Chronic Obstructive Pulmonary Disease: Diagnosis and Treatment

Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality and a considerable drain on health care resources in the industrialized world. In some patients the disease is inherited, but the vast majority of cases are caused by cigarette smoking. Recognizing the signs and symptoms and understanding the disease progression will facilitate a timely diagnosis. Although the disease is incurable, encouraging patients to stop smoking and providing supplemental oxygen can enhance survival. Significant advances in management as outlined by the authors notwithstanding, efforts to reduce the prevalence of cigarette smoking hold the most promise for reducing the disease burden and associated costs.

Fortunata Verdetti, MD

Internal Medicine

Mark G. Graham, MD, FACP

Associate Director

Department of Medicine

Philadelphia, Pa

PRACTICE POINTS

• Diagnosis involves 2 spirometry measurements, 1 before and 1 after bronchodilator therapy, to determine reversibility of airway obstruction. Bronchodilators are the mainstay of therapy and can alleviate symptoms, minimize exacerbations, and improve quality of life.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States.¹ Approximately 10 to 15 million individuals have been diagnosed with COPD in the United States; twice that number have impaired lung function, suggesting the disease is currently underdiagnosed.¹ Alarge retrospective study of 70,000 patients hospitalized with COPD showed a 2.5% in-hospital mortality rate.² In 2000, COPD accounted for 119,000 deaths, 1.5 million emergency department visits, 726,000 hospitalizations, and 8 million office visits.³ The only intervention that has been shown to slow the deterioration of lung function and the progression of disease is smoking cessation.⁴

Definitions

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) is a collaborative project of the US National Heart, Lung, and Blood Institute and the World Health Organization; it was formed to present a COPD management plan with 4 goals: (1) assess and monitor disease; (2) reduce risk factors; (3) manage stable COPD; and (4) manage exacerbations. The GOLD initiative defines COPD as a condition characterized by airflow limitation that is not fully reversible.⁵ The airflow limitation is typically progressive and accompanied by an abnormal inflammatory response of the lungs to noxious particles or gases. This underlying inflammation and the resulting pathology are responsible for the symptoms, functional abnormalities, and complications of the disease.⁵ Clinical evidence of the resulting pathology can be demonstrated by a more rapid decline in forced expiratory volume in 1 second (FEV₁) than would normally be expected.

COPD is also characterized by increased functional residual capacity, decreased exercise tolerance, decreased diffusion capacity, and ultimately, hypoxemia. COPD has several clinical manifestations. Chronic obstructive bronchitis, emphysema, and alpha-1 antitrypsin (AAT) deficiency consistently conform to the GOLD definition of COPD. Patients with chronic and severe asthma also qualify for the diagnosis of COPD. In contrast, although reactive airway disease shares some features with asthma, it lacks the chronicity characteristic of COPD and thus cannot be classified as part of the disease. The interrelationships of these clinical entities are depicted in Figure 1.

Chronic obstructive bronchitis is defined as irreversible obstructive airway disease associated with the obstruction of small airways. In contrast, chronic bronchitis is characterized by the presence of a productive cough for more than 3 consecutive months annually for more than 2 years.⁶ The small-and medium- sized airways are characterized by goblet-cell hyperplasia and increased mucus production. Emphysema is distinct from chronic obstructive bronchitis by its progressive dyspnea without cough or excessive sputum production. The very small terminal bronchioles are the site of airway destruction. Asthmatic bronchitis is a syndrome with overlapping clinical and pathologic features of both chronic obstructive bronchitis and emphysema.

Etiology

The well-established causes of COPD are smoking and AAT deficiency. Smoking is by far the most significant. The likelihood of developing COPD in smokers depends on many factors, including the number of cigarettes smoked daily, the number of years of chronic use, and other host factors, such as genes (eg, AAT deficiency), airway hyperresponsiveness, lung growth, environmental exposure (eg, tobacco, occupational dusts and chemicals, indoor/outdoor air pollution), infections, as well as socioeconomic status.⁵ Some 15% of smokers develop COPD.¹ The best documented genetic risk factor is a severe hereditary deficiency of AAT, a major circulating inhibitor of serine proteases, which accounts for only 2% of COPD cases.⁷AAT syndrome can be suspected when emphysema develops in a nonsmoker, or early in a smoker if it seems to be too severe for smoking to have caused it.

In 2004, asthma was identified as a risk factor for COPD based on a study of 3100 individuals who were followed for more than 20 years. Of these, 192 patients with continuous asthma were found to have a 12.5 times greater risk of developing COPD later in life than those with inactive asthma or without asthma. Although previously thought of as separate entities, asthma can predispose to COPD.⁸

Clinical Presentation

COPD typically occurs in 20+ pack-year smokers or ex-smokers older than 50 years. Persons who smoke only rarely or those who do not smoke but who have symptoms of chronic obstructive bronchitis or emphysema (Table 1) should be suspected of having acute bronchitis or AAT deficiency, respectively. Hypoxemia develops early in the course of chronic obstructive bronchitis, causing reflex pulmonary arteriolar hypertension and cor pulmonale, which account for its characteristic features that include productive cough, cyanosis, and peripheral edema. Early tachypnea in emphysema staves off hypoxemia until this compensatory mechanism is overwhelmed.

Diagnosis

Several tests are beneficial in establishing the diagnosis, form, and severity of COPD (Table 2). By far, the most useful is spirometry.⁹

Spirometry

Since the hallmark of COPD is an obstructive ventilatory defect, pulmonary function testing (PFT) is the only standard for diagnosis. An FEV₁ value divided by forced vital capacity of less than 70% defines an obstructive ventilatory defect.⁹ The severity of airflow obstruction is estimated by the observed percent predicted of FEV₁ (Table 3).

These spirometric measurements of airway obstruction are generally measured twice?once before and once after bronchodilator therapy?to evaluate the degree of reversibility, if any. Serial longitudinal studies are useful when performed after the resolution of acute exacerbations of COPD or as a measuring stick of disease progression.

Several other components of PFT are important. The diffusion capacity for carbon monoxide is useful in assessing degree of emphysema. This value is typically spared or reduced to a lesser degree in patients with predominantly chronic obstructive bronchitis, since their defect is primarily in the airways. It is reduced in patients with emphysema, correlating with the degree of alveolar unit destruction.

Lung volumes are also useful in categorizing COPD type and severity. Total lung volume and residual volume are typically normal or slightly elevated in chronic obstructive bronchitis; both are much increased in emphysema, reflecting hyperinflation and air trapping.

Chest radiography

The chest radiograph in chronic obstructive bronchitis demonstrates increased interstitial markings and, in advanced cases, evidence of right ventricular prominence (Figure 2). In emphysema, the chest radiograph shows a flattened diaphragm, increased retrosternal airspace, a long and narrow cardiac shadow, and hyperlucent lung fields (Figure 3). Bullae in the upper lobes are typical of acquired emphysema, whereas lower lobe bullae suggest AAT deficiency. Chest x-rays are also important to rule out comorbid disease. Apart from the evaluation of selected patients for lung volume reduction surgery, chest computed tomography merely adds to the sensitivity of radiography and is usually unnecessary for diagnosis or for routine care.

Sputum analysis

Sputum analysis can be used to determine the presence of infection and to identify inflammatory cell type (including eosinophils) or malignancy.

Complete blood cell count

The complete blood cell count can provide clues to the type and severity of COPD. Secondary polycythemia indicates chronic hypoxemia or elevated carboxyhemoglobin caused by heavy smoking. Eosinophilia may indicate an allergic component, and leukocytosis suggests bacterial bronchitis or pneumonia.

Electrocardiography

Electrocardiographic evidence of advanced COPD with pulmonary hypertension includes P-pulmonale, right-axis and posterior-axis deviation, and right ventricular enlargement.

Measuring AAT level

In patients with COPD characterized by significant emphysema, particularly with lower lobe bullae, measurement of AAT level may document the responsible protease inhibitor deficiency.

Arterial blood gas

Direct measurements of pH, PO₂, PCO₂, and bicarbonate are important in advanced stages of COPD. These measurements not only guide therapy but also provide justification for home oxygen therapy. A PO₂ of less than 60 mm Hg and/or pulse oximetry reading of less than 88% are required to meet the Centers for Medicare and Medicaid Services guidelines for home oxygen therapy.

The Approach to Treatment

The treatment of COPD is directed toward avoidance of persistent lung injury, reduction of inflammation, bronchodilation, and, in end-stage cases, oxygen supplementation. It is best conducted in a step-wise fashion, based primarily on disease severity, using preventive and therapeutic interventions, as outlined in Table 4.

Patient education on preventive measures

Since COPD is incurable, it is imperative to counsel the patient about the natural history of the disease and how to ameliorate symptoms, delay progression, and limit exacerbations.

Smoking cessation.

The most important measure is avoiding inhaled irritants. Smoking cessation is paramount. Persistent cigarette smoking not only accelerates the disease process but also confounds any salutatory effect of established therapies. Explain to patients that smoking cessation is the only preventive measure that can improve disease survival in COPD.

Pharmacologic aids to smoking cessation include nicotine replacement therapy (transdermal patches, chewing gum, nasal spray) and the antidepressant bupropion HCl (Zyban). However, without a strong desire to stop smoking, these agents usually fail. A new, promising agent is rimonabant, a cannabinoid receptor blocker that is now in phase 3 clinical trials and is expected to be released in the United States in 2006, pending Food and Drug Administration approval. Preliminary reports suggest a 36% quit rate.¹⁰

Air pollution

. Specific counseling about the effects of air pollution may be necessary in problem locales. Take an occupational history, when appropriate, to determine possible chronic exposure to air pollutants and whether measures are needed to avoid ongoing exposure to noxious dusts and fumes.

Vaccinations.

Administer and update vaccinations for pneumococcal disease and influenza. Patients with COPD are particularly susceptible to respiratory infections, which are generally severe, and patients are therefore prone to complications. Annual influenza immunization is 76% effective in reducing the incidence of influenza in patients with COPD.¹¹ Administer and update pneumococcal vaccination (Pneumovax) every 5 years.

Remember the following common-sense topics that are frequently overlooked:

• The importance of maintaining ideal body weight, good physical conditioning, and good nutritional status.
• The need for a good and accessible primary care physician for routine and episodic care.

A detailed patient handout can be downloaded from the GOLD Web site (at www.goldcopd.com, under "GOLD documents and resources").

In addition to patient education, pharmacologic and other medical interventions are used to alleviate symptoms and improve the patient's quality of life but cannot cure the disease.

Inhaled bronchodilators: anticholinergics and

beta₂-agonists

Bronchodilator therapy is the mainstay of COPD treatment. Bronchodilators alleviate symptoms, decrease the number of exacerbations, and improve quality of life.

Inhaled bronchodilators fall into 2 categories: cholinergic antagonists and beta₂-agonists. Anticholinergics block the action of acetylcholine at parasympathetic sites in bronchial smooth muscle, and beta₂-agonists relax bronchial smooth muscle by acting on beta₂-receptors, with little impact on heart rate.

Most data from randomized, placebo-controlled trials that have shown benefit with inhalation therapy for COPD involve short-acting anticholinergics and beta₂-agonists. The most commonly used short-acting agents are the beta₂-agonist albuterol sulfate (AccuNeb, Proventil) and the anticholinergic ipratropium bromide (Atrovent). Both relieve mild airflow limitation and intermittent symptoms and have peak effects that last 4 to 6 hours.¹² Although comparative shortand long-term studies have shown ipratropium to be superior to beta₂-agonists in reducing symptoms, when used together, the 2 agents alleviate symptoms and increase FEV₁ better than either agent alone.¹³ They have been combined into a metered-dose inhaler (Combivent), typically prescribed for 4 times daily use, indefinitely. The home nebulizer formulation (DuoNeb) can be used in more severe cases.

Because bronchodilators do not have anti-inflammatory properties, long-term use does not alter the natural history of the disease,¹⁴ and these medications are not needed when patients are asymptomatic. Their chief role is symptom reduction.¹⁵ However, it is difficult for patients with more advanced COPD, in which symptoms are relentless, to comply with 4 times daily medications indefinitely. In such cases, long-acting preparations of inhaled bronchodilators are useful. Formoterol fumarate (Foradil) and salmeterol xinafoate (Serevent Diskus) are inhaled beta₂-agonists whose peak effects last 8 to 12 hours and thus can be used on a twice-daily schedule. A careful risk-benefit analysis must be made when treating black men, in whom excess and unexplained deaths have occurred in a study using salmeterol.¹⁶

P

Tiotropium bromide (Spiriva) is a new long-acting inhaled anticholinergic preparation that is more efficacious than its short-acting predecessor, ipratropium.¹⁷ Tiotropium is a synthetic quaternary anticholinergic that specifically selects for muscarinic receptors to mediate airway smooth-muscle contraction. Its long duration of action makes it appropriate for oncedaily therapy.¹⁸ Compared with ipratropium 4 times daily use, tiotropium once-daily demonstrated significantly more bronchodilation and significantly less need for albuterol rescue therapy (<.05) in a head-tohead study of 288 COPD patients.¹⁹ In addition, tiotropium has reduced dyspnea, exacerbations, and hyperinflation,²⁰ and improved overnight arterial oxygen saturation compared with placebo.¹⁸

A review of 12 studies investigating the role of long-acting bronchodilators in the management of stable COPD has shown the benefits of these agents as well as considerable differences in efficacy between them.²¹ Tiotropium appears to offer superior bronchodilation and dyspnea improvement, even compared with long-acting beta₂-agonists in patients with stable disease.²² In a study that compared tiotropium, salmeterol, and placebo in more than 1200 patients, tiotropium therapy resulted in significant delay in time to first exacerbation and fewer total exacerbations per patient-year (1.07 exacerbations) than salmeterol (1.23 exacerbations) or placebo (1.49 exacerbations).²² Note that tiotropium is not recommended for initial management of acute exacerbations, since peak effects may not occur for hours. In such cases, current guidelines recommend use of short-acting agents.

Although long-acting beta₂-agonist bronchodilators have demonstrated a prolonged duration of action, thereby decreasing symptoms and number of exacerbations, short-acting beta₂-agonist bronchodilators are necessary for acute symptoms.

Inhaled corticosteroids

The use of inhaled corticosteroids in COPD remains controversial.^4,23 Although one may expect a benefit because of their anti-inflammatory effect, outcome data with these agents are mixed. In patients with severe COPD (FEV₁ <50% predicted), regular treatment with inhaled steroids has been shown to reduce the median exacerbation rate by 25% and improve health status.²⁴ The combination agent fluticasone/salmeterol (Advair Diskus) is a particularly useful inhaler available in an easy-to-use delivery system.

Inhaled corticosteroids appear to have little or no benefit in early COPD, and they do not slow the progression of disease.^23,25

Theophylline

The oral bronchodilator theophylline (eg, Bronkodyl, Elixophyllin, Theolair) can be used as a second-line agent if symptoms persist with inhaled bronchodilators. Arecent meta-analysis showed that it significantly improved virtually all measures of lung function compared with placebo in patients with stable COPD.²⁶ When combined with other bronchodilators, it has been shown to augment improvements in lung function and further reduce symptoms.²⁷ However, results of other studies have failed to show benefit. In addition, theophylline dosing is labor-intense; blood levels below 10 mg/dL are usually ineffective, and those over 20 mg/dL are associated with toxicity, including grand mal seizures. Drug levels can often be affected by other medications, necessitating close monitoring of blood theophylline levels. Because of the questionable benefit and well-established risks, theophylline is considered a second-line agent.

Mucolytic therapies

Mucolytic therapies fall into 2 broad categories: pharmacologic and physical. The 1990 National Mucolytic Study that compared iodinated glycerol to placebo in a double-blind fashion failed to show significant benefit.²⁸ Guaifenesin is routinely used to liquefy copious, thick secretions, but no standard for its use exists.

Evidence for chest physiotherapy is largely derived from patients with bronchiectasis and cystic fibrosis. When performed by a qualified respiratory therapist, it may be helpful for patients with voluminous secretions. Such therapists may also be helpful in coaching patients about deep-breathing practice and therapeutic coughing techniques. In the intensive care unit, frequent suctioning is obviously beneficial.

Several devices are available to aid in the mobilization of pulmonary secretions with external pressure waves. The most advanced, ThAIRapy Vest, is primarily used for children with cystic fibrosis. Its value in adults has not been established, and the cost of the equipment (approximately $16,000) limits its use. A smaller, hand-held device has shown benefit in patients with severe COPD who are using bronchodilator therapy.²⁹

Systemic corticosteroids

Oral corticosteroids are widely used for patients hospitalized with severe COPD exacerbations. Although many show improvement, it is typically not sustained.³⁰ The long-term adverse effects of systemic steroid treatment are legion. The dose should be promptly reduced to the minimum effective level and preferably terminated when the patient returns to baseline status.

Supplemental oxygen

Oxygen therapy is one of the few interventions that can alter the course of COPD. It has been shown to delay the deterioration of FEV₁ and prolong life in advanced disease.³¹ It also improves symptoms and functional capacity. Evidence shows that continuous (24-hour per day) use is superior to intermittent use.³² The need for supplemental oxygen is determined by arterial blood gas values. To avoid excessive retention of carbon dioxide, blood gases should be monitored whenever oxygen therapy is adjusted in patients with hypercapnia. Supplemental oxygen should be administered to increase the PaO² to no less than 60 mm Hg or the oxygen saturation to 90% or more. Indications for home oxygen include:

• PO₂ less than 55 mm Hg at rest on at least 2 determinations
• Significant nocturnal or exercise-induced oxygen desaturations.

Pulmonary rehabilitation

The GOLD guidelines recommend pulmonary rehabilitation for COPD patients with persistent dyspnea, reduced exercise tolerance, or activity restriction, and for those who manifest functional deficits after optimum pharmacotherapy.⁵ Pulmonary rehabilitation was shown to improve functional capacity and sense of well-being in patients with severe COPD who had been hospitalized for an acute exacerbation.³³ However, further research is required to investigate the effects of strength training on functional activities, such as balance, upper-limb function, self-care, or activities of daily life.³⁴

Monoclonal antibody therapy

Since COPD is characterized by inflammation with increased numbers of macrophages and neutrophils, therapy targeted toward blocking the recruitment and/or activation of these cells or inactivating their products is expected to be helpful. A 2004 pilot study of a therapy directed against the chemokine interleukin-8 in COPD patients showed clinical improvement in dyspnea scores.³⁵ Although the results are obviously preliminary and the treatment experimental, they underscore the inflammatory basis of COPD and shed light on the future direction of research and care.

Surgery

As increasing lung parenchyma is destroyed in the progression of COPD, less lung is available for gas exchange. The destruction of lung tissue decreases elastic recoil and expands lung volume, causing loss of the normal mechanical advantages in ordinary breathing and resulting in increased work of breathing and dyspnea. The 3 surgical treatments for emphysema to combat these conditions are bullectomy, lung transplantation, and lung volume reduction surgery. But most patients with emphysema are poor candidates for any such intervention, including thoracic surgery. Therefore, surgery is reserved for those with emphysema who have parenchymal destruction and hyperinflation, with marked impairment (FEV₁ <35% predicted), or with marked restriction in activities of daily living, and when maximal medical treatment cannot correct symptoms.³⁶

Conclusion

COPD is a common, incurable condition for which very few effective therapies are available. Most cases are caused by cigarette smoking. Only smoking cessation after the diagnosis of COPD, and in advanced cases, supplemental oxygen therapy, can prolong the survival of patients with established disease. Attempts to attenuate the inflammation at the root of COPD with monoclonal antibody therapy hold promise for the near future, as does improved pharmacotherapy to facilitate smoking cessation. But only smoking abstinence can substantially reduce the incidence and prevalence of this lethal disease.

SELF-ASSESSMENT TEST

1. Which of the following interventions improves survival in patients with COPD?

• Anti-inflammatory therapy with oral or intravenous steroids
• Bronchodilator therapy with anticholinergics and beta₂-agonists

2. First-line therapy for COPD includes all the following agents, except:

• Oral prednisone
• Inhaled tiotropium

3. All these statements about the treatment of COPD are true, except:

• Inhaled corticosteroids are not appropriate for early COPD
• Mucolytic therapy is the mainstay of treatment in exacerbations of the chronic bronchitic form of COPD

4. Which of these clinical findings suggests an AAT deficiency as the cause of emphysema?

• Upper lobe bullae on chest x-ray
• Blue-bloater

5. Which of these findings is NOT an indication for supplemental oxygen therapy?

• PO₂ of 55 with evidence of cor pulmonale
• Significant exercise-induced oxygen desaturations

(Answers at end of reference list)

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Answers:

1. C; 2. B; 3. D; 4. A; 5. A