Management of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) affects 5% of the adult population and is the fourth leading cause of death and twelfth leading cause of morbidity in the United States. Among persons over the age of 40 years, approximately 10% have evidence of at least moderate airflow resistance. It is the only major cause of death for which both morbidity and mortality rates are increasing. Smoking remains the principal risk factor for the development of COPD; nearly 90% of cases occur in the context of long-term heavy smoking, which increases the risk for COPD 30-fold. The marked increase in COPD prevalence, especially among women, noted since 1980 reflects the heavy smoking habits of the US population in the decades after World War II.

Although COPD is essentially irreversible and is usually marked by a progressive decline in lung function, improvements in functional status and survival are possible with good care, most of which can be managed in the outpatient setting by the primary care physician and medical-home team. The primary physician needs to know the indications for bronchodilators, corticosteroids, oxygen supplementation, antibiotics, immunizations, and rehabilitative measures in addition to the potential value of surgical approaches. A positive attitude and caring engagement on the part of the physician and medical-home team enhances patient motivation and encourages effective self-care, important determinants of successful management of COPD.

PATHOPHYSIOLOGY, CLINICAL PRESENTATION, AND COURSE (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19)

COPD is a heterogeneous disorder marked by obstruction of airflow and a reduction in the expiratory flow rate. It is distinguished from asthma and other obstructive pulmonary diseases in that the airflow limitation is not fully reversible and is in most cases both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases such as those delivered in cigarette smoke.

Pathophysiology

Inflammation

Airway inflammation plays an important pathophysiologic role in obstructive pulmonary diseases. In stable COPD, the inflammation appears to be predominantly neutrophilic. Of the cytokines measured in COPD, those that attract neutrophils (e.g., interleukin-8) are the most markedly elevated. Although lymphocytes are present in increased numbers, they are mainly type 1 helper CD8 T cells. In contrast, the predominant cells in asthma are eosinophils, mast cells, and type 2 helper CD4 T cells. During an acute exacerbation of COPD, the number of eosinophils found in bronchial biopsy specimens is increased 30-fold. These differences in inflammatory cell infiltrates may help to explain the disparate responses to corticosteroids seen in the two conditions and in different phases of COPD (see later discussion).

Despite the differences in inflammatory mechanisms between COPD and asthma, evidence is emerging that the inflammatory pathophysiology of chronic asthma might predispose patients to COPD, especially smokers. Asthmatic patients who smoke manifest an increased rate of deterioration in forced expiratory volume in 1 second (FEV₁) over time in comparison with nonasthmatic smokers and asthmatic patients who do not smoke. Moreover, bronchial hyperresponsiveness to methacholine challenge is a powerful independent predictor
of progression of COPD in smokers. Perhaps the underlying inflammatory process in asthma is an important contributor to the development of COPD in smokers and may account for the steroid responsiveness seen in a subset of COPD patients.

Inflammation of the cells lining the bronchial wall leads to hyperplasia of the mucous glands and narrowing of the small airways. Airway edema, excess mucus production, and loss of ciliary transport result.

As noted, smoking or prolonged exposure to other bronchial irritants is the usual precipitant. However, even after withdrawal of such irritants, the inflammatory process typically continues unabated. Autoimmunity is believed to play an important role in this process, based on such findings as an increase in numbers of pulmonary B and T cells and presence of circulating autoantibodies against pulmonary endothelial and epithelial cells. It is suspected that smokers who develop more severe COPD in response to smoking have among other factors a deficiency of regulatory T cells that prevent an immunologic inflammatory response to autoantigens.

Alveolar Destruction

A second pathophysiologic process is destruction of the alveolar walls leading to pathologic enlargement of the air spaces distal to the terminal bronchioles. This is thought due to imbalance between alveolar protease and antiprotease activity. Alveolar tissue contains both proteases and antiproteases, with neutrophil-derived elastase being the most important protease and α₁-antitrypsin being the prime antiprotease. When antitrypsin activity is reduced or elastase levels are increased, alveolar wall destruction follows. Cigarette smoking may trigger the influx of elastase-rich neutrophils into the alveoli or the oxidative inactivation of antitrypsin. Patients who are homozygous for a hereditary deficiency of α₁-antitrypsin (<80 mg/L) are at greatly increased risk for the development of emphysema. They represent fewer than 2% of cases overall but account for many cases among nonsmokers without other environmental risk factors; they present with the onset of clinical disease before age 50 years and have a positive family history of early-onset emphysema.

The result of the imbalance between protease and antiprotease activity is fragmentation of the pulmonary elastic tissue, which leads to destruction of the alveolar architecture and the capillary bed that lies within the alveolar wall. Because both air space and the vascular bed are destroyed, ventilation and perfusion do not become markedly mismatched, and marked hypoxemia does not ensue. Expiratory flow rates decline with the loss of the normal elastic recoil of the lung and radial traction on airways; the poorly supported noncartilaginous airways collapse during expiration. Inspiratory flow rates can be normal because airway caliber is normal during inspiration. In many patients, a reversible cholinergic component of airway obstruction is also present that is responsive to muscarinic blockade. Pulmonary compliance increases with the decline in elasticity. As destruction of alveolar architecture progresses, the size of the pulmonary capillary bed is reduced, causing the carbon monoxide diffusing capacity to drop. Because the reduction in size of the vascular bed parallels the fall in alveolar surface area, ventilation still roughly matches perfusion, and significant hypoxemia does not ensue.

Small Airway Inflammation and Obstruction

The traditional view of emphysema’s pathology emphasizes destruction of alveoli, but recent research based on micro-computed tomography raises the possibility that inflammatory damage to small airways (terminal bronchioles) and resultant obstruction and destruction may precede alveolar injury. In this model, the consequences of terminal bronchiolar inflammation are obstruction followed by destruction, disrupting elastic fibers that provide recoil of small airways, which in turn compromises alveolar acinar tethering and leads to collapse of the alveolar walls. Confirmation and more work on the implications for treatment are needed, but awareness of the evolving views of pathogenesis can help in understanding the rationale for treatment and prevention.

Oxidative Stress

Oxidative stress caused by inhaled cigarette smoke has been incriminated as a contributor to airway narrowing, both reversible and irreversible, and to alveolar destruction. This stress reflects an imbalance between oxidants and antioxidants similar to that between proteases and antiproteases. Increased levels of oxidation products such as hydrogen peroxide and nitric oxide are found in the breath condensates of patients with COPD. Oxidative stress can directly damage cells and the lung extracellular matrix. It also promotes inflammation through a number of mechanisms and exacerbates the protease/antiprotease imbalance by activating the former and deactivating the latter.

Genetic Predispositions

In addition to the genetically determined susceptibility for emphysema exhibited by persons homozygous for α₁–antitrypsin deficiency, a host of other genetically related factors are being discovered. Single nucleotide polymorphisms (SNPs) in the genes encoding for matrix metalloproteinase 12 (an enzyme in lower airway macrophages) are associated with differing levels of risk for developing COPD, especially with regard to persons who smoke.

Pathophysiology of Exacerbations

Exacerbations of COPD have been linked clinically to exposure to pollutants, acquisition of new bacterial strains, and viral infection as well as concurrent cardiovascular events such as heart failure, pulmonary embolization, and acute ischemia. Smoldering systemic inflammation is suspected of playing a major role in rendering patients susceptible to such insults, a contribution suggested by the finding of a significant increase in risk of a COPD exacerbation associated with elevations in markers of inflammation (C-reactive protein, leukocyte count, and fibrinogen). Enlargement of the pulmonary artery has been found to be an independent predictor of acute exacerbations, suggesting a role for pulmonary hypertension.

A frequent-exacerbation phenotype has been identified, which has an independent association with COPD flares. It consists of a severe airflow obstruction, history of gastroesophageal reflux disease, poor health-related quality of life, and elevated white cell count. This finding suggests to some an underlying biologic, behavioral, or genetic determinant of susceptibility.

Cardiovascular Changes

The classic cardiovascular consequence of severe COPD is cor pulmonale, which ensues in cases of sustained hypoxemia as the resultant pulmonary hypertension leads to right ventricular hypertrophy and/or dilatation and ultimately right heart failure. Cor pulmonale is common in persons with severe disease, found in upward of 40% of COPD patients with an FEV₁ of less than 1.0 L/min, and accompanied by at least mild pulmonary hypertension (mean pulmonary artery pressure ≤40 mm Hg). Less appreciated is impaired left ventricular filling from hyperinflation, which reduces stroke volume and lowers cardiac output without loss of ejection fraction.

Clinical Presentation

Although smoking and other noxious stimuli precipitate both airway inflammation and alveolar destruction, one or the other process may predominate. Historically, the patient with airway
inflammation producing a chronic cough and sputum production for 3 months of 2 consecutive years was characterized as suffering from chronic bronchitis. The patient with alveolar destruction evident on chest x-ray as hyperlucency of the pulmonary parenchyma and lung hyperinflation was given the diagnosis of emphysema. These diagnoses can best be thought of as extremes on the spectrum of COPD, with the clinical picture for any individual patient determined by the relative contribution of airway inflammation and alveolar destruction.

Chronic Bronchitis

For the patient at the chronic bronchitis end of the spectrum, obstruction to airflow occurs with both inspiration and expiration. Widespread bronchial narrowing and mucous plugging produce hypoxemia because of mismatching of ventilation and perfusion. Hypercarbia results from impeded ventilation. Chronic hypoxia and hypercarbia increase pulmonary arterial resistance and may lead to the development of pulmonary hypertension and, eventually, cor pulmonale (altered structure and/or function of the right ventricle from the underlying lung disease). Sudden worsening may precipitate acute right-sided heart failure in severe chronic bronchitis. The patient may appear plethoric and cyanotic. Secondary polycythemia is common.

Emphysema

For the patient on the emphysema end of the spectrum, the clinical picture is dominated by dyspnea, particularly on exertion. Cough is only a minor complaint, and sputum production is scant. The patient with advanced disease is thin and tachypneic, often using accessory muscles of respiration and pursed-lip breathing. The latter helps to keep noncartilaginous airways from collapsing during expiration. Cyanosis is uncommon because the oxygen tension (PO₂) is only minimally reduced. The neck veins may seem distended, but only during expiration. The anterior-posterior diameter of the chest is increased, the percussion note is hyperresonant, and the breath sounds are distant. Usually, no signs of cor pulmonale are present, although the right ventricular impulse may be prominent because of displacement by hyperinflated lungs. As noted, hypoxemia is minimal, and little, if any, carbon dioxide retention occurs until the end stages of the disease. Chest radiography demonstrates hyperinflation and hyperlucency, especially at the apices, except in patients with antitrypsin deficiency, whose radiographic changes are greatest at the bases.

Clinical Course and Prognosis

The traditional view of COPD’s clinical course is one of invariable progression; however, in prospective longitudinal studies, the course proves to be quite variable, with many patients experiencing a slowed or halted progression if they stop smoking. Early on, before the onset of symptoms, one can often detect an increase in the closing volume and a decrease in the maximum midexpiratory flow rate (sensitive measures of small airway disease); measures of large airway resistance are usually within normal limits during this phase of the illness. The presymptomatic, small airway stage (stage 0) of COPD may represent a period of reversible disease; however, early fibrotic changes have been found in airways of such patients. It has not been resolved whether intervention at the time of early small airway abnormalities can halt the pathologic process, stop disease progression, and improve prognosis, but cessation of smoking certainly improves outcomes.

When lung function is studied using the FEV₁ as the functional measure of obstruction, the reported mean annual decrease in flow rate ranges from 30 to 70 mL/s with the rate of change being highly variable; those at greatest risk for an accelerated rate of decline are current smokers, patients with emphysema, and those with bronchodilator reversibility. The rate of decline in FEV₁ can be reduced by over 50% if the patient stops smoking and is able to sustain cessation. Intermittent quitters achieve much less benefit. The earlier in the course of illness one quits smoking, the better the preservation of function.

COPD Exacerbations

As disease severity progresses, COPD exacerbations develop and become more frequent, characterized by an acute worsening of symptoms, typically but, as noted, not always triggered by infection; heart failure, pulmonary embolization, and acute ischemia have also been associated with exacerbations. The best predictor of an exacerbation is a history of a prior exacerbation. Recurrent exacerbations can have serious long-term consequences, including hastened declines in FEV₁, functional capacity, and quality of life and increased risk of death. Although persons with severe disease are at greatest risk for exacerbations, these may also occur in those with more moderate disease severity (FEV₁ >50% predicted).

Prognosis

It remains difficult to predict survival in individual patients. Although the prognosis for patients with COPD is not very good, therapy does prolong survival—cessation of smoking is critical (see later discussion). The onset of recurrent COPD exacerbations, resting tachycardia, or cor pulmonale indicates a poor prognosis. By the time the FEV₁ declines to less than 1 L/s, the mean annual mortality approaches 10%.

DIAGNOSIS AND STAGING (20, 21, 22, 23, 24, 25 and 26)

Diagnosis

The consensus standard for COPD diagnosis is a spirometric functional criterion established by the Global Initiative for Obstructive Lung Disease and typically referred to (in somewhat double entendre fashion) as the GOLD Standard:

COPD = Reduction in the ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC) to less than 70% (i.e., COPD = FEV₁/FVC < 0.70.)

(N.B. Although disease progression is often measured in functional terms by reference to the FEV₁, the FEV₁ by itself is inadequate for diagnosis because other factors which have nothing to do with outflow obstruction [e.g., restrictive disease] can also lower the FEV₁.)

Use of this functional COPD definition for gauging respiratory impairment has been challenged by some experts for its inadequate specificity, categorizing some asymptomatic persons (particularly older persons who have less airway elastic recoil and increased chest wall rigidity) as having COPD when they do not manifest any functional impairment. Instead, they suggest using a statistical standard for the FEV₁/FVC ratio, referred to as the LMS (lambda-sigma-mu) criterion, which depends upon calculation of a Z score for the FEV₁/FVC ratio that takes into account age-related changes in respiratory function. Such Z scoring is familiar to clinicians through its use in bone mineral density interpretation. In a prospective population study of asymptomatic patients aged 65 to 80 years with normal speed, investigators found that the GOLD approach classified 38% as having COPD compared to 12% by the LMS method. Moreover, the LMS approach was more accurate for identifying those who would develop mobility disability over 5 years of follow-up.

Pending a change in consensus, the GOLD standard remains the criterion for spirometric diagnosis of COPD, but clinicians should recognize its potential shortcomings. Of note, most
consensus guidelines take this shortcoming into account, not recommending treatment or screening in asymptomatic persons (see later discussion).

TABLE 47-1 Classification of Severity of Airflow Limitation in COPD (Based on Postbronchodilator FEV₁)

In Patients with FEV₁/FVC < 0.70:
GOLD 1:	Mild	FEV₁ ≥ 80% predicted
GOLD 2:	Moderate	50% ≤ FEV₁ < 80% predicted
GOLD 3:	Severe	30% ≤ FEV₁ < 50% predicted
GOLD 4:	Very Severe	FEV₁ < 30% predicted
Reprinted with permission from the Global Strategy for Diagnosis, Management and Prevention of COPD 2013, © Global Initiative for Chronic Obstructive Lung Disease (GOLD), all rights reserved. Available from http://www.goldcopd.org.

Differentiating COPD patients with predominantly emphysematous physiology from those with chronic bronchitis is done largely through history and physical examination supplemented by chest x-ray and a few other basic tests.

Staging

Being a progressive disease of airway obstruction, COPD can be staged according to degree of functional impairment, as designated in the GOLD staging system. For example, stage 1 is labeled as “mild” COPD and defined by an FEV₁/FVC < 0.70 and an FEV₁ ≥80% of predicted value (see Table 47-1).

WORKUP (15,20, 21, 22, 23, 24, 25 and 26)

History

Description of symptoms should include any limitations of activity experienced in daily life, both at rest and during exercise. A detailed history of smoking and environmental or work exposures to pulmonary irritants is indicated, including everyday exposures to aerosol deodorants, hairsprays, paint sprays, and insecticides. Estimates of exercise capacity (e.g., number of flights of stairs that can be climbed or distance that can be walked on level ground) are helpful, as is some indication of the progression of symptoms over time. The presence of leg edema and worsening exercise tolerance suggest the onset of cor pulmonale and right-sided heart failure in the patient with hypoxic COPD.

Laboratory Studies

Testing is necessary to confirm the diagnosis, assess severity, and identify comorbid conditions, thereby providing a basis for choosing therapy and estimating prognosis.

Spirometry

Spirometry is essential to confirm the diagnosis in patients with symptoms suggestive of COPD, including those with chronic cough and sputum production as well as those who present with dyspnea. The most helpful measurement is the ratio of FEV₁ to VC. As noted, a reduction in this ratio to less than 70% is an indication of significant airflow limitation.

Disease severity in COPD can then be assessed by the progressive decline in the postbronchodilator FEV₁, with results compared with predicted values (Table 47-1). Crude estimates of obstruction can be provided by the FEV₁ alone. Should spirometry be unavailable, prolongation of the forced expiratory time beyond 6 seconds suggests an FEV₁/FVC ratio of less than 50%. Patients with a 50% reduction in FEV₁ are often dyspneic and hypoxemic on exertion; by the time the FEV₁ falls to 25% of the predicted value, they may note shortness of breath at rest.

Bronchodilator Testing.

Although determination of the FEV₁ before and after inhalation of a bronchodilator (e.g., albuterol) has been advocated to rule out asthma and provide a quick estimate of the benefit a patient may derive from bronchodilator therapy, the failure to obtain an improvement in flow rate does not rule out benefit. In fact, it has been shown that short-term changes in FEV₁ in response to bronchodilators are a poor predictor of symptomatic benefit over a 3- to 6-month period of treatment.

Testing Asymptomatic Persons.

Evidence does not support the use of spirometry in asymptomatic patients; limited evidence suggests that subsequent interventions in such patients who do have abnormal results are not effective. Benefits of treatment are limited to patients with bothersome symptoms and with FEV₁ less than 60% of predicted. Modifying therapy based on spirometric results is generally not helpful.

Chest Imaging

Chest radiography is helpful, principally to rule out complications of COPD (e.g., pneumonia, pneumothorax) and other forms of chest disease that may present as dyspnea (e.g., heart failure, interstitial lung disease; see Chapter 40). Of the various forms of COPD, only severe emphysema is diagnosed radiologically; the criteria for radiologic diagnosis are the presence of two or more of the following findings: flattening of the diaphragm and blunting of the costophrenic angle on posterior-anterior view, irregularity of lung field lucency, enlargement of the retrosternal space, and flattening or concavity of the diaphragmatic contour on lateral view. High-resolution chest computed tomography (CT) has been shown to detect emphysema in heavy smokers who are asymptomatic and have normal chest x-rays, but evidence for clinical benefit for the use of CT in this situation is lacking, although proponents of low-dose CT scanning for lung cancer raise the question of an added benefit from such screening (sensitivity 63%, specificity 88%). The degree and pattern of emphysema within the lungs can also be assessed more precisely with chest CT than chest x-ray. However, with the exception of assessment for lung volume reduction surgery and perhaps encouraging persons to stop smoking, these findings have little effect on management decisions.

Measurement of Arterial Oxygen Saturation and Blood Gases

Measurement of arterial oxygen saturation and blood gases is worth considering in patients with an FEV₁ of less than 50% of the predicted value, a point at which hypoxemia is a possibility, especially in persons with chronic bronchitis. Pulse oximetry can be used as a screening test; it provides a measure of arterial oxygen saturation (SaO₂). If the SaO₂ is less than 92%, then measurement of the arterial blood gases is indicated to assess oxygenation and ventilation. Hypoxemia and hypercarbia are indications of severe chronic bronchitis. Blood gas measurement is particularly useful for documenting acute decompensation. In patients with severe chronic bronchitis (stages 3 and 4),
baseline and serial studies of blood gases should be performed so that measurements of gases obtained at times of marked subjective worsening can be compared with baseline determinations.

Hematocrit and Hemoglobin Concentration

Hematocrit and hemoglobin concentration provide a rough indication of the severity and chronicity of hypoxemia and the possible need for phlebotomy. Measurement should be undertaken in persons with arterial oxygen pressure (PaO₂) of less than 50 mm Hg.

Electrocardiogram

Electrocardiogram should be studied for sinus tachycardia, multifocal atrial tachycardia, peaked P waves (P pulmonale), and signs of right ventricular hypertrophy (e.g., tall R wave in lead V1 and deep S wave in lead V6). The electrocardiographic abnormalities that appear in COPD generally reflect the severity of lung disease and the presence of cor pulmonale.

Identification of Persons at Risk for COPD Exacerbations

Given that serious prognostic significance of COPD exacerbations, early identification of persons at increased risk would be helpful. As noted, the best predictor remains a prior history of an exacerbation, which should be sought. Risk also appears to correlate roughly with stage of disease, suggesting a possible benefit from repeated spirometry, but only if it will result in a change in management. Measures of inflammation such as the erythrocyte sedimentation rate, C-reactive protein, and serum fibrinogen level were found predictive in one study, a finding that needs confirmation (interestingly, the strongest predictive value in the study was for the absence of elevations in these markers, associated with the least risk of a COPD flare). Evidence that pulmonary artery enlargement (ratio of pulmonary artery diameter to aorta diameter >1.0) is an independent determinant of exacerbation risk has raised the question of CT scanning for early detection of exacerbation risk, since enlargement may predate exacerbations; evidence of benefit will be needed before such CT scanning can be recommended.

Testing for Alpha Antitrypsin Deficiency

Testing for this condition remains the subject of debate, because there is no definitive evidence that diagnosis results in improved outcomes, but consensus recommendations continue to recommend its consideration, especially with occurrence of early-onset COPD or COPD in families. Testing methods include measurement of the serum or plasma concentrations of the protein, serum or plasma protein phenotyping, and genotyping. The first step is determining concentration. Reduced serum levels are suggestive of the diagnosis, but levels can be difficult to interpret because the protein is an acute-phase reactant, which may increase in the setting of inflammation. A low level is an indication for further testing, which entails protein phenotyping and genetic testing; these should be carried out with the help of expert consultation.

PRINCIPLES OF MANAGEMENT (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 and 95)

The prime goals of treatment are the slowing of disease progression, improvement of respiratory health status, prevention and reduction in number of exacerbations, and prolongation of survival. The principal components of management for achieving these goals are smoking cessation (the only proven means of slowing disease progression), avoidance of other risk factors, use of inhaled bronchodilators and corticosteroids, supplemental oxygen, antibiotics, and pulmonary rehabilitation. Interventional/surgical approaches are reserved for special situations.

TABLE 47-2 Stepped Care Approach to COPD Drug Therapy

Stage (by GOLD Criteria)	Treatment
Stage 1	Inhaled short-acting β₂-agonist or
	Inhaled short-acting anticholinergic or
	Inhaled combination preparation
	Consider LAA or LABA
Stage 2	Addition of inhaled LAA or
	Addition of LABA, and
	Consideration of inhaled LAA + LABA
Stage 3	Combination of inhaled LABA and inhaled LAA or
	Combination of inhaled LABA and inhaled corticosteroid, plus
	Consideration of oral PDE-4 inhibitor for chronic bronchitis
Stage 4	Combination of inhaled LABA/corticosteroid + LAA
	Consideration of oral PDE-4 inhibitor for chronic bronchitis
Exacerbation (regardless of stage)	Initiation of antibiotic therapy and oral corticosteroid therapy plus
	Use of short-acting bronchodilator therapy as needed for acute symptomatic relief;
	Initiation of inhaled corticosteroid therapy for prevention of recurrence
LAA, long-acting anticholinergic; LABA, long-acting beta-agonist.

Treatment Strategy: A Stepped Care Approach (see Table 47-2) (27, 28, 29, 30, 31 and 32)

Being a progressive disease, COPD is typically treated in stepwise fashion according to disease stage. Because available treatments (other than smoking cessation) do not definitively halt disease progression, little or no treatment is indicated at early-stage disease (GOLD stage I) other than a concentrated effort at smoking cessation (which has greatest impact on disease progression when instituted early on—see later discussion). As disease progresses, initiation of pharmacologic treatment and nonpharmacologic measures can improve lung function and health status, reduce exacerbations and hospitalizations, and improve survival, even in persons with advances disease, but especially for patients having moderate to severe disease (GOLD stages II and III).

Only gold members can continue reading. Log In or Register to continue