have severe orthopnea, relieved by leaning forward, whereas others find greatest ease when lying flat. The impact of breathlessness can be assessed on the UK Medical Research Council (MRC) Dyspnea Scale (Table 41-3).

Table 41-3 Modified MRC Dyspnea Scale for Assessing Breathlessness

Data from UK Medical Research Council.

Wheeze (wheezing) is common but not specific to COPD because it results from turbulent airflow in large airways from any cause.

Chest tightness is also common in patients with COPD, resulting from the disease itself, underlying ischemic heart disease, or GERD. Chest tightness is a frequent complaint during periods of worsening breathlessness, particularly during exercise and exacerbations, and this is sometimes difficult to distinguish from ischemic cardiac pain. Pleuritic chest pain may suggest concurrent pneumothorax, pneumonia, or pulmonary infarction. Hemoptysis can be associated with purulent sputum and may be caused by inflammation or infection. However, blood-tinged sputum should also suggest bronchial carcinoma.

Other Aspects of the History

As part of the assessment of patients with COPD, the following factors need to be determined from the history:

Several conditions should be considered in the differential diagnosis in patients with COPD. Asthma can be particularly difficult; scales (e.g., the modified Borg scale) can be used to assess the degree of breathlessness (Table 41-4).

Table 41-4 Modified Borg Scale for Assessing Breathlessness

Clinical Signs

Patients with COPD typically present in the fifth decade of life. The physical examination may be completely negative early in the disease course. The physical signs are not specific and depend on the degree of airflow limitation and pulmonary overinflation. Because of the heterogeneity of COPD, patients may show a range of phenotypic clinical presentations. The sensitivity of physical examination to detect or exclude moderately severe COPD is rather poor.

General Examination

The respiratory rate may be increased. A breathing pattern with a prolonged expiratory phase, with or without pursing of the lips, is characteristic of patients with COPD. A forced expiratory time greater than 5 seconds strongly suggests the presence of airflow limitation. Use of accessory muscles of respiration, particularly the sternocleidomastoids, is often seen in advanced disease, and these patients often adopt a posture in which they lean forward, supporting themselves with their arms to fix the shoulder girdle. This allows use of the pectoral muscles and the latissimus dorsi muscle to increase chest wall movement.

Tar-stained fingers indicate the smoking habit in many patients. In advanced disease, cyanosis may be present, indicating hypoxemia, but it may be masked by anemia or accentuated by polycythemia, and is a fairly subjective sign. The “flapping tremor” associated with hypercapnia is neither sensitive nor specific, and papilledema associated with severe hypercapnia is rare.

As described earlier, weight loss may also be apparent in advanced disease, as well as a reduction in muscle mass. The body mass index (BMI; weight/height²) should be calculated. Finger clubbing is not a feature of COPD and should suggest the possibility of complicating bronchial neoplasm, pulmonary fibrosis, or bronchiectasis.

Chest Examination

In the later stages of COPD, the chest is often barrel-shaped with a kyphosis, resulting in an increased anterior/posterior chest diameter, horizontal ribs, prominence of the sternal angle, and a wide subcostal angle. The distance between the suprasternal notch and the cricoid cartilage (normally 3 fingerbreadths) may be reduced because of the elevation of the sternum. These are all signs of overinflation. An inspiratory tracheal tug may be detected, attributed to contraction of the low, flat diaphragm. The horizontal position of the diaphragm also acts to pull the lower ribs in during inspiration (Hoover sign). The xiphisternal angle widens, and abdominal protuberance results from forward displacement of the abdominal contents, giving the appearance of weight gain. Increased intrathoracic pressure swings may result in indrawing of the suprasternal and supraclavicular fossae and intercostal muscles.

Decreased hepatic and cardiac dullness on percussion indicates overinflation. A useful sign of gross overinflation is the absence of a dull percussion note, normally caused by the underlying heart, over the lower end of the sternum. Breath sounds may have a prolonged expiratory phase or may be uniformly diminished, particularly in the advanced stages of COPD. Wheezing may be present both on inspiration and expiration but is not an invariable sign. Crackles may be heard, particularly at the lung bases, but are usually scant and vary with coughing.

Cardiovascular Examination

Air trapping decreases venous return and compresses the heart. Accordingly, tachycardia is common in COPD patients. The presence of positive alveolar pressure at the end of exhalation (i.e., intrinsic positive end-expiratory pressure, or auto-PEEP) results in the need to create a more negative pleural pressure than usual, manifested by paradoxical pulse. Overinflation makes it difficult to localize the apex beat and reduces the cardiac dullness. The characteristic signs that indicate the presence or consequences of pulmonary hypertension may be detected in advanced cases. The heave of RV hypertrophy may be palpable at the lower left sternal edge or in the subxiphoid regions. Heart sounds are usually soft, although the pulmonary component of the second heart sound may be exaggerated in the second left intercostal space, indicating pulmonary hypertension. An RV gallop rhythm may be detected in the fourth intercostal space to the left of the sternum. The jugular venous pressure can be difficult to estimate in patients with COPD because it swings widely with respiration and is difficult to discern if there is prominent accessory muscle activity. There may be evidence of functional tricuspid incompetence, producing a pansystolic murmur at the left sternal edge. The liver may be tender and pulsatile, and a prominent v wave may be visible in the jugular venous pulse. The liver may also be palpable below the right costal margin as a result of overinflation of the lungs.

Peripheral vasodilation accompanies hypercapnia, producing warm peripheries with a high-volume pulse. Pitting peripheral edema may also be present as a result of fluid retention.

Physiologic Assessment

The degree of airflow limitation cannot be predicted from the symptoms and signs noted on clinical evaluation. Accordingly, the degree of airflow limitation should be assessed in every patient. At an early stage of the disease, conventional spirometry may reveal no abnormality. Results of tests of small airways function, such as the frequency dependency of compliance and closing volume, may be abnormal. However, these tests are difficult to perform, have high coefficient of variation (CV), and are valid only when lung elastic recoil is normal and there is no increase in airway resistance. These tests therefore are not recommended in normal clinical practice.

Other Tests

Lung pressure-volume curves are difficult to measure, requiring assessment of esophageal pressure with an esophageal balloon, and are not part of the routine assessment of patients with COPD. These tests may be necessary in special circumstances.

Measurements of small airways function with nitrogen washout test, helium flow-volume loops, or frequency dependence of compliance have poor reproducibility in patients with COPD. Although these tests can differentiate smokers from nonsmokers, they are not useful for predicting in which smokers COPD will develop, and thus are not used in routine practice.

Health Status

Health-related or health status quality of life is a measure of the impact of the disease on daily life and well-being. Breathlessness in patients with COPD limits exercise, reduces expectation, diminishes daily activity, restricts social activities, disturbs mood, and impairs well-being. Several questionnaires are available to assess health status and are used in hospital rehabilitation programs and research. The Chronic Respiratory Disease Index Questionnaire is sensitive to change but is time-consuming and requires training to administer properly. The Breathing Problems Questionnaire is a self-completed test that is easy to complete but relatively insensitive to change.

The St. George’s Respiratory Questionnaire is a self-completed test with three components—symptoms (distress caused by respiratory symptoms), activity (disturbance in daily activities), and impact (psychosocial function)—summed to give a total score of overall health status. This is the most validated health status tool in COPD. However, a rather poor relationship exists between the St. George’s Respiratory Questionnaire and the FEV₁. It is clear from various studies that there can be improvement in health status without any improvement in FEV₁ in response to treatment. An example of this is the response to pulmonary rehabilitation. The threshold of clinical improvement is a change of four units in the St. George’s Respiratory Questionnaire. Exacerbations of COPD have a clear detrimental effect on health status.

More recently, the COPD Assessment Test (CAT) has been shown to correlate well with the more detailed St. George’s Respiratory Questionnaire. The CAT may be useful clinically in assessing functional status, health status, and response to treatment.

Other Measurements

Erythrocythemia or polycythemia is important to identify in patients with COPD because it predisposes to peripheral vascular, cardiovascular, and cerebrovascular events. Erythrocythemia does not develop until there is clinically important hypoxemia (PaO₂ <55 mm Hg) and is not inevitable even at this level. Polycythemia should be suspected when the hematocrit is greater than 47% in women and 52% in men, and/or the hemoglobin is greater than 16 g/dL in women or 18 g/dL in men, provided other causes of spurious polycythemia from decreased plasma volume (dehydration, diuretics) can be excluded. A complete blood count may reveal the anemia of chronic disease that occurs in COPD.

Alpha₁-antitrypsin deficiency screening with measurements of the level and determination of allelic phenotype are indicated for patients (<45 years old) with early onset of emphysema and in those with a family history of premature emphysema. Because of the potential importance for other family members, some experts recommend that all patients with COPD be screened.

Electrocardiography is not routinely required in the assessment of patients with COPD, except when coexisting cardiac morbidity is suspected. It is an insensitive technique for the diagnosis of cor pulmonale.

Overinflation of the chest increases the retrosternal air space, which transmits sound waves poorly, making echocardiography difficult in patients with COPD. Thus, an adequate examination can be achieved in only 65% to 85% of patients with COPD. Two-dimensional echocardiography has been used in the investigation of right ventricular dimensions. Pulsed-wave Doppler echocardiography is used to assess ejection flow dynamics of the right ventricle in patients with pulmonary hypertension. The tricuspid gradient can be used to calculate the right ventricular systolic pressure. The technique estimates the pressure gradient across the tricuspid regurgitant jet recorded by Doppler ultrasound. The maximum velocity of the regurgitant jet is measured from the continuous-wave Doppler recordings, and the simplified Bernoulli equation is used to calculate the maximum pressure gradient between the right ventricle and the right atrium, P_RV – P_RA = 4v², where P_RV and P_RA are the right ventricular and right atrial pressures and v is the maximum velocity. The right atrial pressure is estimated from clinical examination of the jugular venous pressure.

Imaging