An evidence-based approach to COPD

GREGORY C. KANE, MD, Clinical Associate Professor of Medicine; Program Director, Internal Medicine Residency, Division of Pulmonary Medicine and Critical Care, Department of Medicine, Jefferson Medical College, Philadelphia, Pa

MARK G. GRAHAM, MD, Clinical Assistant Professor of Medicine; Associate Director, Division of Internal Medicine and Primary Care, Department of Medicine, Jefferson Medical College, Philadelphia, Pa

Current medical management can lead to dramatic improvement in functional status and lifestyle for many patients with COPD. An evidence-based approach to the diagnosis and management of various types of COPD is here presented.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides the following definition of chronic obstructive pulmonary disease (COPD) as "a disease state characterized by airflow limitation that is not fully reversible. Airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Symptoms, functional abnormalities, and complications of COPD can all be explained on the basis of this underlying inflammation and the resulting pathology."¹

While obstructive lung disease—probably asthma—was described by Hippocrates, the first detailed description of chronic obstructive lung disease was by Laennec in the early 19th century.² Perhaps owing to the high prevalence of chronic respiratory tract ailments in London at that time, it is not surprising that descriptions of COPD also appeared in the popular literature. Charles Dickens provided the following memorable descriptions of characters so afflicted and perhaps the earliest characterization of the 2 forms of COPD:

Wheezing sounds would be heard, and the Major's [Major J. Bagstock] blue would deepen to purple, at length he burst into a violent paroxysm of cough.

Charles Dickens, Dombey and Son

Time went by and the turnkey began to fail. His chest swelled and his legs got weak and he was short of breath. . . . He sat in an armchair with a cushion and sometimes wheezed so, for minutes together, that he couldn't turn the key.

Charles Dickens, Little Dorrit

EPIDEMIOLOGY AND ETIOLOGY

These days, COPD is the fourth leading cause of chronic morbidity and mortality in the United States.³ The disease is projected to rank fifth in the world by the year 2020.⁴ Presently, there are approximately 10 to 15 million diagnosed cases of COPD in the United States. The third National Health and Nutrition Survey (NHANES III) estimated that there were about 24 million patients in this country with impaired lung function, suggesting COPD is underdiagnosed. COPD accounts for 17 million clinic visits annually and over 100,000 deaths per year, or about 5% of the annual death rate. For years males have been more affected than females, but in 2000 the female mortality rate surpassed that of men (see Figure 1).

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Cigarette smoking remains the most important risk factor for COPD. The number of cigarettes smoked daily and the duration of the habit directly correlate with the occurrence and severity of this lung dysfunction. Pipe and cigar smoking and secondhand smoke exposure all increase the risk for COPD but not as much as cigarette smoking. Air pollution is also a substantial contributing factor. Occupational exposures to coal dust, cement dust, grain dust, and sulfuric acid fumes increase risk for COPD. Individual host susceptibility plays an important role and certainly explains why only 15% of smokers develop clinically recognized COPD. Alpha₁-antitrypsin deficiency accounts for a small percentage of patients with the emphysematous form of COPD.

OBSTRUCTIVE LUNG DISEASES

COPD encompasses many manifestations of chronic bronchitis (CB), emphysema, and asthma, but not all patients with these forms of respiratory disease fit the criteria for COPD. There are subsets of CB and emphysema that do not exhibit airway obstruction.⁵ And many patients with asthma have airway obstruction that is completely reversible. Overlapping manifestations, such as chronic bronchitis or emphysema with a major reversible component, are not uncommon (see Figure 2).

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Chronic bronchitis

Chronic bronchitis is clinically defined as chronic cough productive of sputum for at least 3 months per year in at least 2 successive years. Pathologically, CB is also a disease of the airways, characterized by edema and inflammation with goblet cell hyperplasia, increased mucous production, and occasionally, superimposed infection. Small airways develop the abnormal presence of mucus-secreting cells and chronic inflammation.

Emphysema

Patients with emphysema experience progressive dyspnea with minimal or no productive cough. Pathologically, there is destruction of distal lung units at the level of alveolar septa and abnormal distal air space enlargement. Lung function assessment reveals severe airflow obstruction, air trapping, and a reduced diffusing capacity for carbon monoxide reflecting loss of alveolar surface area for diffusion.

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Asthmatic bronchitis

Asthmatic bronchitis represents an overlap syndrome with features of both asthma and CB. Pathologically, this is characterized by eosinophilic bronchitis. Clinically, the patients usually fall into 2 groups. Some patients have had extensive exposure to tobacco but also have features of classic asthma along with allergies or a history of childhood asthma. Other patients begin with clinical asthma and develop chronic airflow obstruction that persists without reversibility—despite lack of a smoking history.

The common denominator of these various disease expressions is chronic airflow obstruction. A loss of elastic recoil is at the root of the obstruction in emphysema and chronic airway narrowing due to chronic inflammation or muscular bronchospasm—the hallmark of CB and asthma, respectively.

CLINICAL PRESENTATION

CB manifests as a cough that worsens and persists and may first bother the chronic smoker after a viral upper respiratory tract infection. Sputum is usually mucopurulent yellow, green, tan, or brown and may be tenacious leading to violent paroxysms of coughing. Carbon dioxide retention is typical in the advanced stages of CB, so the skin has a bluish hue. Since patients with CB are frequently overweight, these patients have been referred to as "blue bloaters." The chest exam is typically rhonchial with variable amounts of expiratory wheezes.

In contrast, the patient with the emphysema form of COPD typically presents with an exertional breathlessness that is insidious in onset. These patients are leaner and not prone to carbon dioxide retention. Breath sounds are distant and the chest wall is barrel shaped. The expiratory phase is prolonged and the lips are pursed during expiration. These patients have been referred to as "pink puffers."

Since most patient have features of both conditions there is considerable overlap. End-stage forms of COPD may demonstrate right heart failure, so-called cor pulmonale. A right ventricular heave and an accentuated P2 heart sound may be appreciated. Once COPD is advanced, exacerbations characterized by increased cough, change in sputum character and volume, breathlessness, wheeze, or chest tightness can be triggered by colds, exposure to irritants, or high concentrations of pollutants on hot humid days (see Table 1).

 

TABLE 1 Key indicators for considering COPD
Indicator	Comments
Chronic cough	Intermittently or every day; often throughout the day, seldom only at night
Chronic sputum	Any pattern could suggest COPD
Acute bronchitis	Recurrent episodes
Dyspnea	Persistent and progressive; worse after URTI; exercise or activities limited
Risk factors	Tobacco use; pollution; occupational dusts and fumes
Key: COPD, chronic obstructive pulmonary disease; URTI, upper respiratory tract infection.

Diagnosis

Spirometry Spirometric testing is the only criterion standard to demonstrate an obstructive ventilatory defect. It is defined as a forced expiratory volume in 1 second/forced vital capacity (FEV₁/ FVC) ratio that is less than the ratio that would be predicted for that individual. Once airway obstruction has been documented by this reduced ratio, the severity of the obstructive defect can be semiquantified accordingly, based on the percentage of the patient's FEV₁ actual/predicted (see Table 2).

 

TABLE 2 Staging of COPD
FEV1 actual/predicted	Degree of obstructive defect
>70%	Mild
60%-70%	Moderate
50%-60%	Moderately severe
34%-50%	Severe
<34%	Very severe
Key: COPD, chronic obstructive pulmonary disease.

In COPD, the FEV₁/FVC defect is largely irreversible, though the FEV₁ fluctuates with bouts of bronchospasm. If this ratio corrects with therapy, the diagnosis of "asthma" is made in favor of COPD.

It is also useful to track the maximum midexpiratory flow rate or forced expiratory flow (25%-75%) and the diffusing capacity for carbon monoxide via spirometry. Reductions in the former value indicate very small obstruction of airways. Reductions in the latter indicate a significant component of emphysema.

Formal pulmonary function testing with lung volume analysis is also useful in detecting significant components of emphysema. The total lung capacity (TLC) is slightly increased in CB, but TLC and residual volume (RV) are dramatically increased in emphysema.

Chest radiographs The chest radiographs of a patient who has CB most often show increased interstitial markings, but there are no specific findings that could be considered diagnostic of either COPD or CB. The chest radiographic appearance of emphysema, on the other hand, is quite striking. Marked overdistention of the lung fields, flattened diaphragms, and increased retrosternal space are the obvious and classic findings.

Sputum analysis Gram's staining of the sputum can be a useful adjunct in making the diagnosis of COPD, especially the CB type. Macrophages, neutrophils, T lymphocytes, and epithelial cells are seen in greater numbers in patients experiencing an exacerbation of the disease than they are in patients whose condition remains stable.

CBC The CBC should be examined for evidence of eosinophilia, which may be suggestive of asthmatic bronchitis. In advanced cases of CB or emphysema, a secondary polycythemia can be seen. During exacerbations, leukocytosis and a left shift may indicate superimposed acute bronchitis or pneumonia.

ECG In advanced stages of COPD, the ECG may show evidence of right atrial enlargement and/or right ventricular hypertrophy—right axis deviation and a posterior axis deviation.

Alpha₁-protease inhibitor level When a significant component of emphysema is appreciated, the serum alpha₁-protease (AAT) inhibitor should be measured. AAT, which is underrecognized, accounts for 2% to 3% of patients with severe COPD.⁶ The diagnosis of AAT deficiency is typically delayed by more than 5 years.⁷

Prognosis

The best predictor of survival in COPD is the baseline postbronchodilator FEV₁.⁸ Other predictors of an accelerated decline are airway responsiveness, cigarette smoking status, resting heart rate, HIV infection, heavy airway bacterial load, and chronic hypercapnia. At a postbronchodilator FEV₁ determination of more than 50%, there is about a 90% 5-year survival rate. The survival rate drops precipitously to less than 50% at a postbronchodilator FEV₁ determination that is less than 50% and is only 10% at a postbronchodilator FEV₁ determination of less than 20%.

The presence of chronic hypercapnia is an indicator of advanced disease. Survival among patients with chronic hypercapnia was significantly worse than among those patients who had reversible hypercapnia or were normocapnic.

Factors that improve outcomes include use of home oxygen in hypoxic patients and smoking cessation. After 3 years of use of home oxygen by hypoxic COPD patients, more than 60% of the patients who used the oxygen 24 hours a day survived, but only 40% of those who used it during the daytime alone survived.⁹ An exacerbation of COPD that requires the patient to be hospitalized is a risk factor that carries a 2.5% in-hospital mortality rate.¹⁰

TREATMENT

The optimal treatment plan for COPD begins with patient education. The goals of this approach should always include

• Avoidance of inhaled irritants
• Smoking cessation
• Vaccination against influenza and pneumococcal disease
• A review—shared with the patient—of the natural history of this disease, its common comorbid conditions, and the importance of treatment adherence
• A review—shared with the patient—of the importance of nutrition and exercise
• A discussion with the patient of the role of rehabilitation programs.

Inhalation medical therapy

The inhaled route of administration is preferred to the oral or parenteral route because this approach maximizes target tissue effect and minimizes troublesome side effects. Inhalation therapy for COPD can properly begin with either sympathomimetic or anticholinergic agents. Whichever type of agent is used first, the other is used as second-line therapy, when needed.

Sympathomimetic agents such as albuterol are a time-tested first-step approach for the patient with COPD.¹¹ Selective beta₂-agonists are the preferred choice. The rapid onset of action of the short-acting preparations make them useful for either chronic or as-needed therapy. Some controversy still exists about the wisdom of their chronic use because of side effects and concerns about tachyphylaxis. In asthma, there appears to be no difference in outcomes whether these medications are used episodically or regularly.¹² Patients with stable COPD using beta₂-agonists as chronic therapy appear to benefit somewhat from improved lung function, fewer treatment failures, and less dyspnea.¹³ Long-acting beta₂-agonists, such as salmeterol, provide more sustained bronchodilation, but their overall superiority is yet to be proved, and their safety in African American patients has been questioned recently. The degree of bronchodilation achieved with sympathomimetic metered dose inhalers (MDIs) is typically incomplete but dose dependent. At higher doses, troubling systemic side effects or tremor and tachycardia limit the use of these devices.

Anticholinergic agents, such as ipratropium via MDI, are preferred by many clinicians as the first agent of treatment in the management of COPD.^14,15 Ipratropium works by inhibiting smooth muscle tone in the bronchial wall by blocking the muscarinic receptor M3. The degree of bronchodilation with anticholinergic agents is at least as good as it is with sympathomimetic agents, but these preparations produce fewer side effects. The onset of action is slow compared to that of beta-agonists. The combination of ipratropium with albuterol produces a greater improvement in the FEV₁, both immediately and over the long term, than does either agent alone.¹⁶ One MDI formulation—ipratropium bromide and albuterol sulfate (Combivent)—contains both preparations and provides a simple method to realize these advantages.

Other medical therapy

Theophylline preparations remain controversial and are no longer considered an appropriate form of monotherapy. At high dosages, significant toxicity including seizures occur. Blood concentrations should be monitored to maintain a therapeutic but not toxic level between 10 and 20 mg/L of theophylline. Though the use of theophylline in COPD has varied, at least one important study showed that these preparations increase arterial oxygen, FEV₁, FVC, and reduce arterial carbon dioxide and dyspnea.¹⁷ A therapeutic trial of theophylline following patient symptoms and spirometry can settle the controversy about the therapy's role in a given patient, but the theophylline should be used as an add-on treatment along with MDI therapy with sympathomimetic and anticholinergic agents.

Corticosteroids have notorious side effects and are of only modest benefit to most patients with COPD. Many patients show improvement on an initial trial of oral corticosteroids during exacerbations, however. Unfortunately, this initial benefit does not predict sustained benefit.¹⁸ Corticosteroid use is discouraged except when all other modalities have failed and there is evidence of severe airflow reduction. Long-term therapy is only considered when the objective benefit is realized and attempts to taper the dosages and discontinue the drugs have failed. The lowest possible dosage to retain this benefit should be carefully sought. There is no evidence to support the use of corticosteroids via MDI, but their use is commonplace and reasonable and this approach should be used in corticosteroid-responding patients.¹⁹

Treatment of infection is of paramount importance. All patients with COPD should be vaccinated against pneumococcal disease and influenza. They should be revaccinated annually for influenza and every 6 years for pneumococcal disease. Most exacerbations of COPD are associated with infections, and most of these are viral. Nonetheless, the empiric use of antibiotics has been shown to be useful. Examination of the sputum by Gram's stain may help guide therapy, but sputum cultures and sensitivity assays are not cost-effective. Chronic suppressive antibiotics have not been shown to be useful unless the patient has evidence of bronchiectasis.

Supplemental oxygen

Of all the therapies mentioned, only smoking cessation and supplemental oxygen therapy have been shown to improve survival time in patients with COPD.²⁰ There is also evidence that the continuous use of oxygen confers survival benefit over part-time use of same.^9,21 Beyond improving blood oxygen saturation, supplemental oxygen therapy also improves the hematocrit values and pulmonary hemodynamics.

Lung volume reduction surgery

Lung volume reduction surgery (LVRS) is a last-resort option for those COPD patients with severe emphysema. Where advanced bullous disease occurs, LVRS has been shown to decrease lung volumes, improve oxygenation, improve FEV₁, and improve functional capacity and quality of life.²² Those who qualify for this intervention include end-stage emphysema sufferers with severe dyspnea, FEV₁ that is less than 35% predicted, and hyperinflated lungs. Patients who are over 75, have smoked within the previous 3 to 6 months, and have severe comorbid conditions, severe pulmonary hypertension, severe hypercapnia, and are ventilator-dependent do not qualify for LVRS.

Equivocal therapies

Even though there is no evidence which supports their efficacy, a number of other therapies have been commonly used in COPD over the years. They include

• Hydration (unless patient is clinically dehydrated)
• Mechanical clearance (chest percussion, postural drainage)
• Inhaled corticosteroids²³
• Mucoactive agents²⁴
• Cough suppressants.

PRODUCED BY DEBORAH KAPLAN

Note: The authors offer special thanks to Devon Stewart for technical assistance with this manuscript.

Dr Graham and Dr Kane disclose that they have no financial relationships with manufacturers in this therapeutic area.

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An evidence-based approach to COPD. JAAPA April 2004;17.

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