Article Update

Monday, August 10, 2020


Chronic obstructive pulmonary disease (COPD) is a chronic disease that is defined by progressive airflow obstruction that is not completely reversible. COPD is caused by chronic inflammation of the airways and lung parenchyma that develops in response to environmental insults, including cigarette smoke, and manifests clinically with symptoms of cough, dyspnea on exertion, and wheezing. Patients with COPD usually live a number of years with progressive disability and multiple acute exacerbations. Thus, the physician is likely to become involved for many years in the assessment, treatment, and education of a patient with COPD.


COPD is a disorder that is characterized by slow emp- tying of the lung during a forced expiration (see Plate 4-39). In practice, this is measured as the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), and the arbitrary definition of airflow obstruction is generally taken to be an FEV1/FVC ratio lower than 0.70. Because the rate of emptying of the lung decreases with advancing age, many elderly individuals demonstrate airflow obstruction even in the absence of a clinical diagnosis of COPD. The diagnosis of COPD usually describes individuals who have chronic airflow obstruction associated with tobacco smoke or some other environmental insult, although aging of the lung has many features that are similar to those of COPD.
COPD encompasses several clinical subtypes, including chronic bronchitis, emphysema, and some forms of long-standing asthma. Chronic bronchitis is defined by cough and sputum production for at least 3 months of the year for more than 2 consecutive years in the absence of other kinds of endobronchial disease such as bronchiectasis. In practice, though, most patients with chronic bronchitis have perennial chronic productive coughs that are dismissed as “smokers’ cough.” Emphysema is defined as enlargement of the distal airspaces as a consequence of destruction of alveolar septa. The resultant loss of elasticity of the lung (i.e., increased distensibility) causes slowing of maximal airflow, hyperinflation, and air trapping that are the pathophysiologic hallmarks of COPD. Asthma is defined by completely reversible airflow obstruction and airway hyperresponsiveness. Chronic persistent asthma may lead to irreversible airflow obstruction and a subset of those with asthma smoke and have incompletely reversible airflow obstruction, resulting in a population that meets the definition of COPD. Because most patients have
features of more than one subtype and because the treatment approaches are similar, physicians and epidemiologists usually do not distinguish among the various subcategories of COPD. In the future, however, as molecular and imaging methods permit finer distinction of COPD subgroups, it may be possible to more precisely tailor treatments and define prognosis for individual patients.
Patients with COPD often seek medical attention after their disease is already severe. Typically, patients have incurred several decades of damage caused by cigarette smoking before they experience dyspnea limiting their functional capacity. Patients may be treated for recurrent lower respiratory tract infections before a diagnosis of COPD is considered. Clinical presentations vary in the severity of the underlying lung disease, the rate of progression of disease, and the frequency of exacerbations.

COPD is the fourth leading cause of death in the United States, and mortality related to COPD is projected to increase as cigarette smoking increases in developing countries. COPD is also among the leading causes of chronic medical disability and health care costs in the United States. Morbidity and mortality attributable to COPD have continued to increase, in contrast with other chronic diseases. COPD accounts for a great burden of health care costs, including direct costs of health care and indirect costs related to missed work and caregiver support. Historically, COPD was described as a disease that predominantly affected white men. However, the prevalence of COPD among women and minorities has grown in recent decades as the rate of increase in white men has leveled off. In the United States, morbidity and mortality from COPD in women now exceeds in men, which is largely attributable to increases in the prevalence of cigarette smoking among women. The most rapid increase in COPD mortality is among elderly women. In developing nations, indoor burning of biomass fuel has been an important risk factor for COPD among women. As tobacco use has become more widespread in the developing world, the prevalence of COPD has risen among both men and women (see Plate 4-28).
COPD is caused by a combination of environmental exposures and genetic susceptibility. 1-Antitrypsin deficiency is the best documented genetic risk factor for COPD and demonstrates the interaction between genetic predisposition and environmental exposures that results in clinical manifestations of COPD. Other genetic associations have been suggested but are not as well substantiated. Inhalational exposures are the major environmental risk factor for COPD, and cigarette smoking is by far the most common risk factor world-wide. Other inhalational exposures include outdoor atmospheric pollution and indoor air pollution from heating and cooking, especially with the use of biomass fuels in developing countries. Occupational exposures and recurrent bronchial infections have also been implicated as pathogenic factors. Socioeconomic status and poor nutrition are other factors that may predispose individuals to developing COPD, and individuals with reduced maximal lung function in early life are more likely to develop COPD later in life.

COPD is a heterogeneous disorder with the unifying feature of incompletely reversible airflow obstruction, demonstrated by slow emptying of the lungs during a forced expiration. The natural history of the decline in FEV1 in patients with COPD was described by Fletcher and Peto (see Plate 4-28). These investigators reported that most cigarette smokers have a relatively normal rate of decline in FEV1 with aging, but a certain subset of smokers is especially susceptible to cigarette smoke, as demonstrated by an accelerated rate of FEV1 decline. More recent studies have confirmed that normal nonsmoking adults lose FEV1 at a rate of 30 mL per year, a consequence of aging-related loss of elastic recoil of the lung. Studies of patients with COPD show an average annual decline of FEV1 of 45 to 69 mL per year. Smokers that quit may revert to the normal state of decline (Plate 4-28). Persons who develop COPD may start early adulthood with lower levels of lung function and have increased rates of decline. The decline in lung function is asymptomatic for a period of years, and patients adjust their activities to limit strenuous exercise. In middle age, the onset of an intercurrent respiratory infection, ascent to altitude, or progression of the disease beyond a critical threshold may lead to impairment of routine daily activities or even acute respiratory failure. These events lead the patients with COPD to seek medical attention. Thus, the onset of COPD may appear precipitous even though it is the cumulative result of decades of progression.

COPD is a heterogeneous disease that presents with a spectrum of clinical manifestations. Although end-stage COPD has classically been described as having features typical of emphysema or chronic bronchitis, most patients have features of both (see Plates 4-28 to 4-31). Although COPD represents a spectrum of clinical presentations, the presence of airflow limitation is a unifying feature, and spirometry serves as a diagnostic tool and a means of assessing disease severity (see Plates 4-39 and 4-42). Patients typically have some degree of dyspnea and may also experience cough and wheezing. COPD is progressive, and symptoms and clinical features worsen over time despite available treatments.


The classic representation of a patient with a predominance of emphysema is an asthenic patient with a long history of exertional dyspnea and minimal cough productive of only scant amounts of mucoid sputum (see Plate 4-29). Weight loss is common, and the clinical course is characterized by marked, progressive dyspnea. On physical examination, the patient appears distressed and is using accessory muscles of respiration, which serve to lift the sternum in an anterior-superior direction with each inspiration. The sternomastoid muscles are well-developed, but the limbs show evidence of muscle atrophy. The patient has tachypnea, with relatively prolonged expiration through pursed lips, or expiration is begun with a grunting sound. Patients who have active grunting expiration may exhibit well-developed, tense abdominal musculature.
The hyperinflation of the chest leads to widening of the costal angle of the lower ribcage and elevation of the lateral clavicles. The flattened diaphragm causes the lateral ribcage to move inward with each breath. While sitting, the patient often leans forward, extending the arms to brace him or herself in the so-called “tripod” position. Patients who brace themselves on their thighs may develop hyperkeratosis of the upper thighs. The neck veins may be distended during expiration, yet they collapse with inspiration. The lower intercostal spaces and sternal notch retract with each inspiration. The percussion note is hyperresonant, and the breath sounds on auscultation are diminished, with faint, high-pitched crackles early in inspiration, and wheezes heard in expiration. The cardiac impulse, if visible, is seen in the subxiphoid regions, and cardiac dullness is either absent or severely narrowed. The cardiac impulse is best palpated in the subxiphoid region. If pulmonary hypertension is present, a murmur of tricuspid insufficiency may be heard in the subxiphoid region.
The minute ventilation is maintained, the arterial Po2 is often above 60 mm Hg, and the Pco2 is low to normal. Pulmonary function testing demonstrates an increased total lung capacity (TLC) and residual volume (RV), with a decreased vital capacity. The DLCO (diffusing capacity for carbon monoxide) is decreased, reflecting the destruction of the alveolar septa causing reduction of capillary surface area. When the DLCO decreases below 50% predicted, many patients with emphysema have arterial oxygen desaturation with exercise.

Patients with a predominance of chronic bronchitis typically have a history of cough and sputum production for many years along with a history of heavy cigarette smoking (see Plate 4-30). Initially, the cough may be present only in the winter months, and the patient may seek medical attention only during the more severe of his or her repeated attacks of purulent bronchitis. Over the years, the cough becomes continuous, and episodes of illness increase in frequency, duration, and severity. After the patient begins to experience exertional dyspnea, he or she often seeks medical help and is found to have a severe degree of obstruction. Frequently, such patients do not seek out a physician until the onset of acute or chronic respiratory failure. Many of these patients report nocturnal snoring and daytime hypersomnolence and demonstrate sleep apnea syndrome, which may contribute to the clinical manifestations.
Patients with a predominance of bronchitis are often overweight and cyanotic. There is often no apparent distress at rest; the respiratory rate is normal or only slightly increased. Accessory muscle usage is not apparent. The chest percussion note is normally resonant and, on auscultation, one can usually hear coarse rattles and rhonchi, which change in location and intensity after a deep breath and productive cough. Wheezing may be present during resting breathing or may be elicited with a forced expiration.
The minute ventilation is either normal or only slightly increased. Failure to increase minute ventilation in the face of ventilation-perfusion mismatch leads to hypoxemia. Because of impaired chemosensitivity, such patients do not compensate properly and permit hypercapnia to develop with Paco2 levels above 45 mm Hg. The low Pao2 produces desaturation of hemoglobin, which causes hypoxic pulmonary vasoconstriction and eventually irreversible pulmonary hypertension. Desaturation may lead to visible cyanosis, and hypoxic pulmonary vasoconstriction leads to right-sided heart failure (see Plate 4-32). Because of the chronic systemic inflammatory response that occurs with COPD, these patients often do not have a normal erythrocytic response to hypoxemia, so the serum hemoglobin may be normal, elevated, or even decreased.
The TLC is often normal, and the RV is moderately elevated. The vital capacity (VC) is mildly diminished. Maximal expiratory flow rates are invariably low. Lung elastic recoil properties are normal or only slightly impaired; the DLCO is either normal or minimally decreased.

Large Airways Disease (see Plate 4-33)
Chronic bronchitis is associated with hyperplasia and hypertrophy of the mucus-secreting glands found in the submucosa of the large cartilaginous airways. Because the mass of the submucous glands is approximately 40 times greater than that of the intraepithelial goblet cells, it is thought that these glands produce most airway mucus. The degree of hyperplasia is quantitatively assessed as the ratio of the submucosal gland thickness to the overall thickness of the bronchial wall from the cartilage to the airway lumen. This ratio is known as the Reid index. Although the Reid index is often low in the bronchi of patients who do not have symptoms of COPD during life and is frequently high in those with chronic bronchitis, there is sufficient overlap of Reid index values to suggest that a gradual change in the submucous glands may take place. Thus, the sharp distinction of the clinical definition of chronic bronchitis cannot correlate completely with the pathologic changes in large airways. Although patients with chronic mucus hypersecretion with cough and sputum are more prone to respiratory infections and exacerbations of COPD, the presence of cough and sputum are not, by themselves, indicative of a poor prognosis in the absence of airflow obstruction. The magnitude of airflow obstruction is better correlated with the pathologic involvement of the small airways.
Small Airways Disease (see Plate 4-33)
COPD is also associated with changes in the small airways, those less than 2 mm and between the fourth and twelfth generation of airway branching in the lungs. The changes in the small airways may occur independently of changes in the larger airways. Changes in the small airways occur across a spectrum and may range from bland intraluminal secretions to a more cellular infiltrate, with polymorphonuclear neutrophils, macrophages, CD4 cells and other lymphocyte subtypes. The presence of lymphoid follicles in the small airways demonstrates increased immune surveillance of the mucosal surface. In addition to cellular inflammation, airway wall thickening, including changes in the epithelium, lamina propria, and adventitia, corresponds to disease progression. The diffuse changes in small airways con- tribute more to the obstruction and maldistribution of inspired gas than do the abnormalities in large airways. Obstruction of small airways with mucous plugs is associated with increased mortality.

The several types of emphysema are classified according to patterns of septal destruction and airspace enlargement within terminal respiratory units, or acini (see Plates 4-34 to 4-36). The normal acinus is supplied by a terminal bronchiole. The terminal bronchiole undergoes three orders of branching first into respiratory bronchioles with alveolated walls, into alveolar ducts, and finally into alveolar sacs.
If the septal destruction and dilatation are limited to the central portion of the acinus in the region of the terminal bronchiole and respiratory bronchioles, the disorder is called centriacinar or centrilobular emphysema (see Plate 4-35). Because of septal destruction, there is free communication between all orders of respiratory bronchioles. Alveolar sacs at the periphery of the acinus lose volume as the central portions enlarge. Although centriacinar emphysema is often considered to be a diffuse disease process, there is considerable variation in severity from acinus to acinus within the same segment or lobe. In general, however, more of the acini are affected in the upper lung zones than in the lower zones. Extensive centriacinar emphysema is most often found in those with histories of heavy smoking and chronic bronchitis.
In contrast to centriacinar emphysema, panacinar or panlobular emphysema affects the acinus more uniformly with less variability within an individual segment or lobe (see Plate 4-36). There is some tendency for the lower zones to be more severely affected. Panacinar emphysema is the characteristic lesion in 1-antitrypsin deficiency, although smokers with 1-antitrypsin deficiency may have centriacinar emphysema as well. Panacinar emphysema to a mild degree is a common finding after the fifth decade of life and may be extensive in elderly nonsmoking patients who have age related “senile” emphysema. In severe smoking-related chronic obstructive airway disease, both centriacinar and panacinar emphysema are ordinarily found along with chronic bronchitic changes in the airways.
When alveolar wall destruction is restricted to the periphery of the acinus, most often in regions just beneath the visceral pleura, the disorder is designated paraseptal emphysema. This form leads to development of subpleural bullae that may result in episodes of spontaneous pneumothorax in otherwise healthy young adults.

COPD is characterized by chronic inflammation in the peripheral airways and the lung parenchyma (see Plates 4-37 and 4-38). The predominant cells are macrophages, CD8 lymphocytes, and neutrophils. The inflammatory mediators leukotriene B4, tumor necrosis factor- (TNF-), and interleukin-8 (IL-8) are increased in the sputum of patients with COPD and may play an important role. An imbalance between proteases and antiproteases is also likely to be important in the pathogenesis of COPD (see Plate 4-38). Macrophages and neutrophils release many different proteases that break down connective tissue, such as elastin, in the lung parenchyma. The proteases may induce direct destruction of lung tissue as well as trigger cascades of intracellular events that lead to apoptotic cell death. Moreover, proteases are potent promoters of mucus cell metaplasia and mucus cell secretion, contributing to chronic bronchitis. Neutrophil elastase, proteinase 3, and cathepsins all produce emphysema in laboratory animals. Neutrophil elastase is inhibited by 1- antitrypsin and deficiency of this enzyme is the pre-dominant contributor to the emphysema in those with the severe genetic defect. Matrix metalloproteinases (MMPs) from macrophages and neutrophils may also have a key role in inducing emphysema. In the normal state, proteolytic enzymes are counteracted by antiproteases such as 1-antitrypsin and serum leukocyte proteinase inhibitor (SLIPI). By inducing inflammation, smoking increases release of proteases in the terminal airspaces in patients in whom COPD develops. More- over, smoking may also inactivate antiproteases via MMP inhibition of 1-antitrypsin, which itself is an inhibitor of a protease that counteracts the actions of MMPs. By reducing 1-antitrypsin’s inhibition of this protease, known as tissue inhibitor of metalloproteinases (TIMP), the actions of MMPs are enhanced. Smoking also leads to increased reactive oxygen species (ROS), which can promote inflammatory gene transcription by breakdown of the inhibitor of the transcription factor nuclear factor kappa-B (NFB), known as IN-KB. ROS can also inactivate histone deacetylase (HDAC), leading to increased DNA acetylation and gene transcription. Furthermore, CD8+ cells can promote macrophage production of MMPs through interferon-inducible cytokines, such as inducible protein of 10kD (IP-10), interfection-inducible T-cell alpha chemoattractant (l-TAC), and monokine induced by interferon-gamma (MIG). Thus, an insufficient concentration of antiproteases may result in parenchymal damage.
Oxidative stress may also contribute to the injury characteristic of COPD by oxidation of proteins, cell membranes, and nucleic acids, triggering a cellular stress response that ultimately leads to apoptotic cell death. The inflammation in COPD is not only localized to the lungs but is present on a systemic basis. Patients with COPD have elevated concentrations of C-reactive protein and interleukin-6, even during times of stable symptoms. Weight loss and muscle atrophy in COPD have been associated with increased circulating levels of TNF-and soluble TNF-receptors.
The final common pathway of inflammatory cytokines, protease-antiprotease imbalance, and oxidative stress is destruction of alveolar epithelial and capillary endothelial cells by a programmed sequence of cell death, or apoptosis. Because the lung requires replacement of its cellular scaffolding on a continuing basis, any process that leads to an imbalance of cell destruction and cell growth can eventually lead to emphysema. Thus, insufficiency of growth factors is also postulated to contribute to the development of emphysema.
The presence of CD8 cells and airway-associated lymphoid follicles in the lung parenchyma in smokers with COPD has raised the possibility that immunologic processes such as autoimmunity or response to chronic viral infection may also contribute to the pathogenesis of COPD.

Serum levels of α1-antitrypsin are either deficient or absent in some patients with early onset of emphysema associated with particular genotypes (see Plate 4-38). Most people in the normal population have α1-antitrypsin levels in excess of 250 mg/100 mL of serum along with two M genes, designated as Pi-type MM. Several genes are associated with alterations in serum α1-antitrypsin levels, but the most common ones associated with emphysema are the Z and S genes. Individuals who are homozygous ZZ or SS have serum levels of α1-antitrypsin of less than 50 mg/100 mL and develop severe panacinar emphysema at an early age, particularly if they smoke or are exposed to occupational dusts. The MZ and MS heterozygotes have intermediate levels of serum α1-antitrypsin. Although smokers with MZ or MS genotypes may have slightly increased decline in FEV1 if they smoke, the risk of developing COPD is not materially increased beyond other smokers.
α1-antitrypsin deficiency is caused by a single amino acid substitution. The Z mutation is caused by a glutamate to lysine mutation at position 342, and the S mutation is caused by a glutamate to valine mutation at position 264. These mutations lead to misfolding of the protein preventing release from the liver, where it is mainly manufactured. The misfolded protein may be destroyed by proteosomal processes, or if it polymerizes, may be stored in the endoplasmic reticulum and not released into the circulation. Excessive liver storage may lead to inflammatory liver disease and cirrhosis, particularly in affected infants and children.
The precise way that antitrypsin deficiency produces emphysema is unclear. In addition to inhibiting trypsin,α1-antitrypsin effectively inhibits elastase and collagenase, as well as several other enzymes. α1-antitrypsin is an acutephase reactant, and the serum levels increase in association with many inflammatory reactions and with estrogen administration in all except homozygotes. It has been proposed, with some supporting experimental evidence, that the structural integrity of lung elastin and collagen depends on this antiprotease, which protects the lung from proteases released from leukocytes. Proteases released by lysed leukocytes in the alveoli may be uninhibited and consequently free to damage the alveolar walls themselves. Alternative theories suggest that the unopposed protease activity may lead to an ongoing immune-mediated inflammatory response or acceleration of natural programmed cell death.

Whether bronchitis or emphysema predominates, by the time a patient with COPD begins to have symptoms, airflow limitation is readily demonstrable as an obstructive ventilatory defect. The most easily measured indexes of obstruction are taken from the volume-time plot of a forced expiratory VC maneuver, classically measured with a spirometer coupled to a rotating drum kymograph. Although volume-measuring spirometers are stable, rugged, and linear instruments, most modern spirometry systems use flow-measuring devices (pneumotachometers) interfaced with a microprocessor that integrates flow over time to produce a time-based record of forced expired volume (see Plate 4-39). The FEV1 is low both as a percentage of the value predicted for a given gender, age, and height category and as a percentage of the patient’s own FVC. Depending on the purpose of the pulmonary function test, an obstructive ventilatory defect is defined either as an FEV1/FVC ratio of less than 70% or less than the 95th percentile for the demographic category.

With COPD, static lung volumes are often abnormal. Plate 4-39 depicts the normal lung volumes and those often found in COPD. The functional residual capacity (FRC) is the lung volume at the end of a quiet exhalation and, in normal subjects, is the volume at which the inward recoil of the lung is equal and opposite to the outward recoil of the relaxed chest wall. An elevated FRC in individuals with COPD results from the loss of the static elastic recoil properties of the lung as well as initiation of inspiration before the static balance volume is reached (so-called “dynamic hyperinflation”). TLC is determined by pressures exerted by the diaphragm and muscles of the chest wall in relation to the static elastic recoil properties of both the chest wall and lung. When TLC is elevated in COPD, a significant degree of emphysema is present, although the TLC can also be elevated during acute episodes of asthma. RV is elevated early in the clinical course of COPD and is a sensitive sign of airflow limitation. Early in the course of the disease, elevation of RV is thought to be caused by closure of airways, but late in the disease, emphysematous bullae may also contribute to the elevation in RV. Because the TLC does not increase as much as the RV increases, the VC (i.e., TLC  RV) decreases with advancing COPD.
The measurement of static lung volumes in COPD is subject to some technical issues (see Plate 2-3). Resident gas methods using helium dilution or nitrogen may underestimate the true lung volumes because of incomplete gas mixing or washout in regions with impaired ventilation. Plethysmographic lung volumes that depend on Boyle’s law relying on the compressibility of resident gas in the lung are more accurate but are subject to overestimation of the true lung volume if the panting frequency is too rapid to permit equilibration of the mouth and alveolar pressures. Because the difference between the resident gas and plethysmographic measure is caused by regions of lung with little or no ventilation, the difference between the two methods has been called “trapped gas” and used as an indicator of COPD severity (see Section 2).
In addition to the easily demonstrable obstructive abnormalities during forced exhalation, there are significant alterations in the pressure-flow relationships during ordinary breathing in COPD. This contrasts with exhalation in normal subjects who can increase expiratory flow during tidal breathing (see Plate 4-39). Because of the slow emptying of the lung in COPD, the next breath is initiated before the respiratory system can return to the static FRC. This means that the individual breathes at higher lung volumes to maintain adequate expiratory airflow, a condition referred to as dynamic hyperinflation (see Plate 4-39). Although breathing at high lung volumes has the advantage of increasing airflow because of the increased lung elastic recoil, it requires an increase in the work of breathing and a decrease in the efficiency of breathing. Increasing respiratory rate accentuates dynamic hyperinflation and can worsen the sensation of dyspnea. Pursed-lip breathing causes patients to slow their respiratory rate and can relieve dyspnea by diminishing dynamic hyperinflation.
The physiologic hallmark of emphysema is a reduction in lung elastic recoil caused by destruction of alveolar septal elements. This causes the pressure-volume curve of the lung to be shifted upward and to the left, resulting in decreased static recoil pressure at a specific lung volume and an increase in the compliance of the lung (see Plates 4-39 and 4-40).
The surface area of the alveolar-capillary membrane is reduced as a consequence of emphysema. This results in decreased transfer of diffusion-limited gases such as carbon monoxide across the alveolar-capillary membrane. This is measured in the pulmonary function laboratory as the DLCO. The DLCO correlates roughly with the magnitude of reduction in maximum elastic recoil of the lung as well as the anatomic extent of emphysema assessed by imaging with computed tomography (CT). In chronic bronchitis, the DLCO may be preserved, and in asthma, the DLCO tends to be elevated.
With the progression of COPD comes progressive exercise limitation. This is caused by the increased work of breathing as ventilation increases with exercise. With increased respiratory rate, patients develop dynamic hyperinflation, a condition in which the end-expiratory lung volume does not return to the static end- expiratory volume of FRC (see Plate 4-40). The hyper- inflation that occurs causes an increased work of breathing and exacerbates dyspnea. An indicator of dynamic hyperinflation is the inspiratory capacity (IC), which progressively decreases with increasing ventilation. Measures that reduce dynamic hyperinflation, increasing IC, can improve exercise capacity. These include alterations in breathing pattern, oxygen supplementation, helium inhalation, and use of inhaled bronchodilators, particularly long-acting, and lung volume reduction surgery.

Chronic Bronchitis
On plain chest radiographs, thickening of bronchial walls is often seen as parallel or tapering shadows, referred to as tram tracking or ring shadows of airways that are visualized in cross-section. A generalized increase in lung markings at the bases is also frequently seen and is referred to as dirty lungs. In patients who have been exposed to occupational dusts, these markings may be accentuated but do not necessarily indicate the presence of pneumoconiosis.
The CT may show airway wall thickening or mucoid impactions in patients with COPD even in the absence of emphysema. The magnitude of these abnormalities, however, does not necessarily correlate with the severity of airflow obstruction or the extent of emphysema, and it remains to be seen whether there are prognostic or therapeutic implications of these findings.
In evaluating plain radiographs, a range of findings can represent emphysema. These include attenuation of the pulmonary vasculature peripherally, irregular radiolucency of lung fields, flattening or inversion of the diaphragm as seen on both posteroanterior (PA) and lateral projections, and an increase in the retrosternal space on the lateral projection. The latter two findings have correlated best with the severity of emphysema as assessed at subsequent postmortem examination.
High-resolution CT examination of the chest is now considered the best indicator of the extent and distribution of emphysema (see Plate 4-41). Qualitative visual assessments can assess the presence of thin-walled bullae and regions of diminished vascularity. Quantitative assessments use the degree of attenuation of x-rays to estimate the air-tissue ratio as a measure of airspace enlargement. Regions of the lung on thinsection CT scans that approach the radiodensity of air (1000 Hounsfield units [HU]) are considered to be emphysema. For example, the emphysema index is calculated as the percentage of image voxels in the lung regions that have a density 950 HU). Other methods rely on the statistical distribution of lung densities, quantifying the severity of emphysema by the lung density at the lowest 15th percentile of voxels.

Patient Education
Educating patients about the chronic nature of their disease and preventive measures is an important, ongoing process that will not be completed in one visit. The health care provider should focus on topics that are most pertinent to the needs of the patient and to the stage of disease. Topics that should be covered include the nature and prognosis of COPD, proper use of inhalers and adherence to medications, role of exercise and pulmonary rehabilitation, nutrition, and use of supplemental oxygen. Providing written materials in addition to office-based education is beneficial. Special counseling is needed for patients with α1-antitrypsin deficiency and their family members to determine whether genetic testing is necessary or desired. For those with advanced disease, discussions about end-of- life planning and advance directives regarding life support is often welcomed by patients and facilitates communication between the patient and his or her family.

Smoking Cessation
Smoking cessation is the single most effective intervention to slow the progression of COPD. and should be a primary goal emphasized by physicians caring for COPD patients. A smoking history should be obtained at each patient encounter. For patients who smoke, a direct, unambiguous, and personalized smoking cessation message should be given by the physician. Assistance with pharmacologic adjuncts and referral to more intensive smoking counseling groups should be offered. A combination of counseling and pharmacotherapy, including nicotine replacement therapy, varenicline, and bupropion, has been shown to be the most effective means of achieving smoking cessation. Guidelines recommend comprehensive tobacco control programs with consistent, clear, and repeated nonsmoking messages that are delivered at every medical encounter.
The Lung Health Study demonstrated the impact of smoking cessation in a landmark trial of more than 5800 smokers with spirometric signs of early COPD who were randomly assigned to smoking intervention plus placebo, smoking intervention plus bronchodilator, or no intervention. Randomization to the smoking cessation intervention was shown to reduce the rate of decline in FEV1 and to improve mortality, mainly related to cardiovascular disease and lung cancer. Throughout the study, some patients reverted from being smokers to quitters and vice versa. When patients were followed for 11 years, those who successfully quit smoking had a small initial increase in FEV1 followed by a slow, normal rate of FEV1 decline. Quitters who reverted to cigarette smoking showed a more rapid FEV1 decline than those who were sustained quitters. At 14.5 years, those randomized to the 10-week smoking cessation had a reduced mortality rate compared with those randomized to usual care.
Persons who quit smoking with earlier disease have better outcomes relative to those who continue to smoke than those who quit smoking later in the disease. When the disease is advanced, the inflammatory response persists, and the rate of decline of lung function tends to progress. Because there are many years of asymptomatic decline in lung function, it is possible to diagnose COPD with forced expiratory spirometry before the disease is apparent and to implement aggressive smoking intervention programs. There is no consensus whether it is necessary to screen for COPD among all cigarette smokers, but there is evidence that presentation of a person’s FEV1 in terms of “lung age” does assist in smoking cessation.
Reduce Harmful Environmental Exposures
Reduction of secondhand smoke and other environmental pollutants is important in preventing the progression of COPD. Reducing exposure to indoor and outdoor pollutants requires a combination of public policy to define and uphold air quality standards and steps taken at the individual level to minimize exposure to elevated concentrations of pollutants in the indoor or outdoor environments. Occupational exposures should be ascertained with attention to fumes and dusts, and vigorous measures should be taken to eliminate harmful exposures. Respiratory protective equipment should be worn by COPD patients exposed to heavy dust concentrations. Although there is no level of FEV1 that absolutely prohibits the use of respiratory protective equipment, some COPD patients will need to change their work environment if they cannot tolerate protective devices.

Minimize Infectious Risks
Although it is not possible to completely eliminate exposure to the many infectious agents, patients should keep away from large crowds and persons with obvious respiratory infections, especially during influenza season. Handwashing or hand sanitization should be emphasized.  Patients should be educated about early signs of exacerbations and treated promptly. Some patients may want to keep a prescription or supply of antibiotics or steroids available at home. Pneumococcal vaccination is recommended, although the evidence of its particular efficacy in COPD is lacking. Annual influenza immunization can prevent or attenuate this potentially fatal infection.
Exercise and Rehabilitation
Regular, prudent, self-directed exercise is recommended for all individuals with COPD to prevent the muscle deconditioning that often accompanies the disorder. Individuals should be encouraged to perform at least 20 to 30 minutes of constant low-intensity aerobic exercise such as walking at least three times per week. This is usually feasible even in more severely impaired patients. It is important to instruct patients that they should exercise to a level of dyspnea that is tolerable for the entire exercise period. Supplemental oxygen for exercise is necessary for patients who desaturate with exercise and may benefit some patients without demonstrable oxygen desaturation in terms of exercise capacity and training effect.
Formal rehabilitation programs are established as an effective component of COPD management and should be offered to patients who have substantial limitation in daily activities (see Plate 5-11). The goals of pulmonary rehabilitation are to improve quality of life, reduce symptoms, and increase physical and emotional participation in daily activities. To achieve these goals, pulmonary rehabilitation programs use a multidisciplinary approach, including exercise training, nutrition, education, and psychological support. Smoking cessation programs are often linked to pulmonary rehabilitation programs. Exercise training typically consists of bicycle ergometry or treadmill exercise. Upper extremity weight training is often included as a component of strength training. Practical advice on energy conservation and pacing during activities of daily living can be delivered individually or in group sessions. Proper use of inhalers, oxygen supplementation, and good nutrition are goals of education programs.

The goals of treatment of COPD are to prevent progression and complications of the disease, relieve symptoms, improve exercise capacity, improve quality of life, treat exacerbations, and improve survival. In addition to smoking intervention and treatment of hypoxemia with supplemental oxygen, pharmacologic therapy is available for treatment of patients with COPD. See the section on pharmacology (Plates 5-1 to 5-10) for a more detailed description of many of the drugs discussed below.
The current goals of drug therapy are not only to improve lung function, but also to improve quality of life and exercise capacity and to prevent exacerbations. The recommended approach to drug treatment for COPD is to sequentially add agents using the minimum number of agents and the most convenient dosing schedule, starting with the agents having the greatest benefit, best tolerance, and lowest cost (see Plate 4-42).
Inhaled bronchodilators, including-agonists and anticholinergic agents, are the foundation of treatment for patients with COPD. They are given on a regular basis to maintain bronchodilation and on an as-needed basis for relief of symptoms. Both-agonist and anti-cholinergic classes are available in short-duration (4-6 hour) and long-duration (12-24 hour) forms. Evidence suggests that long-acting agents are more effective than short-acting agents, but the choice of medication should also account for cost considerations and patient preference. Combination of different classes of bronchodilators is often more effective than increasing the dose of a single agent, and combination inhalers can simplify treatment regimens. Individuals with frequent exacerbations or more severe COPD may benefit from a combination inhaler of corticosteroids and long-acting bronchodilator. Long-acting oral theophylline can also be used as adjunctive therapy. Chronic use of systemic corticosteroids should be reserved for individuals with very frequent or life-threatening exacerbations who cannot tolerate their discontinuation.
Replacement therapy with α1-antitrypsin should be considered for individuals with severe deficiency. Observational studies suggest that individuals with moderate degrees of impairment (FEV1 35%-65% predicted) seem to benefit most in terms of preservation of lung function and improved survival.
Patient education about pharmacotherapy is important to ensure proper use of medications, as well as to enhance adherence. Inhaled agents are administered by metered-dose inhalers or dry powder inhalers or as a nebulized solution. The selection of route of administration is made by cost and convenience of the device because all are similarly effective if used properly. Proper use of inhaled medications is difficult for many patients to learn and retain. Adherence with inhaled medication, particularly when it does not provide immediate symptom relief, is poor. Typically, about half of patients do not take their medication in the dose or quantity prescribed. Reasons for this include a lack of understanding of the role of the medication, failure of the medication to provide meaningful benefit, complexity of the treatment program, and expense of the treatment. Many patients do not want to confide poor adherence to their physician, so it is important for the physician to ascertain this information in a way that does not interfere with the relationship with the patient. If nonadherence is a problem, the treating physician can undertake actions to improve adherence such as simplification of the medication program, education about the benefits of treatment, linking drug use to established habits such as meals or tooth brushing, or prescribing less costly drugs.

COPD exacerbations are characterized by worsening dyspnea, cough, and increased sputum production. There are several formal definitions of a COPD exacerbation, but a useful working definition is that a COPD exacerbation is a worsening of dyspnea, cough, or sputum production that exceeds day-to-day variability and that persists for more than 1 or 2 days. On average, patients with COPD have two to three exacerbations per year, but there is wide variation, and the frequency of exacerbations is only roughly correlated with severity of airflow obstruction. The best predictor of future exacerbations is a history of frequent exacerbations, and these are more common in patients with chronic cough and sputum production. Precipitating events include respiratory and nonrespiratory infections; exposure to respiratory irritants and air pollution; and comorbid conditions such as heart failure, pulmonary embolism, myocardial ischemia, or pneumothorax.
For patients treated at home, increasing the frequency and intensity of inhaled short-acting bronchodilators for several days is effective in mild exacerbations. A nebulizer may be needed for those who have difficulty using inhalers or in those with severe dyspnea. Increasing dyspnea accompanied by a change in the quantity or color of phlegm is usually an indication of bacterial infection and should prompt initiation of antibiotics. A course of corticosteroids, equivalent to 30 to 60 mg of prednisone for 7 to 14 days, will shorten the duration of symptoms for patients with exacerbations managed as outpatients.
For patients admitted to the hospital, intensification of inhaled bronchodilator treatment, systemic corticosteroids, and antibiotics should be administered.
Controlled oxygen supplementation should be provided at the lowest level needed to reverse hypoxemia and minimize the induction of hypercapnia. The selection of the oral or intravenous route for antibiotics and corticosteroids is determined by the severity of the illness and the ability of the patient to tolerate oral medication.
Treatment in an intensive care setting should be undertaken for patients with severe life-threatening exacerbations and those who require more constant attention. For patients with respiratory failure, noninvasive mask ventilation has proven to be an effective strategy to avert endotracheal intubation, shorten the duration of illness, and improve outcomes. When non-invasive mask ventilation is not successful in sustaining ventilation or if the patient is too ill to use the mask, endotracheal intubation and mechanical ventilation are needed to treat respiratory failure. The mechanical ventilator should be set to provide a provide a prolonged duration of expiration to minimize dynamic hyperinflation (“intrinsic positive end-expiratory pressure”), which can lead to dyspnea, ventilator dyscoordination, and barotrauma. Care should be taken not to overventilate the patient and cause alkalemia, which may ultimately impede liberation from the ventilator. Survival after an episode of acute respiratory failure for COPD is about 50% at 2 years after discharge, with about 50% of the patients being readmitted to the hospital within 6 months.

Patients with advanced COPD are prone to developing secondary complications of the disease. The goals of treatment are to restore functional status as quickly and as much as possible and to alleviate distress and discomfort.
Acute worsening of dyspnea may result from a pneumothorax, which patients with bullous emphysema are prone to have. Treatment involves use of highconcentration oxygen and drainage with a catheter or chest tube connected to a valve or vacuum drainage system. Patients with recurrent, life-threatening, or bilateral pneumothorax are candidates for pleurodesis to prevent recurrence.
Cor Pulmonale
The pulmonary vascular bed normally has an impressive reserve that accommodates large increases in cardiac output with minimal elevations of pulmonary artery pressures (see Plate 4-32). In COPD, there is a decrease in the total cross-sectional area of the pulmonary vascular bed caused by anatomic changes in the arteries; constriction of smooth muscle in response to alveolar hypoxia; and, to the extent that emphysema is present, a loss of pulmonary capillaries. Therefore, the pressures that must be generated by the right ventricle are elevated, and dilatation and hypertrophy of the right ventricle result. Overt right ventricular failure often occurs in association with endobronchial infections, which leads to worsening hypoxemia and hypercapnia. Such episodes are more frequent in patients in whom bronchitis is dominant.
Patients with cor pulmonale are cyanotic and have distended neck veins that do not collapse with inspiration, hepatic engorgement with a tender and enlarged liver, and pitting edema of the extremities. The heart may or may not appear enlarged on a PA chest radiograph, but pulmonary vessels are prominent. Physical examination may disclose a palpable right ventricular heave and an audible early diastolic gallop that is accentuated by inspiration. On occasion, there is dilatation of the tricuspid ring with secondary tricuspid insufficiency; this disappears with effective treatment. The electrocardiogram may show changes of right ventricular hypertrophy. Echocardiographic findings may be inconsistent, especially because of difficulty obtaining good-quality views of the right ventricle because of overlying hyperinflation of the lungs. Thus, in patients suspected to have pulmonary hypertension, a right- sided heart catheterization is the most definitive means of making the diagnosis.
Treatment of hypoxemia is the mainstay of prevention and treatment of cor pulmonale. Supplemental oxygen should be prescribed to maintain adequate oxygen saturations regardless of the development of hypercapnia (see Plates 5-12 to 5-14). The presence of sleep apnea is common in patients with COPD and pulmonary hypertension. Thus, evaluation with a sleep study is often helpful to determine the need for nocturnal oxygen or continuous positive airway pressure (see Plates 4-165 to 4-166). In occasional patients who have severe pulmonary hypertension with minimal COPD, pulmonary thromboembolism should be ruled out. Rarely, pulmonary vasodilators may be used when the magnitude of pulmonary hypertension seems disproportionate to the severity of the COPD and hypoxemia.

Lung Volume Reduction Surgery
(see Plate 5-32)
Lung volume reduction surgery (LVRS) is a surgical procedure that involves stapled resection of 20% to 30% of the lung bilaterally, usually from the apices (see section on LVRS). Although some patients show sub-stantial physiologic and symptomatic improvement after LVRS, many do not. The group of patients that fares best with LVRS is those who have emphysema predominantly in the upper lung zones and who have low exercise capacity despite pulmonary rehabilitation. These patients have improved survival after LVRS and show improved functional status and quality of life. Conversely, patients without upper lobe predominance (i.e., lower lobe emphysema or homogeneous emphysema) and who have adequate exercise capacity after rehabilitation have worse outcomes after LVRS.
Surgical resection of a single large bulla is rarely indicated for treatment of COPD. Isolated giant bullae are usually the result of an expanding congenital cyst. The generally accepted indication for resection of a single large bulla is that it occupies more than one-third of the hemithorax and causes compression of normal lung. Some believe that a preserved DLCO is an indicator of those most likely to improve after bullectomy.
Lung Transplantation (see Plate 5-33)
In younger patients with advanced disease, lung transplantation should be a treatment consideration (see Plate 5-33). Criteria for lung transplantation referral in patients with COPD is an FEV1 below 25% predicted, severe hypercapnia, or severe pulmonary hyper- tension in patients younger than age 60 to 65 years. The traditional recommendation is that patients should be referred for transplantation when their life expectancy is less than 2 years because this is the average waiting time on a transplant recipient list. In recent years, the waiting time has lengthened to closer to 4 years, so this may influence physicians to make earlier referrals. Other comorbid conditions, such as poor nutritional status, obesity, chronic mycobacterial infection, or severe osteoporosis, as well as suboptimal psychosocial support, are considered relative contraindications. Current smoking, recent malignant disease, major organ system failure (particularly renal or chronic hepatitis B or C infections) are considered absolute contraindications. Lung transplantation may be either unilateral or bilateral depending on the availability of donor organs and the preference of the transplant surgeon. Generally, younger patients and those with accompanying bronchiectasis are considered more suitable candidates for bilateral lung transplantation.
In the past, COPD has been the most common indication for lung transplantation, accounting for nearly 40% of all lung transplants and about 50% of single lung transplants. This is accounted for by the high prevalence of COPD as well as the better survival rate for patients with COPD than those with other transplant indications while awaiting donor organs. However, current criteria for prioritization of transplant recipients based on diagnosis rather than waiting time alone are likely to diminish the likelihood that COPD patients will receive donor organs. Early survival for patients with COPD after lung transplant is slightly better than that of other diagnostic groups in the first few years. Overall, 30-day survival is 9 %, 3-year survival is 61%, and 5-year survival is 45%.

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