6: Chronic obstructive pulmonary disease

OUTLINE

Etiology and Pathogenesis, 89

Smoking, 89

Environmental and Indoor Pollution, 91

Infection, 91

Genetic Factors, 92

Pathology, 92

Pathophysiology, 95

Functional Abnormalities in Airway Disease, 95

Functional Abnormalities in Emphysema, 96

Mechanisms of Abnormal Gas Exchange, 97

Pulmonary Hypertension, 98

COPD Phenotypes, 98

Clinical Features, 99

Diagnostic Approach and Assessment, 100

Treatment, 101

The term chronic obstructive pulmonary disease (COPD) refers to chronic disorders that disturb airflow, whether the most prominent process is within the airways or within the lung parenchyma. The two most common disorders included in this category are chronic bronchitis and emphysema. Although the pathophysiology of airflow obstruction is somewhat different in the two disorders, patients frequently have features of both, so it is appropriate to discuss them together. Asthma could logically also be in this category, but it is discussed in Chapter 5 because the term COPD, as commonly used, does not usually include bronchial asthma. Importantly, although patients with asthma typically regain normal lung function between exacerbations, patients with COPD have obstructive lung disease that is “chronic,” that is, their lung function is always abnormal.

Other terms synonymous with COPD are chronic airflow limitation, chronic airflow obstruction,

chronic obstructive airways disease, and chronic obstructive lung disease. Because COPD is the term

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in most common use, it is used here as well. Emphysema is discussed in this section of the textbook dealing with airway disease, even though the most obvious and visible pathologic manifestations of emphysema affect the lung parenchyma via alveolar destruction.

Chronic bronchitis is a clinical diagnosis used for patients with chronic cough and sputum production. The condition has certain pathologic features, but the diagnostic label refers to the specific clinical presentation. For epidemiologic purposes, the formal definition is the presence of a chronic productive cough on most days during at least 3 months per year for 2 or more consecutive years. However, for clinical purposes, the physician does not necessarily adhere to this formal time requirement. Patients with chronic bronchitis frequently have periods of worsening or exacerbation, often precipitated by respiratory tract infection. Unlike patients with asthma, however, patients with pure chronic bronchitis have residual clinical disease even between exacerbations, and their disease is not primarily one of airway hyperreactivity. The diagnosis of asthmatic bronchitis has often been given to patients with chronic bronchitis and a prominent component of airway hyperreactivity, because features of both chronic bronchitis and asthma are present. More recently, the label of asthma-COPD overlap syndrome has begun to be applied to these patients who have features of both asthma and COPD.

Chronic bronchitis is a diagnosis made on the basis of chronic cough and sputum production.

In contrast to the clinical diagnosis of chronic bronchitis, emphysema is formally a pathologic diagnosis, although certain clinical, radiographic, and laboratory features are also highly suggestive of the disease. Pathologically, emphysema is characterized by the destruction of alveolar walls and larger regions of lung parenchyma, and the enlargement of air spaces distal to the terminal bronchiole. The region of the lung from the respiratory bronchioles down to the alveoli is involved, and determination of the particular type of emphysema depends on the pattern of destruction within the acinus. Antemortem diagnosis of emphysema obviously does not have the kind of confirmation offered by postmortem examination of the lung, and the diagnosis is based on clinical and radiographic evidence.

Emphysema is a diagnosis made on the basis of destruction of lung parenchyma and enlargement of air spaces distal to the terminal bronchiole.

Because chronic bronchitis and emphysema coexist to a variable extent in different patients, the broader term COPD is frequently more accurate. That these two disorders are tied so closely together is not surprising. A single etiologic factor—cigarette smoking—is primarily responsible for both processes. Inflammation induced by cigarette smoke, from the large airways down to the alveolar walls of the pulmonary parenchyma, is believed to be the common thread that ties together many of the varied manifestations of COPD. Throughout this chapter, specific reference is made to chronic bronchitis or to emphysema because some of the clinical and pathophysiologic features are distinct enough to warrant separate consideration. However, patients usually do not fit neatly into these separate diagnostic categories.

The public health problems posed by COPD are enormous. Globally, the World Health Organization estimates that approximately 65 million people have moderate or severe COPD, accounting for approximately 3 million deaths per year. In the United States alone, approximately 15 million people have a diagnosis of COPD, and it is the third most common cause of death. Morbidity in terms of chronic symptoms, days lost from work, and permanent disability is even more staggering. Unlike many diseases encountered by the physician, COPD is preventable in the majority of cases, because the main etiologic factor is well established and totally avoidable. Fortunately, since 1964, when the first Surgeon General’s report on smoking and health was published, the prevalence of smoking among American adults has

decreased from 40% to approximately 14%. Nevertheless, there are still more than 36 million current smokers and a large reservoir of former smokers who have placed themselves at high risk for COPD and other smoking-related diseases. It is important to note that the vast majority of smokers start smoking in their teens and early 20s; smoking avoidance programs are most effective when aimed at this age group. Worldwide, an increasing prevalence of smoking in developing countries has made COPD the third most common cause of death worldwide since 2019.

Etiology and pathogenesis

Factors that have been implicated in causing or contributing to the risk of COPD include smoking, including second-hand smoke, environmental and indoor air pollution, infection, and genetics. Of these four, smoking is clearly the most important, and the one that will receive most attention here. Yet the fact that symptomatic COPD develops in only approximately 20% of smokers indicates that other factors modify an individual’s risk. One well-defined genetic risk factor for COPD, inherited deficiency of the protein α1-antitrypsin, is discussed in detail in this section, but it is likely that other as yet unidentified polygenetic factors also affect the risk.

Smoking is the key etiologic factor for chronic bronchitis. Environmental and indoor pollutants and genetics are potential additional factors in exposed individuals. Respiratory tract infection is an important cause of disease exacerbations.

Smoking

Smoking affects the lung at multiple levels: bronchi, bronchioles, and pulmonary parenchyma. In the larger airways—the bronchi—smoking has a prominent effect on the structure and function of the mucussecreting apparatus, the bronchial mucous glands. An increase in the number and size of these glands is responsible for excessive mucus within the airway lumen. The airway wall becomes thickened because of the hypertrophied and hyperplastic mucous glands as well as an influx of inflammatory cells (especially macrophages, neutrophils, and cytotoxic [CD8+] T lymphocytes) into the airway wall. Thickening of the wall diminishes the size of the airway lumen, and mucus within the lumen further compromises its crosssectional area. Release of a variety of mediators from the inflammatory cells, including leukotriene B4, interleukin-8, and tumor necrosis factor-α, contributes to tissue damage and amplifies the inflammatory process in both the airways and the lung parenchyma. Similarly, oxidative stress due to reactive oxygen species present in cigarette smoke or released from inflammatory cells contributes to the overall pathologic process.

At the same time as more mucus is produced in the larger airways, clearance of mucus is altered by the effects of cigarette smoke on the cilia lining the bronchial lumen. Structural changes in cilia after longterm exposure to cigarette smoke have been well documented, and functional studies have demonstrated impaired mucociliary clearance as a consequence of cigarette smoking.

The combined effects of smoking on mucus production, mucociliary clearance, and airway inflammation easily explain the epidemiologic data demonstrating a significant correlation between cigarette smoking and the symptoms of chronic bronchitis: cough and sputum production. Pipe and cigar smoking are also predisposing factors in the development of chronic bronchitis, but the risk is significantly less than that from cigarette smoking, probably because pipe and cigar smoke is generally not inhaled as extensively.

Small airways (bronchioles less than approximately 2 mm in diameter) are prominently affected by

smoking. Smoking induces bronchiolar narrowing, inflammation, and fibrosis, with resulting airflow

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obstruction. These changes in the small airways or bronchioles are responsible for an important component of the airflow obstruction in COPD and are likely the primary factor in patients with mild COPD (discussed later under Pathophysiology).

In the pulmonary parenchyma, smoking results in the eventual development of emphysema. An understanding of the concepts about how smoking leads to the destruction of alveolar walls, which is characteristic of emphysema, requires familiarity with the protease-antiprotease hypothesis. According to this theory, emphysema results from destruction of the connective tissue matrix of alveolar walls by proteolytic enzymes (proteases) released by inflammatory cells in the alveoli. Studies in animals have demonstrated that the injection of certain proteolytic (i.e., capable of breaking down protein) enzymes into the airways of animals results in pathologic and physiologic changes similar to those of clinical emphysema.

Cigarette smoking is responsible for most cases of emphysema. Deficiency of serum α1-antitrypsin is a predisposing factor for emphysema in a small proportion of cases.

The particular proteolytic enzymes thought to contribute to emphysema are those capable of breaking down elastin, a complex structural protein found in the walls of the alveoli. Elastase, one of several enzymes within the category of serine proteases, appears to be the most important of the proteolytic enzymes. Neutrophils are the major source of elastase within the lungs; therefore, the enzyme is commonly called neutrophil elastase. If elastase were allowed to exert its proteolytic effect on elastin whenever it was released from a neutrophil, destruction of this important structural protein of the alveolar wall would ensue. Fortunately, an inhibitor of neutrophil elastase, usually called α1-antitrypsin, but also sometimes called α1-antiprotease or α1-protease inhibitor, is normally produced in the liver, released into the bloodstream, and is present in the lung. It is believed that a balance between neutrophil elastase and its inhibitor prevents diffuse destruction of the alveolar walls. When this balance is disturbed, either by an increase in neutrophil elastase activity or by a decrease in antielastase activity, damage to elastin and to the alveolar wall can result, with the eventual production of emphysema.

Theories postulate that proteolytic enzymes (especially elastase) are balanced by α1-antitrypsin. If smoking or α1-antitrypsin deficiency disturbs this balance in favor of proteolytic enzymes, emphysema can result.

The damage induced by cigarette smoke is believed to be mediated, in part, by disturbing the balance between elastases and antielastases. An increased number of neutrophils can be found in the lungs of smokers, providing a source for increased amounts of neutrophil elastase, which, therefore, shifts the balance toward a more proteolytic destruction of elastin. In addition, oxidant stress related to oxidants derived from cigarette smoke and inflammatory cells is thought to be injurious to the airway epithelium as well as to important structural components of the lung, including elastin and collagen. This pathogenetic sequence hypothesized for the development of COPD, including emphysema, is summarized in Fig. 6.1.

respectively) does appear to be an important factor contributing to COPD, particularly chronic bronchitis. In addition, in parts of the world where biomass fuels are used for indoor cooking, environmental exposure to pollutants in confined indoor spaces may play an important role in development of COPD and may help explain the greater risk for women to develop COPD in these circumstances because of greater time spent in the home environment.

Infection

Infections do not initiate COPD, but they do cause transient worsening of symptoms and pulmonary function in patients with preexisting COPD. Of the different types of respiratory tract infection, viral infection appears to be responsible for a large number of clinical exacerbations of symptoms. Bacterial infections probably play a less important role but can cause superinfection of patients already harboring an acute viral infection.

An interesting additional role for infection is suggested by data indicating that childhood respiratory tract infections may increase the risk for subsequent development of COPD. This may be one of the factors helping explain why development of COPD is not uniform in all smokers. Childhood respiratory infection might contribute to later risk for developing COPD by affecting lung growth and function during childhood. The smoker who starts with a lower level of function because of childhood respiratory infections may be more likely to suffer functionally important consequences from heavy smoking in later life.

Genetic factors

Genetic factors presumably contribute to the risk for development of COPD, but the nature of the predisposition is poorly defined. The one hereditary factor best established as predisposing to emphysema is deficiency of the serum protein α1-antitrypsin. α1-Antitrypsin is a glycoprotein of the serine protease inhibitor (serpin) family that is produced by the liver and normally circulates in blood. Minor changes in the SERPINA1 gene, which codes for α1-antitrypsin, produce alterations in the structure of the protein that can be detected by biochemical methods. More than 100 different alleles of α1-antitrypsin have been identified. Each person has two genes coding for α1-antitrypsin: one of maternal origin and one of paternal origin. The normal (and most common) allele is the M allele, and the normal complement of two M genes is called MM. A person with the MM genotype has approximately 200 mg/dL (2.0 g/L) of the M type of protease inhibitor circulating in the blood. With one of the variant alleles, termed Z, the amino acid sequence of the protein is slightly altered, impairing secretion of the protein from its site of production in the liver. Hence, the abnormal protein remains in globules in the liver, where it may result in liver disease, and only small amounts enter the blood. Individuals who are homozygous for the Z gene (i.e., with the ZZ genotype) have circulating levels of α1-antitrypsin that are approximately 15% of normal. Heterozygotes with one M and one Z gene (the MZ genotype) have intermediate levels of circulating α1-antitrypsin in the range of 50% to 60% of normal levels. In the presence of a genotype associated with α1-antitrypsin deficiency, a blood level less than 1.1 g/L puts a patient at risk for development of clinical disease. It should be noted, however, that not all individuals with levels below this threshold ultimately develop clinical disease.

The most important form of α1-antitrypsin deficiency is associated with the ZZ genotype.

The ZZ genotype is a strong risk factor for premature development of emphysema, particularly if the individual is a smoker. Emphysema frequently develops as early as the third or fourth decade of life in