The three most common symptoms in COPD are cough, sputum production, and exertional dyspnea. Many patients have such symptoms for months or years before seeking medical attention. Although the development of airflow obstruction is a gradual process, many patients date the onset of their disease to an acute illness or exacerbation. A careful history, however, usually reveals the presence of symptoms prior to the acute exacerbation. The development of exertional dyspnea, often described as increased effort to breathe, heaviness, air hunger, or gasping, can be insidious. It is best elicited by a careful history focused on typical physical activities and how the patient's ability to perform them has changed. Activities involving significant arm work, particularly at or above shoulder level, are particularly difficult for patients with COPD. Conversely, activities that allow the patient to brace the arms and use accessory muscles of respiration are better tolerated. Examples of such activities include pushing a shopping cart, walking on a treadmill, or pushing a wheelchair. As COPD advances, the principal feature is worsening dyspnea on exertion with increasing intrusion on the ability to perform vocational or avocational activities. In the most advanced stages, patients are breathless doing simple activities of daily living.
Accompanying worsening airflow obstruction is an increased frequency of exacerbations (described below). Patients may also develop resting hypoxemia and require institution of supplemental oxygen.
In the early stages of COPD, patients usually have an entirely normal physical examination. Current smokers may have signs of active smoking, including an odor of smoke or nicotine staining of fingernails. In patients with more severe disease, the physical examination is notable for a prolonged expiratory phase and may include expiratory wheezing. In addition, signs of hyperinflation include a barrel chest and enlarged lung volumes with poor diaphragmatic excursion as assessed by percussion. Patients with severe airflow obstruction may also exhibit use of accessory muscles of respiration, sitting in the characteristic "tripod" position to facilitate the actions of the sternocleidomastoid, scalene, and intercostal muscles. Patients may develop cyanosis, visible in the lips and nail beds.
Although traditional teaching is that patients with predominant emphysema, termed "pink puffers," are thin and noncyanotic at rest and have prominent use of accessory muscles, and patients with chronic bronchitis are more likely to be heavy and cyanotic ("blue bloaters"), current evidence demonstrates that most patients have elements of both bronchitis and emphysema and that the physical examination does not reliably differentiate the two entities.
Advanced disease may be accompanied by systemic wasting, with significant weight loss, bitemporal wasting, and diffuse loss of subcutaneous adipose tissue. This syndrome has been associated with both inadequate oral intake and elevated levels of inflammatory cytokines (TNF-α). Such wasting is an independent poor prognostic factor in COPD. Some patients with advanced disease have paradoxical inward movement of the rib cage with inspiration (Hoover's sign), the result of alteration of the vector of diaphragmatic contraction on the rib cage as a result of chronic hyperinflation.
Signs of overt right heart failure, termed cor pulmonale, are relatively infrequent since the advent of supplemental oxygen therapy.
Clubbing of the digits is not a sign of COPD, and its presence should alert the clinician to initiate an investigation for causes of clubbing. In this population, the development of lung cancer is the most likely explanation for newly developed clubbing.
The hallmark of COPD is airflow obstruction (discussed above). Pulmonary function testing shows airflow obstruction with a reduction in FEV1 and FEV1/FVC (Chap. 252). With worsening disease severity, lung volumes may increase, resulting in an increase in total lung capacity, functional residual capacity, and residual volume. In patients with emphysema, the diffusing capacity may be reduced, reflecting the lung parenchymal destruction characteristic of the disease. The degree of airflow obstruction is an important prognostic factor in COPD and is the basis for the Global Initiative for Lung Disease (GOLD) redundant classification (Table 260-1). More recently it has been shown that a multifactorial index incorporating airflow obstruction, exercise performance, dyspnea, and body mass index is a better predictor of mortality rate than pulmonary function alone.
Table 260-1 Gold Criteria for COPD Severity |Favorite Table|Download (.pdf)
Table 260-1 Gold Criteria for COPD Severity
|0||At Risk||Chronic cough, sputum production||Normal|
|I||Mild||With or without chronic cough or sputum production||FEV1/FVC <0.7 and FEV1 ≥80% predicted|
|IIA||Moderate||With or without chronic cough or sputum production||FEV1/FVC <0.7 and 50% ≤FEV1 <80% predicted|
|III||Severe||With or without chronic cough or sputum production||FEV1/FVC <0.7 and 30% ≤FEV1 <50% predicted|
|IV||Very Severe||With or without chronic cough or sputum production|
FEV1/FVC <0.7 and FEV1 <30% predicted
FEV1 <50% predicted with respiratory failure or signs of right heart failure
Arterial blood gases and oximetry may demonstrate resting or exertional hypoxemia. Arterial blood gases provide additional information about alveolar ventilation and acid-base status by measuring arterial PCO2 and pH. The change in pH with PCO2 is 0.08 units/10 mmHg acutely and 0.03 units/10 mmHg in the chronic state. Knowledge of the arterial pH therefore allows the classification of ventilatory failure, defined as PCO2 >45 mmHg, into acute or chronic conditions. The arterial blood gas is an important component of the evaluation of patients presenting with symptoms of an exacerbation. An elevated hematocrit suggests the presence of chronic hypoxemia, as does the presence of signs of right ventricular hypertrophy.
Radiographic studies may assist in the classification of the type of COPD. Obvious bullae, paucity of parenchymal markings, or hyperlucency suggests the presence of emphysema. Increased lung volumes and flattening of the diaphragm suggest hyperinflation but do not provide information about chronicity of the changes. Computed tomography (CT) scan is the current definitive test for establishing the presence or absence of emphysema in living subjects (Fig. 260-4). From a practical perspective, the CT scan does little to influence therapy of COPD except in those individuals considering surgical therapy for their disease (described below).
Chest CT scan of a patient with COPD who underwent a left single-lung transplant. Note the reduced parenchymal markings in the right lung (left side of figure) as compared to the left lung, representing emphysematous destruction of the lung, and mediastinal shift to the left, indicative of hyperinflation.
Recent guidelines have suggested testing for α1AT deficiency in all subjects with COPD or asthma with chronic airflow obstruction. Measurement of the serum α1AT level is a reasonable initial test. For subjects with low α1AT levels, the definitive diagnosis of α1AT deficiency requires protease inhibitor (PI) type determination. This is typically performed by isoelectric focusing of serum, which reflects the genotype at the PI locus for the common alleles and many of the rare PI alleles as well. Molecular genotyping of DNA can be performed for the common PI alleles (M, S, and Z).
Treatment: Chronic Obstructive Pulmonary Disease
Only three interventions—smoking cessation, oxygen therapy in chronically hypoxemic patients, and lung volume reduction surgery in selected patients with emphysema—have been demonstrated to influence the natural history of patients with COPD. There is currently suggestive, but not definitive, evidence that the use of inhaled glucocorticoids may alter mortality rate (but not lung function). All other current therapies are directed at improving symptoms and decreasing the frequency and severity of exacerbations. The institution of these therapies should involve an assessment of symptoms, potential risks, costs, and benefits of therapy. This should be followed by an assessment of response to therapy, and a decision should be made whether or not to continue treatment.
Smoking Cessation (See Also Chap. 395)
It has been shown that middle-aged smokers who were able to successfully stop smoking experienced a significant improvement in the rate of decline in pulmonary function, returning to annual changes similar to that of nonsmoking patients. Thus, all patients with COPD should be strongly urged to quit and educated about the benefits of quitting. An emerging body of evidence demonstrates that combining pharmacotherapy with traditional supportive approaches considerably enhances the chances of successful smoking cessation. There are three principal pharmacologic approaches to the problem: bupropion, originally developed as an antidepressant medication; nicotine replacement therapy available as gum, transdermal patch, inhaler, and nasal spray; and varenicline, a nicotinic acid receptor agonist/antagonist. Current recommendations from the U.S. Surgeon General are that all adult, nonpregnant smokers considering quitting be offered pharmacotherapy, in the absence of any contraindication to treatment.
In general, bronchodilators are used for symptomatic benefit in patients with COPD. The inhaled route is preferred for medication delivery as the incidence of side effects is lower than that seen with the use of parenteral medication delivery.
Ipratropium bromide improves symptoms and produces acute improvement in FEV1. Tiotropium, a long-acting anticholinergic, has been shown to improve symptoms and reduce exacerbations. Studies of both ipratropium and tiotropium have failed to demonstrate that either influences the rate of decline in FEV1. In a large randomized clinical trial, there was a trend toward reduced mortality rate in the tiotropium-treated patients that approached, but did not reach, statistical significance. Side effects are minor, and a trial of inhaled anticholinergics is recommended in symptomatic patients with COPD.
These provide symptomatic benefit. The main side effects are tremor and tachycardia. Long-acting inhaled β agonists, such as salmeterol, have benefits comparable to ipratropium bromide. Their use is more convenient than short-acting agents. The addition of a β agonist to inhaled anticholinergic therapy has been demonstrated to provide incremental benefit. A recent report in asthma suggests that those patients, particularly African Americans, using a long-acting β agonist without concomitant inhaled corticosteroids have an increased risk of deaths from respiratory causes. The applicability of these data to patients with COPD is unclear.
Although a recent trial demonstrated an apparent benefit from the regular use of inhaled glucocorticoids on the rate of decline of lung function, a number of other well-designed randomized trials have not. Patients studied included those with mild to severe airflow obstruction and current and ex-smokers. Patients with significant acute response to inhaled β agonists were excluded from many of these trials, which may impact the generalizability of the findings. Their use has been associated with increased rates of oropharyngeal candidiasis and an increased rate of loss of bone density. Available data suggest that inhaled glucocorticoids reduce exacerbation frequency by ~25%. The impact of inhaled corticosteroids on mortality rates in COPD is controversial. A meta-analysis and several retrospective studies suggest a mortality benefit, but in a recently published randomized trial, differences in mortality rate approached, but did not reach, conventional criteria for statistical significance. A trial of inhaled glucocorticoids should be considered in patients with frequent exacerbations, defined as two or more per year, and in patients who demonstrate a significant amount of acute reversibility in response to inhaled bronchodilators.
The chronic use of oral glucocorticoids for treatment of COPD is not recommended because of an unfavorable benefit/risk ratio. The chronic use of oral glucocorticoids is associated with significant side effects, including osteoporosis, weight gain, cataracts, glucose intolerance, and increased risk of infection. A recent study demonstrated that patients tapered off chronic low-dose prednisone (~10 mg/d) did not experience any adverse effect on the frequency of exacerbations, health-related quality of life, or lung function. On average, patients lost ~4.5 kg (~10 lb) when steroids were withdrawn.
Theophylline produces modest improvements in expiratory flow rates and vital capacity and a slight improvement in arterial oxygen and carbon dioxide levels in patients with moderate to severe COPD. Nausea is a common side effect; tachycardia and tremor have also been reported. Monitoring of blood theophylline levels is typically required to minimize toxicity.
Supplemental O2 is the only pharmacologic therapy demonstrated to unequivocally decrease mortality rates in patients with COPD. For patients with resting hypoxemia (resting O2 saturation ≤88% or <90% with signs of pulmonary hypertension or right heart failure), the use of O2 has been demonstrated to have a significant impact on mortality rate. Patients meeting these criteria should be on continual oxygen supplementation, as the mortality benefit is proportional to the number of hours/day oxygen is used. Various delivery systems are available, including portable systems that patients may carry to allow mobility outside the home.
Supplemental O2 is commonly prescribed for patients with exertional hypoxemia or nocturnal hypoxemia. Although the rationale for supplemental O2 in these settings is physiologically sound, the benefits of such therapy are not well substantiated.
N-acetyl cysteine has been used in patients with COPD for both its mucolytic and antioxidant properties. A prospective trial failed to find any benefit with respect to decline in lung function or prevention of exacerbations. Specific treatment in the form of IV α1AT augmentation therapy is available for individuals with severe α1AT deficiency. Despite sterilization procedures for these blood-derived products and the absence of reported cases of viral infection from therapy, some physicians recommend hepatitis B vaccination prior to starting augmentation therapy. Although biochemical efficacy of α1AT augmentation therapy has been shown, a randomized controlled trial of α1AT augmentation therapy has not definitively established the efficacy of augmentation therapy in reducing decline of pulmonary function. Eligibility for α1AT augmentation therapy requires a serum α1AT level <11 μM (approximately 50 mg/dL). Typically, PiZ individuals will qualify, although other rare types associated with severe deficiency (e.g., null-null) are also eligible. Since only a fraction of individuals with severe α1AT deficiency will develop COPD, α1AT augmentation therapy is not recommended for severely α1AT-deficient persons with normal pulmonary function and a normal chest CT scan.
Patients with COPD should receive the influenza vaccine annually. Polyvalent pneumococcal vaccine is also recommended, although proof of efficacy in this patient population is not definitive.
This refers to a treatment program that incorporates education and cardiovascular conditioning. In COPD, pulmonary rehabilitation has been demonstrated to improve health-related quality of life, dyspnea, and exercise capacity. It has also been shown to reduce rates of hospitalization over a 6- to 12-month period.
Lung Volume Reduction Surgery (LVRS)
Surgery to reduce the volume of lung in patients with emphysema was first introduced with minimal success in the 1950s and was reintroduced in the 1990s. Patients are excluded if they have significant pleural disease, a pulmonary artery systolic pressure >45 mmHg, extreme deconditioning, congestive heart failure, or other severe comorbid conditions. Patients with an FEV1 <20% of predicted and either diffusely distributed emphysema on CT scan or diffusing capacity of lung for carbon monoxide (DlCO) <20% of predicted have an increased mortality rate after the procedure and thus are not candidates for LVRS.
The National Emphysema Treatment trial demonstrated that LVRS offers both a mortality benefit and a symptomatic benefit in certain patients with emphysema. The anatomic distribution of emphysema and postrehabilitation exercise capacity are important prognostic characteristics. Patients with upper lobe–predominant emphysema and a low postrehabilitation exercise capacity are most likely to benefit from LVRS.
Lung Transplantation (See Also Chap. 266)
COPD is currently the second leading indication for lung transplantation (Fig. 260-4). Current recommendations are that candidates for lung transplantation should be <65 years; have severe disability despite maximal medical therapy; and be free of comorbid conditions such as liver, renal, or cardiac disease. In contrast to LVRS, the anatomic distribution of emphysema and the presence of pulmonary hypertension are not contraindications to lung transplantation. Unresolved issues concerning lung transplantation and COPD include whether single- or double-lung transplant is the preferred procedure.
Exacerbations are a prominent feature of the natural history of COPD. Exacerbations are episodes of increased dyspnea and cough and change in the amount and character of sputum. They may or may not be accompanied by other signs of illness, including fever, myalgias, and sore throat. Self-reported health-related quality of life correlates with frequency of exacerbations more closely than it does with the degree of airflow obstruction. Economic analyses have shown that >70% of COPD-related health care expenditures go to emergency department visits and hospital care; this translates to >$10 billion annually in the United States. The frequency of exacerbations increases as airflow obstruction increases; patients with moderate to severe airflow obstruction [GOLD stages III, IV (Table 260-1)] on average have one to three episodes per year. However, some individuals with very severe airflow obstruction do not have frequent exacerbations; the history of prior exacerbations is a strong predictor of future exacerbations.
The approach to the patient experiencing an exacerbation includes an assessment of the severity of the patient's illness, both acute and chronic components; an attempt to identify the precipitant of the exacerbation; and the institution of therapy.
Precipitating Causes and Strategies to Reduce Frequency of Exacerbations
A variety of stimuli may result in the final common pathway of airway inflammation and increased symptoms that are characteristic of COPD exacerbations. Bacterial infections play a role in many, but by no means all, episodes. Viral respiratory infections are present in approximately one-third of COPD exacerbations. In a significant minority of instances (20–35%), no specific precipitant can be identified.
Despite the frequent implication of bacterial infection, chronic suppressive or "rotating" antibiotics are not beneficial in patients with COPD. This is in contrast to their efficacy in patients with bronchiectasis due to cystic fibrosis, in whom suppressive antibiotics have been shown to reduce frequency of hospital admissions.
The role of pharmacotherapy in reducing exacerbation frequency is less well studied. Chronic oral glucocorticoids are not recommended for this purpose. Inhaled glucocorticoids reduce the frequency of exacerbations by 25–30% in most analyses. The use of inhaled glucocorticoids should be considered in patients with frequent exacerbations or those who have an asthmatic component, i.e., significant reversibility on pulmonary function testing or marked symptomatic improvement after inhaled bronchodilators. Similar magnitudes of reduction have been reported for anticholinergic and long-acting beta-agonist therapy. The influenza vaccine has been shown to reduce exacerbation rates in patients with COPD.
An attempt should be made to establish the severity of the exacerbation as well as the severity of preexisting COPD. The more severe either of these two components, the more likely that the patient will require hospital admission. The history should include quantification of the degree of dyspnea by asking about breathlessness during activities of daily living and typical activities for the patient. The patient should be asked about fever; change in character of sputum; any ill contacts; and associated symptoms such as nausea, vomiting, diarrhea, myalgias, and chills. Inquiring about the frequency and severity of prior exacerbations can provide important information.
The physical examination should incorporate an assessment of the degree of distress of the patient. Specific attention should be focused on tachycardia, tachypnea, use of accessory muscles, signs of perioral or peripheral cyanosis, the ability to speak in complete sentences, and the patient's mental status. The chest examination should establish the presence or absence of focal findings, degree of air movement, presence or absence of wheezing, asymmetry in the chest examination (suggesting large airway obstruction or pneumothorax mimicking an exacerbation), and the presence or absence of paradoxical motion of the abdominal wall.
Patients with severe underlying COPD, who are in moderate or severe distress or those with focal findings should have a chest x-ray. Approximately 25% of x-rays in this clinical situation will be abnormal, with the most frequent findings being pneumonia and congestive heart failure. Patients with advanced COPD, those with a history of hypercarbia, those with mental status changes (confusion, sleepiness), or those in significant distress should have an arterial blood-gas measurement. The presence of hypercarbia, defined as a PCO2 >45 mmHg, has important implications for treatment (discussed below). In contrast to its utility in the management of exacerbations of asthma, measurement of pulmonary function has not been demonstrated to be helpful in the diagnosis or management of exacerbations of COPD.
There are no definitive guidelines concerning the need for inpatient treatment of exacerbations. Patients with respiratory acidosis and hypercarbia, significant hypoxemia, or severe underlying disease or those whose living situation is not conducive to careful observation and the delivery of prescribed treatment should be admitted to the hospital.
Typically, patients are treated with an inhaled β agonist, often with the addition of an anticholinergic agent. These may be administered separately or together, and the frequency of administration depends on the severity of the exacerbation. Patients are often treated initially with nebulized therapy, as such treatment is often easier to administer in older patients or to those in respiratory distress. It has been shown, however, that conversion to metered-dose inhalers is effective when accompanied by education and training of patients and staff. This approach has significant economic benefits and also allows an easier transition to outpatient care. The addition of methylxanthines (such as theophylline) to this regimen can be considered, although convincing proof of its efficacy is lacking. If added, serum levels should be monitored in an attempt to minimize toxicity.
Patients with COPD are frequently colonized with potential respiratory pathogens, and it is often difficult to identify conclusively a specific species of bacteria responsible for a particular clinical event. Bacteria frequently implicated in COPD exacerbations include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. In addition, Mycoplasma pneumoniae or Chlamydia pneumoniae are found in 5–10% of exacerbations. The choice of antibiotic should be based on local patterns of antibiotic susceptibility of the above pathogens as well as the patient's clinical condition. Most practitioners treat patients with moderate or severe exacerbations with antibiotics, even in the absence of data implicating a specific pathogen.
Among patients admitted to the hospital, the use of glucocorticoids has been demonstrated to reduce the length of stay, hasten recovery, and reduce the chance of subsequent exacerbation or relapse for a period of up to 6 months. One study demonstrated that 2 weeks of glucocorticoid therapy produced benefit indistinguishable from 8 weeks of therapy. The GOLD guidelines recommend 30–40 mg of oral prednisolone or its equivalent for a period of 10–14 days. Hyperglycemia, particularly in patients with preexisting diagnosis of diabetes, is the most frequently reported acute complication of glucocorticoid treatment.
Supplemental O2 should be supplied to keep arterial saturations ≥90%. Hypoxemic respiratory drive plays a small role in patients with COPD. Studies have demonstrated that in patients with both acute and chronic hypercarbia, the administration of supplemental O2 does not reduce minute ventilation. It does, in some patients, result in modest increases in arterial PCO2, chiefly by altering ventilation-perfusion relationships within the lung. This should not deter practitioners from providing the oxygen needed to correct hypoxemia.
Mechanical Ventilatory Support
The initiation of noninvasive positive-pressure ventilation (NIPPV) in patients with respiratory failure, defined as PaCO2 >45 mmHg, results in a significant reduction in mortality rate, need for intubation, complications of therapy, and hospital length of stay. Contraindications to NIPPV include cardiovascular instability, impaired mental status or inability to cooperate, copious secretions or the inability to clear secretions, craniofacial abnormalities or trauma precluding effective fitting of mask, extreme obesity, or significant burns.
Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated for patients with severe respiratory distress despite initial therapy, life-threatening hypoxemia, severe hypercarbia and/or acidosis, markedly impaired mental status, respiratory arrest, hemodynamic instability, or other complications. The goal of mechanical ventilation is to correct the aforementioned conditions. Factors to consider during mechanical ventilatory support include the need to provide sufficient expiratory time in patients with severe airflow obstruction and the presence of auto-PEEP (positive end-expiratory pressure), which can result in patients having to generate significant respiratory effort to trigger a breath during a demand mode of ventilation. The mortality rate of patients requiring mechanical ventilatory support is 17–30% for that particular hospitalization. For patients age >65 admitted to the intensive care unit for treatment, the mortality rate doubles over the next year to 60%, regardless of whether mechanical ventilation was required.