Until results are published from the major ongoing trials with inhaled corticosteroids in COPD, the best clinicians can do is to make efforts to clearly differentiate the condition from asthma by using spirometry to investigate reversibility

ZoidisThe term “chronic obstructive pulmonary disease” (COPD) refers to a spectrum of chronic pulmonary diseases characterized by shortness of breath, coughing, sputum production, airflow limitation, and impaired gas exchange.1 The bulk of patients with COPD have either chronic bronchitis or emphysema. Collectively, these diseases affect between 11 million and 30 million people in the United States,1-4 and represent the fifth leading cause of death.1,3-5

The death rate from COPD has increased by 22% in the past decade.1,5 The mortality rate 10 years after diagnosis is greater than 50%, and this percentage is on the rise.1,5 Cigarette smoking is an important etiologic factor. Prevalence, incidence, and mortality increase with age, and are higher in males than in females.2 Prevalence is especially increasing in females, largely as a result of increased cigarette smoking by women.2

COPD is characterized by permanent abnormal airspace enlargement. 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.4,6

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, cough, 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 initially associated 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 (ABG) evaluation usually reveals evidence of hypoxemia (PO2, 45-55 mm Hg), carbon dioxide retention (PCO2, 50-60 mm Hg), and compensated respiratory acidosis (pH, 7.38-7.42).4 Pink puffers do not have secondary polycythemia, and edema is not present. They have less hypoxemia (PO2, 60-80 mm Hg) and no carbon dioxide retention (PCO2, 30-40 mm Hg).4 Many patients have features of both conditions.

General Principles of Management
The general principles of management of the patient with COPD are as follows: slow disease progression; prevent infection; treat reversible symptoms; and educate patients. The respiratory care practitioner is intimately involved in all four cornerstones of care.

Slow Disease Progression
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 therapy with supplemental oxygen.

Prevent Infection
Patients with COPD should be encouraged to have annual influenza vaccinations. Some authorities also recommend vaccination against pneumococcal disease. Many bacterial and other organisms have been found in the sputum of patients with chronic pulmonary disease. These include: Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus viridans, Klebsiella species, Moraxella (formerly called Branhamella) catarrhalis, Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans (a fungus). Broad-spectrum antibiotic prophylaxis has not been shown to decrease the frequency of infections, but may decrease the severity and duration of symptoms.

Treat Reversible Symptoms
Pharmacotherapy with b-agonists and long-acting theophylline preparations may reverse the symptoms of airway obstruction. The use of inhaled corticosteroids is reviewed in this article.

Educate Patients
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 they desire additional information. Medication issues should be addressed. If appropriate, the subject of intubation and resuscitative intervention should be reviewed and the patient’s desires should be delineated.

Surgical procedures for COPD are very rare. They are expensive and often not 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. In January 1996, the government temporarily suspended Medicare payments for lung reduction surgery.

•Lung Transplantation. Lung transplantation has been successfully employed in some patients with end-stage COPD. In the hands of an experienced team, the 1-year survival rate is more than 70%.

• Lung Volume Reduction. These procedures remove 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.

Pulmonary Rehabilitation
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 (CPAP), relaxation techniques, breathing exercises and techniques (such as pursed lip breathing), and methods for mobilizing and removing secretions.

Use of 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 having COPD. The British Thoracic Society COPD guidelines7 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 vast majority of patients. A spirometric response is considered positive if the FEV1 increases by 200 mL and 15% from the baseline value. 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,8 the association between these changes, lung function, and the therapeutic response to corticosteroids has not yet been established clearly. Whether a response to 30 mg of prednisolone over 2 weeks predicts an ongoing improvement with inhaled corticosteroid treatment is debatable and results are awaited from ongoing studies.9

Several uncontrolled retrospective studies suggest that long-term oral cortico-steroids may slow the decline in FEV1 in patients with COPD.10,11 However, long-term use of oral corticosteroids would not generally be recommended, because of the risk of systemic side effects. Inhaled corticosteroids offer an option for achieving similar benefits with fewer systemic side-effects.

An early trial suggested an improvement in FEV1 and reduction in the decline in FEV1 over 1 year of treatment with inhaled beclomethasone.12 A 2-year study with inhaled budesonide (1,600 µg/day) showed 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 to 60 mL/year in the placebo group). The number of patients withdrawing due to pulmonary problems was significantly higher in the placebo group.13

What is needed to clarify the position is data from long-term studies investigating the use of inhaled corticosteroids in COPD. Three major multicenter trials are currently underway—the Copenhagen Lung Study,14,15 the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study,16 and the European Respiratory Society Study in Chronic Obstructive Pulmonary Disease (EUROSCOP).17

The Copenhagen Lung Study
This study aims to assess the long-term efficacy of inhaled budesonide by measuring changes in FEV1 in patients with moderate COPD.14,15 It is part of the Copenhagen City Heart Study,18 which has been following up more than 14,000 people since the mid 1970s. COPD is being studied in people aged 30 to 70 years, with FEV1/FVC ratios <0.7 (70%) and little reversibility to b2-agonists. They have been randomized to 6 months of treatment with budesonide (1,200 µg daily) or placebo, followed by an additional 6 months of treatment with budesonide (800 µg daily) or placebo. Lung function was measured every 2 weeks at the start of treatment, at 6 months, and at the end of the trial. A total of 1,118 subjects were identified with obstructive lung disease. Of the 604 tested for reversibility, 290 were found to be suitable for inclusion. The average FEV1 was 79% of predicted.

The ISOLDE Study
This was a United Kingdom-based, multicenter, double-blind, placebo-controlled study of fluticasone (500 µg twice daily) in patients with moderate-to-severe COPD, with the main outcome measure being the rate of decline of postbronchodilator FEV1 over 3 years.16 Secondary endpoints were the frequencies of 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 aged 40 to 75 years, and had postbronchodilator FEV1 values less than 70% of predicted. A total of 753 patients have been randomized, 46% of whom are current smokers. The average prebronchodilator FEV1 was 1.24 L, suggesting the group has 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 vs 50 mL/year). The yearly exacerbation rate was lower in the fluticasone group than in the placebo group (0.99 vs 1.32 per year; P=0.026). This resulted in three patients treated with high-dose fluticasone for a year (at a retail pharmacy cost in the United States of $1,500 per patient) to prevent one exacerbation requiring steroids or antibiotics (number needed to treat =3). Health status, measured by the increase in questionnaire score, declined at a slower rate in the fluticasone group than the placebo group (2.0 vs 3.2 units/year; P=0.004). 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. According to the investigators, because a trial of oral steroids was not useful in selecting patients more likely to benefit from this intervention, the decision to use inhaled steroids should be made on other clinical grounds and monitored periodically to determine effectiveness.

EUROSCOP compared budesonide, 400 µg bid, to placebo in actively smoking subjects with mild COPD (mean FEV1, 2.54 L) over a period of 3 years.17 The primary outcome was the rate of postbronchodilator decline in FEV1. Over the first 6 months of the study, 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 treatment 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.

Based on major trials of inhaled cortico-steroids in COPD, there is only minimal evidence of efficacy.

Until results are published from the major ongoing trials with inhaled cortico-steroids in COPD, the best clinicians can do is to make efforts to clearly differentiate the condition from asthma, ideally by using spirometry to investigate reversibility. Smoking cessation is the single most important management step in COPD. Treatment should be tailored to the individual patient, monitoring lung function and symptomatic response to inhaled therapy and targeting use of inhaled corticosteroids to those patients who respond to a 2-week trial.

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

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