Chronic Obstructive Pulmonary Disease

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Chronic Obstructive Pulmonary Disease



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 disorders generally included in this category are chronic bronchitis and emphysema. Although the pathophysiology of airflow obstruction is 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.


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 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.


Chronic bronchitis is a clinical diagnosis used for patients with chronic cough and sputum production. The condition has certain pathologic features, but the diagnosis refers to the specific clinical presentation. For epidemiologic purposes, a more formal definition has been used, one requiring 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 usually have residual clinical disease even between exacerbations, and their disease is not primarily one of airway hyperreactivity. The diagnosis of asthmatic bronchitis is often given to patients with chronic bronchitis and a prominent component of airway hyperreactivity, because features of both chronic bronchitis and asthma are present.



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 and laboratory features are also highly suggestive of the disease. Pathologically, emphysema is characterized by destruction of lung parenchyma and 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, but indirect support for the diagnosis is still useful and reasonably reliable.



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 frequently do not fit neatly into these separate diagnostic categories.


The public health problems posed by COPD are enormous. Globally, it is estimated COPD affects 210 million people and accounts for 2.9 million deaths per year. In the United States alone, 16 million people have 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 in the United States has decreased from 40% to approximately 22%. Nevertheless, there are still more than 45 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 is contributing to the World Health Organization’s prediction that COPD will be the third most common cause of death worldwide in the year 2020.



Etiology and Pathogenesis


Factors that have been implicated in causing COPD include smoking, environmental 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 about 20% of smokers suggests that other factors modify the risk. One other well-defined risk factor is discussed in detail in this section: inherited deficiency of the protein α1-antitrypsin. Other potential risk factors are discussed only briefly.



Smoking is the key etiologic factor for chronic bronchitis. Environmental pollutants and respiratory tract infection cause exacerbations, but generally have an insignificant etiologic role.



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 mucus-secreting 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 patency. Release of a variety of mediators from the inflammatory cells, including leukotriene B4, interleukin (IL)-8, and tumor necrosis factor (TNF)-α, contributes to tissue damage and amplifies the inflammatory process in both the airways and 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 more mucus is produced in the larger airways, clearance of mucus is altered by effects of cigarette smoke on the cilia lining the bronchial lumen. Structural changes in cilia after long-term 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 obstruction. These changes in the small airways or bronchioles are believed to be responsible for much of the airflow obstruction demonstrable in patients with mild COPD (discussed later under Pathophysiology).


In the pulmonary parenchyma, smoking results in 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 injection of several 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 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 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 anti-elastase activity, damage to elastin and to the alveolar wall can result, with eventual production of emphysema.



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


In smokers, the balance between elastase and anti-elastase is thought to be disturbed in more than one way by cigarette smoke. First, an increased number of neutrophils can be found in the lungs of smokers, providing a source for increased amounts of neutrophil elastase. Second, evidence indicates that oxidants derived from cigarette smoke and inflammatory cells can oxidize a critical amino acid residue of α1-antitrypsin at or near the site where the protease inhibitor binds to elastase. Oxidation of this amino acid interferes with the inhibitory activity of α1-antitrypsin, again tipping the balance in favor of increased elastase activity. Hence, cigarette smoking may be a compound insult, increasing the amount of neutrophil elastase in the lung and decreasing the normal inhibitory mechanism that serves to limit uncontrolled elastin breakdown by the enzyme. This pathogenetic sequence hypothesized for the development of emphysema is summarized in Figure 6-1.



In addition to degrading elastin in the alveolar wall, neutrophil elastase, when released in the airways, stimulates secretion of mucus. The primary defense against the action of neutrophil elastase in the airway is provided by secretory leukoprotease inhibitor, an antiprotease produced by airway epithelial and mucus-secreting cells.


Elastase is not the only proteolytic enzyme that has been implicated in the development of smoking-related damage and emphysema. Recent interest has focused on an additional group of enzymes called the matrix metalloproteinases, which are produced by macrophages and neutrophils and are capable of breaking down a variety of structural components of the alveolar wall. Like the relationship between elastase and its inhibitor α1-antitrypsin, the matrix metalloproteinases have a number of natural inhibitors, appropriately called tissue inhibitors of matrix metalloproteinases. Because of the influx of neutrophils and macrophages induced by cigarette smoke, it is believed that an increased burden of matrix metalloproteinases may result from smoking, potentially overwhelming the capability of the metalloproteinase inhibitors and contributing to the breakdown of alveolar walls.




Infection


Infections do not initiate the disease, 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 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, or 30 mg/dL. 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.



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 persons with the ZZ genotype (who are commonly said to have α1-antitrypsin deficiency because of low serum levels). As mentioned earlier, the structural integrity of alveolar walls appears to depend on the balance between elastin degradation by elastase and protection from this destruction afforded by α1-antitrypsin. In patients with α1-antitrypsin deficiency, lack of the elastase inhibitor is believed to permit elastase action to proceed in an unchecked fashion, and early development of emphysema is the consequence.


Another factor of interest, one that presumably is at least partially genetically determined, is the degree of the patient’s preexisting bronchial hyperresponsiveness. Data support the hypothesis that accelerated decline in lung function occurs in patients who have greater levels of bronchial responsiveness. However, this is an area of controversy, in part because the potential for smoking to induce changes in bronchial responsiveness makes it difficult to determine cause/effect relationships.



Pathology


Much of the pathology in chronic bronchitis relates to mucus and the mucus-secreting apparatus in the airways. Mucus-secreting glands and goblet cells are responsible for production of bronchial secretions, but the mucous glands are the more important source (see Chapter 4). In chronic bronchitis, enlargement (hypertrophy and hyperplasia) of the mucus-secreting glands has been objectively assessed by comparing the relative thickness of the mucous glands with the total thickness of the airway wall. This ratio, known as the Reid index, is increased in patients with chronic bronchitis. In general, the number of goblet cells in the airways is increased as well, and these particular cells are abundant in airways more peripheral than usual. These alterations in the mucus-secreting apparatus increase the quantity of airway mucus, and its composition is likely altered as well. In practice, the secretions found in patients often are thick and more viscous than usual. Bronchial walls demonstrate evidence of an inflammatory process, with cellular infiltration and variable degrees of fibrosis.



Chronic bronchitis is characterized by enlargement of the mucus-secreting glands and an increased number of goblet cells.


In the smaller airways (e.g., bronchioles), inflammation, fibrosis, intraluminal mucus, and an increase in goblet cells all contribute to a decrease in luminal diameter. Because the resistance of airways varies inversely with the fourth power of the radius, even small changes in bronchiolar size may result in major impairment to airflow at the level of the small airways. These pathologic changes in the small airways are thought to be the primary cause of airflow obstruction in patients with mild COPD.


In patients with severe chronic airflow obstruction, the most important process responsible for airflow obstruction is emphysema. As mentioned earlier, the pathology of emphysema is characterized by destruction of alveolar walls and enlargement of terminal air spaces (Fig. 6-2). Several types of emphysema have distinct pathologic features, primarily dependent on the distribution of the lesions. The most important types are panacinar (panlobular) emphysema and centriacinar (centrilobular) emphysema (Fig. 6-3). Panacinar emphysema is characterized by a relatively uniform involvement of the acinus, the region beyond the terminal bronchiole, including respiratory bronchioles, alveolar ducts, and alveolar sacs. Examination of a section of lung with panacinar emphysema shows that the damage in an involved area is relatively diffuse (Fig. 6-4). Typically the lower zones of the lung are more involved than the upper zones. Panacinar emphysema is the usual type of emphysema described in patients who have α1-antitrypsin deficiency, although the condition is not limited to this clinical setting.



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Jun 12, 2016 | Posted by in RESPIRATORY | Comments Off on Chronic Obstructive Pulmonary Disease

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