Chronic obstructive pulmonary disease rates are growing. Is use of inhaled corticosteroids an efficacious treatment?

Chronic obstructive pulmonary disease (COPD) refers to a spectrum of chronic diseases characterized by shortness of breath, coughing, sputum production, airflow limitation, and impaired gas exchange.¹ Most patients with COPD have either chronic bronchitis or emphysema. Collectively, these diseases affect up to 30 million people in the United States^2-4 and represent the fifth leading cause of death.^3,5 The death rate from COPD has increased 22% over the past decade.⁵ The mortality rate 10 years after diagnosis is greater than 50%, and this percentage is on the rise.⁵ Cigarette smoking is by far the most important etiologic factor. Although progress has been made in reducing US smoking rates, COPD prevalence and mortality are still increasing in most of the world and probably will continue to rise in response to increases in smoking (particularly by women and adolescents).²

Emphysema is characterized pathophysiologically by permanent, abnormal airspace enlargement.⁶ This enlargement occurs distal to the terminal bronchioles, and is associated with destruction of the airspace walls. Chronic bronchitis is characterized by chronic cough, sputum production, and inflammation of the mucosal surfaces of the larger airways.

Clinical Manifestations
The preclinical course of patients with COPD is highly variable. Patients with a history of lung disease early in life may exhibit reduced pulmonary function in adulthood. Smoking in patients with a history of childhood lung disease may lead to a progressive decline in lung function. Other patients who smoke probably begin adulthood with normal lung function. Forced expiratory volume in 1 second (FEV1) usually remains within normal limits until middle age, when a rapid decline in pulmonary function ensues. Generally, this decline stops in patients who quit smoking. The clinical symptoms of COPD generally will appear in patients who continue to smoke.

Patients with COPD usually present with shortness of breath, coughing, and/or wheezing. Coughing usually indicates excess mucus production. The shortness of breath is a result of increased work of breathing through obstructed airways, and is usually associated, initially, with increasing levels of exertion. Over time, the dyspnea worsens to the point of occurring at rest. Wheezing occurs as a result of airway narrowing, mucosal edema, and retained secretions. Typically, patients with chronic pulmonary disease have been described as either blue bloaters or pink puffers. Blue bloaters have central cyanosis with secondary polycythemia and edema. Arterial blood gas evaluation usually reveals evidence of hypoxemia (a PO2 of 45 to 55 mm Hg), carbon dioxide retention (a PCO2 of 50 to 60 mm Hg), and compensated respiratory acidosis (a pH of 7.38 to 7.42).⁷ Pink puffers do not have secondary polycythemia, and edema is not present. They have less hypoxemia (a PO2 of 60 to 80 mm Hg) and no carbon dioxide retention (a PCO2 of 30 to 40 mm Hg).7 Many patients have features of both conditions.

General Management
The general principles of management of patients with COPD are to slow disease progression, prevent infection, treat reversible symptoms, and educate patients. The RT is intimately involved in all four cornerstones of care.

If the extent of disease is not completely irreversible (end stage), progression of disease can be slowed by smoking cessation, reduction of exposure to environmental or occupational irritants, and supplemental oxygen therapy.

Infection is usually considered the main cause of acute exacerbation in COPD; however, many COPD patients have evidence of bacterial colonization of the lower respiratory tract even during periods of remission.⁸ In fact, potentially pathogenic organisms can be recovered from the respiratory-tract secretions of virtually all patients with COPD at some time during the course of their disease.8 Many bacterial and other organisms have been found in the sputum of patients with chronic pulmonary disease. These include Haemo-

philus influenzae, Streptococcus pneumoniae, Streptococcus viridans, Klebsiella species, Moraxella (formerly called Branhamella) catarrhalis, Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans (a fungus). Nonetheless, the role of antibiotic therapy in acute exacerbations of COPD remains controversial. Broad-spectrum antibiotic prophylaxis has not been shown to decrease the frequency of infections, but may decrease the severity and duration of symptoms. Recent evidence⁹ has shown that bacterial colonization is associated with enhanced airway inflammation, and that resolution of bronchial inflammation following acute exacerbations of chronic bronchitis may be related to bacterial eradication. Patients with COPD should be encouraged to have annual influenza vaccinations. Some authorities also recommend vaccination against pneumococcal disease. Pharmacotherapy using beta-2-agonists and long-acting theophylline preparations may reverse the symptoms of airway obstruction.

Education should be an integral part of chronic pulmonary disease management. Patients and their families should be given basic facts about the disease process and offered a list of resources in the event that they desire additional information. Medication issues should be addressed. If appropriate, the subjects of intubation and resuscitative intervention should be reviewed and the patient’s desires should be delineated.

Surgery and Rehabilitation
Surgical procedures for COPD are very rare. They are expensive and are not often covered by insurance. The great majority of patients cannot be helped by surgery, and no single procedure is ideal for those who can be helped.

Lung transplantation has been successfully employed in some patients with end-stage COPD. After transplantation, pulmonary function is usually markedly improved. Postoperatively, dyspnea at rest is abolished in most patients, and dyspnea on exertion is significantly diminished. Supplemental oxygen usually is no longer required, and exercise tolerance is markedly improved. Unfortunately, lung transplantation is associated with potentially severe complications, including pulmonary edema, ventilation-perfusion abnormalities, and organ rejection. Patients in the hands of an experienced team have a 3-year survival rate of approximately 50%.^10,11

Lung-volume–reduction surgery removes 20% to 30% of severely diseased lung tissue; the remaining parts of the lung are joined together. Mortality rates can be as high as 15%, and complication rates are even higher. When the operation is successful, patients report significant improvement in symptoms.¹²

A structured, outpatient pulmonary rehabilitation program improves functional capacity in certain patients with COPD. Services may include general exercise training, administration of oxygen and nutritional supplements, intermittent mechanical ventilatory support, continuous positive airway pressure, relaxation techniques, breathing exercises and techniques (such as pursed-lip breathing), and methods for mobilizing and removing secretions.

Inhaled Corticosteroids
Inhaled corticosteroids are used for long-term maintenance treatment in COPD; however, the efficacy of these agents is controversial. There are at least two possible reasons why COPD patients might respond to anti-inflammatory treatment, despite the general acknowledgment that the loss of lung-tissue elasticity is relatively fixed. Some asthma patients may be misdiagnosed as COPD patients. The British Thoracic Society’s COPD guidelines¹³ point out that the differentiation of severe COPD from chronic severe asthma can be difficult because some degree of reversibility (shown as improvement in FEV1) can be achieved in the majority of patients. The pathological changes of bronchial asthma in the large airways can coexist with those of COPD, which predominantly affects the small airways. Patients with COPD who respond to corticosteroids may have a degree of inflammation that may be a component specific to the disease.

While the presence of inflammatory changes in the airways of patients with COPD provides a rationale for the use of corticosteroids,¹⁴ the association between these changes, lung function, and the therapeutic response to corticosteroids has not yet been established clearly. Several uncontrolled retrospective studies^15,16 performed in the 1980s suggested that long-term treatment with oral corticosteroids might slow the decline in FEV1 in patients with COPD. Long-term use of oral cortico-

steroids would not generally be recommended, however, because of the risk of systemic side effects. Inhaled corticosteroids offer an option for achieving similar benefits with fewer systemic side effects. More recent investigations evaluating the efficacy of corticosteroids in COPD have focused on inhaled agents.

An early trial¹⁷ of inhaled corticosteroids in COPD suggested an improvement in FEV1 and reduction in the decline in FEV1 over a year of treatment using inhaled beclomethasone. A 2-year study¹⁸ of inhaled budesonide (1,600 µg/day) showed a significant reduction in respiratory symptoms, with a halving of the median decline in FEV1 in a group of nonallergic patients with COPD (30 mL/year in the budesonide group, compared with 60 mL/year in the placebo group). The number of patients withdrawing due to pulmonary problems was significantly higher in the placebo group.

The Inhaled Steroids in Obstructive Lung Disease Study¹⁹ was a UK-based, multicenter, double-blind, placebo-controlled study of fluticasone (500 µg, given twice daily) in 753 patients with moderate-to-severe COPD, with the main outcome measure being the rate of decline of postbronchodilator FEV1 over 3 years. Secondary endpoints were the frequency rates for exacerbations, changes in health status, withdrawals because of respiratory disease, morning serum cortisol concentrations, and adverse events. Patients recruited had a diagnosis of COPD, were 40 to 75 years old, and had postbronchodilator FEV1 levels that were less than 70% of the predicted values. The average prebronchodilator FEV1 was 1.24 L, suggesting that the group had severe COPD. There was no difference in the decline of respiratory function, as measured by FEV1, over the 3 years of the study in the fluticasone or placebo groups (59 mL/year versus 50 mL/year). The yearly exacerbation rate was lower in the fluticasone group than in the placebo group (0.99 versus 1.32 per year; P=.026). This resulted in three patients being treated with high-dose fluticasone for a year (at a US retail pharmacy cost of $1,500 per patient) to prevent one exacerbation requiring steroids or antibiotics. Health status, measured by the increase in a questionnaire score, declined at a slower rate in the fluticasone group than in the placebo group (2 versus 3.2 units per year; P=.004). Adverse effects were similar in each group. The only clinical benefit seen in this trial was a decrease in the frequency of exacerbations requiring oral steroid or antibiotic treatment.

The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease²⁰ compared budesonide (400 µg, given twice daily) to placebo in actively smoking subjects with mild COPD (mean FEV1=2.54 L) over a period of 3 years. The primary outcome was the rate of post-bronchodilator decline in FEV1. Over the first 6 months of the study, the FEV1 improved by about 10 mL in the budesonide group while it declined by about 40 mL in the placebo group. Thereafter, the rates of FEV1 decline were nearly similar in the two groups. Patients receiving active treatment experienced significantly more skin bruising and adverse upper airway effects. Thus, relatively large doses of inhaled corticosteroids given for 3 years to smokers with mild COPD were associated with some side effects and limited benefit.

A recent meta-analysis²¹ of five randomized, placebo-controlled trials of inhaled corticosteroids in patients with COPD was performed to evaluate the long-term effects of these agents on the rate of FEV1 decline in patients with COPD. The use of inhaled corticosteroids did not change the rate of FEV1 decline in 3,571 patients followed for 24 to 54 months.

Investigators have evaluated, in a randomized, double-blind, parallel-group, placebo-controlled study,²² whether the combination of inhaled beta-2-agonists and inhaled corticosteroids provides better pulmonary outcomes than treatment with either agent alone in patients with COPD. Subjects were treated with 50 µg of salmeterol, given twice daily (n=372); 500 µg of fluticasone, given twice daily (n=374); a combination of both drug regimens (n=358); or placebo (n=361) for 12 months. All of the active treatments improved lung function, pulmonary symptoms, and health status, and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly better than placebo, salmeterol alone, or fluticasone alone. Combination treatment also produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. Based on these results, the investigators suggested that the combination of inhaled long-acting beta-2-agonists and corticosteroids be considered for patients with COPD.

Summary
The evidence base showing efficacy for inhaled corticosteroids in COPD is growing, but the results of major trials are still mixed, and the use of inhaled corticosteroids is still controversial. The therapy chosen for COPD should be tailored to the individual patient. Some clinicians suggest targeting use of inhaled corticosteroids to those patients who respond to a 2-week trial of these agents.

John D. Zoidis, MD, is a contributing writer for RT.

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