Robert A. Wise
Mark C. Liu
Obstructive lung diseases are the most common chronic pulmonary diseases encountered in ambulatory practice. Asthma, chronic bronchitis, and emphysema are the most common disorders. Chronic bronchitis and emphysema often coexist. Both are predominantly caused by tobacco smoking, so they both usually are referred to as chronic obstructive pulmonary disease (COPD). Less common conditions that lead to COPD include bronchiectasis, chronic forms of bronchiolitis, and cystic fibrosis. These disorders have different clinical presentations, causes, and prognoses, but all share the same physiologic abnormality, namely, airflow limitation.
Epidemiology
COPD is increasing in prevalence and severity throughout the world and is projected to become the fifth leading cause of disease burden worldwide by 2020 (1). Between 1979 and 1999, the mortality rate of chronic bronchitis and emphysema increased by 40%, which is notable because the all-cause death rate fell by 18% in the same period (2,3). Since then, COPD mortality in men has stabilized, whereas it continues to increase in women. Overall, COPD is the fourth leading cause of death in the United States, accounting for 120,000 deaths per year, equally distributed between men and women. Eleven million Americans alive today have been diagnosed with COPD, including three million with emphysema. The direct health care costs for COPD are $21 billion ($US) per year.
Asthma occurs at some time in approximately 11% of the general population, with 31 million Americans reporting a lifetime history of asthma and 20 million reporting currently active asthma. The disease is more prevalent among African American and Hispanic minorities, who suffer the greatest morbidity and mortality from the disease. Approximately 5,000 deaths per year are caused by asthma, occurring disproportionately in inner-city minorities. Since 1996, there has been a slow downward trend in asthma mortality (4). The direct medical costs from asthma are $9 billion per year, with approximately half resulting from hospitalization. Asthma is the most common chronic condition leading to missed school days in children, costing more than $1.4 billion dollars in indirect health costs (2).
Pathophysiologic Abnormalities in Obstructive Lung Disease
The diagnosis, severity, clinical course, and response to treatment can best be established by objective tests of lung function. How these disorders lead to chronic airflow limitation and how this limitation is measured in the ambulatory patient are discussed.
Forced Expiratory Spirometry
Obstructive lung diseases cause the lung to empty slowly during a forced expiratory maneuver. Normal people can forcefully expel all of the air that can leave their lungs (vital capacity) within 4 to 6 seconds. People with established obstructive lung disease may continue to expire during a forced expiratory maneuver for 10 to 20 seconds or more.
Forced Expiratory Vital Capacity and Forced Expiratory Volume in 1 Second
The forced expiratory vital capacity test is used to diagnose and follow the course of obstructive lung diseases.
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The test is performed by having the patient blow forcefully into a device that records the volume of air leaving the lungs as a function of time. The record of the maneuver is called a spirogram, and the test itself is called forced expiratory spirometry. Devices that record the spirogram may either measure flow directly (a pneumotachometer) and calculate volume electronically or measure volume directly (a spirometer). Many such devices are commercially available and are accurate and reliable, but it is important to ascertain that the devices meet established standards that are promulgated for either screening or diagnostic purposes (5). More common than inaccurate equipment is the inability of the technician to elicit maximum effort from the test subject. A good spirometry technician must be both enthusiastic and demanding. Although diagnostic spirometers require daily calibration, office spirometers do not (5). Anyone caring for patients with obstructive lung diseases should have ready access to spirometry. Table 60.1 lists indications for spirometry.
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TABLE 60.1 Indications for Spirometry |
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The forced expiratory maneuver is performed by having the patient take a maximal inspiration and then forcefully blow all of the air into the spirometer. A technically satisfactory maneuver is one that has a rapid onset, has a smooth contour without hesitation or coughing, and is prolonged until airflow ceases, with a minimum duration of 6 seconds. The test is repeated until three technically satisfactory maneuvers are obtained, two of which give reproducible measurements. Reproducible measurements are defined as being within 5% of each other or within 150 mL, whichever is greater (Table 60.2).
Many measures can be derived from the forced expiratory spirogram, but the most useful are FVC (forced vital capacity; total amount of air leaving the lung); FEV1 (forced expiratory volume in the first second; amount of air leaving the lung in the first second); and FEV1/FVC or FEV1% (percentage of total air leaving the lung in 1 second). The volume measures are expressed as absolute values adjusted to reflect the volume of gas at body temperature with 100% humidity (BTPS). FEV1 and FVC are compared to predicted values based on age, gender, race, and height from a healthy reference population, usually as a percent of predicted. Airflow limitation is present when FEV1/FVC is reduced below the value found in 95% of healthy nonsmokers (Table 60.3), although many people use an operational definition of FEV1/FVC <0.70. The severity of airflow obstruction is determined by the reduction in FEV1. Because diseases of airflow limitation also cause increased trapping of gas in the lung at the end of a forced expiration, FVC commonly is reduced as well. This should not, however, be confused with disorders that are associated with small lungs, the restrictive lung diseases (see Chapter 59). Despite the low FVC, the maximum gas volume of the lung—the total lung capacity (TLC) (see below)—usually is normal or increased in patients with obstructive disease. Typically, restrictive lung diseases cause an increased FEV1/FVC in combination with reduced FVC (Table 60.4 and Fig. 60.1).
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TABLE 60.2 Criteria for Good Spirometry Session |
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The degree to which airflow limitation can be reversed rapidly is measured by performing spirometry before and after treatment with an inhaled bronchodilator. A positive response of either FEV1 or FVC to bronchodilators is defined as a >12% increase above baseline and an increment of at least 200 mL. Although this test is helpful in determining the potential for improvement when there is a rapid response to inhaled bronchodilators, many patients without a rapid response show improvement after several weeks or months of treatment with bronchodilators or anti-inflammatory agents.
Patient Experience
Forced expiratory spirometry can be safely and accurately performed on people with normal lung function as well as those with advanced lung disease, even those who are critically ill. After a nose clip is attached, the patient inspires deeply and then forcefully expires for approximately 6 seconds. Because of the high pleural pressures, patients occasionally experience light-headedness during the maneuver. This can be minimized by having the patient sit during the test. Some patients experience soreness of the chest wall or abdomen for 1 to 2 days after the test, although analgesics are rarely needed.
Flow–Volume Loops
Forced expiratory airflow is high during the initial part of expiration and gradually falls to zero throughout the maneuver. The forced expiratory maneuver can be plotted as flow in relation to volume. If this is also done during a forced inspiration, the resultant display is called a flow–volume loop. Flow–volume loops can be readily calculated
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and displayed with small computers attached to flow or volume measuring devices. The flow–volume loop does not give information about the presence of obstructive airway disease that is not present in the traditional volume–time tracing of the spirogram and does not allow the easy hand measurement of FEV1 that can be done with volume–time tracings. The flow–volume loop is useful for detecting upper airway disorders that affect the early portions of the forced expiration or that impede forced inspiration. Such disorders include laryngeal tumors, tracheal stenosis, and vocal cord paralysis (Fig. 60.2). Because these disorders of the upper airway may mimic the dyspnea and wheezing of obstructive lung diseases and because they are potentially curable, the flow–volume loop can provide important information when the diagnosis is uncertain.
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TABLE 60.3 Predicted Normal and Lower Limits of Normal FEV1/FVC for 68-Inch Tall Person |
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Other Lung Function Tests
Ordinarily, tests of lung function other than spirometry are not feasible to implement in the clinic or office setting and require referral to a pulmonary function laboratory. They are mainly helpful in the initial diagnostic evaluation of patients with lung disease.
Measurement of lung volume by helium dilution, nitrogen washout, or body plethysmography are helpful tests to establish the diagnosis of obstructive lung disease. TLC usually is increased (hyperinflation), as is the residual volume (air trapping), in both emphysema and acute asthma. In contrast, restrictive disorders such as sarcoidosis, asbestosis, or interstitial pulmonary fibrosis cause reduction in lung volume. Because helium dilution and nitrogen washout measure lung volume only in units of lung that are well ventilated, they tend to underestimate the true lung volume in people with emphysematous bullae or acute asthma with air trapping. Body plethysmography, which measures compressible gas volume in the chest, is more accurate in these conditions but, because of the expense and technical difficulty of this measurement, often is unavailable. In most circumstances, the dilution or washout methods provide sufficient accuracy to distinguish obstructive lung diseases from restrictive lung diseases.
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TABLE 60.4 Interpretation of Spirometry |
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Patient Experience (Lung Volume Measurements)
With the helium dilution and nitrogen washout methods, the patient quietly breathes either a mixture of helium and oxygen or pure oxygen for 5 to 7 minutes. Because these tests require complete collections of expired gas, the patient must be able to form a tight seal around a mouthpiece. After the resident gas in the lung (functional residual capacity [FRC]) is measured, the patient performs two or three slow vital capacity maneuvers for calculation of the subdivisions of lung volume.
With the body plethysmography method, the patient sits in a tightly sealed box, approximately the size of a small closet, and breathes through a mouthpiece. At intervals, the technician closes a shutter on the mouthpiece and instructs the subject to perform a panting maneuver against the closed mouthpiece. The test is safe and painless, although occasionally individuals find the box too confining. After the resident compressible gas in the lung is measured (thoracic gas volume [TGV]), the patient performs several slow vital capacity maneuvers.
Measurement of the diffusing capacity (of lung) for carbon monoxide diffusing capacity (DCo) by the single-breath
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method measures the effective area of the alveolar–capillary membrane available for gas transfer. Because of the destruction of alveolar septa, DCo is reduced in emphysema. The magnitude of reduction in DCo is correlated with the physiologic severity of emphysema, as well as the amount of emphysema found in high-resolution computerized tomographic scans of the chest (6).
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FIGURE 60.1. Spirographic tracings of forced expiration. Exhaled volume is plotted against time. A: Normal spirogram. B: Spirogram from a patient with mild obstructive airway disease. C: Spirogram from a patient with severe obstructive defect. If the spirogram were incorrectly terminated after 2 seconds, FVC would be artificially reduced (see text). When it is performed correctly (dotted lines), it is obvious that there is airway obstruction and that there is no restrictive disease. D: Spirogram showing restrictive pulmonary disease (FEV1/FVC is normal but FVC is reduced). FEV1, forced expiratory volume in the first second; FVC, forced vital capacity (total volume expired). |
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FIGURE 60.2. Flow–volume curves (loops) of maximal forced expiration (upper) and maximal inspiration (lower). Expiratory and inspiratory flow is plotted against lung volume expressed as a percentage of vital capacity. The dotted line can be used to compare flow rates at 50% of vital capacity, where inspiratory flow rates normally exceed expiratory flow rates. A: Normal flow–volume curves. B:Flow–volume curves illustrating expiratory airflow obstruction showing decreased flow rates at all points in lung volume throughout maximal expiration. C: Fixed extrathoracic airway obstruction (cancer or stenosis of the larynx) produces a pattern where there is a decrease and flattening of both inspiratory and expiratory flow–volume curves. Inspiratory flow rate at 50% of vital capacity is equal to similar expiratory flow rate. D: Variable extrathoracic obstruction (vocal cord paralysis) produces a pattern where there is a decrease and flattening of maximal inspiratory flow–volume curves. Inspiratory flow rates at 50% of vital capacity are less than similar expiratory flow. (Modified from Hyatt RE, Black LF. The flow-volume curve: a current perspective. Am Rev Respir Dis 1973;107:191 , with permission.) |
Because DCo also is reduced in diseases that affect the interstitium of the lung (e.g., pulmonary fibrosis and sarcoidosis) and diseases that affect the pulmonary blood vessels (e.g., pulmonary emboli and pulmonary arterial hypertension), a reduction in DCo must be interpreted in the context of other lung function tests and clinical findings. Because DCo often is elevated in asthma and is decreased in emphysema, it helps to determine the degree of reversibility of lung function that can be expected. When the diffusing capacity is <50% to 60% of the predicted value, approximately half of the individuals with obstructive lung disease have oxygen desaturation with exercise and may benefit from supplemental oxygen (7). When DCo exceeds 60% of predicted, oxygen desaturation with exercise is uncommon.
Patient Experience (Diffusing Capacity)
The patient takes in a full vital capacity breath of gas containing a small concentration of carbon monoxide and holds his or her breath for 10 seconds. The maneuver is conducted two or three times to obtain reproducible measurements. The amount of carbon monoxide taken up does not cause appreciable increases in carboxyhemoglobin, and the test can be safely performed on patients who are anemic or who have coronary artery disease.
The expired alveolar air is analyzed to determine the rate of uptake of carbon monoxide. The test requires a 10-second breath-hold and approximately 1 L of vital capacity to collect an accurate sample of alveolar gas. Therefore, those who are unable to hold their breath because of dyspnea or coordination or who have <1 L of vital capacity often cannot perform this test.
Mechanisms of Airflow Limitation
Because the common finding of this group of diseases is a reduction in forced expiratory airflow, it is important to understand the mechanism by which this reduction occurs. During forceful expiration, the pleural pressure rises around both the alveoli and the conducting airways. The pressure in the alveoli is slightly higher than the pleural pressure because the lung has elastic properties that tend to compress the alveolar gas, similar to an inflated latex balloon. This pressure difference between the alveoli and the pleural space is called the elastic recoil pressure and is equal to the distending pressure that prevents collapse of the alveolus. During expiration, the pressure near the alveoli is close to alveolar pressure but falls along the length of the airways because of the airway resistance. As pleural pressure is increased, the expiratory flow increases and the pressure drop along the airway becomes greater. When the pressure in the airway falls below a critical level with respect to the surrounding pleural pressure, the condition of flow limitation occurs. Under the condition of flow limitation, further increases in pleural pressure do not increase airflow. The precise mechanism by which flow limitation occurs is not fully understood, but it has been hypothesized that there is development of a narrowing at a site in the airway that acts like a nozzle or a fluttering of the airway that creates turbulence.
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TABLE 60.5 Mechanisms of Airflow Limitation |
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Although what occurs at the site of flow limitation in the airway is not exactly understood, the general pathophysiologic processes that lead to reduced flows during forced expiration are known (Table 60.5). Everyone has flow limitation during a forced expiration, but people with obstructive airway disease demonstrate flow limitation with less effort and at lower airflow. The three lung abnormalities that reduce flow during forced expiration are decreased lung recoil pressure, increased resistance of the airways, and increased tendency of airways to collapse. Decreased lung recoil pressure causes a lower distending pressure between the airway and the surrounding pleural pressure, thereby promoting the tendency of the airways to narrow. Increased resistance of the airways, particularly in the periphery of the lung, causes increased pressure drops along the airways during expiration, promoting the tendency of the airways to narrow. Increased airway collapsibility caused by bronchial smooth muscle constriction, inflammatory products encroaching upon the airway lumen, and decreased tethering of the airway by the alveolar septa also cause airways to collapse more easily.
In general, the airflow limitation in emphysema can be attributed to the decreased elastic recoil of the lung, airflow limitation in chronic bronchitis to increased peripheral airway resistance, and airflow limitation in asthma to the increased tendency of airways to collapse. Although all of these disorders are classified as obstructive lung
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diseases, it must be emphasized that physical obstruction of the airways is not the only mechanism causing reduced forced expiratory flow.
Asthma
Definition
Asthma is a disorder characterized symptomatically by cough, chest tightness, shortness of breath, and wheezing associated with limitation of airflow. The symptoms may be acute and episodic, or they may wax and wane over long periods. One or more of the symptoms may be dominant, but usually all are present. The airflow obstruction is variable and may return to the normal range between exacerbations. Between episodes, most asthmatics are symptom free, but they are susceptible to attacks of wheezing, cough, and chest tightness when exposed to various “triggers.” Table 60.6 lists common triggers for asthma attacks. Nearly all asthmatics with active disease have inflammation of the airways and bronchial hyperreactivity (8).
Approximately one in 14 residents of the United States currently has active asthma, and approximately one in 10 had asthma at some time in their lives. Approximately half of the asthmatics in the United States have disease onset during childhood. In the prepubertal age group, the disease is more common in males, whereas the reverse is true for adults. Approximately half of the children with asthma will have spontaneous resolution of their disease by young adulthood, although the disease may recur in the third or fourth decade.
Most childhood asthmatics have an allergy to common aeroallergens, and chronic allergic exposure is considered a potential underlying cause in the development of childhood asthma as well as an exacerbating trigger. In the older population, specific allergies are not as tightly linked to the presence of asthma, although those with allergies are more likely to have asthma than those without allergies (9).
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TABLE 60.6 Common Triggers for Asthma |
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Pathophysiology
Airway Reactivity
In asthmatics, bronchospasm can be induced by allergic, irritant, or physicochemical stimuli. This increased tendency to have bronchospasm is synonymously called bronchial reactivity, airway reactivity, bronchial hyperreactivity, or bronchial hyperresponsiveness. This characteristic is defined by exaggerated declines in lung function after inhalation challenge with nonspecific bronchoconstrictor agents such as methacholine and histamine, with physical agents such as cold dry air ventilation and exercise-induced hyperpnea, or specific allergenic agents such as inhaled antigens.
Virtually all asthmatics with active disease display airway reactivity, and the degree of reactivity correlates roughly with the severity of asthma. Approximately one in eight individuals without clinical asthma also shows laboratory evidence of airway reactivity. Most smokers with mild chronic obstructive lung disease without clinical evidence of asthma have airway reactivity (10). Therefore, laboratory evidence of airway reactivity is not by itself diagnostic of asthma. However, testing for airway reactivity is useful when a negative result can rule out the diagnosis of active asthma. This is particularly useful in the person with chronic persistent cough (see Chapter 59), episodic unexplained dyspnea (see Chapter 59), or occupationally associated respiratory symptoms. Although the testing procedure for airway reactivity is not complex, it is not performed on a regular basis except in specialty clinics and therefore usually requires referral to a pulmonary function laboratory.
Patient Experience (Airway Reactivity Testing)
The testing procedure is safe if the baseline level of lung function is no more than moderately impaired (FEV1 ≥60% predicted). Before the test, the patient should not use oral theophylline for 48 hours, short-acting inhaled bronchodilators for 8 hours, or long-acting inhaled bronchodilators for 24 hours. Oral or inhaled corticosteroids or other anti-inflammatory drugs can be continued. The patient breathes increasing concentrations of methacholine, through either repeated vital capacity breaths or quiet tidal breathing. After each concentration, spirometry is performed. When the FEV1 falls by ≥20% or the highest concentration is reached, the test is terminated and the bronchoconstriction is reversed with an inhaled bronchodilator. When conducted in a supervised setting, the test is safe, although some people with reactive airways experience coughing or chest tightness (11).
Specific airway inhalation challenge with antigen rarely is needed for clinical purposes unless it is absolutely necessary to document whether a specific agent exacerbates asthma, such as a work-related exposure where employment decisions must be made. However, the response to
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specific antigen challenge does give insight into the pathogenesis of chronic asthma. After inhalation of an antigen of sufficient dose, acute bronchoconstriction lasts for 20 to 60 minutes, the early phase reaction. Left untreated, this early bronchospasm resolves within 1 to 2 hours, although it may be reversed earlier with inhaled bronchodilators. Approximately 4 to 24 hours later, however, bronchospasm recurs in less than half of allergic people. It is generally thought that the early-phase reaction is the result of bronchial smooth muscle constriction but that the late-phase reaction is the consequence of inflammatory cell recruitment with consequent airway mucosal edema and bronchoconstriction.
Exercise-induced bronchospasm is present in nearly all asthmatics if challenged sufficiently. Following cessation of vigorous exercise, normal individuals show a small amount of bronchodilation. In contrast, susceptible asthmatics develop bronchoconstriction 5 to 20 minutes after stopping exercise. Similar responses can be elicited by breathing cold, dry air. Postulated causes for exercise-induced bronchoconstriction include increases in the osmolality of the airway fluid lining layer because of drying of the airways causing release of inflammatory mediators, direct response of the airways to cooling during exercise hyperpnea, and vascular engorgement of the bronchial mucosa (12,13). Exercise-induced bronchospasm can be effectively prevented by pretreatment with an inhaled β2-adrenergic agonist, a leukotriene inhibitor, or a mast-cell stabilizer such as nedocromil. If a patient does not report improvement of exercise-induced symptoms with β agonists, pretreatment exercise-induced bronchospasm usually is not demonstrated on formal testing (14).
Patient Experience (Exercise Bronchoprovocation)
The patient should avoid bronchodilators in the same fashion as for methacholine challenge testing and leukotriene antagonists and mast-cell stabilizing agents such as cromolyn or nedocromil for 24 hours. The patient exercises on a bicycle ergometer or treadmill to tolerance. After stopping exercise, spirometry is performed several times for the following 30 minutes. If bronchospasm occurs, it is reversed with an inhaled bronchodilator (11).
Airway Inflammation and Remodeling
The mechanisms that cause nonspecific airway reactivity are not completely understood; however, it is now recognized that airway inflammation is linked to the presence of airway reactivity. Even mild asymptomatic asthmatics show submucosal infiltration with neutrophils, eosinophils, monocytes, T lymphocytes, and mast cells; edema; vascular engorgement; subepithelial collagen and fibronectin deposition; and epithelial desquamation. Patients with more long-standing asthma show hyperplasia of smooth muscle, goblet cell metaplasia, and mucous gland hypertrophy. It is thought that the chronic changes in airway morphology contribute to the nonreversible changes in lung function found in long-standing asthmatics (15,16).
Numerous theories explaining how airway inflammation leads to airway reactivity and remodeling have been advanced. It is likely that asthma is the common expression of several mechanisms or that one mechanism is predominant in some situations but not others. Whatever the mechanism, there is strong evidence that treatment of the underlying airway inflammation can reduce airway reactivity and improve asthma symptoms (17). There is no evidence, however, that anti-inflammatory treatment can prevent remodeling of the airways and improve long-term lung function (18).
Pathophysiology of the Acute Asthmatic Attack
The acute asthmatic attack may occur suddenly as a consequence of exposure to an allergic or irritant substance producing severe bronchospasm in an individual with previously well-controlled asthma and normal lung function. More commonly, the attack occurs after many days of progressive reductions in lung function, increasing lability of lung function, progressive exertional dyspnea and cough, nocturnal awakening, and increasing requirements for symptomatic use of inhaled bronchodilators.
During the acute attack, bronchospasm, mucosal edema, and mucous plugging lead to narrowing and closure of small peripheral airways. This causes an increase in resistance to inspiratory and expiratory airflow and, more important, trapping of air. The patient must breathe at high volume to keep the airways open. The consequences of this hyperinflation are increased work of breathing, impaired mechanical advantage of the shortened respiratory muscles and of the flattened diaphragm, pulmonary hypertension, and markedly negative inspiratory swings in pleural pressure to initiate airflow. If the attack is severe or prolonged, respiratory muscle fatigue can occur with consequent hypoventilation, carbon dioxide retention, hypoxemia, respiratory failure, and death. Arterial blood gas tensions in nonsevere asthma attacks usually show hypocapnia from hyperventilation. A normal arterial carbon dioxide tension may indicate either resolution of the attack or impending respiratory failure and therefore must be correlated with other clinical features. Ventilation–perfusion mismatch accounts for the hypoxemia that accompanies an asthma attack; however, treatment with β-adrenergic bronchodilators usually worsens ventilation–perfusion matching, causing transient worsening hypoxemia as the asthma attack improves. Resolution of the attack often is preceded by expectoration of copious secretions with small mucous plugs. As the attack resolves, dyspnea and chest tightness disappear before wheezing
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resolves, whereas abnormalities of lung function can persist for many days or weeks.
Clinical Presentations
Clinical presentations of asthma differ with regard to chronicity and inciting factors. There is broad overlap between these categories of asthma, and they should not necessarily be considered to have differing underlying mechanisms.
Extrinsic or allergic asthma is a condition in which worsening of the asthma can be clearly associated with exposure to a specific allergen (Table 60.6). In >80% of cases, allergic asthma is associated with allergic rhinitis. The most common perennial allergens associated with worsening of asthma include molds (particularly Alternaria), house dust mite feces, cockroach trailings, cat secretions, and mouse feces (19,20). The most common seasonal allergens are ragweed (autumn), tree pollen (spring), and grass pollens (summer). Diagnosis of a specific allergen triggering asthma requires a history of worsening asthma after exposure, improvement of the asthma when the allergen is removed, and positive wheal and flare reaction to the offending agent on allergy skin testing. Clear association of asthma with a specific allergen is important because control of environmental exposure or specific immunotherapy can be time consuming, expensive, or impractical. When an aeroallergen is clearly associated with asthma symptoms, immunotherapy with weekly allergy injections may lead to mild, although transient, improvement in the disease (21). In most cases, however, asthma is adequately treated in the absence of immunotherapy (22). When allergic asthma is severe and does not respond to usual treatments, maintenance treatment with monoclonal antibodies to immunoglobulin (Ig)E (i.e., omalizumab [Xolair] 150–375 mg by subcutaneous injection every 2–4 weeks based on body weight and IgE level) may be helpful (23,24).
Intrinsic or nonallergic asthma is a condition in which there is no clear association with specific allergen exposure. This form of asthma is more common in adults than in children, and it is more common in women than in men. Typically, the asthma symptoms are perennial. Acute episodes may be triggered by viral illnesses, but often no specific provocative stimulus can be found. In approximately half of the cases, the asthma persists or worsens throughout life, leading to incompletely reversible abnormalities of pulmonary function. When this is associated with chronic cough and sputum production, it often is called chronic asthmatic bronchitis and may be difficult to distinguish from smoking-related chronic obstructive lung disease. The cause of this form of asthma is unclear. Many patients show some traits of allergic tendencies with elevation of serum IgE levels and eosinophilic airway inflammation, but allergy skin testing is negative. In some cases, it appears that the onset of disease followed a severe lower respiratory tract viral infection, whereas in others it may be associated with long-term exposure to specific allergens or respiratory irritants.
Occupational asthma (see Chapter 8) is a condition in which a specific occupational exposure leads to cough, wheezing, and chest tightness. If exposure to the offending antigen persists, a chronic asthmatic condition with sensitivity to nonspecific agents may occur. If exposure to the sensitizing agent is stopped soon enough, symptoms and nonspecific airway reactivity often resolve, although it may take up to 2 years. Because the prognosis for remission is better in those who cease exposure early, the treating clinician needs to diagnose occupational asthma early and initiate steps to avoid continued exposure (25). Table 60.7 lists common substances that may cause occupational asthma.
Reactive airways dysfunction syndrome (RADS) is a disorder that follows an intense short-term exposure to a toxic, nonallergenic substance, such as sulfuric acid, nitric acid, chlorine, or hydrochloric acid fumes. After the exposure—often the result of an industrial accident or fire—and resolution of the resultant acute lung injury, the individual is left with chronic airway reactivity to nonspecific physicochemical agents such as tobacco smoke or cold air. The disorder may resolve after several months but can lead to chronic airway reactivity (26).
Exercise-induced bronchospasm is present in most asthmatics, although some children and young adults experience asthma only after exercise. Although this syndrome may be confused with exertional dyspnea or angina, careful questioning will reveal that the dyspnea occurs after a 5- to 20-minute symptom-free interval after the cessation of exercise. Exercise-induced bronchospasm is thought to be caused by airway cooling and drying leading to hyperosmolar airway lining fluids and release of bronchoconstrictor and vasodilator mediators (13). For this reason, exercise-induced bronchospasm often is worse in cold, dry environments whereas warm, humid environments, such as indoor swimming pools, often are well tolerated. The symptoms can be prevented by inhalation of a β-agonist bronchodilator or nedocromil approximately 20 minutes before exercise or by regular use of a leukotriene antagonist (see below for a discussion of these agents).
Triad asthma (Samter syndrome) is a syndrome of nasal polyps, asthma, and aspirin sensitivity. One of three asthmatics with nasal polyps has aspirin sensitivity, in comparison to one in 15 asthmatics without nasal polyps. These individuals often have severe chronic asthma and occasionally experience systemic anaphylactic reactions to aspirin or aspirinlike compounds, including nonsteroidal anti-inflammatory drugs (NSAIDs) (27). Even asthmatics who are aware that they are sensitive to aspirin (10% of asthmatics) may inadvertently use compounded drugs that contain aspirin (see Chapter 30 for a list of common medicines that contain aspirin). The mechanism
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by which this occurs is thought to involve blockade of cyclooxygenase-derived prostaglandins and the induction of lipoxygenase-derived leukotrienes from inflammatory cells. The asthma may improve with surgical removal of the nasal polyps, but the polyps often recur and require long-term topical or systemic corticosteroid treatment. If aspirin is required for treatment of another condition, rapid desensitization can be performed, but daily maintenance doses of aspirin are required to sustain the effect. Aspirin-sensitive asthma is an indication for use of leukotriene antagonists or inhibitors such as montelukast, zafirlukast, or zileuton because increased leukotriene production is a prominent feature of this syndrome. Specific cyclooxygenase-2 inhibitors appear to be well tolerated by patients with aspirin sensitivity, likely because of the lack of effect on the constitutive form of cyclooxygenase (28,29). Some epidemiologic evidence also suggests that acetaminophen use may be associated with asthma. However, in most people with asthma, acetaminophen is a safe analgesic and should be avoided only in individuals who demonstrate an association of its use with worsening asthma symptoms (30).
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TABLE 60.7 Occupational Exposures Causing Asthma |
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Cough-variant asthma is a condition in which wheezing, dyspnea, and chest tightness are minimal symptoms, but chronic cough is the major complaint. Approximately 30% of patients with chronic persistent cough for >8 weeks have airway reactivity and respond to treatment with bronchodilators and corticosteroids (31,32).
Allergic bronchopulmonary aspergillosis (ABPA) is an uncommon form of asthma that is difficult to treat and can lead to chronic respiratory failure. The disorder is caused by local allergic reaction to noninvasive Aspergillus or to other fungal species colonizing the airway.Aspergillus fumigatus, a ubiquitous saprophyte, is the most common organism, but other fungi can cause the syndrome. The chronic inflammatory condition leads to dilation and bronchiectasis of the central airways, recurrent mucous plugging and segmental atelectasis, and eventually fibrotic destruction of lung parenchyma. Criteria for the diagnosis of ABPA include recurrent atelectasis and pulmonary infiltrates; radiographic evidence of proximal bronchiectasis or mucoid impactions, blood, and sputum eosinophilia; immediate skin test reactivity toAspergillus; serum precipitins to Aspergillus; elevated serum IgE; and specific IgG and IgE antibodies to Aspergillus by radioallergosorbent test (RAST) or enzyme-linked immunosorbent assay (ELISA) testing (see below). Individuals with variants of the cystic fibrosis transmembrane regulator gene and certain HLA-DR genotypes are predisposed to develop ABPA (33,34).
The usual treatment for ABPA consists of systemic corticosteroids with starting dosages of 0.5 to 1.0 mg/kg/day of prednisone or equivalent. At least 6 months of therapy usually is required, but many patients are never able to tolerate permanent steroid cessation. Inhaled or systemic antifungal therapy is not helpful in eradicating the offending agent, although evidence indicates that long-term treatment with oral agents such as itraconazole may permit a reduction in the steroid dose (35,36). Early diagnosis and treatment are necessary to prevent the progressive bronchiectasis and lung fibrosis that can occur. The effectiveness of therapy is monitored with serum IgE levels and chest x-ray films. Because ABPA is found in approximately 10% of cystic fibrosis patients, the clinician should consider screening for cystic fibrosis with sweat chloride concentrations or genetic analysis in patients with ABPA.
Refractory or severe asthma is defined as dyspnea, wheezing, and frequent exacerbations despite maximum
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therapy with bronchodilators and inhaled and systemic corticosteroids (37). When symptoms are intractable, the possibility should be considered that a condition that mimics asthma (see below) is present. Other circumstances that may contribute to intractable asthma include an occult persistent exposure to an allergen or irritant at home or at work, use of β-blockers either systemically or as eye drops, use of aspirin or related drugs, exposure to dietary chemicals such as sulfites, hypothyroidism or hyperthyroidism, gastroesophageal reflux, sinusitis, bronchopulmonary aspergillosis, and mucocutaneous fungal infection. However, the most likely cause of intractable asthma is nonadherence to prescribed treatment, a behavior that often is underestimated (38). When aggravating factors are eliminated, some patients still have episodes of life-threatening asthma. The inflammatory profile in these patients is quite variable; some exhibit persistent airway eosinophilia whereas others show neutrophilia or little cellular inflammation (39).
Catastrophic asthma occurs in individuals who experience rapid deterioration of asthma with fatal or near-fatal consequences. In most cases this occurs in people with severe underlying disease, but it can occur in those without such a history. The severity of the attack often is not recognized by the patient or caregiver, and the ability to predict such events is poor. Approximately one third of fatal asthma attacks are preceded by recurrent hospitalizations, but only one of 20 is preceded by previous near-fatal attacks. The prognosis of patients who had a near-fatal attack of asthma is poor, with 10% dying within 1 year (40).
A wheezing condition not due to asthma may be confused with asthma, often as an intractable case, by the patient or clinician. Such conditions include congestive heart failure, mitral stenosis, cystic fibrosis, immotile cilia syndrome, immunoglobulin deficiency, laryngeal tumors, vocal cord paralysis, laryngospasm, airway foreign body, hypereosinophilic syndromes, endobronchial sarcoidosis, bronchiolitis obliterans, Churg–Strauss vasculitis, multiple pulmonary emboli, reaction to angiotensin-converting enzyme inhibitors, pertussis, and diphtheria. A common disorder mimicking severe episodic asthma is paroxysmal vocal cord dysfunction syndrome, where inspiration is accompanied by paradoxical closure of the vocal cords. Careful examination may allow differentiation of upper airway conditions from asthma. Upper airway obstructions cause monophonic (i.e., single-pitch) inspiratory or inspiratory–expiratory high-pitched sounds (stridor) heard loudest over the central airways. In contrast, asthmatic wheezing causes polyphonic expiratory sounds that are heard loudest over the chest. When there is a question of upper airway obstruction, laryngoscopy and flow–volume loops should be obtained, particularly during a symptomatic episode. A variant of paroxysmal vocal cord dysfunction is the “irritable larynx” syndrome, which is characterized by severe episodes of cough, stridor, and dysphonia. This syndrome may follow exposure to an inhaled irritant or a viral syndrome and often is exacerbated by gastroesophageal reflux and anxiety (41). Another common disorder that is sometimes confused with asthma is the syndrome of “sighing dyspnea” or “functional dyspnea.” The characteristic presentation of this syndrome is the episodic sensation that a deep breath is not adequately refreshing or that the lungs cannot expand enough. In contrast to most intrinsic lung disorders, the symptoms are relieved by exercise. In some cases, particularly if it occurs in a background setting of asthma or if the symptoms are described as chest tightness and associated with anxiety, sighing dyspnea can be misdiagnosed as asthma (42).
Evaluation of Chronic Asthma
Medical History and Clinical Interview
A thorough medical history is essential for establishing the diagnosis of asthma and for guiding treatment. The following factors should be evaluated: duration, frequency, and severity of attacks; seasonal variation of disease; specific triggers; occupational and recreational exposures; home conditions; other allergic conditions; and medication use and adherence.
Asthmatics describe their episodic shortness of breath differently than do patients with other forms of lung disease or heart failure. Asthmatics use terms such as chest tightness and wheeziness rather than air hunger, suffocation, or rapid breathing. Asthmatics often say the site of obstruction is in their neck. They tend to report more difficulty with inspiration than expiration, in contrast to patients with emphysema, who cannot distinguish inspiratory from expiratory distress (43,44).
Asthma should not be considered well controlled if patients have more than occasional requirement for symptomatic use of inhaled bronchodilators or experience nocturnal awakening with symptoms. The presence of nocturnal symptoms is such a characteristic feature of asthma that the absence of this history should stimulate the investigation of other causes of episodic wheezing and chest tightness. Although pollen seasons and common aeroallergens vary geographically, asthma that is worse in the early fall suggests ragweed allergy; worse in the summer, grass pollen allergy; and worse in the spring, tree pollen allergy. Specific asthma triggers (Table 60.6) should be elicited. Because the symptoms of asthma may follow an allergic exposure by 2 to 24 hours, elicitation of such exposures requires careful questioning or the maintenance of a prospective asthma diary recording exposures, symptoms, and peak flow. Occupational exposures may be obvious (Table 60.7) but also can occur from operations in an adjacent workspace or via ventilation systems. Supportive evidence of an occupational trigger exposure is the absence of symptoms on weekends and during vacations. Occasionally
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a worksite inspection performed by an expert in occupational medicine is necessary (see Chapter 8).
In cases where the importance of home exposure is unclear, the patient should be questioned about whether the asthma worsened upon moving to a new home and whether it improves during periods away from home. Perennial allergen and irritant exposures at home contribute to the chronic airway inflammation that causes asthma, particularly in children. House dust mites feed on desquamated human skin and produce allergenic feces that are easily respirable. Dust mites thrive in humid, warm environments, particularly feather pillows, comforters, carpets, upholstered furniture, and mattresses. Cockroaches and their excreta are highly allergenic. Pets, particularly cats and dogs, secrete antigen in their saliva that may persist in the home environment many years after the pets are no longer present. Frequent vacuuming, although useful in eliminating home allergens, also disperses antigen into the air for several hours. Smokers in the home also disperse irritant sidestream smoke that worsens asthma. Humidifiers or other causes of high ambient humidity promote the growth of molds as well as of dust mites. Some exposures may be difficult to uncover. Urea–formaldehyde foam insulation can cause low-level irritant exposure that is a potential aggravator of asthma. Newly varnished floors or furniture can give off isocyanate fumes that worsen asthma. Toluene diisocyanate (TDI) exposure can trigger severe asthma in those who use polyurethane paint or varnish (45). Heavy mold exposure occurs in those who engage in water sports or boating. Seminal fluid allergy can rarely occur in those who have coitus (46).
Knowledge of associated allergic conditions is helpful. Histories of allergic rhinitis, eczema, and urticaria can assist in determining specific asthma triggers and would support more specific therapies directed toward those allergens. Chronic allergic or infectious sinusitis can exacerbate asthma, and symptoms or sinus pain or drainage should be elicited (47).
Gastroesophageal reflux, often otherwise asymptomatic, may trigger nocturnal asthma either through reflex distention and irritation of the esophagus or through aspiration of gastric contents into the larynx and lower airways (48, 49, 50). Tartrazine (yellow dye no. 5) is found in yellow or orange foods, particularly powdered orange juice substitutes. Although tartrazine once was thought to be a common cause of asthma in aspirin-sensitive individuals, true tartrazine sensitivity now is considered to be exceedingly rare (51). Sulfites, present in dried fruits, wines, processed potatoes, seafood, and salad greens, can cause acute asthma attacks. The mechanism is thought to be associated with production of sulfur dioxide. Although some patients attribute asthma symptoms to ingestion of monosodium glutamate, sometimes found in Asian cooking or snack foods, this trigger rarely can be verified objectively (52). It should not be assumed that asthmatics do not smoke cigarettes. As many as 30% of asthmatics are cigarette smokers. Evidence indicates that cigarette-smoking asthmatics receive less benefit from inhaled steroids and leukotriene antagonists. Air pollution (particularly respirable particulates, ozone, SO2, and NO2) has been implicated as an exacerbating factor for asthma during atmospheric inversions in the summer (53,54).
Only approximately 50% of asthmatics adhere to their prescribed drug regimen, often without admitting this to the treating practitioner. Adherence worsens as the drug program becomes more complex, and there is less adherence with drugs that prevent but do not relieve symptoms (55). It is important to elicit in a friendly and supportive manner whether the patient actually is following the prescribed program. This can be aided by questions such as, “How often do you have difficulty taking your medications on a routine basis?” or “What problems have you had in taking your medicines?” Barriers to adherence (see Chapter 4) include failure to accept or understand the benefit and purpose of medication and environmental controls, the high cost of drugs and supplies, frequent dosing of multiple drugs, side effects of treatment, and disorganized, stressful living conditions. These elements need to be explored and modified when possible.
Obesity is a risk factor for the development of asthma, particularly in women. The pathophysiologic link between asthma and obesity is not known but may be related to mechanical effects of obesity preventing periodic dilation of airways with tidal breathing, production of inflammatory adducts by adipose cells, or predisposition to gastroesophageal reflux (56).
Physical Examination
Physical examination of the patient with asthma should be directed toward confirming the diagnosis, estimating the severity of disease, evaluating related conditions, and ruling out other disorders that mimic asthma.
During an acute asthmatic attack, the patient appears frightened and fatigued. The respiratory pattern is deep and slow with a prolonged expiratory phase but may progress to rapid shallow breathing with expiratory grunting that heralds the onset of respiratory failure. Speech is telegraphic or absent. Coughing is ineffective. The chest appears hyperinflated, with reduced tidal expansion compared to the strong respiratory efforts. The sternomastoid muscles are contracted with each inspiration during severe episodes. Hyperinflation of the lungs causes the lower lateral rib cage to move inward with each inspiratory contraction of the flattened diaphragm rather than outward as normally occurs. Tachycardia is present, with weakening of the pulse during inspiration. An inspiratory fall in systolic blood pressure (pulsus paradoxus) of >15 mm Hg is present in severe attacks but may disappear with the onset of respiratory failure (57). The chest has diffuse
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polyphonic expiratory wheezes, but in the most severe attacks may be silent. Inspiratory wheezing suggests the presence of upper airway obstruction, whereas localized or monophonic wheezing suggests mechanical bronchial obstruction from tumor or foreign body. Absent breath sounds in one hemithorax with wheezing in the other should raise the possibility of pneumothorax, a potentially lethal complication.
In chronic asymptomatic asthma, the chest examination often is normal. The presence of mild airflow obstruction can be determined by listening for wheezes during a forced expiration. However, this finding is neither sensitive nor specific for asthma. Associated allergic rhinitis causes the nasal mucosa to be pale and edematous. Nasal polyps appear as tan–gray mucoid lesions that obstruct the nasal aperture.
Examination should be directed at disorders that mimic asthma. Listening over the neck during forced inspiration or with the arm extended over the head can bring out inspiratory stridor with upper airway obstruction. Findings of congestive heart failure, such as chest crackles, cardiomegaly, or mitral regurgitation, should be carefully evaluated. High-pitched monophonic localized inspiratory squeaks suggest the presence of bronchiolitis.
Laboratory Testing
Spirometry (see above) should be performed in all asthmatics in the asymptomatic phase and periodically during the course of therapy to establish a baseline severity and to monitor therapy. Persistent abnormalities of pulmonary function, which form the basis for recurrent attacks of asthma, are present in the asymptomatic phase. The chest x-ray film usually is normal in asymptomatic asthma but shows hyperinflation during acute attacks. ABPA shows characteristic central bronchiectasis and ovoid shadows that are signs of mucus impaction. During severe acute asthma attacks, pneumothorax or pneumonia may require specific treatment. Peripheral blood eosinophilia is common in the patient with asthma, particularly if the patient is not receiving corticosteroids. Microscopic examination of unstained sputum can distinguish eosinophils from neutrophils in the presence of purulence, guiding the need for corticosteroids versus antibiotics. In severe corticosteroid-treated asthma, however, neutrophils may predominate in the absence of bacterial infection (58). Other features characteristic of asthmatic sputum are Charcot–Leyden crystals, which are spear-shaped crystals derived from eosinophil granules;Curschmann spirals, which are mucous casts of small airways; and Creola bodies, which are clumps of desquamated ciliated epithelial cells.
Skin testing for specific allergens is helpful for diagnosing specific allergies, particularly when environmental control procedures are costly or difficult, such as changing occupations or residences or eliminating a beloved pet. However, positive allergy skin tests do not indicate allergy to a particular substance as the cause of asthma unless there is a compatible history. RASTs measure allergen-specific IgE in the blood and may be substituted for skin testing. Total serum IgE is elevated in asthma but is useful mainly for diagnosis and monitoring of ABPA (see above). Methacholine challenge is helpful when the diagnosis of asthma is uncertain. A normal methacholine challenge in a symptomatic person virtually eliminates the diagnosis of active asthma. Flow–volume loops and nasopharyngoscopy are useful tests for determining whether vocal cord dysfunction is mimicking asthma.
Treatment
The goals of asthma treatment are to keep the patient symptom-free day and night, with full activity levels, normal lung function, absent side effects, and satisfaction with the process of care. For most patients who can adhere to a comprehensive asthma management plan, these goals are realistically attainable.
Treatment in the ambulatory setting has four major components: monitoring of symptoms and lung function, control of environmental triggers, education of the patient and family, and drug therapy (Table 60.8).
Home Monitoring of Lung Function
Monitoring lung function with objective tests is important in asthmatics who must use symptomatic bronchodilator treatments more than twice per week or who have experienced severe attacks. Inexpensive peak flow monitors are commercially available. Recording peak flow gives an indication of maximal lung function, can forecast the worsening of asthma before severe symptoms develop, allows objective identification of harmful environmental or occupational exposures, and facilitates telephone contact between the patient and medical caregivers. A practical regimen is to record the peak flow daily in the morning. If the value is <80% of the patient's personal best level, additional recordings during the day are warranted. The determination of a patient's personal best level can be obtained during a 2- or 3-week period of intensive asthma treatment and should be periodically updated. Asthma diaries are helpful for recording patterns of peak flow variation, symptoms, and use of symptomatic bronchodilators (Fig. 60.3).
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TABLE 60.8 Components of Asthma Treatment |
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FIGURE 60.3. Asthma symptom and peak flow diary. |
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Control of Environmental Triggers and Complicating Conditions
Environmental controls for asthma include the identification and removal of nonspecific irritants and the reduction of exposure to specific allergens. Smoking should be discouraged, and smoking cessation may require repeated strong personalized messages, referral to smoking cessation group programs, and drug therapy (see Chapter 27). Household members should be discouraged from
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smoking, or they should be encouraged to smoke outdoors or to confine smoking to parts of the home not occupied by the asthma patient.
Gastroesophageal reflux may worsen asthma, but whether treatment is indicated in the absence of reflux symptoms is controversial. Small, frequent feedings; elevation of the bed; and antacids, histamine-2 receptor blockers, or proton pump blockers may be prescribed (seeChapter 42) (references above). Allergic or infectious sinusitis should be aggressively treated with antibiotics, intranasal steroids, or surgical procedures (59).
Common specific perennial allergen sources include house dust mites, cockroaches, molds, and pets. House dust mites can be controlled by maintaining low humidity and by removing carpeting and stuffed furniture from the bedroom. Impermeable bedding covers have not been found to be an effective treatment for dust-sensitive asthma (60). Asthmatics should avoid vacuuming or entering a freshly vacuumed area for 1 to 2 hours, or they should wear a protective face mask. High-efficiency vacuum cleaners are available but are of unproven value. Bedding should be washed weekly in hot water (>130°F) to eliminate dust mites. Fur-bearing animals shed allergenic saliva and urine, and they should be eliminated from the household if they exacerbate asthma. If the patient or family is unwilling to part with the pet, other partially effective measures include washing the pet frequently, excluding the pet from the asthmatic's bedroom, and blocking forced hot air vents in the asthmatic's bedroom (61). Cockroach infestation is a particularly important cause of asthma in inner cities and can be controlled with insecticides, although repeat treatment is required. The preferred methods of cockroach control are boric acid powder, poison baits, and traps (62). Insecticide sprays, particularly cholinesterase inhibitors, can cause severe asthma exacerbations by themselves. Molds can be controlled in the home by using dehumidifiers and providing adequate ventilation in the kitchen and bathroom.Mouse antigens are ubiquitous in the inner city. They have an uncertain relationship to asthma, but elimination of mice is a prudent measure. Indoor air cleaning devices using high-efficiency filters or electrostatic filters can diminish suspended particles of tobacco smoke and mold spores, but they have not been found to improve asthma symptoms in controlled studies (63). Therefore, they are not recommended for routine use and do not substitute for other methods of environmental control. Room or house humidifiers should be avoided because they can increase concentrations of mold spores and house dust mites.
During specific pollen allergy seasons or high air pollution days, asthmatics should stay indoors at midday when pollen concentration is highest and air quality is worst. Outdoor exercise during high air pollution periods should be avoided because high levels of ventilation increase the damaging effect of air pollutants. Closing doors and windows and using a recirculating air conditioner minimize indoor pollen and air pollution exposure.
Exposure to occupational allergens should be controlled by ventilation changes in the workplace. If not possible, personal respiratory protection or job reassignment are required to control exposures. Sources of nonspecific respiratory irritants should be avoided. These include unvented gas, kerosene, or wood-burning stoves and heaters. In highly sensitive individuals, aerosol sprays and perfumed cosmetics may worsen asthma and should be eliminated.
Drugs that worsen asthma, such as aspirin, other NSAIDs, and β-adrenergic blockers, should be avoided or should be monitored closely if no alternatives are possible. Many over-the-counter medications for upper respiratory infections, sinusitis, gastroenteritis, musculoskeletal pain, or menstrual pain contain aspirin, which can worsen asthma in susceptible unaware individuals, and use of such drugs should be avoided. β-Adrenergic blockers may inadvertently be used as eye drops for treatment of glaucoma, with the potential for severe asthma exacerbation. Angiotensin-converting enzyme inhibitors may worsen cough in patients with asthma (64).
Although not based on experimental evidence, annual influenza vaccination is recommended for asthmatics of all ages because the infection can precipitate severe and prolonged exacerbations of asthma (65). Influenza immunization does not induce asthma exacerbations (66).
Education of the Asthmatic
Education of the asthmatic patient is an important obligation of the practitioner. Excellent materials to assist in this process are available from volunteer and government agencies (67, 68, 69). The specific aims of education should be to teach the patient to recognize the signs and symptoms of asthma, to use the peak flow meter correctly, to take medication properly, to establish and follow treatment plans for exacerbations, to avoid and control asthma triggers, and to make appropriate use of urgent medical care. Table 60.9 lists important specific topics.
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TABLE 60.9 Components of Asthma Education |
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Asthmatic patients must be instructed on the proper use of metered-dose inhalers (MDIs) for delivery of inhaled medications. Patients should be observed using their inhaler during office visits, and proper technique should be repeatedly taught because some studies have shown that 40% of asthmatics do not use their inhalers properly. Proper technique (Table 60.10) involves the following steps: gently shake the MDI; hold the MDI 2 inches away from the open mouth; trigger the device at the onset of inspiration from normal end-tidal lung volume; inhale slowly to TLC over 5 seconds; hold the breath at TLC for 5 to 10 seconds; and exhale slowly. For patients who cannot perform this maneuver properly despite training and practice, the effectiveness of the MDI can be enhanced by use of a spacer or reservoir device. Some drugs are available in single-dose or multiple-dose dry-powder inhalers or breath-triggered MDIs. These devices are breath activated and are effective for people with poor coordination; however, they require good inspiratory flows to work properly. In uncommon cases where use of an MDI is not effective, small electrically powered nebulizers can deliver bronchodilators. However, use of nebulizers is limited by their lack of portability, their expense, and the need for meticulous cleaning and preparation of solutions. Rinsing the mouth after inhalation of drugs effectively reduces local oropharyngeal side effects and minimizes systemic absorption.
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TABLE 60.10 Proper Use of Metered-Dose Inhaler |
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Each asthmatic should have a well-understood action plan for treatment of exacerbations and should be able to recognize the signs of worsening asthma and know what action to take. Such a plan should be based on the patient's history of severity of exacerbations, access to health care, and reliability. Table 60.11 gives a typical action plan.
Drug Treatment for Asthma
Drugs should be used in the treatment of asthma in a stepped approach to normalize activity levels and lung function and to minimize exacerbations (Table 60.12). Once control of asthma is achieved, the program can be slowly tapered to maintain the lowest necessary drug dosage. It is important to distinguish between drugs that are used for short-term relief of symptoms and drugs that are used for long-term control of the underlying disease. The patient's failure to understand this distinction often leads to underuse of anti-inflammatory agents and to overreliance on inhaled short-acting bronchodilators, with consequent failure to meet the goals of asthma care.
Inhaled short-acting selective β2-agonists should be prescribed for patients with mild asthma. Use should be confined to the minimum number of inhalations needed to control symptoms. Table 60.13 lists several selective β2-agonists available in MDIs. The choice of which β2-agonist to use initially should be based on symptomatic relief of the patient and cost, because little else distinguishes most of the agents available by prescription in the United States. Nonprescription asthma inhalers should be avoided
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because many contain epinephrine, which has potentially serious cardiovascular side effects from its α- and β1-adrenergic properties. For this reason, most of these inhalers have been taken off the retail market. Because selective β2-agonists are so effective in relieving symptoms of bronchospasm but do not treat the underlying airway inflammation, they have the potential for permitting patients to increase exposure to harmful agents and delay more definitive treatment. Because there are neither harmful nor beneficial effects from regular use of short-acting bronchodilators compared to symptomatic use, it is reasonable to limit their use to control of symptoms only (70). There is evidence that certain β-receptor genotypes, which are more prevalent in African Americans, can predispose to deterioration of asthma control with regular β-agonist use in individual patients (71).
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TABLE 60.11 Self-Management of Acute Exacerbations |
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TABLE 60.12 Stepwise Approach to Asthma Care |
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TABLE 60.13 ββ-Sympathomimetic Agonists |
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Long-acting selective β-agonists may lead to the development of tolerance to their protective effect against nonspecific bronchial challenge while the acute bronchodilating effects of these drugs are unchanged (72). The typical MDI contains 200 to 300 inhalations and therefore should last approximately 3 to 4 weeks or longer. More frequent use of bronchodilator MDIs usually indicates the need for more intensive anti-inflammatory therapy. In general, however, modern selective β agonists are safe and effective drugs, and they should not be withheld from the symptomatic asthmatic. The most common side effects are tremor and cardiac arrhythmias. An often neglected side effect of chronic use of β-agonists is hypokalemia (apparently caused by an intracellular shift of potassium), which can be corrected with supplemental potassium (see Chapter 50). Long-acting β-agonists, such as salmeterol (Serevent) or formoterol (Foradil), which have a slower onset and longer duration of action, are used for long-term control of symptoms. The use of such agents for short-term relief of symptoms may lead to excessive adrenergic stimulation. Therefore, drugs in this class should be prescribed in conjunction with a shorter-acting agent to be used for acute relief of symptoms. Monotherapy with a long-acting β-agonist should not be substituted for inhaled corticosteroids for prevention of asthma symptoms (73,74).
If bronchodilators are used to treat asthma symptoms more than twice weekly (excluding prophylactic use for exercise), an inhaled anti-inflammatory agent should usually be prescribed. Inhaled nonsteroidal antiallergy drugs include cromolyn (Intal-2 metered sprays four times per day) and nedocromil (Tilade-2 metered sprays two to four times per day). These agents have few side effects but have limited efficacy for control of asthma. However, these agents are effective in preventing exercise-induced bronchospasm. Their use is limited by the lack of availability of the high-concentration preparations that have been shown to be most effective and by the recommended frequency of dosing. For patients with mild persistent asthma, particularly those who exhibit aspirin sensitivity, leukotriene inhibitors and antagonists are effective (75, 76, 77, 78). However, some patients show little or no response to leukotriene inhibitors, which may reflect genetic polymorphisms of the enzymes that produce leukotrienes (79).
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TABLE 60.14 Approximate Comparative Daily Dosages for Inhaled Corticosteroids in Adults |
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Inhaled corticosteroids are important anti-inflammatory agents and have become the mainstay of treatment for patients with persistent asthma symptoms. They reduce airway inflammation and airway reactivity (80). Although daily inhaled corticosteroids improve asthma control, there is no evidence that daily inhaled corticosteroid treatment of mild persistent asthma improves long-term lung function compared to intermittent symptom-based treatment (81). Most of the side effects are caused by local effects such as oral candidiasis and dysphonia, which can be prevented by use of a spacer/reservoir device or by rinsing the mouth with water after each use. Although biochemical evidence of chemical adrenal suppression and increased bone metabolism is found with high-dose inhalation (>1,200 µg/day) of these agents, clinically noteworthy systemic toxicity is rarely observed. However, reports of increased prevalence of cataracts and bone fractures in older people receiving large doses of inhaled steroids and transiently decreased growth in children receiving moderate doses of inhaled steroids emphasize the importance of using the smallest effective dose (82,83). Inhaled corticosteroids available in the United States include beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone.
Mometasone and ciclesonide likely will be available in the United States in the near future. All have approximately equivalent efficacy and side effects, although some have more convenient dosages and delivery devices. The drug usually is started at a dosage that is adequate to control asthma symptoms and is decreased to the lowest effective dosage (84). The effect of a change in dosage of inhaled corticosteroids may take 3 to 4 weeks to ascertain. Increasing the dose of inhaled steroids during deterioration of asthma control does not seem to be an effective strategy, and often a better strategy is to add a second class of drugs (85). Table 60.14 lists the equivalence of available formulations of inhaled corticosteroids.
If inhaled corticosteroids do not control symptoms and optimize lung function, consideration should be given to adding a second long-acting drug, such as an oral or inhaled long-acting β-agonist, a leukotriene inhibitor, or a long-acting oral theophylline preparation, to control asthma (86, 87, 88, 89, 90). Long-acting agents are particularly helpful when symptoms occur at night. Addition of a long-acting β-agonist has become the most widely used and effective combination therapy. A long-acting theophylline preparation may be given at a dosage of 400 to 1,200 mg/day in one or two daily doses. Theophylline should be started at a low dosage that is increased at weekly or longer intervals with monitoring of symptoms. Whether monitoring of blood levels is necessary in the absence of side effects is not clear. Theophylline is a mild bronchodilator that also has a modest anti-inflammatory effect (91,92). Side effects of theophylline include anorexia, nausea, gastroesophageal reflux, anxiety, and palpitations. Serious toxic effects at serum levels >20 µg/mL include seizures and atrial and ventricular tachyarrhythmias. Because theophylline is metabolized by the liver, theophylline interacts with numerous other drugs. Erythromycin, ciprofloxacin and other quinolones, and cimetidine decrease theophylline metabolism and elevate serum levels. Cigarette smoking and hyperthyroidism are associated with increased metabolism and decreased theophylline levels. Congestive heart failure and hepatic insufficiency require a dosage reduction or use of an alternative agent.
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Albuterol (2- to 4-mg tablets), an oral, long-acting β-agonist, can be given twice daily. Maximal doses of oral β-adrenergic agonists often are limited by tremor and a sensation of nervousness; therefore, they should be titrated upward starting at half to one quarter the maximum recommended dose. Tolerance to this side effect occurs over several weeks, whereas the bronchodilator action is retained. The availability of inhaled long-acting β-agonists, such as salmeterol and formoterol, has supplanted the use of oral agents except in circumstances where cost, adherence, or patient preference dictate their use.
Antileukotriene drugs, leukotriene D4 receptor antagonists (zafirlukast [Accolate], 20 mg twice per day; montelukast [Singulair] 10 mg once daily), are useful in some asthmatics. The 5-lipoxygenase inhibitor zileuton (Zyflo 600 mg four times daily) has a broader leukotriene inhibitory profile but requires monitoring of liver enzymes. Antileukotriene drugs are best reserved for the patient with mild or moderate asthma, the patient with aspirin sensitivity, the athlete who suffers from exercise-induced asthma, and the patient who is unwilling or unable to use adequate doses of inhaled steroids. Rarely, patients treated with leukotriene antagonists develop a syndrome similar to Churg–Strauss vasculitis, which may reflect unmasking of an underlying disease after tapering of systemic steroids (93). Some patients do not respond to these agents, likely because of genetic predisposition; therefore, treatment should be abandoned if there is no apparent benefit.
Inhaled anticholinergic drugs (e.g., ipratropium bromide) are safe and effective bronchodilators in asthma, and they add some marginal benefit when added to β2-adrenergic agonists, particularly during an acute exacerbation (94).
When these measures are ineffective in controlling asthma or when previously stable asthma is punctuated by an exacerbation, oral corticosteroids should be used. They can be prescribed as a 5- to 14-day course starting at 30 to 60 mg/day of prednisone or equivalent prednisolone, either stopping abruptly or tapering gradually. In more severe cases, tapering of the steroids may take several months or require chronic treatment with daily or every-other-day prednisone. In dosages >20 mg/day for long periods, serious complications, including diabetes mellitus, posterior subcapsular cataracts, osteoporosis with compression fractures, and hypothalamic–pituitary–adrenal axis suppression, are common. Because of the serious side effects of chronic steroid use, vigorous efforts should be made to optimize adherence with environmental controls and maximum inhalational drug therapy in these patients. Other disorders that mimic asthma should be investigated. If long-term steroids are necessary, tuberculin skin testing should be considered, although the benefit of isoniazid prophylaxis compared with monitoring with chest x-ray films in this setting is controversial. In those receiving long-term corticosteroid therapy, particularly postmenopausal women, prophylaxis of corticosteroid-induced osteoporosis with vitamin D and calcium supplements or bisphosphonates is recommended (see Chapter 103).
For asthmatic patients who cannot taper steroids, treatment with monoclonal antibodies to IgE should be considered for those with underlying allergies (95). Omalizumab (Xolair) is approved for treatment of moderate to severe allergic asthma. It is given by subcutaneous injection every 2 to 4 weeks. Dosing is based on body weight and total IgE level. For those without atopy, several options may be considered, although none is well established at present. These include methotrexate, cyclosporine, troleandomycin, oral gold salts, hydroxychloroquine, dapsone, inhaled lidocaine, and intravenous immunoglobulin infusions (96, 97, 98). If gastroesophageal reflux and associated asthma exacerbations can be documented by esophageal pH probe recording and medical treatment is not helpful, surgical treatment of the reflux should be considered (99) (see Chapter 42). Initiation of these treatments should be undertaken by someone familiar with the treatment of steroid-dependent asthmatics because many such patients will have other diagnoses or can be successfully tapered with consistent comprehensive asthma care.
Emergency Treatment of the Acute Asthma Attack
When asthma fails to respond to home management (Table 60.12), the patient should be instructed to receive immediate treatment in a hospital emergency department or a similarly equipped facility. Both patients and practitioners should understand that untreated severe asthma can be fatal and should recognize the individual at risk (100) (Table 60.15). Treatment should be initiated with nebulized treatments of selective β-adrenergic agonists given as three treatments in the first 60 to 90 minutes (Table 60.16). MDI administration of four to eight inhalations using a reservoir device is as effective as nebulizer therapy and can be used when a nebulizer is not available.
Supplemental oxygen should be given to patients who are hypoxemic or to those in whom arterial oxygen saturation is unknown. Because bronchodilators initially can worsen ventilation–perfusion matching, oxygen saturation
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may fall during the early phases of treatment even as lung function is improving. Peak flow measurement or spirometry should be performed on admission and after each nebulizer treatment to determine response. Arterial blood gases should be checked in patients who appear severely ill to determine whether hypercapnia is present and whether mechanical ventilation might be required. A chest x-ray film should be obtained for patients in whom the possibility of pneumonia, pulmonary edema, or pneumothorax is suspected. Serum theophylline levels should be measured in patients taking theophylline to guide possible therapy with this drug. Serum electrolytes may reveal hypokalemia from excess β-agonist use.
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TABLE 60.15 Risk Factors for Fatal Asthma |
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TABLE 60.16 Dosages of Inhaled ββ-Adrenergic Agonists in Acute Asthma Exacerbations in Adults |
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If the initial treatment is unsuccessful, systemic corticosteroids at a dosage of 60 to 125 mg prednisolone intravenously every 6 hours should be initiated (101). Hourly treatments with nebulized bronchodilators should be continued and the response measured. If no response to nebulized bronchodilators is observed over the first 2 to 3 hours, subcutaneous epinephrine 0.2 to 0.4 mg or terbutaline 0.25 mg may be administered. In patients with peak flow <50% of baseline, intravenous theophylline may be beneficial in improving lung function and preventing hospital admission, starting with an infusion of 0.6 mg/kg lean body weight (102). The infusion rate should be 0.3 mg/kg for patients with hepatic disease or for those taking drugs that diminish aminophylline metabolism. In patients not previously taking theophylline, a loading dose of 5 to 6 mg/kg should be given. In those who have been taking theophylline, the dosage should be guided by serum levels, with no more than a 3 mg/kg loading dose. Intravenous fluids should be given for dehydration, but excessive administration of intravenous fluids may worsen the asthma by promoting airway edema.
After the initial treatment, if the patient shows peak flow or FEV1 <25% of baseline, develops altered sensorium, has an arterial oxygen tension <60 mm Hg on supplemental oxygen, or has arterial carbon dioxide tension >40 mm Hg, the patient should be transferred to an intensive care facility for further treatment, monitoring, and possible mechanical ventilation. In some circumstances, noninvasive positive-pressure ventilation or inhalation of a helium–oxygen mixture may prevent the need for intubation (103).
In most circumstances, the response to the first 4 hours of therapy should determine whether the patient requires hospital admission. Considerations favoring hospitalization include peak flow <40% of baseline, continued severe symptoms, recent history of failed emergency treatment, history of respiratory failure, and inadequate home support or access to medications.
Management of the Pregnant Asthma Patient
Pregnancy has an unpredictable effect on asthma; approximately one third of patients experience no change in symptoms, one third improve, and one third worsen. Poorly controlled asthma may pose an increased risk for prematurity, intrauterine growth retardation, and perinatal morbidity (104). Prolonged or severe asthmatic attacks with hypoxemia or acid–base disturbances pose risks to the fetus, which has borderline oxygenation. Thus, prompt and aggressive management of acute asthmatic episodes should take precedence over concerns that the medications used to manage asthma may pose theoretical risks to the fetus.
In pregnant women, initial treatment during an acute asthmatic attack should include supplemental oxygen to maintain an oxygen saturation >95% for prevention of fetal hypoxemia. Fetal monitoring should be instituted for all but mild asthma attacks.
In general, management of pregnant and nonpregnant asthmatics is the same. Control of symptoms should be attempted with minimal use of medications, but no special attempt to discontinue medications is indicated.
β2-Adrenergic agents and theophylline are smooth muscle relaxants and therefore may inhibit uterine contractions during labor. They have been used for decades and generally are safe for the fetus. Epinephrine causes vasoconstriction because of its α-adrenergic properties and may diminish placental and fetal blood flow; therefore, it should be avoided if possible. Prednisone and prednisolone, the most commonly used systemic corticosteroids, cross the placenta poorly, so steroid production by the fetus is unaffected. Adrenal steroid suppression in the mother, however, may require administration of supplemental corticosteroids during the stresses of labor and delivery. Long-term use of oral steroids in other conditions has been associated with lower-birth-weight infants, so maximizing inhaled forms of therapy before instituting long-term oral steroids is prudent. The benefits of inhaled steroids outweigh any potential risk to the pregnant asthmatic or her fetus. Controlled trials have shown similar perinatal outcomes with theophylline versus inhaled steroids in pregnant women with asthma, although the inhaled corticosteroids result in greater improvement of FEV1 (105). As a general rule, relying on drugs that have
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a long record of safe experience in pregnant asthmatics is prudent (see National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program Asthma and Pregnancy Working Group, at http://www.hopkinsbayview.org/PAMreferences).
Course and Prognosis
Asthma that begins at an early age generally improves, and rates of prolonged remission from 30% to 70% have been reported. The severity of asthma correlates with the remission rate, so children with mild disease likely will experience remission, whereas those with severe disease often continue to be symptomatic. Some childhood asthmatics experience a remission but then have a recurrence of asthma in adulthood. Such patients tend to develop disease that is persistent and severe and have deficits in pulmonary function (106).
Patients who first develop asthma as adults have more rapid decline of lung function with aging, which may lead to irreversible airway obstruction. Additional risk factors, such as cigarette smoking, environmental exposures, and infection, may influence the progression of asthma to COPD (see below).
Death from asthma or one of its complications is uncommon, with overall death rates in the United States of approximately 1.5 per 100,000 population. However, asthma mortality increased 31% between 1980 and 1990, with the greatest burden of death sustained by inner-city African-American males. Since 1988, the United States death rate from asthma has tended to stabilize or decrease in association with the wider use of inhaled corticosteroids (4). Similar trends have been documented in other countries (107).
Chronic Obstructive Pulmonary Disease
Definition
The American Thoracic Society and the European Respiratory Society have adopted similar definitions: “Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterised by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences” (108). COPD can be subclassified further into emphysema and chronic bronchitis.
Emphysema is defined by morphologic criteria as abnormal dilation of the terminal airspaces of the lung with destruction of alveolar septa in the absence of interstitial fibrosis (109). Whereas a formal diagnosis of emphysema requires gross anatomic inspection of the lung, a clinical diagnosis can be reasonably based on a compatible history, physical examination, pulmonary function tests, and radiographic studies.Panacinar emphysema is a condition in which all of the airspaces in an acinus are equally dilated. Typically, the bases of the lung are more involved than the apices. This is the typical finding in patients with α1-antitrypsin deficiency and in some elderly nonsmoking individuals.Centroacinar emphysema describes the more prevalent condition in which the respiratory bronchiole at the proximal end of the acinus is more dilated than other portions of the acinus. Commonly, the apices of the lung are more involved in this disorder, which occurs predominantly in cigarette smokers. Peripheral airway disease is commonly associated with centroacinar emphysema, manifested by inflammation, fibrosis, and tortuosity of the terminal and respiratory bronchioles. The physiologic abnormality is the consequence of both the emphysema and the small airway narrowing and fibrosis (110).
Chronic bronchitis is a condition of chronic cough and sputum production that excludes other specific disorders such as bronchiectasis, tuberculosis, or cystic fibrosis. The formal epidemiologic definition of this disorder is the presence of cough and sputum production for the majority of days of the week for at least 3 months of the year for at least 2 years in a row. However, nearly everyone with chronic bronchitis has cough and sputum production on a perennial basis. Chronic bronchitis is common in cigarette smokers and often is incorrectly perceived by the patient to be a normal smoker's cough. The morbid anatomy of chronic bronchitis shows hyperplasia and hypertrophy of the mucous glands of the large central airways with central mucous plugging, variable degrees of smooth muscle hyperplasia, and airway wall thickening and inflammation (111). Chronic bronchitis can occur in the absence of major physiologic abnormalities, and the extent to which it contributes to mortality and morbidity in COPD is controversial. In patients with advanced COPD, mortality is best predicted by the postbronchodilator FEV1, with little additional information provided by other clinical factors (112). Some epidemiologic studies of people with less severe disease have shown some excess mortality associated with cough and phlegm, but the magnitude is not large (113). Approximately 30% of those with abnormal lung function report cough and phlegm, and the magnitude of the physiologic abnormality is worse in those who report more severe cough and phlegm. COPD patients with chronic cough and phlegm are more prone to exacerbations of COPD than are those without. Some smokers with chronic bronchitis develop severe airflow limitation without emphysema. These individuals are best classified as having chronic obstructive bronchitis or, when there is prominent reversible airflow obstruction, chronic asthmatic bronchitis.
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Natural History
COPD is a chronic disease that has its origins in early adulthood, or possibly even childhood, but it does not produce symptoms or impairment of activity until the disease is far advanced, usually in late middle-age or in the elderly. The normal aging process causes slowly progressive degeneration of lung function after the third decade, so a normal person loses approximately 20% of vital capacity and approximately 25% of FEV1 between the ages of 25 and 75 years. The average decline in FEV1 is approximately 30 mL/year, with some acceleration after age 65 years. These changes result from the loss of elastic recoil in the lung from degradation of elastin fibers, similar to the changes that occur in the skin and cause wrinkles. In most cigarette smokers, the rate of decline of FEV1 is normal or only moderately increased. In susceptible smokers, however, degeneration of lung function is accelerated, at 60 to 150 mL/year loss of FEV1 (114). Over the course of several decades, the degeneration leads to progressive breathlessness and, if unchecked, to disability, respiratory failure, and death. It has been suggested that children who have serious respiratory ailments or exposure to respiratory toxins, such as passive cigarette smoke, will be at increased risk for development of COPD because of impaired lung function when they are young adults and consequently will have less reserve capacity (Fig. 60.4).
Because of the reserve capacity of the lungs, the early stages of COPD do not cause any limitation of activity. When FEV1 reaches approximately 50% of predicted, there is ventilatory limitation of exercise capacity, but this often is ignored or attributed to deconditioning, and heavy exercise is progressively curtailed. Respiratory infections may cause severe and prolonged symptoms in this phase of the disease, prompting the patient to seek medical care. When FEV1 reaches approximately 30% to 35% of predicted (approximately 1.2 L in men and 1.0 L in women), symptoms prevent normal execution of daily living and work activities, and approximately half of afflicted individuals stop working. With continued decline in FEV1, chronic hypoxemia, hypercapnia, and cor pulmonale develop. Viral infections, mucus plugging, or respiratory irritants—including exposure to air pollutants— can precipitate episodes of acute respiratory failure, leading to hospitalization, mechanical ventilation, or death. More than half of patients with COPD compatible with emphysema die within 10 years after initial diagnosis, whereas approximately 15% of those with chronic asthmatic bronchitis die in the first decade after diagnosis (115).
Cigarette smoking is a major risk factor for development of COPD. Both observational studies and clinical trials have shown that cessation of smoking earlier in the course of disease can slow the rate of degeneration of lung function to the normal or near-normal range and can prolong life expectancy (116, 117, 118).
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FIGURE 60.4. Effect of risk factors from smoking on loss of lung function (forced expiratory volume in the first second [FEV1]). Upper curves are derived from subjects who do not smoke or are not susceptible to the effects of smoking. They lose lung function gradually throughout adult life (15–30 mL/year). Lower curves show accelerated loss of lung function in subjects who are susceptible to the effects of cigarette smoke. At age 65 years there is respiratory disability because FEV1 has decreased to 25% to 30% of predicted (1–1.2 L), and further functional deterioration eventually will cause death because of complications of respiratory insufficiency. If the subject stops smoking, life may be prolonged but a respiratory death still eventually will result. If intervention is initiated earlier in life (age 40–50 years) when chronic obstructive pulmonary disease (COPD) is mild, accelerated loss of lung function is reversible and a respiratory death will be prevented. Although this figure illustrates theoretical loss of FEV1 for an adult cigarette smoker, susceptible smokers will lose lung function at different rates, thereby becoming disabled at different ages. (Modified from Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645 , with permission.) |
Pathogenesis
It is impossible to predict which individuals are susceptible to COPD. However, several risk factors that increase an individual's risk for developing COPD have been identified (119) (Table 60.17). Among these risk factors, cigarette smoking is the most prominent and potentially the most amenable to change. The mechanism by which cigarette smoking leads to COPD is thought to be mediated by proinflammatory components of cigarette smoke, such as the hydrocarbon compound acrolein. Fourfold to fivefold increases in the numbers of activated neutrophils are present in the terminal airspaces and the peribronchial regions in smokers. These cells produce elastase, which can destroy the elastin elements in the alveolar walls and induces emphysema in animal models. Normally, the small amount of neutrophil elastase is inactivated by antiproteases present in serum and lung liquid lining layer, with α1-antitrypsin present in the largest quantities. Increasing evidence indicates that proteases secreted by alveolar macrophages and alveolar lining cells, including the cathepsins and matrix metalloproteinases (MMPs), play a pathobiologic role in the development of emphysema (120,121). These enzymes degrade a range of matrix proteins and inactivate the antiproteases that protect the lung from enzymatic
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destruction. Animals exposed to high levels of cigarette smoke are protected from emphysema if they are genetically unable to produce matrix metalloelastase (MMP-12). Animals that overexpress matrix metallocollagenase (MMP-1) are highly susceptible to development of emphysema, and this enzyme has been found in increased quantities in smokers who develop emphysema (121). Thus, although we are not certain which enzymes are critical to the development of pulmonary emphysema, it seems likely that the balance between free protease activity within the alveolus and alveolar duct and local antiprotease activity determines the rate of destruction of the lung parenchyma. Oxidative lung injury and other pathways that promote apoptosis of endothelial or epithelial cells that form the alveolar structure also may play a role in development of emphysema (122).
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TABLE 60.17 Risk Factors for Developing Chronic Obstructive Pulmonary Disease |
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α1-Antitrypsin deficiency is an uncommon genetic disorder (found in approximately one in 2,500 white individuals of European descent) in which the circulating levels of antiproteases are <10% of normal. Normal α1-antitrypsin activity is produced by the allele Pi-M (protease inhibitor M), for which approximately 90% of the population is homozygous. Pi-S is an allele with intermediate antiprotease activity, and Pi-Z is an allele with marked reduction in antiprotease activity. More than 75 minor alleles of the Pi gene have been identified, although most are rare and are uncommonly associated with disease. Individuals who are homozygous for the Pi-Z phenotype are at greatest risk for developing premature emphysema. Such individuals account for approximately 1% to 2% of cases of emphysema. The Pi-Z phenotype is the result of a single DNA base substitution causing an amino acid substitution that prevents secretion of the material from liver cells (123). Serum levels are <15% of normal despite hepatic intracellular accumulation of the enzyme inhibitor. In addition, the Pi-Z inhibitor has a slower reaction rate in neutralizing proteases, so the material that is secreted is less effective. Most studies have shown little increased risk for emphysema in people with intermediate α1-antitrypsin levels, that is, the Pi-MS, Pi-MZ, and Pi-SZ phenotypes, suggesting that there is a threshold level of antiprotease activity for development of premature emphysema in deficient patients. Although affected people present for medical care with severe emphysema in the third and fourth decades, many people with α1-antitrypsin deficiency have normal or only mildly abnormal lung function if they do not smoke (124).
Other genetic polymorphisms involved in the inflammatory and antioxidant pathways may play a role in susceptibility to COPD, but they are poorly understood (125).
Occupational exposure to dusts, fumes, and noxious gases has been implicated in the development of COPD (126). In most of these circumstances, however, the offending agents are additive to the effects of cigarette smoking, and it is uncommon to find occupationally related symptomatic COPD in the absence of cigarette smoking. The mechanism is presumed to be the result of nonspecific irritation or activation of alveolar macrophages, enhancing lower respiratory inflammation. Although far-advanced silicosis and asbestosis may be associated with airflow obstruction, the predominant lesion in these disorders is fibrosis with localized compensatory emphysema and honeycombing leading to restrictive ventilatory defects. Occupational exposure to sensitizing agents found in grain, wood, and cotton dust and to polyurethane compounds not only may cause asthma but may lead to fixed airflow obstruction with chronic asthmatic bronchitis if the exposure is prolonged. In nonindustrialized countries, however, intense exposure to particulates from biomass fuels has been implicated as a common cause of COPD in the absence of tobacco smoke exposure.
Nonspecific airway reactivity occurs in approximately 70% of people with COPD, even those with mild abnormalities and minimal symptoms, and is more common in women than in men (127). However, the interpretation of this finding is controversial. One school of thought, the so-called Dutch hypothesis, holds that this is a constitutional state that predisposes the individual to develop accelerated degeneration of pulmonary function when exposed to cigarette smoke or to other environmental agents (128). The alternative viewpoint is that airway reactivity is a marker for inflammatory or geometric changes that have already occurred and therefore is the result, not the cause, of the disease process.
The magnitude of airway reactivity correlates with the rate of decline of lung function (129,130) as well as with markers of inflammation. Whereas inflammatory
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mediators or airway wall thickening may contribute to increased tendency for airways to narrow, it also is possible that destruction of alveolar septal attachments and thickening of airway walls, which are the result of smoking-induced inflammation and early emphysema, lead to the increased tendency of the airways to constrict. This hypothesis is supported by the findings that airway reactivity is inversely correlated with baseline lung function in smokers, does not disappear with smoking cessation, and is induced in animals with emphysema caused by proteolytic enzymes (131).
Abnormal lung function, particularly FEV1/FVC during early adulthood, is a predictor of accelerated degeneration in lung function, a phenomenon known as the horse race effect (132). People with lower lung function have already experienced some increased decline in lung function. Even individuals within the normal range of lung function who show lower spirometric indices have increased mortality from lung disease and other causes.
Aging is normally associated with changes in lung function, including reduction in vital capacity and FEV1 and increases in residual volume and FRC. Physiologically, all of these changes can be attributed to a reduction in the elastic recoil of the lung that accompanies the aging process. The mechanism for these changes is unknown but is presumed to be the cumulative effect of endogenous and exogenous factors that degrade the elastin in the lung and the balance of processes that repair or prevent this damage. Emphysema of the panacinar type, which is similar to that occurring with α1-antitrypsin deficiency, is found in some elderly nonsmoking individuals, particularly women. Development of emphysema in smokers may reflect either the additive effects of toxic exposure that accelerate the normal aging of the lung or interference with the processes that inhibit such degeneration. Most of the increased mortality from COPD over the last 2 decades has been confined to individuals older than 65 years, raising the possibility that the disease is being unmasked as mortality from heart disease, stroke, and infectious diseases is declining (133).
COPD is more common among the poor and poorly educated. Although cigarette smoking is more common in lower socioeconomic groups, the indigent have worse lung function even when adjusted for smoking status. Race is not thought to be a component; some evidence suggests that African Americans are less susceptible to COPD than whites (134). Factors that may contribute include crowded living conditions with exposure to frequent viral respiratory infections, indoor air pollutants from heating or cooking devices in poorly ventilated homes, poor nutrition, exposure to passive cigarette smoke, inadequate access to medical care for childhood respiratory infections, or increased exposure to respiratory irritants and toxins in the workplace. Although COPD mortality rates are highest in white men, women and African Americans have shown disproportionate increases in COPD mortality over the past decade, likely reflecting changing smoking patterns over the past 30 years (133).
The evidence that high levels of air pollution are important in the genesis of COPD is suggestive but not definitive. In animal models, high levels of NO2 and ozone can induce emphysema independently and can potentiate protease-induced emphysema, suggesting that oxidant air pollutants inhibit lung protective mechanisms. There is more convincing evidence that acid aerosols, ozone, and fine particulates contribute to COPD exacerbations, hospitalizations, and death (135, 136, 137).
Whereas allergic tendencies are strongly associated with the presence of asthma and symptoms of cough and wheeze in nonsmokers, the effect of atopy on respiratory symptoms and decline in lung function in smokers is less clear, possibly in part because of the tendency of adolescents and young adults with highly reactive airways to avoid cigarette smoking. Some evidence suggests that allergies or nonspecific elevation of serum IgE levels contribute to the development of fixed airway obstruction in smokers.
Evaluation of the Patient with Chronic Obstructive Pulmonary Disease
History
COPD must be considered a diagnostic possibility in all individuals who smoke, even in the absence of respiratory symptoms. The clinician should inquire about smoking habits in every patient encounter. Specific questioning about the age at onset of smoking, average number of packs smoked per day, and number and duration of quit attempts should be elicited. Often patients report being nonsmokers to the practitioner when they have only recently quit smoking. Other respiratory symptoms, such as cough, phlegm, and exertional dyspnea, should be quantified. Morning sputum production often is erroneously considered to be normal by smokers. Shortness of breath can be detected by asking whether the individual has trouble keeping up with peers performing routine activities such as walking, sports, and work functions. More advanced dyspnea is roughly quantified by distance walked or flights of stairs walked before stopping. Sleep disturbance is a common and often overlooked symptom of COPD and may impair quality of life more than exertional dyspnea.
Physical Examination
Although historical and physical findings of COPD (see below) may confirm the diagnosis when they are present, they usually are apparent only with advanced disease (see below for spirometric guidelines). The absence of these findings is not sufficiently sensitive to exclude the diagnosis in the person at risk (Table 60.18) (138,139).
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TABLE 60.18 Sensitivity and Specificity of History and Physical Findings for Diagnosis of Moderate Chronic Obstructive Pulmonary Disease |
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In advanced COPD, general physical findings include those caused by hyperinflation: increase in resting chest anteroposterior diameter, elevation of the clavicles, widening of the xiphocostal angle, and increase in the intercostal spaces. The distance between the larynx and the sternal notch is reduced to <4 cm (139). With inspiration there is diminished movement of the rib cage and increased movement of the abdominal wall. The patient has hypertrophied and well-defined abdominal and sternomastoid muscles but diminished muscle mass in the arms, thighs, and legs. The characteristic seated posture is leaning forward with both hands on the knees to fix the shoulders, permitting more effective use of the accessory cervical muscles. This may lead to hyperkeratosis of the anterior thighs. Pursed-lip breathing and prolonged time of expiration are spontaneously adopted to diminish the energy expenditure of breathing. The fingers often show tobacco staining. Clubbing of the nails is rare and suggests the presence of bronchiectasis or bronchogenic carcinoma. Chest percussion shows increased resonance and low diaphragms that move poorly with full inspiration and expiration. Auscultation shows diminished transmission of breath sounds over areas of emphysema and is the most reliable physical finding indicative of chronic airflow limitation. Early inspiratory crackles indicate opening of closed airways and are common in COPD, whereas late and pan-inspiratory crackles are more common with interstitial lung diseases (140). Wheezing may be elicited in most COPD patients by forced expiration, but the presence of wheezing during quiet breathing is more common with reversible bronchospasm.
In far-advanced disease with cor pulmonale, elevated right atrial pressures cause neck vein distention, peripheral edema, and hepatomegaly. The pulmonary hypertension and distention of the right ventricle cause a pronounced cardiac impulse in the epigastrium. Tricuspid regurgitation from dilation of the right ventricle and pulmonary hypertension causes a systolic murmur over the
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epigastrium that increases with inspiration. In contrast to other forms of pulmonary hypertension, a ventricular heave and increased intensity of the second heart sound usually are not appreciated because of the interposed emphysematous lung.
Additional Studies
The ability to blow out a paper match from >10 cm away with an open mouth is a rudimentary lung function test that is helpful when abnormal, but the test is not sensitive. Another simple bedside lung function test is to measure the forced expiratory time with a stethoscope over the trachea during an FVC maneuver. However, the test is not sufficiently sensitive in practice to screen for airflow limitation (141).
The chest x-ray film is abnormal only in advanced disease. Signs of COPD include hyperinflation with flattening of the diaphragm, increased retrosternal airspace on the lateral view, narrow cardiac silhouette, paucity and tapering of peripheral blood vessels, and bullae. In some smokers with COPD, particularly those with bronchitis symptoms, small rounded opacities or increased linear markings representing thickened airway walls may be seen.
High-resolution computerized tomography of the chest is becoming the standard for evaluation of emphysema in the absence of an anatomic diagnosis. In practice, however, this study rarely is necessary because less expensive tests of lung function—spirometry and diffusing capacity—usually are adequate to distinguish asthma from emphysema and to follow the course of the disease and the response to treatment.
Spirometry (see above) should be performed initially for diagnosis and assessment of severity. Whether spirometry should be performed for COPD screening in asymptomatic smokers is not clear, because the sole effective means of halting disease progression, smoking cessation, should be universally promoted regardless of lung function. After initial diagnosis of COPD, however, spirometry should be repeated to monitor disease progression and response to treatment, particularly when the patient's health status changes (142). As a general rule, FEV1measurement >80% predicted indicates mild obstruction, 50% to 80% predicted indicates moderate obstruction, 30% to 50% predicted indicates severe obstruction, and <30% predicted indicates very severe obstruction. Peak flow monitoring, useful in asthma, may be misleading in COPD because the peak flow can be well maintained despite worsening airflow obstruction.
Sensitive tests, such as the single-breath nitrogen washout test, measure the function of the small airways. Such tests are abnormal in most smokers and do not predict who will develop symptomatic COPD, so these tests are not routinely recommended. In smokers, forced expiratory spirometry is effective in screening for COPD. With serial measures of spirometry, it is possible to identify individuals who are demonstrating accelerated declines in lung function before symptoms intervene. Of spirometric indices, FEV1/FVC <70% predicts future decline in lung function (132).
Bronchodilator testing can reveal reversible bronchospasm, and the postbronchodilator measure of FEV1 is the best overall predictor of life expectancy in COPD. Failure to respond rapidly to a single dose of an inhaled bronchodilator does not indicate that lung function will not improve with more long-term treatment or at different times (143). Approximately one in five patients who do not demonstrate a rapid bronchodilator response will show improvement in lung function after several weeks of treatment with bronchodilators or corticosteroids (144). Abnormal methacholine reactivity is common in COPD but usually does not provide sufficient information to warrant its routine use.
The carbon monoxide diffusing capacity test (see above) is helpful for distinguishing emphysema from asthma. Cigarette smokers without emphysema have mild reductions in diffusing capacity because of accumulation of carbon monoxide in the blood, which is only partially reversible with smoking cessation. A diffusing capacity <70% of the predicted value is present with emphysema but also may be found with interstitial fibrosis and pulmonary vascular diseases. In chronic asthmatic bronchitis, the diffusing capacity tends to be preserved (145,146).
Measurements of lung volume (see above) help distinguish obstructive lung diseases from restrictive lung diseases. They are particularly helpful during the initial assessment or when the presence of an interstitial process is unclear, such as that caused by occupational exposure to silica or asbestos. Some patients experience significant improvement in symptoms after bronchodilator treatment as a consequence of reversal of resting or exercise-induced dynamic hyperinflation with little change in FEV1. However, it often is not necessary to follow response to bronchodilator treatment with lung volume measurements if simple spirometric measures improve. Measurements of airway resistance and lung compliance often are abnormal in COPD but do not add useful clinical information in most circumstances.
Exercise testing is indicated in individuals who demonstrate reduction in diffusing capacity <50% to 60% of predicted and who are not hypoxemic at rest, if supplemental oxygen is being considered for improving exercise capacity. Exercise testing should be performed in a monitored facility. Measurement of oxygen saturation with a pulse oximeter usually suffices to determine whether oxygen should be prescribed. More complex and invasive exercise testing with measurement of arterial blood gas tensions, oxygen consumption, and ventilation are used for evaluation of disability (see Chapter 9) or if the cause of dyspnea is
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unclear. Maximum exercise capacity on a cycle ergometer before and after an exercise training program is useful in selecting individuals who are good candidates for lung volume reduction surgery (see below). Measurement of the distance that an individual can walk in 6 minutes, the six-minute walk test, is used as an indicator of functional ability and is one of several predictors of survival in COPD (147).
Arterial blood gas measurements may reveal disorders of oxygenation or ventilation. Hypoxemia occurs in COPD as a consequence of ventilation–perfusion mismatching. In those with advanced disease, particularly obese individuals, hypoventilation also promotes hypoxemia. With exercise, particularly at higher altitude, hypoxemia can worsen because of impaired diffusion of oxygen across the alveolar–capillary membrane. Arterial oxygen saturation should be measured in patients who have moderately advanced disease and FEV1 <1.5 L, because this group is at risk for chronic hypoxemia and development of cor pulmonale. At higher altitudes, hypoxemia develops with less severe pulmonary involvement, and oxygen tensions should be measured more liberally. When the FEV1 falls to <1.0 L, chronic hypercapniabecomes more common, often in patients with the least dyspnea.
Other blood tests are indicated only as needed for the general care of the patient. An elevated hematocrit value is uncommon in COPD in comparison with similar levels of hypoxemia at altitude, but when it does occur should alert the clinician to the possible presence of chronic hypoxemia. Anemia is not uncommon in COPD patients with comorbidities and is a reversible cause of fatigue and dyspnea in patients with COPD (148). Hypokalemia and hypomagnesemia are common as a consequence of β-adrenergic agonists in conjunction with diuretics and, if severe, may contribute to fatigue or respiratory muscle failure.
Screening for severe α1-antitrypsin deficiency can be accomplished with serum protein electrophoresis to evaluate for a marked decrease in α1-globulin level. Genotyping or measurements of protease inhibitor levels are more specific and can detect intermediate deficiencies. Screening should be done for persons with a family history suggesting α1-antitrypsin deficiency, for patients with symptomatic airflow limitation at a relatively young age, and for those with unexplained liver disease or necrotizing panniculitis. Although recommended by some, it is not clear that adequate evidence of effective treatment is sufficiently well established to recommend screening in typical older smokers presenting with advanced disease (149).
Cystic fibrosis may present in adulthood with chronic cough and phlegm associated with chronic airflow limitation. It should be suspected if the patient has radiographic evidence of bronchiectasis, has a family history of cystic fibrosis or severe chronic childhood lung disease, has ABPA, or if sputum cultures persistently grow mucoid colonies of Pseudomonas. Elevations of chloride in sweat iontophoresis samples confirm the diagnosis, but genetic testing now is widely available to test for polymorphisms of the CFTR gene.
The electrocardiogram in COPD shows a vertical or indeterminate heart axis and low voltage. Enlarged P waves, right-axis deviation, or right ventricular hypertrophy is present with cor pulmonale. Echocardiography can confirm right ventricular dilation and tricuspid regurgitation.Doppler studies of tricuspid retrograde flow can be used to estimate pulmonary artery pressures but may be inaccurate with severe lung hyperinflation. Transesophageal echocardiography (see Chapter 65) provides better views, but the more invasive nature of the procedure limits its application. In most circumstances, echocardiography should be reserved for patients in whom there is a question of associated left ventricular dysfunction or valve disease.
Sputum examination by Gram stain or wet preparation during exacerbations can help determine whether there is a predominance of neutrophils or eosinophils, guiding the choice between corticosteroids and antibiotics. The presence of green phlegm, a marker for neutrophil myeloperoxidase, is a sensitive finding for the presence of a high bacterial load in phlegm (150). Culture of the sputum is unnecessary unless pneumonia is present or unusual or resistant organisms are suspected. Lower respiratory tract bacterial infections are associated with COPD exacerbations in approximately half of the events, often following colonization of the lower respiratory tract with immunologically new strains of previously colonizing species (151). Common pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella (Branhamella) catarrhalis can be found in the lower airways in approximately half of COPD flares (152).
Management
The components of care in COPD consist of education about the disease, prevention of disease progression, treatment of complications, drug treatment to maximize lung function, and rehabilitation to optimize activity levels.
Education is important so that the patient can develop an understanding of what COPD is, what causes it, and what possible courses the disorder may take. The patient should be given realistic expectations about the chronic but variable course of the disease, tempered by the understanding that temporary periods of worsening are preventable and treatable. The patient should try to achieve maximum social and physical functioning and to make use of whatever family, social, and medical support is available. Simple measures such as the availability of special parking areas for the disabled, wheelchairs and motorized carts in shopping malls and airports, portable oxygen, and oxygen supplementation during air travel are not always known by patients with advanced COPD, who may unnecessarily confine themselves to home and become socially
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isolated. Local volunteer health associations commonly sponsor groups in which these issues are discussed, and they often provide instructional materials via the Internet (American Lung Association at http://www.lungusa.org; National Heart, Lung, and Blood Institute athttp://www.nhlbi.nih.gov/health/public/lung/index.htm). Patients and their families should understand that the dyspnea that occurs with exertion is not harmful to the lung and that, with appropriate pacing of activities, a certain level of dyspnea actually is desirable to achieve and maintain physical conditioning. Inquiries about sexual functioning should not be avoided. Education of the patient's bed partner on techniques to limit the patient's level of exertion and on the use of prophylactic bronchodilators and oxygen can establish more normal sexual functioning, even with severe disease. Advance directives regarding intensive or long-term medical care should be discussed with patients and their families, and the physician should encourage this communication. Both clinician and patient should understand that episodes of acute respiratory failure in COPD requiring mechanical ventilation often are successfully treated but that the long-term survival is poor, although unpredictable, in those who have incapacitating dyspnea, cor pulmonale, poor nutrition, or persistent hypercapnia (153,154).
Prevention of disease progression and complications is one of the most important goals of treatment. By the time most patients present with advanced disease, they have discontinued smoking, although a sizable minority have not. Many with mild or moderate disease continue to smoke, unaware of their illness and the potential for arresting its progression by smoking cessation. Chapter 27 discusses the practical approaches to smoking cessation. In the patient with lung disease, the physician should deliver a strong personalized smoking cessation message that emphasizes the definite and progressive nature of the disease, the likelihood of early disability with continued smoking, and the potential for arresting the disease when smoking is stopped. Referral to a smoking group program and use of bupropion and nicotine replacement therapy improve smoking cessation rates.
Exposure to respiratory irritants should be avoided in the workplace as well as the home. If the disease is complicated by allergy or overlaps with allergic asthma, environmental control measures should be instituted. Smoking of marijuana and cocaine may cause airway irritation, and although there is little evidence that they contribute to airway reactivity or to development of COPD, their use should be discouraged.
Pneumococcal vaccination (see Chapter 18) is recommended, although evidence of its particular efficacy in COPD is lacking (155). Influenza vaccination taken annually (see Chapter 18) or amantadine/rimantadine prophylaxis for unimmunized individuals during an influenza epidemic can prevent or attenuate this potentially fatal infection. During influenza epidemics, the use of neuraminidase inhibitors such as zanamivir and oseltamivir can minimize the severity of infection if taken within 48 hours of onset of illness (156).
Patients with α1-antitrypsin deficiency are candidates for intravenous replacement therapy with protease inhibitors, although the long-term benefits of this treatment are not proven, particularly in those with mild impairment and those with severe impairment (157, 158, 159).
Treatment of Complications
Tracheobronchial infections are common in COPD, heralded by a change in the quantity, viscosity, or color of sputum. Although many infections are initiated by viruses, bacterial contamination or superinfection of the lower respiratory tract is common. Inexpensive broad-spectrum antibiotics, such as doxycycline, erythromycin, amoxicillin, or trimethoprim–sulfamethoxazole, can shorten the duration of these symptoms if they are suggestive of infection (160). When the patient is intolerant of first-line antibiotics, has severe underlying disease, has frequent exacerbations, or manifests evidence of resistant organisms, amoxicillin–clavulanate, ketolide, macrolide, or quinolone antibiotics should be prescribed (161). Antibiotics generally should be given only in exacerbations manifesting the triad of increased cough, worsening dyspnea, and change in sputum color or quantity. The oral route of administration is preferred, if tolerated by the patient.
Chronic hypoxemia causes pulmonary hypertension and cor pulmonale, a condition associated with poor survival if untreated. Oxygen therapy prolongs survival and improves physical and psychologic functioning in hypoxemic patients with COPD (162,163). When indicated (Table 60.19), oxygen can be administered with a nasal cannula. Oxygen concentrators, compressed oxygen tanks, and liquid oxygen storage reservoirs all are suitable for home use. Portable liquid oxygen systems and small compressed oxygen tanks with reservoir devices or demand valves allow mobility out of the home and should be used whenever possible. Oxygen should be prescribed at the lowest level necessary to maintain an arterial oxygen saturation ≥90%, usually 1 to 4 L/min. Supplemental oxygen must be used for at least 18 hours/day to have a significant survival benefit. The patient should understand that oxygen is used to prevent cardiac complications and not just to relieve dyspnea. Transtracheal oxygen catheters are used for the
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occasional patient who requires high oxygen concentrations or who cannot tolerate a nasal cannula (164).
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TABLE 60.19 Indications for Continuous Oxygen Therapy |
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If desaturation occurs with exercise, increased flows of oxygen during activity can improve exercise tolerance and enhance the ability to engage in an exercise conditioning program. Nocturnal hypoxemia in COPD is common and often unsuspected. The importance of screening for nocturnal oxygen desaturation and the benefit of treatment in terms of survival are not known. Preliminary evidence suggests that nocturnal oxygen prevents progression of pulmonary hypertension in COPD patients with nocturnal desaturation (165,166). Nonetheless, testing for nocturnal hypoxemia (in a sleep center or a hospital) in individuals who have erythrocytosis, unexplained peripheral edema without waking abnormalities of blood gases, or daytime hypersomnolence is prudent.
When pulmonary hypertension and cor pulmonale are present, treatment consists of continuous oxygen to overcome hypoxemia and diuretics to control peripheral edema. Digitalis is not useful unless there is concomitant left ventricular disease or atrial tachyarrhythmias. Calcium channel blockers can vasodilate the pulmonary circulation, but they often worsen hypoxemia, and their benefit is not established. Almitrine, a respiratory stimulant not available in the United States, improves arterial oxygen tension through improved ventilation–perfusion matching but does not reduce pulmonary artery pressure (167,168). Phlebotomy increases exercise capacity when hematocrit is >55%, but persistent erythrocytosis suggests inadequate oxygen supplementation or another cause (169). Anticoagulation, which is considered beneficial in severe pulmonary vascular hypertension (e.g., primary pulmonary hypertension), is of uncertain benefit in patients with pulmonary hypertension caused by COPD.
Supraventricular tachyarrhythmias are common in patients with COPD, as a consequence of right atrial enlargement, increased endogenous adrenergic tone, hypoxemia, and drug treatment, particularly with theophylline. Anticholinergic inhalers also have been implicated as an uncommon cause of supraventricular tachyarrhythmias (170). Treatment is similar to that in nonpulmonary patients (see Chapter 64). However, the presence of COPD should not prevent evaluation for treatable causes of arrhythmias, such as pulmonary embolism, hyperthyroidism, or valvular heart disease, which may be difficult to diagnose in these patients.
Control of mucus hypersecretion with use of expectorants and physical means such as high-frequency chest wall oscillation is not of proven benefit in improving lung function, although symptoms sometimes improve (171).
Hypercapnia may be an adaptive response to obstructive lung disease by decreasing the work of breathing, preventing respiratory muscle fatigue, and allowing a diminished sensation of dyspnea. Therefore, respiratory stimulants may be detrimental over long periods. Bronchospasm (see below), obesity (see Chapter 83), and sleep apnea (see Chapter 7) are reversible conditions that can contribute to hypercapnia and therefore should be treated. Narcotics and sedatives with potential for respiratory depression should be avoided.
Malnutrition is present in 50% of patients with advanced COPD, usually when the FEV1 is <35% of predicted. This is the consequence of increased metabolic demands, insufficient caloric intake, and possibly elaboration of cachexia-producing cytokines such as tumor necrosis factor-α and interleukin-6. Body weight <90% of ideal is associated with increased mortality and decreased exercise capacity in patients with otherwise similar lung function. Muscle wasting and loss of bone mass may be present even in patients who have a normal body mass index (172). Although results of clinical trials of nutritional supplementation have been disappointing, monitoring body weight in COPD patients and prescribing caloric supplementation as needed are prudent because those patients who do gain weight show improved survival (173).
Drug Therapy to Maximize Functional Status
Bronchodilators and anti-inflammatory agents are used in patients with COPD to reverse bronchospasm and prevent bronchoconstriction in response to provocative agents. Small amounts of bronchoconstriction and air trapping can cause marked deterioration in symptoms; conversely, small amounts of bronchodilation can cause considerable improvement in functional capacity. Inhaled corticosteroids do not alter the progression of COPD but do reduce the frequency of exacerbations. Inhaled corticosteroids should be reserved for patients who have an asthmatic component to their disease or those who have frequent exacerbations (174, 175, 176, 177).
Stepped drug treatment should use the minimum number of agents and the least frequent dosing schedule possible, starting with the agents having the greatest benefit and least toxicity. Bronchodilators are given to COPD patients on a regular basis to maintain bronchodilation and on an as-needed basis for relief of symptoms. Most breathless patients benefit from regular use of a bronchodilator. Both β-agonist and anticholinergic classes are available in short-acting (4- to 6-hour duration) and long-acting (12- to 24-hour duration) preparations. The choice between class of bronchodilator and duration of effect depends upon the cost of the preparation and the clinician's preference. A combination of different classes of bronchodilators often is more effective than increasing the dose of a single agent. Many patients with advanced COPD require a combination of bronchodilators, including long-acting maintenance anticholinergics and β-agonists as well as symptomatic use of shorter-acting bronchodilators. In individuals who have frequent exacerbations, inhaled corticosteroids or a combination inhaler of inhaled corticosteroids and long-acting bronchodilator may be added. Theophylline in long-acting oral preparations is a useful
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adjunct to therapy in cases where inhaled medication is too expensive or not acceptable for the patient. Chronic use of systemic corticosteroids should be reserved for individuals with very frequent or life-threatening exacerbations who cannot tolerate their discontinuation. Response to treatment is judged by symptomatic improvement, functional status, and spirometry.
Ipratropium bromide (Atrovent) is an inhaled anticholinergic drug that causes 4 to 8 hours of bronchodilation through inhibition of vagal stimulation of the airways. Although it usually is more expensive than β-agonists, it is the usual choice for first-line therapy. The dosage is started at two MDI inhalations three times daily and can be increased to six inhalations four times daily. Systemic side effects are uncommon, even with relatively high doses (178). Local side effects include mouth irritation and cough, which can be diminished by good inhaler technique or by use of a spacer. Although ipratropium provides sustained benefit in patients with moderate disease, it does not inhibit progression of the disease if smoking is continued (116). Tiotropium (Spiriva) is an anticholinergic bronchodilator that has the benefit of once-daily dosing and is more effective than usual doses of ipratropium in bronchodilation, quality of life, and reducing exacerbations (179, 180, 181). Tolerance does not develop with prolonged use. It is inhaled once daily from a capsule inserted into a dry-powder inhaler. Proper instruction on use of the inhaler is needed, but the dry-powder inhaler does not require as much coordination as an MDI.
β-Adrenergic agonists are used at dosages comparable to those used for asthma (see above). The dosages of inhaled selective β-agonists should be increased before oral agents are prescribed so that tremor and hypokalemia are minimized. Long-acting inhaled β-agonists such as salmeterol (Serevent) and formoterol (Foradil) are useful because of the long duration of action and documented benefit on quality of life (182,183). Both are available in dry-powder inhaler formulations that do not require as much hand-breathing coordination as MDIs. Combination inhaler therapy with a β-agonist and a short-acting anticholinergic provides better bronchodilation than either agent alone, and the simplified treatment regimen may aid compliance (184,185). Combinations of inhaled corticosteroids and long-acting bronchodilators provide more bronchodilation than either alone in patients with chronic bronchitis and airflow obstruction (186).
Theophylline is best taken in a long-acting preparation once or twice daily. Although monitoring of blood levels is possible, there is only a rough correlation between side effects and serum levels. If typical side effects such as nausea, vomiting, tremor, or tachyarrhythmias occur, the dose should be adjusted irrespective of serum levels. Use of theophylline in COPD has diminished because of the availability of long-acting inhaled agents, but it still is an effective and inexpensive second-line drug. Although the bronchodilating effects of theophylline are moderate compared with inhaled drugs, it has other putative pharmacologic actions that improve the well-being of the COPD patient, including improvement in diaphragm function, prevention of respiratory muscle fatigue, increased ventilatory drive, potentiation of catecholamine function, prevention of increased microvascular permeability, increased mucociliary clearance, prevention of late-phase antigen responses, inhibition of mast cell histamine release, and suppression of leukocyte activation (187,188). Clinical trials showing improvement in functional status beyond that gained from the effects of bronchodilation are consistent with improvement in respiratory muscle function (189). New drugs that are more specific inhibitors of phosphodiesterase-4 have not yet been marketed in the United States but hold the promise of similar efficacy with less toxicity.
Oral corticosteroids are effective for treatment of COPD exacerbations (190,191). Among chronic symptomatic patients, 10% to 20% show substantial short-term improvement, defined as ≥25% increase in FEV1. In general, the patients studied had far-advanced disease and did not differ from other COPD patients except with regard to their steroid response. Some have suggested that long-term low-dose oral steroids may slow the progression of the disease, but the evidence is not strong in comparison to the well-defined side effects of such treatment. Most patients with COPD who are on chronic corticosteroid therapy can safely taper the dose at the equivalent of 5 mg prednisone per week and reserve their use exclusively for exacerbations (192). In selected cases, long-term low doses of oral corticosteroids may be prescribed for patients who cannot afford or tolerate inhaled agents.
Inhaled corticosteroids do not alter the progression of COPD in those who continue to smoke (174,176,177). They are most useful in patients who have an overlap between asthma and COPD and those with more advanced disease who have frequent exacerbations. Inhaled corticosteroids can reduce the frequency of exacerbations and improve airway reactivity (174,176). Combined with long-acting bronchodilators, inhaled corticosteroids can reduce symptoms and improve quality of life (186).
Treatment of Chronic Obstructive Pulmonary Disease Exacerbations
COPD exacerbations are characterized by worsening dyspnea, cough, and increased phlegm production. On average, patients with COPD have two to three exacerbations per year, but the number varies widely. Only half of these cases come to the attention of treating practitioners. Precipitating events include respiratory and nonrespiratory infections, exposure to respiratory irritants and air pollution, or comorbid conditions such as heart failure, pulmonary embolism, myocardial ischemia, or pneumothorax. The management of these exacerbations depends upon the severity (193). Patients with severe acute onset of dyspnea; evidence of hypoxemia such as mental confusion, cyanosis
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or desaturation; new onset of chest pain, edema, or arrhythmias; and those with important comorbidities or inadequate social support should be referred for hospitalization. Arterial blood gas studies and chest radiographs are useful for evaluating etiology and severity of acutely ill patients. Increasing the frequency and intensity of inhaled short-acting bronchodilators for several days is effective in mild exacerbations and usually can be managed by patients at home. A hand-held inhaler and spacer usually is adequate, but a nebulizer may be needed for those who cannot coordinate well. Patients who have increasing dyspnea accompanied by a change in the quantity or color of phlegm should be prescribed an antibiotic, with the choice of antibiotic determined by the severity of the underlying disease and the likelihood of treatment failure. A course of corticosteroids, equivalent to 30 to 60 mg prednisone for 7 to 14 days, will shorten the duration of symptoms for ambulatory patients with exacerbations.
Pulmonary Rehabilitation
In patients lacking the capacity to restore damaged lung parenchyma, efforts should be made to optimize activity levels through rehabilitation programs. The content of such programs varies widely but includes some or all of the following elements: education about COPD and its treatment, nutritional counseling, psychological support, pacing and energy conservation training for daily activities, aerobic exercise conditioning, and upper-extremity strength training. Generally, these programs have demonstrated improved exercise endurance and sense of well-being without changes in lung function. The benefits of some components of these programs are better documented than others (194). If a coordinated rehabilitation program is not accessible, many of these elements can be provided individually to ambulatory patients. For example, a regular daily walk for 15 to 30 minutes at a pace that induces mild to moderate dyspnea can be safely prescribed for most patients with COPD. Even with severe COPD, most patients should be able to achieve a goal of walking at 1 to 1.5 mph for 30 min/day. Ambulatory oxygen may be particularly helpful as an adjunct for those with oxygen desaturation during exercise. Instructional materials and support groups for patients and families are widely available through volunteer agencies and the Internet.
Surgery
Surgical resection of bullae is rarely indicated for treatment of COPD. An individual with a single large bulla that occupies more than one third of the hemithorax with preserved carbon monoxide diffusing capacity is likely to do best after bullectomy. Unilateral or bilateral lung transplantation is indicated in some patients with advanced emphysema, usually in individuals younger than 60 years when FEV1 is <25% predicted or if severe pulmonary hypertension is present (195). The goal of lung transplantation is to improve quality of life, but whether that goal is achieved is unclear (196). Lung transplantation is limited by the availability of donor organs and accessibility to transplant centers. Lung volume reduction surgery is a useful procedure in highly selected patients. In this operation, lung tissue is resected, increasing elasticity of the remaining lung and improving the contour and function of the diaphragm. The operative mortality from the procedure ranges from 4% to 10%. Patients who have emphysema most severe in the upper lung regions and severe exercise limitation after rehabilitation are most likely to benefit from this operation (197). Patients with very low diffusion capacity or diffuse emphysema and low FEV1 are at highest surgical risk (198). Chapter 93 discusses the perioperative management of patients with COPD.
Prognosis
In general, the prognosis of patients with chronic airway obstruction (see Natural History) can be estimated from the FEV1 obtained when the patient is clinically stable. One study showed that in moderate obstruction, when FEV1 was >1.25 L, the 5-year survival of patients was only slightly decreased from that of matched controls. If FEV1 was between 0.75 and 1.25 L, 5-year survival decreased to approximately 66% of expected, and if FEV1 was <0.75 L, 5-year survival decreased to 33% of expected (115). Cardiac disease, resting tachycardia, hypercapnia, hypoxemia, and frequent exacerbations pose additional risks to survival, whereas a significant response to bronchodilator therapy (>10% improvement in FEV1) is associated with improved survival. Serial tests of lung function intervals help identify patients with excessive rates of decline.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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