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.

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.

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.

In centrilobular emphysema, the predominant involvement and dilation are found in the proximal part of the acinus, the respiratory bronchiole. The appearance of a lung section with centrilobular emphysema is different from that with panacinar emphysema. In centrilobular emphysema, involvement in an affected area seems to be more irregular, with apparently spared alveolar tissue between the dilated respiratory bronchioles at the center of the acinus (Fig. 6-5). This type of emphysema is the typical form seen in smokers. It is reasonable to speculate that the prominent involvement focused around the respiratory bronchiole is a consequence of extension of the bronchiolar inflammation in mild COPD.

Pathophysiology

Underlying a discussion of the pathophysiology of COPD is the fact that cigarette smoking affects the large airways, small airways, and pulmonary parenchyma. The pathophysiologic consequences resulting from disease at each of these levels contribute to the overall clinical picture of COPD. In addition, the degree of airway reactivity, which probably is affected by genetic and environmental factors, appears to modify the clinical expression of disease in a given patient. This section simplifies, summarizes, and places into a conceptual framework some of the information regarding structure-function correlations for each of these aspects of COPD.

Clinical Features

Symptoms most commonly experienced by patients with COPD include dyspnea and cough, frequently with sputum production. Cough and sputum production may precede development of dyspnea by many years. Most patients are symptomatic, but some are symptom free, and the diagnosis of COPD is determined on the basis of pulmonary function tests.

Frequently patients have a certain level of chronic symptoms, but their disease course is punctuated by periods of exacerbation. An exacerbation is defined as an acute event characterized by worsening of symptoms that requires a change in medication. The precipitating factor producing an exacerbation is often a respiratory tract infection, particularly of viral origin. In addition, bacteria may be chronically present in the tracheobronchial tree, which normally should be sterile, and an acute bacterial infection, often due to acquisition of a new strain of the colonizing bacteria, can sometimes be implicated in acute exacerbations. Other factors that cause acute deterioration in patients include exposure to air pollutants, bronchospasm (particularly if patients have a superimposed asthmatic component to their disease), and congestive heart failure. However, in up to a third of cases, the cause of an exacerbation cannot be identified. When exacerbations are severe, patients may go into frank respiratory failure, a complication discussed in Chapter 27.

In addition to chronic symptoms of dyspnea, cough, or both, which may worsen during periods of acute exacerbation, patients may experience secondary cardiovascular complications of their lung disease (i.e., cor pulmonale). Patients with chronic hypoxemia and hypercarbia are particularly at increased risk for cor pulmonale.

Early in the course of the disease, physical examination may be normal or show only a prolonged expiratory time. As the process becomes more severe, characteristic findings are common. Breath sounds are generally decreased in intensity, and expiration is prolonged. Wheezing may be heard but does not necessarily reflect reversible bronchospasm. Some patients do not wheeze during normal tidal breathing but do so when asked to give a forced exhalation. In patients with profuse airway secretions, coarse gurgling sounds labeled as rhonchi are frequently appreciated. Examination of the chest often discloses an increased anteroposterior diameter, indicating hyperinflation of the lungs. When diaphragmatic excursion is assessed by percussion of the lung bases during inspiration and expiration, diminished movement is noted.

In advanced COPD, patients may use accessory muscles of respiration (e.g., sternocleidomastoid and trapezius muscles), and the intercostal muscles may retract with each inspiration. The patient may assume a characteristic “tripod” position, leaning forward on straight arms allowing fixation of the clavicles and more effective use of accessory muscles. Severe disease may also be complicated by weight loss and muscle wasting. When cor pulmonale is present, with or without frank right ventricular failure, patients have the cardiac findings described in Chapter 14.

Smoking not only is the primary factor that initiates COPD, it is also a major risk factor that determines the prognosis of a patient’s illness. Patients who continue to smoke appear to have the greatest further deterioration of pulmonary function over time. Exacerbations and respiratory tract infections frequently cause acute deterioration in lung function, but their effect on the long-term rate at which pulmonary function is lost is not well established. Nonetheless, infections are the most important cause of acute mortality in patients with COPD, pointing to the need for influenza and pneumococcal vaccination, as well as rapid appropriate treatment of bacterial respiratory infections.

A wide spectrum of severity is characteristic of COPD, so morbidity from the disease varies tremendously among patients. Patients with mild disease are able to continue their usual work and lifestyle with minimal if any changes. Patients with severe disease are quite limited in their capacity for any exertion, are subject to frequent hospitalizations, and may have a life expectancy of less than 5 years.

Diagnostic Approach and Assessment

In most cases, the diagnosis of COPD is suspected on the basis of history and physical examination, but spirometry with evidence of persistent airflow obstruction is still required to confirm the diagnosis in this clinical context. Chronic bronchitis is actually a clinical diagnosis, and the history is particularly crucial. Although emphysema is formally a pathologic diagnosis, a lung biopsy is not performed to make the diagnosis. Pathologic confirmation is generally obtained only at postmortem examination, if one is performed.

Chest radiographs have poor sensitivity in detecting COPD but are valuable in excluding other processes that cause dyspnea, such as congestive heart failure, pulmonary fibrosis, or pleural disease. Patients with chronic bronchitis alone frequently have a normal chest radiograph. When present, chest radiographic findings suggestive of COPD include signs of hyperinflation such as large lung volumes, flat diaphragms, an increased retrosternal air space, increased anteroposterior diameter (seen on the lateral view), and a paucity of vascular markings. Hyperinflation associated with decreased vascular markings in the lungs results from destruction of alveolar septa and enlargement of alveolar spaces and has been called the arterial deficiency pattern of emphysema (Fig. 6-8). In patients with α₁-antitrypsin deficiency and early onset of emphysema, the arterial deficiency pattern is quite striking in the lower lobes, where there may be almost a complete loss of vascular markings.

When cor pulmonale develops in patients with COPD, findings of pulmonary hypertension may be seen. These include enlargement of the proximal pulmonary arteries, pronounced tapering of the distal vessels, and cardiomegaly indicative of right ventricular hypertrophy or dilation.

High-resolution computed tomography (HRCT) is recognized as a more sensitive imaging method than plain chest radiography for detecting emphysema. Because it is expensive and rarely changes the management plan in this setting, it should not be considered part of the usual diagnostic evaluation for most COPD patients. However, HRCT is an important step in characterizing the extent and distribution of emphysema in patients for whom lung volume reduction surgery is being considered.

The most useful physiologic adjuncts in evaluating patients with COPD are pulmonary function tests and arterial blood gas analysis. Pulmonary function tests demonstrate airflow obstruction, with decreases in FVC, FEV₁, FEV₁/FVC ratio, and MMFR. Measurements of lung volume generally give evidence of air trapping, with an elevation in RV. In patients whose lung compliance is increased (i.e., patients with emphysema), TLC is generally elevated. FRC is elevated as a result of either increased compliance (decreased elastic recoil) in emphysema or insufficient expiratory time in the face of significant airflow obstruction. Whether emphysema is present can be indirectly assessed by measuring the diffusing capacity for carbon monoxide. In patients with emphysema, in whom the surface area for gas exchange is lost, the diffusing capacity typically is decreased. In pure airway disease (e.g., chronic bronchitis without emphysema), the diffusing capacity is generally normal.

Pulse oximetry is routinely used to evaluate patients with COPD, since supplemental oxygen is an important treatment in patients with hypoxemia (see later.) If the clinician is concerned about CO₂ retention or the accuracy of pulse oximetry, arterial blood gases are necessary. Typically, patients with mild to moderate COPD have an increased alveolar-arterial oxygen gradient and mild hypoxemia. In more severe disease, hypoxemia worsens, and hypercarbia (CO₂ retention) may develop. With chronic elevation in PCO₂, the kidneys retain bicarbonate in an attempt to compensate and return the pH toward normal. With acute exacerbations of COPD, hypoxemia frequently worsens and CO₂ retention becomes more pronounced, such that the pH may drop from the stable compensated value.

Treatment

Several modalities of treatment, used either individually or in combination, are available for patients with COPD. Although bronchoconstriction in these patients is considerably less than in patients with bronchial asthma, bronchodilators remain an important part of the treatment of many COPD patients. The agents used are identical to those discussed in Chapter 5, including sympathomimetic agents (β₂ agonists), anticholinergic drugs, and methylxanthines. Short-acting inhaled β₂ agonists (e.g., albuterol), short-acting anticholinergic agents (e.g., ipratropium), or both are most commonly used as needed for patients with mild disease who require only infrequent therapy. For patients with more severe disease who require regular therapy, either a long-acting β₂ agonist (e.g., salmeterol, formoterol, arformoterol), a long-acting anticholinergic agent (e.g., tiotropium), or both are commonly used, although regular use of short-acting agents is an alternative. The methylxanthine theophylline is another option, but concern for systemic side effects often relegates it to a secondary role in comparison with the inhaled bronchodilators.

Corticosteroid use for COPD treatment is evolving and dependent on the clinical setting. A 10- to 14-day course of systemic corticosteroids is frequently administered at the time of an acute exacerbation, and most studies suggest a benefit of improved pulmonary function and reduced treatment failure in this setting. On the other hand, only a minority of patients with chronic, stable, but severe disease show improved pulmonary function after a regimen of oral corticosteroids. Inhaled corticosteroids have little use in the setting of acute exacerbations of COPD. However, a trial of inhaled corticosteroids should be considered in patients with moderate to severe COPD who have frequent exacerbations, because some evidence indicates that inhaled corticosteroids may reduce the frequency or severity of exacerbations.

Newly available medications for treatment of COPD include indacaterol and roflumilast. Indacaterol is an ultralong-acting β₂ agonist and functions through the same pathways as other β₂ agonists. Roflumilast is a phosphodiesterase-4 inhibitor and represents a new class of medications for COPD. Phosphodiesterase-4 inhibitors decrease inflammation and promote airway smooth muscle relaxation and bronchodilation. The specific role of these new medications in treating COPD is still uncertain.

Patients with COPD who develop an acute respiratory tract infection, or patients with an exacerbation of their disease without a clear precipitant, are often treated with antibiotics. The primary usefulness of antibiotics is treatment of bacterial infections. A bacterial cause is difficult to document with certainty, however, and many exacerbations are thought to be either noninfectious or triggered by viral respiratory infections. In practice, patients are frequently treated with antibiotics when a change in quantity, color, and/or thickness of sputum in comparison with the usual pattern of sputum production is noted, regardless of whether a bacterial infection is documented. Of the potential bacterial pathogens, those most frequently implicated are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. As a result, the choice of antibiotic should provide coverage for these organisms.

An important therapy is administration of supplemental O₂ to patients with significant hypoxemia (i.e., systemic arterial oxygen saturation ≤ 88% or arterial PO₂ ≤ 55 mm Hg). Fortunately, the PO₂ of hypoxemic patients with COPD usually responds quite well to even relatively small amounts of supplemental O₂ (range, 24%–28% O₂). A low flow rate of O₂ (1–2 L/min) given by nasal prongs is an effective, well-tolerated method for achieving these concentrations of inspired O₂. Oxygen is particularly important in patients with pulmonary hypertension and in those with secondary polycythemia, because each of these complications is largely due to hypoxemia and responsive to treatment for it. Evidence suggests that long-term survival of hypoxemic patients with COPD can be improved by chronic administration of supplemental O₂. For hypoxemic patients, administering supplemental O₂ has been shown to alter the natural history of the disease and improve long-term survival.

The goal of O₂ therapy is to shift PO₂ into the range where hemoglobin is almost fully saturated (i.e., PO₂ > 60–65 mm Hg). Ideally, O₂ saturation should be well maintained on a continuous basis throughout the day and night. In some COPD patients who are not significantly hypoxemic during the day, a substantial drop in PO₂ and O₂ saturation can occur at night. In these patients, nocturnal O₂ theoretically may be of benefit, although this has not been proven.

For patients in whom airway secretions cause significant symptoms, chest physiotherapy and postural drainage are sometimes used to help mobilize and clear secretions. These techniques use percussion of the chest wall to loosen secretions and induce cough, followed by positional changes to allow gravity to aid in drainage of secretions. Handheld mucus-clearing devices are also available. To use these devices, the patient exhales into the apparatus, which applies oscillatory positive end-expiratory pressure, allowing more efficient clearance of secretions. However, the usefulness of chest physiotherapy and postural drainage or mucus-clearing devices is not generally accepted because outcome studies have not clearly supported their benefit.

In the small subgroup of patients with COPD who have α₁-antitrypsin deficiency, therapy is available in the form of intravenous α₁-antitrypsin concentrate prepared from pooled human plasma. The rationale for this therapy is to replace the deficient protease inhibitor and attempt to inhibit or prevent unchecked proteolytic destruction of alveolar tissue. Although intravenous infusions of α₁-antitrypsin have been shown to increase concentrations of this antiprotease in alveolar epithelial lining fluid, whether such replacement therapy alters the accelerated decline in pulmonary function is not definitively known.

In patients with impaired exercise tolerance secondary to COPD, a rehabilitation program focusing on education and a regimen of exercise training often is quite beneficial. Most patients participating in such a program report an improved sense of well-being at the same time they experience an improvement in exercise tolerance. Smoking cessation education and assistance are absolutely critical parts of any comprehensive therapeutic program. Pharmacologic assistance to ameliorate the effects of nicotine withdrawal—nicotine replacement therapy, bupropion, or varenicline—is often a valuable component of smoking cessation efforts. Vaccination against influenza and pneumococcus is indicated for all patients as a preventive strategy and a component of the overall therapeutic regimen.

Two surgical approaches have been used for patients with severe COPD who remain markedly symptomatic despite optimal therapy. One approach, lung volume reduction surgery, initially seems counterintuitive because it involves removing portions of both lungs from patients whose pulmonary reserve is marginal at best. However, two interesting pathophysiologic rationales underlie this approach. First, removal of some lung tissue diminishes overall intrathoracic volume, allowing the flattened and foreshortened diaphragm to return toward its normal position and resume its usual curved configuration. A flattened, foreshortened diaphragm is an inefficient respiratory muscle, and the changes in its position and shape following surgery facilitate its effectiveness during inspiration. Second, when the most diseased regions of lung are selectively removed (i.e., the regions with the least elastic recoil), the overall elastic recoil of the lung improves. Lung elastic recoil is an important determinant of expiratory flow and airway collapse, and improving elastic recoil has secondary benefits on airway patency and expiratory flow. Although lung volume reduction surgery is a novel and potentially attractive approach, it appears to be beneficial only in well-selected patients. Critical aspects of patient selection include the severity of disease and the anatomic distribution of emphysematous changes.

The other surgical approach to treatment of end-stage COPD is lung transplantation. However, this is not a practical approach for large numbers of individuals because of the resources needed, the shortage of donor organs, and the age of most patients with COPD. Patients whose emphysema is due to α₁-antitrypsin deficiency, in whom the disease occurs at an early age, may be a particularly appropriate subgroup to consider for lung transplantation.

When acute respiratory failure supervenes as a part of COPD, mechanical ventilation may be necessary to support gas exchange and maintain acceptable arterial blood gas values. Such ventilatory assistance with intermittent positive pressure may be delivered via either a mask (noninvasive positive-pressure ventilation) or an endotracheal tube. More detailed information about the treatment of acute respiratory failure superimposed on chronic disease of the obstructive variety is covered in Chapter 27. Mechanical ventilation is discussed in Chapter 29.

References