COPD: Diagnosis and Treatment Update on the Nation’s Fourth Leading Killer

Chronic obstructive pulmonary disease (COPD) affects approximately 30 million Americans and claims 112,000 lives annually. It is the fourth most common cause of death in the United States, and the only one of the four that is increasing in frequency. The American Lung Association estimated in 1999 that the total national cost of COPD care was more than $30 billion, divided almost equally between direct costs for care providers, medications, and hospitalizations and indirect costs associated with lost productivity. COPD is largely, but not exclusively, a disease of tobacco smokers, occurring most frequently in individuals over 40 years of age who have smoked an average of 20 cigarettes per day for 20 years or more. COPD in non-smokers involves other pulmonary toxins such as some solvents and fume-producing chemicals used in manufacturing processes.

In 2001, a Global Initiative for Chronic Obstructive Lung Disease undertaken jointly by the World Health Organization (WHO) and the National Heart, Lung, and Blood Institute (NHLBI) resulted in a Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. This strategy, known simply as the GOLD guidelines, includes criteria for staging the disease and a treatment algorithm. In this symposium, the faculty discussed the diagnosis and treatment of COPD, emphasizing the application of these guidelines.

The goal of drug therapy for allergic rhinitis is to provide relief from symptoms and abatement of comorbidities and complications without inducing sedation, a common side effect associated with antihistamines. Treatment-induced sedation and psychomotor deficits are often cited as causes of motor vehicle and industrial accidents.

This program was supported by an unrestricted educational grant from GlaxoSmithKline.

Recent Advances in the Diagnosis and Management of COPD

Eugene R. Bleecker, MD (Wake Forest University) defined COPD as airflow limitation or airway obstruction that is usually progressive, but which has a reversible component. It is associated with an abnormal inflammatory response in the airway to environmental irritants and pollutants that differs in some ways from asthma, and is also associated with altered lung mechanics. These characteristics result in the typical spectrum of symptoms by which the disease is recognized: cough and mucous production from airway irritation, and breathlessness and wheezing from altered lung function. Approximately 20% of patients with COPD report frequent awakenings due to shortness of breath.

COPD frequently presents as a productive cough with or without acute chest pain following flu or an upper respiratory tract infection. In non-acute cases, the gradual loss of respiratory efficiency results in corresponding inability to maintain normal daily activities. The earlier in disease progression the individual seeks medical intervention, the greater the probability of arresting or reversing some components of the pathogenic process. Removal of environmental causes is an integral part of therapy. Smoking cessation is essential, as 20% to 25% of chronic smokers are prone to this disease.

The large degree of overlap between the clinical manifestations of COPD and those of other obstructive airway diseases—asthma, chronic bronchitis, and emphysema—complicates the differential diagnosis. For example, although airway obstruction in COPD is generally irreversible but reversible in asthma, it may be difficult to differentiate COPD patients with a reversible asthma-like component from patients with asthma who have elements of irreversible disease. This is further complicated in patients with asthma who smoke. This overlap led to competing hypotheses in the 1960s as to the genesis of COPD. The “British hypothesis” dismissed the similarities with asthma and regarded COPD as a disease caused by exposure to tobacco smoke followed by infection and irreversible destruction of lung tissue. The “Dutch hypothesis” recognized the similarities between COPD and asthma, but also postulated that because only about one in five chronic smokers develops COPD, there might be an element of genetic susceptibility. Advocates of this view thought that both diseases involve genetic predisposition related to altered immune or atopic responses to irritants and pollutants resulting in bronchial hyperresponsiveness. In Dr. Bleecker’s view, both diseases involve hereditary susceptibility and environmental factors, with exposure to allergens and viral respiratory pathogens of primary importance in asthma and pollutants, especially tobacco smoke, the primary agents in COPD.

Despite the overlap between asthma and COPD, they differ in important ways. One is that the inflammatory patterns differ, with asthma characterized by eosinophilic allergic inflammation and, in more severe forms, by neutrophilic inflammation. Patients with COPD typically have mononuclear and neutrophilic inflammation. Patients with COPD have more hypersecretion and may eventually undergo changes in mucous-producing cells, whereas epithelial damage in the respiratory tree is typical of asthma. Changes in airway smooth muscle and basement membrane thickening may occur in patients with asthma. Alveolar destruction occurs in patients with COPD who progress to emphysema. Impaired mucous clearance is characteristic of both diseases. The most profound difference between the two diseases is at the extremes: reversible allergy-induced asthma at one end and advanced COPD with emphysema (destroyed lung tissue, loss of elastic recoil, and airway collapse) at the other.

The diagnosis of COPD is based on symptoms, irritants to which the respiratory system has been exposed, and spirometry. Spirometry is the diagnostic gold standard, the standard means of monitoring disease severity and progression, and the basis for predicting outcomes and evaluating therapeutic response. Forced expiratory volumein one second over vital capacity (FEV1/FVC) is easily measured and reproducible. Airway obstruction is defined as FEV1/FVC of less than 0.70. The value of FEV1, represented as a percentage of predicted, defines disease severity. In the GOLD criteria, for example, severe obstruction is defined as FEV1 less than 30%, with risk of death from respiratory failure increasing at an FEV1 level of 40%. Thus it is essential to maintain patients above this level using therapeutic lifestyle modifications and pharmacologic intervention.

The GOLD guidelines are designed to increase awareness of COPD and to decrease morbidity and mortality by providing evidence-based treatment standards. A ranking system indicates the quality of evidence underlying each recommendation. The A category is based on a rich body of evidence from randomized, controlled studies; the B category on limited evidence from such trials; the C category on data from non-randomized or observational trials; and the D category on expert judgment and the study panel’s consensus. For the overall management of COPD, GOLD recommends bronchodilators, preferably inhaled, as needed or chronically (category A), with the choice of agents based on efficacy, individual response, and side effects. Smoking cessation, exercise training, and vaccination against influenza are category A recommendations as is oxygen therapy in cases of respiratory failure. Avoidance of indoor and outdoor occupational exposures is recommended based on category B evidence. Vaccination against S. pneumoniae is
recommended without documentary evidence.

The GOLD staging criteria for COPD appear in Table 1. The majority of patients who require maintenance therapy are in stages II and A and B and stage III.

Inhaled long-acting bronchodilators are the cornerstone of maintenance treatment for COPD because of efficacy, minimal systemic exposure, and convenience for patients. Category B evidence indicates that inhaled corticosteroids improve lung function by more than 12% and that they may reduce the frequency of exacerbations. Chronic use of oral corticosteroids is not recommended (category A) because of an unfavorable benefit-to-risk ratio, but they are useful for acute therapy during exacerbations. Because so many COPD patients have progressive disease, maintenance therapy is typically a step-up process, with a general preference for adding agents rather than increasing doses.

Dr. Bleecker concluded his presentation by emphasizing the importance of COPD prevention, early recognition, and timely intervention. The vital link in the healthcare chain for achieving these is not the specialist to whom the symptomatic patient is referred, but the community of primary care clinicians.

Therapeutic Options for COPD

Although many patients with stage IIB or stage III COPD visit pulmonologists because they are continuously breathless, “the most important thing we see in our practices are the acute exacerbations of COPD [AECOPD],” according to James F. Donohue, MD (University of North Carolina). These events occur most frequently during the winter months. Patients typically present with breathlessness, wheeze, cough, and increased production of sputum that may be either mucoid (white) or purulent (yellow or green). AECOPD may result from viruses, environmental causes, allergy, or, most importantly, bacterial infection. Because fever is not a typical component of AECOPD, escalation of symptoms is the principal diagnostic guide.

The bacteria most frequently associated with AECOPD are Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Legionella and strains of Mycoplasma and Chlamydia are seen less often. Patients who suffer frequent exacerbations may be infected with Staphylococcus or with Gram negative organisms. Pseudomonas aeruginosa is frequently isolated in cases of end-stage respiratory failure. Because AECOPD can be life-threatening in patients with stage IIB or stage III disease, Gram stains are usually omitted in outpatients. Treatment is empiric. The treatment algorithm for bacterial infection in AECOPD is outlined in Table 2.

Monitoring lung function during exacerbations is important because the severity of airflow obstruction correlates with the patient’s risk for respiratory failure. At an FEV1 level of approximately 30%, older patients may begin to retain CO2 and go into respiratory failure. In younger individuals, the threshold is approximately 25%. In either case, an FEV1 value of less than 40% is a risk factor for a poor outcome. Other risk factors are age, comorbid conditions (e.g., nearly half of COPD patients have concurrent heart disease), frequent exacerbations, mucus hypersecretion, need for oral corticosteroid therapy, and continued smoking. Each AECOPD accelerates the downward spiral, thus underscoring the importance of preventing exacerbations with aggressive maintenance therapy and minimizing the cumulative damage of exacerbations by escalating antibiotic treatment.

In approximately 2% of COPD patients, almost exclusively Caucasian, a severe form of the disease is inherited as a1-antitrypsin deficiency. This deficiency reduces protection against neutrophil elastase and leads to destruction of lung parenchyma and early-onset emphysema. Irritation caused by smoke and other environmental agents recruits neutrophils to the lungs. When the neutrophils break down, they release elastase. In individuals who are homozygous for the deficiency, less than 15% of a1-antitrypsin is released from the liver, where it is produced. The twin consequences are inadequate neutralization of neutrophil elastase in the lungs and the development of severe hepatic disease including cirrhosis and hepatoma. Based on this pattern, Dr. Donohue suggested that younger patients with COPD and liver disease who have family histories of COPD be tested for this deficiency. The only therapy currently approved is weekly or biweekly intravenous infusion of human a1-antitrypsin 60 mg/kg. The efficacy of the same agent administered by inhalation is currently being investigated.

Patients with stage IIB and stage III COPD are at risk for hypoxemia, cor pulmonale, hypercapnia, and dyspnea. Hypoxemia adversely affects cellular metabolism and may lead to pulmonary hypertension or cor pulmonale. Because the signs and symptoms of hypoxemia are nonspecific, accurate identification requires arterial blood gas measurements. Pulse oximetry is of less value. Nocturnal symptoms present in 25% to 45% of patients with late-stage COPD. Oxygen supplementation is the mainstay of therapy.

Hypercapnia is characterized as an arterial CO2 value of 44% or higher. In COPD, this correlates with an FEV1 level of approximately 30%. The suggested therapy in respiratory failure is noninvasive ventilation. Hypercapnia in association with higher FEV1 levels is most likely due to obstructive sleep apnea.

Cor pulmonale, a complication of hypoxemia and an indicator of poor prognosis, is treated almost exclusively with oxygen. Pulmonary vasodilators offer no clear benefits, and may intensify hypoxemia. Diuretics may improve ventricular function, but must be monitored closely for side effects. Digoxin is contraindicated except as may be required to treat concurrent left-sided congestive heart failure.

Inhaled corticosteroids (beclometha-sone, budesonide, flunisonlide, fluticasone, and triamcinolone) decrease the frequency and severity of AECOPD and improve the quality of the patient’s life, but five large studies ranging in duration from 6 months to 3 years indicate that inhaled corticosteroids do not modify the long-term decline in FEV1. Older normal lungs lose approximately 24 cc per year of lung function. For patients with COPD, loss accelerates to approximately 50 cc per year (85 cc per year with a1-antitrypsin deficiency). Thus, a patient with a baseline FEV1 of 700 cc will be unable to breathe in a few years.

The use of inhaled corticosteroids may be associated with skin bruising in older patients. These agents may also complicate osteopenia/osteoporsis in postmenopausal women and men under treatment for benign prostatic hyperplasia. Inhaled corticosteroids do reduce both exacerbations and the risk of readmission to the hospital, and may reduce mortality. More data are needed to confirm these benefits.

In the general treatment of COPD, it was once thought that long-acting b2-agonists should be restricted to patients who respond to short-acting agents, but this has been rejected on the basis of clinical evidence. Anthonisen and colleagues demonstrated in 1986 that 50% of patients responded to albuterol after one visit and an additional 33% responded over the next six visits (Anthonisen NR et al. Am Rev Respir Dis 1986;133:14). Consequently, a 2-month trial course is needed to determine if a patient is a responder. In another study of bronchodilation using albuterol, ipratropium, and a combination of the two, Dorinsky et al. determined that more than 80% of patients got relief from combination therapy within 120 minutes of administration compared with approximately 70% with each of the drugs individually (Dorinsky PM et al. Chest 1999;115: 966). In addition to bronchodilation, long-acting b2-agonists have several functions. They reduce airway edema, improve mucociliary clearance, and reduce the frequency of exacerbations. Figure 1 depicts the complementary effects of combining corticosteroids with long-acting b2-agonists.

The study by Dorinsky et al. is one of many indicating the potential value of combining drugs of different classes to augment clinical benefit. Combinations of corticosteroids and long-acting b2-agonists have been shown to have additive effects. Currently, formulations that combine (i) fluticasone and salmeterol (already approved for asthma) and (ii) budesonide and formoterol are under investigation.

Cholinergic mechanisms play a prominent role in COPD, suggesting that anticholinergic agents might be therapeutically useful by reducing vagal tone and, with it, resistance of the airway muscles. The GOLD guidelines recommend the combination of long-acting b2-agonists such as salmeterol or formoterol with anticholinergic agents such as ipratropium. In a COPD bronchodilation trial using salmeterol and ipratropium in combination compared with salmeterol alone or placebo, combination therapy was significantly (p<0.05) more effective than salmeterol monotherapy at all time points: 4, 8, and 12 weeks (van Noord et al. Eur Respir J 2000;15:878). Tiotropium, a new, once-daily inhaled anticholinergic agent, was recently approved for use in Europe but is not available in the United States. In a pivotal randomized and controlled comparison with salmeterol, improvement in the mean FEV1 level was significantly greater in the tiotropium arm than in the salmeterol arm at all time points up to 169 days except on day 1 (Donohue JF. Chest 2002;122:47).

Theophyllines are also good agents in COPD, having both bronchodilatory and mild anti-inflammatory properties. They have a very narrow therapeutic index, however, and should be used with care.

Dr. Donohue concluded his presentation by reiterating that COPD patients are extensive users of the healthcare system. Consequently, office and clinic visits provide the primary opportunity for improving disease management and for decreasing the frequency of acute attacks in severely ill patients.