Chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is characterized by partially reversible airway obstruction caused by an abnormal inflammatory response to exposure to toxins, often cigarette smoke.

Alpha-antitrypsin deficiency and various occupational pollutants are less common causes of this pathology in non-smokers. Symptoms develop over the years - productive cough and dyspnea; weakened breathing and wheezing are common signs. Severe cases may be complicated by weight loss, pneumothorax, right ventricular failure, and respiratory failure. Diagnosis is based on history, physical examination, chest radiography, and pulmonary function tests. Treatment is with bronchodilators and glucocorticoids; oxygen therapy is administered if necessary. Approximately 50% of patients die within 10 years of diagnosis.

Chronic obstructive pulmonary disease (COPD) includes chronic obstructive bronchitis and emphysema. Many patients have signs and symptoms of both conditions.

Chronic obstructive bronchitis is chronic bronchitis with airflow obstruction. Chronic bronchitis (also called chronically increased sputum secretion syndrome) is defined as productive cough lasting at least 3 months during 2 consecutive years. Chronic bronchitis becomes chronic obstructive bronchitis if spirometric evidence of airflow obstruction develops. Chronic asthmatic bronchitis is a similar, overlapping condition characterized by chronic productive cough, wheezing, and partially reversible airflow obstruction in smokers with a history of asthma. In some cases, it is difficult to distinguish chronic obstructive bronchitis from asthmatic bronchitis.

Emphysema is the destruction of the lung parenchyma, resulting in loss of elasticity and destruction of the alveolar septa and radial stretching of the airways, which increases the risk of airway collapse. Hyperinflation of the lungs, limitation of airflow, impede the passage of air. Air spaces enlarge and may eventually develop into bullae.

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Epidemiology of COPD

In 2000, approximately 24 million people in the United States had COPD, of whom only 10 million were diagnosed. That same year, COPD was the fourth leading cause of death (119,054 cases, compared with 52,193 in 1980). Between 1980 and 2000, COPD deaths increased by 64% (from 40.7 to 66.9 per 100,000 population).

Prevalence, incidence, and case fatality rates increase with age. Prevalence is higher in men, but overall case fatality rates are similar for men and women. Case fatality rates and incidence are generally higher among whites, blue-collar workers, and people with lower levels of education; this is probably due to the higher rates of smoking in these populations. Familial cases of COPD do not appear to be associated with alpha-antitrypsin (alpha-antiprotease inhibitor) deficiency.

The incidence of COPD is increasing worldwide due to increased smoking in unindustrialized countries, decreased mortality due to infectious diseases, and widespread use of biomass fuels. COPD caused an estimated 2.74 million deaths worldwide in 2000 and is expected to become one of the world's top five diseases by 2020.

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What causes COPD?

Cigarette smoking is the major risk factor in most countries, although only about 15% of smokers develop clinically apparent COPD; a history of 40 or more pack-years of smoking is particularly predictive. Smoke from burning biofuels for home cooking is an important etiologic factor in underdeveloped countries. Smokers with preexisting airway reactivity (defined as increased sensitivity to inhaled methacholine chloride), even in the absence of clinical asthma, have a higher risk of developing COPD than individuals without it. Low body weight, childhood respiratory disease, passive smoking, air pollution, and occupational pollutants (eg, mineral or cotton dust) or chemicals (eg, cadmium) contribute to the risk of COPD but are of little importance compared with cigarette smoking.

Genetic factors also play a role. The best-studied genetic disorder, alpha-antitrypsin deficiency, is a proven cause of emphysema in nonsmokers and influences susceptibility to the disease in smokers. Polymorphisms in the genes for microsomal epoxide hydrolase, vitamin D-binding protein, IL-1p, and IL-1 receptor antagonist are associated with rapid declines in forced expiratory volume in 1 s (FEV) in selected populations.

In genetically susceptible individuals, inhalation exposures induce an inflammatory response in the airways and alveoli, leading to disease development. The process is thought to occur through increased protease activity and decreased antiprotease activity. In normal tissue repair, lung proteases—neutrophil elastase, tissue metalloproteinases, and cathepsins—destroy elastin and connective tissue. Their activity is balanced by antiproteases—alpha-antitrypsin, respiratory epithelial secretory leukoproteinase inhibitor, elafin, and tissue inhibitor of matrix metalloproteinases. In patients with COPD, activated neutrophils and other inflammatory cells secrete proteases during inflammation; protease activity exceeds antiprotease activity, resulting in tissue destruction and increased mucus secretion. Activation of neutrophils and macrophages also results in accumulation of free radicals, superoxide anions, and hydrogen peroxide, which inhibit antiproteases and cause bronchospasm, mucosal edema, and increased mucus secretion. As with infection, neutrophil-induced oxidative damage, release of profibrotic neuropeptides (eg, bombesin), and decreased production of vascular endothelial growth factor play a role in pathogenesis.

Bacteria, especially Haemophilus influenzae, colonize the normally sterile lower airways in approximately 30% of patients with active COPD. In more severely ill patients (eg, after previous hospitalizations), Pseudomonas aeruginosa is frequently isolated. Some experts suggest that smoking and airway obstruction result in decreased clearance of mucus in the lower airways, predisposing to infection. Repeated infections result in an exacerbated inflammatory response, accelerating disease progression. However, it is unclear whether long-term antibiotic use slows the progression of COPD in susceptible smokers.

The cardinal pathophysiological feature of COPD is airflow limitation caused by emphysema and/or airway obstruction due to increased mucus secretion, sputum retention, and/or bronchospasm. Increased airway resistance increases the work of breathing, as does lung hyperinflation. The increased work of breathing may lead to alveolar hypoventilation with hypoxia and hypercapnia, although hypoxia is also caused by ventilation/perfusion (V/Q) mismatch. Some patients with advanced disease develop chronic hypoxemia and hypercapnia. Chronic hypoxemia increases pulmonary vascular tone, which, if diffuse, causes pulmonary hypertension and cor pulmonale. Administration of 02 in this setting may worsen hypercapnia in some patients by reducing the hypoxic ventilatory response, leading to alveolar hypoventilation.

Histologic changes include peribronchiolar inflammatory infiltrates, bronchial smooth muscle hypertrophy, and airspace compromise due to loss of alveolar structures and septal destruction. The enlarged alveolar spaces sometimes coalesce to form a bulla, defined as an airspace greater than 1 cm in diameter. The bulla may be completely empty or may include areas of lung tissue, crossing them in areas of advanced emphysema; bullae sometimes occupy the entire hemithorax.

Symptoms of COPD

COPD takes years to develop and progress. A productive cough is usually the first sign in patients in their 40s and 50s who have smoked more than 20 cigarettes per day for more than 20 years. Dyspnea that is progressive, persistent, expiratory, or worsens during respiratory infections eventually appears by the time patients are over 50 years of age. COPD symptoms usually progress rapidly in patients who continue to smoke and who have higher lifetime exposure to tobacco. Headache in the morning, which is indicative of nocturnal hypercapnia or hypoxemia, develops in later stages of the disease.

COPD is characterized by periodic acute exacerbations, characterized by worsening symptoms. A specific cause for any exacerbation is almost always impossible to identify, but exacerbations are often attributed to viral ARIs or acute bacterial bronchitis. As COPD progresses, exacerbations tend to become more frequent (an average of three episodes per year). Patients who have had an exacerbation are likely to have recurrent episodes of exacerbations.

Symptoms of COPD include wheezing, increased airiness of the lungs manifested by weakening of heart and breath sounds, and an increase in the anteroposterior diameter of the chest (barrel chest). Patients with early emphysema lose weight and experience muscle weakness due to immobility; hypoxia; release of systemic inflammatory mediators such as tumor necrosis factor (TNF)-a; and increased metabolic rate. Symptoms of advanced disease include retracted lip breathing, involvement of accessory muscles with paradoxical retraction of the lower intercostal spaces (Hoover sign), and cyanosis. Symptoms of cor pulmonale include cervical venous distension; splitting of the second heart sound with an accentuated pulmonary component; tricuspid murmur and peripheral edema. Right ventricular heave is rare in COPD due to hyperventilated lungs.

Spontaneous pneumothorax also frequently occurs as a result of bulla rupture and is suspected in any patient with COPD whose pulmonary status deteriorates rapidly.

Systemic diseases that may have a component of emphysema and/or airflow obstruction that mimics the presence of COPD include HIV infection, sarcoidosis, Sjogren's syndrome, bronchiolitis obliterans, lymphangioleiomyomatosis, and eosinophilic granuloma.

Diagnosis of COPD

The diagnosis is suggested by history, physical examination, and imaging findings and confirmed by pulmonary function tests. Differential diagnosis includes asthma, heart failure, and bronchiectasis. COPD and asthma are sometimes easily confused. Asthma is distinguished from COPD by the history and reversibility of airway obstruction on pulmonary function tests.

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Pulmonary function tests

Patients suspected of having COPD should undergo pulmonary function testing to confirm airflow obstruction and to quantify its severity and reversibility. Pulmonary function testing is also necessary to diagnose subsequent disease progression and to monitor response to treatment. The main diagnostic tests are FEV, which is the volume of air forcefully exhaled in the first second after a full inspiration; forced vital capacity (FVC), which is the total volume of air exhaled with maximal force; and the volume-flow loop, which is a simultaneous spirometric recording of airflow and volume during a forced maximal expiration and inspiration.

Decreases in FEV1, FVC, and the FEV1/FVC ratio indicate airway obstruction. The flow-volume loop shows a dip in the expiratory segment. FEV1 declines by up to 60 mL/yr in smokers, compared with a more gradual decline of 25–30 mL/yr in nonsmokers, beginning at about age 30 years. In middle-aged smokers, who already have a low FEV1, the decline progresses more rapidly. When FEV1 falls below about 1 L, patients become dyspneic with exercise; when FEV1 falls below about 0.8 L, patients are at risk of hypoxemia, hypercapnia, and cor pulmonale. FEV1 and FVC are easily measured with in-office spirometers and indicate disease severity because they correlate with symptoms and mortality. Normal levels vary according to the patient's age, sex, and height.

Additional pulmonary function tests are needed only in certain circumstances, such as lung volume reduction surgery. Other tests that may be investigated may include increased total lung capacity, functional residual capacity, and residual volume, which may help differentiate COPD from restrictive lung diseases in which these parameters are decreased; vital capacity is decreased; and the diffusing capacity for carbon monoxide in a single breath (DBC) is decreased. A decreased DBC is nonspecific and is decreased in other disorders that damage the pulmonary vasculature, such as interstitial lung disease, but may help differentiate COPD from asthma, in which DBC is normal or increased.

COPD imaging techniques

Chest radiography is characteristic, although not diagnostic. Changes consistent with emphysema include hyperinflation of the lung, manifested by flattening of the diaphragm, narrow cardiac shadow, rapid hilar vasoconstriction (in the anteroposterior projection), and enlargement of the retrosternal airspace. Flattening of the diaphragm due to hyperinflation causes the angle between the sternum and anterior diaphragm to increase to greater than 90° on the lateral radiograph, compared with the normal 45°. Radiolucent bullae greater than 1 cm in diameter, surrounded by arcaded diffuse opacities, indicate focally severe changes. Predominant emphysematous changes at the lung bases suggest alpha1-antitrypsin deficiency. The lungs may appear normal or hyperlucent due to parenchymal loss. Chest radiographs of patients with chronic obstructive bronchitis may be normal or show bilateral basilar enhancement of the bronchovascular component.

An enlarged hilar is consistent with the enlargement of the central pulmonary arteries seen in pulmonary hypertension. The right ventricular dilation seen in cor pulmonale may be masked by increased pulmonary air content or may be seen as a retrosternal widening of the cardiac shadow or a widening of the transverse cardiac shadow compared with previous chest radiographs.

CT data can help clarify changes seen on chest radiography that are suspicious for underlying or complicating diseases such as pneumonia, pneumoconiosis, or lung cancer. CT helps evaluate the extent and distribution of emphysema by visually assessing or analyzing the distribution of lung density. These parameters can be useful in preparing for lung volume reduction surgery.

Additional studies for COPD

Alpha-antitrypsin levels should be measured in patients <50 years of age with symptomatic COPD and in nonsmokers of any age with COPD to detect alpha-antitrypsin deficiency. Other factors that support antitrypsin deficiency include a family history of early-onset COPD or early childhood liver disease, lower lobe distribution of emphysema, and COPD associated with ANCA-positive vasculitis. Low alpha-antitrypsin levels should be confirmed phenotypically.

An ECG is often performed to exclude cardiac causes of dyspnea, usually revealing diffusely low QRS voltage with a vertical cardiac axis caused by increased pulmonary airiness and increased wave amplitude or rightward deviation of the wave vector caused by right atrial dilation in patients with severe emphysema. Evidence of right ventricular hypertrophy, rightward axis deviation > 110 without right bundle branch block. Multifocal atrial tachycardia, an arrhythmia that may accompany COPD, manifests as a tachyarrhythmia with polymorphic P waves and variable PR intervals.

Echocardiography is sometimes useful for assessing right ventricular function and pulmonary hypertension, although it is technically difficult in patients with COPD. The test is most often ordered when concomitant left ventricular or valvular disease is suspected.

A complete blood count is of little diagnostic value in diagnosing COPD but may reveal erythrocythemia (Hct > 48%), reflecting chronic hypoxemia.

[ 15 ], [ 16 ], [ 17 ], [ 18 ]

Diagnosis of COPD exacerbations

Patients with exacerbations associated with increased work of breathing, lethargy, and low O2 saturation on oximetry should have arterial blood gases measured to quantify hypoxemia and hypercapnia. Hypercapnia may coexist with hypoxemia. In these patients, hypoxemia often provides a greater ventilatory drive than hypercapnia (which is normal), and oxygen therapy may worsen hypercapnia by decreasing the hypoxic ventilatory response and increasing hypoventilation.

Values of partial pressure of arterial oxygen (PaO2) less than 50 mmHg or partial pressure of arterial carbon dioxide (Pa-CO2) more than 50 mmHg in conditions of respiratory acidemia define acute respiratory failure. However, some patients with chronic COPD live with such values for long periods of time.

Chest radiography is often ordered to rule out pneumonia or pneumothorax. Rarely, an infiltrate in a patient receiving chronic systemic glucocorticoids may be due to Aspergillus pneumonia.

Yellow or green sputum is a reliable indicator of the presence of neutrophils in the sputum, suggesting bacterial colonization or infection. Gram stain usually reveals neutrophils and a mixture of organisms, often gram-positive diplococci (Streptococcus pneumoniae) and/or gram-negative rods (H. influenzae). Other oropharyngeal flora, such as Moraxella (Branhamella) catarrhalis, occasionally cause exacerbations. In hospitalized patients, Gram stain and culture may reveal resistant gram-negative organisms (eg, Pseudomonas) or, rarely, gram-positive staphylococcal infection.

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Treatment of COPD

Treatment of chronic stable COPD is aimed at preventing exacerbations and maintaining long-term normal lung function and condition through drug and oxygen therapy, smoking cessation, exercise, improved nutrition, and pulmonary rehabilitation. Surgical treatment of COPD is indicated in selected patients. COPD management involves treating both chronic stable disease and exacerbations.

Drug treatment of COPD

Bronchodilators are the mainstay of COPD control; drugs include inhaled beta-agonists and anticholinergics. Any patient with symptomatic COPD should use drugs from one or both classes, which are equally effective. For initial therapy, the choice between short-acting beta-agonists, long-acting beta-agonists, anticholinergics (which have greater bronchodilation), or a combination of beta-agonists and anticholinergics is often based on cost, patient preference, and symptoms. There is now evidence that regular use of bronchodilators slows the decline in lung function, and the drugs rapidly reduce symptoms and improve lung function and performance.

In the treatment of chronic stable disease, administration of metered-dose inhalers or dry powder inhalers is preferable to nebulizer home therapy; home nebulizers become contaminated quickly due to incomplete cleaning and drying. Patients should be taught to exhale as much as possible, inhale the aerosol slowly to achieve total lung capacity, and hold their breath for 3-4 seconds before exhaling. Spacers ensure optimal distribution of the drug to the distal airways, so that coordination of inhaler activation with inhalation is less important. Some spacers do not allow the patient to inhale if he or she inhales too quickly.

Beta-agonists relax bronchial smooth muscle and increase clearance of ciliated epithelium. Salbutamol aerosol, 2 puffs (100 mcg/dose) inhaled from a metered-dose inhaler 4 to 6 times daily, is usually the drug of choice because of its low cost; regular use offers no advantage over as-needed use and has more adverse effects. Long-acting beta-agonists are preferred for patients with nighttime symptoms or for those who find frequent use of an inhaler inconvenient; salmeterol powder, 1 puff (50 mcg) twice daily, or formoterol powder (Turbohaler 4.5 mcg, 9.0 mcg, or Aerolizer 12 mcg) twice daily, or formoterol MDI 12 mcg twice daily may be used. Powder forms may be more effective for patients who have difficulty coordinating when using a metered-dose inhaler. Patients should be advised of the difference between short-acting and long-acting preparations because long-acting preparations used as needed or more than twice daily increase the risk of developing cardiac arrhythmias. Side effects are common with any beta-agonist and include tremor, restlessness, tachycardia, and mild hypokalemia.

Anticholinergics relax bronchial smooth muscle through competitive inhibition of muscarinic receptors. Ipratropium bromide is commonly used because of its low cost and availability; it is given as 2–4 puffs every 4–6 hours. Ipratropium bromide has a slower onset of action (within 30 minutes; peak effect is achieved in 1–2 hours), so a beta-agonist is often given with it in a combination inhaler or separately as an essential rescue drug. Tiotropium, a long-acting quaternary anticholinergic, is M1- and M2-selective and may therefore have an advantage over ipratropium bromide because M receptor blockade (as with ipratropium bromide) may limit bronchodilation. The dose is 18 mcg once daily. Tiotropium is not available in all countries. The effectiveness of tiotropium in COPD has been proven in large-scale studies as a drug that reliably slows the decline in FEV in patients with moderate COPD, as well as in patients who continue to smoke and have stopped smoking, and in people over 50 years of age. In patients with COPD, regardless of the severity of the disease, long-term use of tiotropium improves quality of life, reduces the frequency of exacerbations and the frequency of hospitalizations in patients with COPD, and reduces the risk of mortality in COPD. Side effects of all anticholinergic drugs include dilated pupils, blurred vision, and xerostomia.

Inhaled glucocorticoids inhibit airway inflammation, reverse beta-receptor downregulation, and inhibit cytokine and leukotriene production. They do not alter the pattern of decline in lung function in patients with COPD who continue to smoke, but they do improve short-term lung function in some patients, enhance the effect of bronchodilators, and may reduce the incidence of COPD exacerbations. Dosage depends on the drug; eg, fluticasone 500-1000 mcg daily and beclomethasone 400-2000 mcg daily. Long-term risks of long-term use of inhaled glucocorticoids (fluticasone + salmeterol) in randomized controlled clinical trials have established an increased incidence of pneumonia in patients with COPD, in contrast to long-term treatment of COPD with budesonide + formoterol, which does not increase the risk of pneumonia.

Differences in the development of pneumonia as a complication in patients with COPD receiving long-term inhaled glucocorticoids in fixed-dose combinations are due to different pharmacokinetic properties of glucocorticoids, which may lead to different clinical effects. For example, budesonide is cleared from the respiratory tract more rapidly than fluticasone. These differences in clearance may be increased in individuals with significant obstruction, leading to increased accumulation of drug particles in the central respiratory tract and decreased absorption by peripheral tissues. Thus, budesonide may be cleared from the lungs before it leads to a significant decrease in local immunity and to bacterial proliferation, which provides an advantage, since bacteria are constantly present in the respiratory tract in 30-50% of patients with moderate to severe COPD. Possible complications of steroid therapy include cataract formation and osteoporosis. Patients using these drugs long-term should have periodic ophthalmological monitoring and bone densitometry and should take additional calcium, vitamin D, and bisphosphonates.

Combinations of a long-acting beta-agonist (eg, salmeterol) and an inhaled glucocorticoid (eg, fluticasone) are more effective than either drug alone in the treatment of chronic stable disease.

Oral or systemic glucocorticoids can be used to treat chronic stable COPD, but they are likely to be effective in only 10–20% of patients, and the long-term risks may outweigh the benefits. Formal comparisons between oral and inhaled glucocorticoids have not been made. Initial doses of oral agents should be prednisolone 30 mg once daily, and response should be monitored by spirometry. If FEV improves by more than 20%, the dose should be tapered by 5 mg prednisolone per week to the lowest dose that maintains improvement. If an exacerbation occurs during tapering, inhaled glucocorticoids may be helpful, but returning to a higher dose is likely to provide more rapid resolution of symptoms and recovery of FEV. In contrast, if the increase in FEV is less than 20%, the glucocorticoid dose should be tapered rapidly and discontinued. Alternating dosing may be an option if it reduces the number of side effects while still providing the daily effect of the drug itself.

Theophylline has a minor role in the treatment of chronic stable COPD and COPD exacerbations now that safer and more effective drugs are available. Theophylline reduces smooth muscle spasm, increases ciliated epithelial clearance, improves right ventricular function, and reduces pulmonary vascular resistance and blood pressure. Its mode of action is poorly understood but probably differs from that of beta-agonists and anticholinergics. Its role in improving diaphragmatic function and reducing dyspnea during exercise is controversial. Low-dose theophylline (300–400 mg daily) has anti-inflammatory properties and may enhance the effects of inhaled glucocorticoids.

Theophylline may be used in patients who do not respond adequately to inhalers and if symptomatic efficacy is observed with the drug. Serum drug concentrations do not require monitoring as long as the patient is responsive, has no symptoms of toxicity, or is contactable; slow-release oral theophylline formulations, which require less frequent dosing, increase compliance. Toxicity is common and includes insomnia and gastrointestinal disturbances, even at low blood concentrations. More serious adverse effects, such as supraventricular and ventricular arrhythmias and seizures, tend to occur at blood concentrations greater than 20 mg/L. Hepatic metabolism of theophylline is markedly altered by genetic factors, age, cigarette smoking, liver dysfunction, and by concomitant use of small amounts of drugs such as macrolide and fluoroquinolone antibiotics and nonsedating H2-receptor antagonists.

The anti-inflammatory effects of phosphodiesterase-4 antagonists (roflumipast) and antioxidants (N-acetylcysteine) in the treatment of COPD are being investigated.

Oxygen Therapy for COPD

Long-term oxygen therapy prolongs survival in patients with COPD whose PaO2 is consistently less than 55 mmHg. Continuous 24-hour oxygen therapy is more effective than 12-hour nocturnal oxygen therapy. Oxygen therapy normalizes hematocrit, modestly improves neurological status and psychological status, apparently due to improved sleep, and reduces pulmonary hemodynamic impairment. Oxygen therapy also improves exercise tolerance in many patients.

Sleep studies should be performed in patients with advanced COPD who do not meet criteria for long-term oxygen therapy but whose clinical examination suggests pulmonary hypertension in the absence of daytime hypoxemia. Nocturnal oxygen therapy may be considered if sleep studies show episodic desaturations < 88%. This treatment prevents progression of pulmonary hypertension, but its effect on survival is unknown.

Patients recovering from an acute respiratory illness who meet the above criteria should be given O2 and have their room air values re-examined after 30 days.

O is administered via a nasal catheter at a flow rate sufficient to achieve a PaO2 > 60 mmHg (SaO > 90%), typically 3 L/min at rest. O2 is supplied from electric oxygen concentrators, liquid O2 systems, or compressed gas cylinders. Concentrators, which limit mobility but are the least expensive, are preferred for patients who spend most of their time at home. Such patients may have small O2 reservoirs for backup in the absence of electricity or for portable use.

Liquid systems are preferred for patients who spend a lot of time away from home. Portable liquid O2 canisters are easier to carry and have a larger capacity than portable compressed gas cylinders. Large compressed air cylinders are the most expensive way to provide oxygen therapy, so they should be used only if other sources are unavailable. All patients should be advised of the dangers of smoking while using O.

Various devices allow the patient to conserve oxygen, for example by using a reservoir system or by delivering O only during inspiration. These devices control hypoxemia as effectively as continuous delivery systems.

Some patients require supplemental O2 during air travel because of the low cabin pressure of commercial airliners. Eucapnic COPD patients with a sea level PaO2 greater than 68 mmHg have an average PaO2 greater than 50 mmHg in flight and do not require supplemental oxygen. All COPD patients with hypercapnia, significant anemia (Hct < 30), or underlying cardiac or cerebrovascular disease should use supplemental O2 during long flights and should notify the airline at the time of reservation. Patients are not allowed to carry or use their own O2. Airlines provide O2 through their own system, and most require at least 24 hours' notice, physician confirmation of need, and O discharge before flight. Patients should provide their own nasal cannulae because some airlines provide masks only. Provision of equipment in the destination city, if required, should be arranged in advance so that the supplier can meet the traveller at the airport.

Stopping smoking

Stopping smoking is both extremely difficult and extremely important; it slows but does not stop the progression of airway inflammation. The best results come from using a combination of smoking cessation methods: setting a quit date, behavior modification methods, group sessions, nicotine replacement therapy (gum, transdermal therapeutic system, inhaler, lozenges, or nasal spray), bupropion, and medical support. The quit rate is approximately 30% per year even with the most effective method, a combination of bupropion and nicotine replacement therapy.

Vaccine therapy

All patients with COPD should receive annual influenza vaccination. Influenza vaccine can reduce the severity and mortality of disease in patients with COPD by 30-80%. If a patient cannot be vaccinated or if the predominant influenza strain is not included in the vaccine form for that year, prophylactic treatment with influenza outbreak prophylaxis (amantadine, rimantadine, oseltamivir, or zanamivir) is appropriate during influenza outbreaks. Pneumococcal polysaccharide vaccine has minimal adverse effects. Vaccination with polyvalent pneumococcal vaccine should be given to all patients with COPD aged 65 years and older and to patients with COPD with an FEV1 < 40% predicted.

Physical activity

Skeletal muscle fitness deteriorated by inactivity or prolonged hospitalization for respiratory failure may be improved by a graded exercise program. Specific respiratory muscle training is less useful than general aerobic training. A typical exercise program begins with slow, unloaded walking on a treadmill or cycling on a bicycle ergometer for a few minutes. The duration and intensity of exercise are progressively increased over 4 to 6 weeks until the patient can exercise for 20 to 30 minutes nonstop with controlled dyspnea. Patients with very severe COPD can usually achieve a 30-minute walk at 1 to 2 miles per hour. Exercise should be performed 3 to 4 times per week to maintain fitness. O2 saturation is monitored and supplemental O2 is given as needed. Upper extremity endurance training is helpful for activities of daily living such as bathing, dressing, and cleaning. Patients with COPD should be taught energy-saving ways to perform daily tasks and distribute their activities. Sexual problems should also be discussed and counseling should be given on energy-saving ways to have sexual intercourse.

Nutrition

Patients with COPD are at increased risk of weight loss and decreased nutritional status due to a 15-25% increase in respiratory energy expenditure, higher postprandial metabolism and heat production (ie, the thermic effect of nutrition), possibly because the distended stomach prevents the already flattened diaphragm from descending and increases the work of breathing, higher energy expenditure during activities of daily living, a mismatch between energy intake and energy requirements, and the catabolic effects of inflammatory cytokines such as TNF-α. Overall muscle strength and O2 efficiency are impaired. Patients with poorer nutritional status have a worse prognosis, so it is prudent to recommend a balanced diet with adequate calories, combined with exercise, to prevent or reverse muscle wasting and malnutrition. However, excessive weight gain should be avoided, and obese patients should aim for a more normal body mass index. Studies examining the contribution of diet to patient rehabilitation have failed to show improvement in pulmonary function or exercise capacity. The role of anabolic steroids (eg, megestrol acetate, oxandrolone), growth hormone therapy and TNF antagonists in correcting nutritional status and improving functional status and prognosis in COPD has not been adequately studied.

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Pulmonary rehabilitation for COPD

Pulmonary rehabilitation programs are an adjunct to drug therapy to improve physical function; many hospitals and health care facilities offer formal multidisciplinary rehabilitation programs. Pulmonary rehabilitation includes exercise, education, and behavior modification. Treatment should be individualized; patients and families are educated about COPD and treatment, and the patient is encouraged to take maximum responsibility for his or her own health. A well-integrated rehabilitation program helps patients with severe COPD adjust to physiological limitations and gives them realistic ideas about the possibilities for improving their condition.

The effectiveness of rehabilitation is manifested in greater independence and improvement in quality of life and exercise tolerance. Small improvements are seen in increased lower extremity strength, endurance, and maximal O2 consumption. However, pulmonary rehabilitation does not usually improve lung function or prolong life. To achieve a positive effect, patients with severe disease require at least three months of rehabilitation, after which they should continue to engage in maintenance programs.

Specialized programs are available for patients who remain on mechanical ventilation after acute respiratory failure. Some patients can be weaned completely, while others may only be kept off mechanical ventilation for a day. If adequate conditions exist at home and if family members are well trained, discharge from the hospital on mechanical ventilation may be possible.

Surgical treatment of COPD

Surgical approaches to treating severe COPD include lung volume reduction and transplantation.

Reduction of lung volume by resection of functionally inactive emphysematous areas improves exercise tolerance and two-year mortality in patients with severe emphysema, predominantly in the upper lungs, who have initially low exercise tolerance after pulmonary rehabilitation.

Other patients may experience symptom relief and improved performance after surgery, but mortality is unchanged or worse than with medical therapy. Long-term outcome is unknown. Improvement is less common than with lung transplantation. Improvement is thought to result from increased lung function and improved diaphragmatic function and V/P ratio. Surgical mortality is approximately 5%. The best candidates for lung volume reduction are patients with an FEV 20-40% predicted, MAP greater than 20% predicted, significantly impaired exercise tolerance, heterogeneous lung disease on CT with predominant upper lobe involvement, PaCO less than 50 mmHg, and the absence of severe pulmonary arterial hypertension and coronary artery disease.

Rarely, patients have bullae so large that they compress functional lung. These patients may benefit from surgical resection of the bullae, resulting in resolution of symptoms and improvement in pulmonary function. In general, resection is most effective for bullae that occupy more than one-third of the hemithorax and an FEV of about one-half the predicted normal volume. Improvement in pulmonary function depends on the amount of normal or minimally abnormal lung tissue that is compressed by the resected bulla. Serial chest radiographs and CT are the most useful studies to determine whether a patient's functional status is due to compression of viable lung by a bulla or to generalized emphysema. A markedly decreased RR0 (< 40% predicted) indicates widespread emphysema and suggests a more modest response to surgical resection.

Since 1989, single lung transplantation has largely replaced double lung transplantation in patients with COPD. Candidates for transplantation are patients younger than 60 years with an FEV ≤25% predicted or with severe pulmonary arterial hypertension. The goal of lung transplantation is to improve quality of life because life expectancy is rarely increased. Five-year survival after transplantation in emphysema is 45-60%. Patients require lifelong immunosuppression, which carries a risk of opportunistic infections.

Treatment of acute exacerbation of COPD

The immediate goal is to ensure adequate oxygenation, slow the progression of airway obstruction, and treat the underlying cause of the exacerbation.

The cause is usually unknown, although some acute exacerbations result from bacterial or viral infections. Factors that contribute to exacerbations include smoking, inhalation of irritating pollutants, and high levels of air pollution. Moderate exacerbations can often be managed on an outpatient basis if home conditions permit. Elderly, frail patients and those with underlying medical conditions, a history of respiratory failure, or acute changes in arterial blood gas parameters are admitted to hospital for observation and treatment. Patients with life-threatening exacerbations with unresponsive hypoxemia, acute respiratory acidosis, new arrhythmias, or worsening respiratory function despite inpatient treatment, as well as patients who require sedation for treatment, should be admitted to an intensive care unit with continuous respiratory monitoring.

Oxygen

Most patients require supplemental O2, even if they do not require it chronically. O2 administration may worsen hypercapnia by decreasing the hypoxic respiratory response. The PaO2 on room air should be rechecked after 30 days to assess the patient's need for supplemental O2.

Respiratory support

Noninvasive positive pressure ventilation [eg, pressure support or bilevel positive airway pressure ventilation via face mask] is an alternative to full mechanical ventilation. Noninvasive ventilation probably reduces the need for intubation, shortens the length of hospital stay, and reduces mortality in patients with severe exacerbations (defined as pH < 7.30 in hemodynamically stable patients without imminent respiratory arrest). Noninvasive ventilation does not appear to have any effect in patients with less severe exacerbations. However, it may be considered in this group of patients if arterial blood gases deteriorate despite initial drug therapy or if the patient is a potential candidate for full mechanical ventilation but does not require intubation for airway management or sedation for treatment. If the patient deteriorates on noninvasive ventilation, invasive mechanical ventilation should be considered.

Deterioration of blood gases and mental status and progressive respiratory muscle fatigue are indications for endotracheal intubation and mechanical ventilation. Ventilatory options, treatment strategies, and complications are discussed in Chapter 65, page 544. Risk factors for ventilator dependence include FEV < 0.5 L, stable blood gases (PaO2 < 50 mmHg and/or PaCO2 > 60 mmHg), significant limitation of exercise capacity, and poor nutritional status. Therefore, the patient's wishes regarding intubation and mechanical ventilation should be discussed and documented.

If a patient requires prolonged intubation (e.g., more than 2 weeks), a tracheostomy is indicated to provide comfort, communication, and nutrition. With a good multidisciplinary recovery program, including nutritional and psychological support, many patients requiring long-term mechanical ventilation can be successfully weaned off the machine and returned to their previous level of functioning.

Drug treatment of COPD

Beta-agonists, anticholinergics and/or corticosteroids should be given concomitantly with oxygen therapy (regardless of how oxygen is administered) to reduce airway obstruction.

Beta-agonists are the mainstay of drug therapy for exacerbations. The most widely used is salbutamol 2.5 mg via nebulizer or 2-4 inhalations (100 mcg/inhalation) via metered-dose inhaler every 2-6 hours. Inhalation via metered-dose inhaler results in rapid bronchodilation; there is no evidence that nebulizers are more effective than metered-dose inhalers.

Ipratropium bromide, the most commonly used anticholinergic agent, has been shown to be effective in acute exacerbations of COPD; it should be given concomitantly or alternately with beta-agonists via a metered-dose inhaler. The dosage is 0.25-0.5 mg via nebuliser or 2-4 inhalations (21 mcg/breath) via metered-dose inhaler every 4-6 hours. Ipratropium bromide usually provides bronchodilator effects similar to those of beta-agonists. The therapeutic value of tiotropium, a prolonged-release anticholinergic agent, has not been established.

Glucocorticoids should be started immediately for all, even moderate, exacerbations. Choices include prednisolone 60 mg once daily orally, tapering the dose over 7-14 days, and methyl prednisolone 60 mg once daily intravenously, tapering the dose over 7-14 days. These drugs are equivalent in acute effects. Of the inhaled glucocorticoids used in the treatment of COPD exacerbations, budesonide suspension is recommended as nebulizer therapy at a dose of 2 mg 2-3 times a day in combination with solutions of short-acting, preferably combination bronchodilators.

Methylxanthines, once considered the mainstay of treatment for COPD exacerbations, are no longer used. Their toxicity outweighs their effectiveness.

Antibiotics are recommended for exacerbations in patients with purulent sputum. Some physicians prescribe antibiotics empirically when sputum color changes or nonspecific changes in chest X-ray. There is no need for bacteriological and bacterioscopic examination before prescribing treatment unless an unusual or resistant microorganism is suspected. Antibacterial therapy for uncomplicated exacerbation of COPD in individuals < 65 years, FEV > 50% predicted includes amoxicillin 500-100 mg 3 times a day or second-generation macrolides (azithromycin 500 mg 3 days or clarithromycin 500 mg twice a day), second- or third-generation cephalosporins (cefuroxime axetil 500 mg twice a day, cefixime 400 mg once a day) given for 7-14 days, are effective and inexpensive first-line drugs. The choice of drug should be dictated by the local bacterial susceptibility pattern and the patient's medical history. In most cases, treatment should be initiated with oral drugs. Antibacterial therapy for complicated exacerbation of COPD with risk factors with FEV 35-50% of the predicted value includes amoxicillin-potassium clavulanate 625 mg 3 times a day or 1000 mg 2 times a day; fluoroquinolones (levofloxacin 500 mg once daily, moxifloxacin 400 mg once daily, or gatifloxacin 320 mg once daily). These drugs are given orally or, if necessary, following the principle of "step therapy" for the first 3-5 days parenterally (amoxicillin-clavulanate 1200 mg 3 times a day or fluoroquinolones (levofloxacin 500 mg once daily, moxifloxacin 400 mg once daily). These drugs are effective against beta-lactamase-producing strains of H. influene and M. catarrhalis, but were not superior to first-line drugs in most patients. Patients should be taught to recognize signs of exacerbation by a change in sputum from normal to purulent and begin a 10-14-day course of antibiotic therapy. Long-term Antibiotic prophylaxis is recommended only for patients with structural changes in the lungs such as bronchiectasis or infected bulla.

If Pseudomonas spp. and/or other Enterobactereaces spp. are suspected, parenteral ciprofloxacin 400 mg 2-3 times a day, then orally 750 mg 2 times a day, or parenteral levofloxacin 750 mg 1 time per day, then 750 mg per day orally, ceftazidime 2.0 g 2-3 times a day.

COPD prognosis

The severity of airflow obstruction predicts survival in patients with COPD. Mortality in patients with an FEV ≥50% is thought to be slightly higher than in the general population. Five-year survival is approximately 40–60% for FEV 0.75–1.25 L; approximately 30–40% for FEV ≤0.75 L. Cardiac disease, low body weight, resting tachycardia, hypercapnia, and hypoxemia reduce survival, whereas a significant response to bronchodilators is associated with improved survival. Risk factors for death in patients with acute exacerbations requiring hospitalization include advanced age, high PaCO2 values, and chronic use of oral glucocorticoids.

Mortality in COPD in patients who have stopped smoking is often due to intercurrent illnesses rather than progression of the underlying disease. Death is usually caused by acute respiratory failure, pneumonia, lung cancer, cardiac failure, or pulmonary embolism.