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Chronic Obstructive Pulmonary Disease (COPD)

By Robert A. Wise, MD, Johns Hopkins University School of Medicine

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Patient Education

Chronic obstructive pulmonary disease (COPD) is partially reversible airflow limitation caused by an inflammatory response to inhaled toxins, often cigarette smoke. α1-Antitrypsin deficiency and various occupational exposures are less common causes in nonsmokers. Symptoms are productive cough and dyspnea that develop over years; common signs include decreased breath sounds, prolonged expiratory phase of respiration, and wheezing. Severe cases may be complicated by weight loss, pneumothorax, frequent acute decompensation episodes, right heart failure, and acute or chronic respiratory failure. Diagnosis is based on history, physical examination, chest x-ray, and pulmonary function tests. Treatment is with bronchodilators, corticosteroids, and, when necessary, O2 and antibiotics. About 50% of patients with severe COPD die within 10 yr of diagnosis.

COPD comprises

  • Chronic obstructive bronchitis (clinically defined)

  • Emphysema (pathologically or radiologically defined)

Many patients have features of both.

Chronic obstructive bronchitis is chronic bronchitis with airflow obstruction. Chronic bronchitis is defined as productive cough on most days of the week for at least 3 mo total duration in 2 successive 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; it occurs predominantly in smokers with a history of asthma. In some cases, the distinction between chronic obstructive bronchitis and chronic asthmatic bronchitis is unclear.

Emphysema is destruction of lung parenchyma leading to loss of elastic recoil and loss of alveolar septa and radial airway traction, which increases the tendency for airway collapse. Lung hyperinflation, airflow limitation, and air trapping follow. Airspaces enlarge and may eventually develop bullae.


In the US, about 24 million people have airflow limitation, of whom about half have a diagnosis of COPD. COPD is the 3rd leading cause of death, resulting in 135,000 deaths in 2010—compared with 52,193 deaths in 1980. From 1980 to 2000, the COPD mortality rate increased 64% (from 40.7 to 66.9/100,000) and has remained steady since then. Prevalence, incidence, and mortality rates increase with age. Prevalence is now higher in women, but total mortality is similar in both sexes. Incidence and mortality are generally higher in whites and lower income groups, probably because these groups have a higher prevalence of smoking. COPD seems to aggregate in families independent of α1-antitrypsin (α1-antiprotease inhibitor) deficiency (see Alpha-1 Antitrypsin Deficiency).

COPD is increasing worldwide because of the increase in smoking in developing countries, the reduction in mortality due to infectious diseases, and the widespread use of biomass fuels such as wood, grasses, or other organic materials. COPD mortality may also affect developing nations more than developed nations. COPD affects 64 million people and caused > 3 million deaths worldwide in 2005 and is projected to become the 3rd leading cause of death globally by the year 2030.


There are several causes of COPD:

  • Smoking (and less often other inhalational exposures)

  • Genetic factors

Inhalational exposure

Of all inhalational exposures, cigarette smoking is the primary risk factor in most countries, although only about 15% of smokers develop clinically apparent COPD; an exposure history of 40 or more pack-years is especially predictive. Smoke from indoor cooking and heating is an important causative factor in developing countries. Smokers with preexisting airway reactivity (defined by increased sensitivity to inhaled methacholine), even in the absence of clinical asthma, are at greater risk of developing COPD than are those without.

Low body weight, childhood respiratory disorders, and exposure to passive cigarette smoke, air pollution, and occupational dust (eg, mineral dust, cotton dust) or inhaled chemicals (eg, cadmium) contribute to the risk of COPD but are of minor importance compared with cigarette smoking.

Genetic factors

The best-defined causative genetic disorder is α1-antitrypsin deficiency (see Alpha-1 Antitrypsin Deficiency), which is an important cause of emphysema in nonsmokers and influences susceptibility to disease in smokers.

In recent years, > 30 genetic variants have been found to be associated with COPD or decline in lung function in selected populations, but none has been shown to be as consequential as α1-antitrypsin.


Various factors cause the airflow limitation and other complications of COPD.


Inhalational exposures can trigger an inflammatory response in airways and alveoli that leads to disease in genetically susceptible people. The process is thought to be mediated by an increase in protease activity and a decrease in antiprotease activity (see Alpha-1 Antitrypsin Deficiency). Lung proteases, such as neutrophil elastase, matrix metalloproteinases, and cathepsins, break down elastin and connective tissue in the normal process of tissue repair. Their activity is normally balanced by antiproteases, such as α1-antitrypsin, airway epithelium–derived secretory leukoproteinase inhibitor, elafin, and matrix metalloproteinase tissue inhibitor. In patients with COPD, activated neutrophils and other inflammatory cells release proteases as part of the inflammatory process; protease activity exceeds antiprotease activity, and tissue destruction and mucus hypersecretion result. Neutrophil and macrophage activation also leads to accumulation of free radicals, superoxide anions, and hydrogen peroxide, which inhibit antiproteases and cause bronchoconstriction, mucosal edema, and mucous hypersecretion. Neutrophil-induced oxidative damage, release of profibrotic neuropeptides (eg, bombesin), and reduced levels of vascular endothelial growth factor may contribute to apoptotic destruction of lung parenchyma.

The inflammation in COPD increases as disease severity increases, and, in severe (advanced) disease, inflammation does not resolve completely despite smoking cessation. This chronic inflammation does not seem to respond to corticosteroids.


Respiratory infection (which COPD patients are prone to) may amplify progression of lung destruction.

Bacteria, especially Haemophilus influenzae, colonize the lower airways of about 30% of patients with COPD. In more severely affected patients (eg, those with previous hospitalizations), colonization with Pseudomonas aeruginosa or other gram-negative bacteria is common. Smoking and airflow obstruction may lead to impaired mucus clearance in lower airways, which predisposes to infection. Repeated bouts of infection increase the inflammatory burden that hastens disease progression. There is no evidence, however, that long-term use of antibiotics slows the progression of COPD.

Airflow limitation

The cardinal pathophysiologic feature of COPD is airflow limitation caused by airway obstruction, loss of elastic recoil, or both.

Airway obstruction is caused by inflammation-mediated mucus hypersecretion, mucus plugging, mucosal edema, bronchospasm, peribronchial fibrosis, and destruction of small airways or a combination of these mechanisms. Alveolar septa are destroyed, reducing parenchymal attachments to the airways and thereby facilitating airway closure during expiration.

Enlarged alveolar spaces sometimes consolidate into bullae, defined as airspaces 1 cm in diameter. Bullae may be entirely empty or have strands of lung tissue traversing them in areas of locally severe emphysema; they occasionally occupy the entire hemithorax.

These changes lead to loss of elastic recoil and lung hyperinflation.

Increased airway resistance increases the work of breathing, as does lung hyperinflation. Increased work of breathing may lead to alveolar hypoventilation with hypoxia and hypercapnia, although hypoxia is also caused by ventilation/perfusion (V/Q) mismatch.


In addition to airflow limitation and sometimes respiratory insufficiency, complications include

  • Pulmonary hypertension

  • Respiratory infection

  • Weight loss and other comorbidities

Chronic hypoxemia increases pulmonary vascular tone, which, if diffuse, causes pulmonary hypertension (see Pulmonary Hypertension) and cor pulmonale (see Cor Pulmonale). The increase in pulmonary vascular pressure may be augmented by the destruction of the pulmonary capillary bed due to destruction of alveolar septa.

Viral or bacterial respiratory infections are common among patients with COPD and cause a large percentage of acute exacerbations. It is currently thought that acute bacterial infections are due to acquisition of new strains of bacteria rather than overgrowth of chronic colonizing bacteria.

Weight loss may occur, perhaps in response to decreased caloric intake and increased levels of circulating tumor necrosis factor (TNF)-α.

Other coexisting or complicating disorders that adversely affect quality of life and survival include osteoporosis, depression, coronary artery disease, lung cancer, muscle atrophy, and gastroesophageal reflux. The extent to which these disorders are consequences of COPD, smoking, and the accompanying systemic inflammation is unclear.

Symptoms and Signs

COPD takes years to develop and progress. Most patients have smoked 20 cigarettes/day for > 20 yr. Productive cough usually is the initial symptom, developing among smokers in their 40s and 50s. Dyspnea that is progressive, persistent, exertional, or worse during respiratory infection appears when patients are in their late 50s or 60s. Symptoms usually progress quickly in patients who continue to smoke and in those who have a higher lifetime tobacco exposure. Morning headache develops in more advanced disease and signals nocturnal hypercapnia or hypoxemia.

Acute exacerbations occur sporadically during the course of COPD and are heralded by increased symptom severity. The specific cause of any exacerbation is almost always impossible to determine, but exacerbations are often attributed to viral URIs, acute bacterial bronchitis, or exposure to respiratory irritants. As COPD progresses, acute exacerbations tend to become more frequent, averaging about 1 to 3 episodes/yr.

Signs of COPD include wheezing, increased expiratory phase of breathing, lung hyperinflation manifested as decreased heart and lung sounds, and increased anteroposterior diameter of the thorax (barrel chest). Patients with advanced emphysema lose weight and experience muscle wasting that has been attributed to immobility, hypoxia, or release of systemic inflammatory mediators, such as TNF-α. Signs of advanced disease include pursed-lip breathing, accessory muscle use, paradoxical inward movement of the lower intercostal interspaces during inspiration (Hoover sign), and cyanosis. Signs of cor pulmonale include neck vein distention, splitting of the 2nd heart sound with an accentuated pulmonic component, tricuspid insufficiency murmur, and peripheral edema. Right ventricular heaves are uncommon in COPD because the lungs are hyperinflated.

Spontaneous pneumothorax may occur (possibly related to rupture of bullae) and should be suspected in any patient with COPD whose pulmonary status abruptly worsens.


  • Chest x-ray

  • Pulmonary function testing

Diagnosis is suggested by history, physical examination, and chest imaging and is confirmed by pulmonary function tests. Similar symptoms can be caused by asthma, heart failure, and bronchiectasis (see Table: Differential Diagnosis of COPD). COPD and asthma are sometimes easily confused.

Differential Diagnosis of COPD



Imaging Results

Other Features


Middle age

Sometimes lung hyperinflation, bullae, increased retrosternal air space, and/or bronchial wall thickening

Slowly progressive symptoms

History of smoking or exposure to tobacco or other types of smoke


Early in life (often during childhood)

Usually normal, possibly hyperinflation or segmental atelectasis

Airflow obstruction usually largely reversible

Symptoms often worse at night or early morning

History of allergies or eczema

Often family history of asthma

Heart failure

All ages, but most often in older or middle age

Enlarged heart, pleural effusion, fluid in major fissure, sometimes pulmonary edema (seen on chest x-ray)

Volume restriction without airflow limitation (detected by pulmonary function tests)


All ages, but most often in older or middle age

Bronchial dilation and bronchial wall thickening (seen on chest x-ray or chest CT)

Often large amounts of purulent sputum

Often history of recent bacterial infection


All ages

Multinodular infiltrates, sometimes calcified hilar nodes (seen on chest x-rays)

Confirmed by microbiologic testing

Usually in areas with high prevalence of TB

Data adapted from The Global Strategy for the Diagnosis, Management and Prevention of COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2013. Available at

Systemic disorders that may have a component of airflow limitation may suggest COPD; they include HIV infection, abuse of IV drugs (particularly cocaine and amphetamines), sarcoidosis, Sjögren syndrome, bronchiolitis obliterans, lymphangioleiomyomatosis, and eosinophilic granuloma. COPD can be differentiated from interstitial lung diseases (ILD) by chest imaging, which shows increased interstitial markings in ILD, and pulmonary function testing, which shows a restrictive ventilatory defect rather than an obstructive ventilatory defect. In some patients, COPD and ILD coexist (combined pulmonary fibrosis and emphysema [CPFE]) in which lung volumes are relatively preserved, but gas exchange is severely impaired.

Pulmonary function tests

Patients suspected of having COPD should undergo pulmonary function testing (see also Overview of Tests of Pulmonary Function) to confirm airflow limitation, to quantify its severity and reversibility, and to distinguish COPD from other disorders. Pulmonary function testing is also useful for following disease progression and monitoring response to treatment. The primary diagnostic tests are

  • FEV1, which is the volume of air forcefully expired during the first second after taking a full breath

  • Forced vital capacity (FVC), which is the total volume of air expired with maximal force

  • Flow-volume loops, which are simultaneous spirometric recordings of airflow and volume during forced maximal expiration and inspiration

Reductions of FEV1, FVC, and the ratio of FEV1/FVC are the hallmark of airflow limitation. Flow-volume loops show a concave pattern in the expiratory tracing (see Figure: Flow-volume loops.). FEV1 declines up to 60 mL/yr in smokers, compared with a less steep decline of 25 to 30 mL/yr in nonsmokers, beginning at about age 30. In young adult smokers who already have a low FEV1, the decline occurs more rapidly. When the FEV1 falls below about 1 L, patients develop dyspnea with activities of daily living (although dyspnea is more closely related to the degree of dynamic hyperinflation [progressive hyperinflation due to incomplete exhalation] than to the degree of airflow limitation); when the FEV1 falls below about 0.8 L, patients are at risk of hypoxemia, hypercapnia, and cor pulmonale. FEV1 and FVC are easily measured with office spirometry and define severity of disease (see Table: Classification and Treatment of COPD) because they correlate with symptoms and mortality. Normal reference values are determined by patient age, sex, and height.

Additional pulmonary function testing is necessary only in specific circumstances, such as before lung volume reduction surgery (see Surgery). Other test abnormalities may include increased total lung capacity, functional residual capacity, and residual volume, which can help distinguish COPD from restrictive pulmonary disease, in which these measures are diminished; decreased vital capacity; and decreased single-breath diffusing capacity for carbon monoxide (DLco). Decreased DLco is nonspecific and is reduced in other disorders that affect the pulmonary vascular bed, such as interstitial lung disease, but can help distinguish emphysema from asthma, in which DLco is normal or elevated.

Classification and Treatment of COPD

Patient Group



Alternative Treatments

All patients

Avoidance of risk factors (eg, smoking)

Influenza vaccine annually

Pneumococcal polysaccharide vaccine

Treatment of complications

A (low risk, few symptoms)

FEV1 > 50% predicted

0–1 exacerbation/yr

MRCDS*: 0–1

SABA or SAC, as needed






B (low risk, more symptoms)

FEV1 > 50% predicted

0–1 exacerbation/yr








C (high risk, few symptoms)

FEV1 < 50% predicted

≥ 2 exacerbations/yr

MRCDS: 0–1





D (high risk, more symptoms)

FEV1 < 50% predicted

≥ 2 exacerbations/yr

MRCDS: ≥ 2




ICS plus LAC


ICS plus LABA plus LAC


ICS plus LABA plus PDE4I




LAC plus PDE4I

*The COPD Assessment Test (CAT) may be used instead of the MRCDS to evaluate symptoms. For MRC definitions, see Modified Medical Research Council Dyspnea Scale.

FEV1 = forced expiratory volume in 1 sec; ICS = inhaled corticosteroid; LABA = long-acting β-agonist; LAC = long-acting anticholinergic; MRCDS = Medical Research Council dyspnea scale; PDE4I = phosphodiesterase-4 inhibitor; SABA = short-acting β-agonist; SAC = short-acting anticholinergic.

Data from the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (revised 2011).

Modified Medical Research Council Dyspnea Scale


Shortness of Breath


None except during strenuous exercise


Occurring when hurrying on level ground or walking up a slight incline


Resulting in walking more slowly than people of the same age on level ground


Resulting in stopping for breath when walking at own pace on level ground


Resulting in stopping for breath after walking about 90 m (100 yards) or after a few minutes on level ground


Severe enough to prevent the person from leaving the house


Occurring when dressing or undressing

Adapted from Mahler DA, Wells CK: Evaluation of clinical methods for rating dyspnea. Chest 93:580–586, 1988.

Imaging tests

Chest x-ray may have characteristic findings. In patients with emphysema, changes can include lung hyperinflation manifested as a flat diaphragm (ie, increase in the angle formed by the sternum and anterior diaphragm on a lateral film from the normal value of 45° to > 90°), rapid tapering of hilar vessels, and bullae (ie, radiolucencies > 1 cm surrounded by arcuate, hairline shadows). Other typical findings include widening of the retrosternal airspace and a narrow cardiac shadow. Emphysematous changes occurring predominantly in the lung bases suggest α1-antitrypsin deficiency (see Alpha-1 Antitrypsin Deficiency). The lungs may look normal or have increased lucency secondary to loss of parenchyma. Among patients with chronic obstructive bronchitis, chest x-rays may be normal or may show a bibasilar increase in bronchovascular markings as a result of bronchial wall thickening.

Prominent hila suggest large central pulmonary arteries that may signify pulmonary hypertension. Right ventricular enlargement that occurs in cor pulmonale may be masked by lung hyperinflation or may manifest as encroachment of the heart shadow on the retrosternal space or by widening of the transverse cardiac shadow in comparison with previous chest x-rays.

Chest CT may reveal abnormalities that are not apparent on the chest x-ray and may also suggest coexisting or complicating disorders, such as pneumonia, pneumoconiosis, or lung cancer. CT helps assess the extent and distribution of emphysema, estimated either by visual scoring or with analysis of the distribution of lung density. Indications for obtaining CT in patients with COPD include evaluation for lung volume reduction surgery, suspicion of coexisting or complicating disorders that are not clearly evident or excluded by chest x-ray, and suspicion of cancer.

Adjunctive tests

α1-Antitrypsin levels should be measured in patients < 50 yr with symptomatic COPD and in nonsmokers of any age with COPD to detect α1-antitrypsin deficiency (see Alpha-1 Antitrypsin Deficiency). Other indications of possible α1-antitrypsin deficiency include a family history of premature COPD or unexplained liver disease, lower-lobe distribution of emphysema, and COPD associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. If levels of α1-antitrypsin are low, the diagnosis should be confirmed by genetic testing to establish the α1-antitrypsin phenotype.

ECG, often done to exclude cardiac causes of dyspnea, typically shows diffusely low QRS voltage with a vertical heart axis caused by lung hyperinflation and increased P-wave voltage or rightward shifts of the P-wave vector caused by right atrial enlargement in patients with advanced emphysema. Findings of right ventricular hypertrophy include an R or R wave as tall as or taller than the S wave in lead V1; an R wave smaller than the S wave in lead V6; right-axis deviation >110° without right bundle branch block; or some combination of these. Multifocal atrial tachycardia, an arrhythmia that can accompany COPD, manifests as a tachyarrhythmia with polymorphic P waves and variable PR intervals.

Echocardiography is occasionally useful for assessing right ventricular function and pulmonary hypertension, although air trapping makes it technically difficult in patients with COPD. Echocardiography is most often indicated when coexistent left ventricular or valvular heart disease is suspected.

CBC is of little diagnostic value in the evaluation of COPD but may show erythrocythemia (Hct > 48%) if the patient has chronic hypoxemia. Patients with anemia (for reasons other than COPD) have disproportionately severe dyspnea. Serum electrolytes are of little value but may show an elevated HCO3 level if patients have chronic hypercapnia.

Evaluation of exacerbations

Patients with acute exacerbations usually have combinations of increased cough, sputum, dyspnea, and work of breathing, as well as low O2 saturation on pulse oximetry, diaphoresis, tachycardia, anxiety, and cyanosis. However, patients with exacerbations accompanied by retention of CO2 may be lethargic or somnolent, a very different appearance. All patients requiring hospitalization for an acute exacerbation should undergo testing (eg, ABG sampling) to quantify hypoxemia and hypercapnia. Hypercapnia may exist without hypoxemia.

Findings of Pao2< 50 mm Hg or Paco2> 50 mm Hg in the setting of respiratory acidemia define acute respiratory failure (see Respiratory Failure and Mechanical Ventilation). However, some patients chronically manifest such levels of Pao2 and Paco2 in the absence of acute respiratory failure.

A chest x-ray is often done to check for pneumonia or pneumothorax. Very rarely, among patients receiving chronic systemic corticosteroids, infiltrates may represent Aspergilluspneumonia.

Yellow or green sputum is a reliable indicator of neutrophils in the sputum and suggests bacterial colonization or infection. Culture is usually done in hospitalized patients but is not usually necessary in outpatients. In samples from outpatients, Gram stain usually shows neutrophils with a mixture of organisms, often gram-positive diplococci (Streptococcus pneumoniae), gram-negative bacilli (H. influenzae), or both. Other oropharyngeal commensal organisms, such as Moraxella (Branhamella) catarrhalis, occasionally cause exacerbations. In hospitalized patients, cultures may show resistant gram-negative organisms (eg, Pseudomonas) or, rarely, Staphylococcus.


Severity of airway obstruction predicts survival in patients with COPD. The mortality rate in patients with an FEV1 50% of predicted is slightly greater than that of the general population. If the FEV1 is 0.75 to 1.25 L, 5-yr survival is about 40 to 60%; if < 0.75 L, about 30 to 40%.

More accurate prediction of death risk is possible by simultaneously measuring body mass index (B), the degree of airflow obstruction (O, which is the FEV1), dyspnea (D, which is measured with a Modified Medical Research Council [MMRC] dyspnea scale—see Table: Modified Medical Research Council Dyspnea Scale), and exercise capacity (E, which is measured with a 6-min walking test); this is the BODE index. Also, older age, heart disease, anemia, resting tachycardia, hypercapnia, and hypoxemia decrease survival, whereas a significant response to bronchodilators predicts improved survival. Risk factors for death in patients with acute exacerbation requiring hospitalization include older age, higher Paco2, and use of maintenance oral corticosteroids. (Details for calculating the BODE index are available at Medical Criteria.)

Patients at high risk of imminent death are those with progressive unexplained weight loss or severe functional decline (eg, those who experience dyspnea with self-care, such as dressing, bathing, or eating). Mortality in COPD may result from intercurrent illnesses rather than from progression of the underlying disorder in patients who have stopped smoking. Death is generally caused by acute respiratory failure, pneumonia, lung cancer, heart disease, or pulmonary embolism.

Treatment of Stable COPD

  • Inhaled bronchodilators, corticosteroids, or both

  • Supportive care (eg, smoking cessation, O2 therapy, pulmonary rehabilitation)

COPD management involves treatment of chronic stable disease and of exacerbations. Treatment of cor pulmonale, a common complication of long-standing, severe COPD, is discussed elsewhere (see Cor Pulmonale).

Treatment of chronic stable COPD aims to prevent exacerbations and improve lung and physical function through drug and O2therapy, smoking cessation, exercise, enhancement of nutrition, and pulmonary rehabilitation. Surgical treatment of COPD is indicated for selected patients.

Drug therapy

Recommended drug therapy is summarized in Classification and Treatment of COPD.

Inhaled bronchodilatorsare the mainstay of COPD management; drugs include

  • β-agonists

  • Anticholinergics (antimuscarinics)

These two classes are equally effective. Patients with mild (group A) disease are treated only when symptomatic. Patients with group B, C, or D COPD should be taking drugs from one or both of these classes regularly to improve pulmonary function and increase exercise capacity. The frequency of exacerbations can be reduced with the use of anticholinergics, inhaled corticosteroids, or long-acting β-agonists. However, there is no evidence that regular bronchodilator use slows deterioration of lung function. The initial choice among short-acting β-agonists, long-acting β-agonists, anticholinergics (which have a greater bronchodilating effect), and combination β-agonist and anticholinergic therapy is often a matter of tailoring cost and convenience to the patient’s preferences and symptoms.

For home treatment of chronic stable disease, drug administration by metered-dose inhaler or dry-powder inhaler is preferred over administration by nebulizer; home nebulizers are prone to contamination due to incomplete cleaning and drying. Therefore, nebulizers should be reserved for people who cannot coordinate activation of the metered-dose inhaler with inhalation or cannot develop enough inspiratory flow for dry powder inhalers. For metered-dose inhalers, patients should be taught to exhale to functional residual capacity, inhale the aerosol slowly to total lung capacity, and hold the inhalation for 3 to 4 sec before exhaling. Spacers help ensure optimal delivery of drug to the distal airways and reduce the importance of coordinating activation of the inhaler with inhalation. Some spacers alert patients if they are inhaling too rapidly. Newer metered-dose inhalers that use hydrofluoroalkane (HFA) propellants require slightly different techniques than inhalers containing older environmentally damaging chlorinated fluorocarbon propellants; inhalers containing HFA require 2 to 3 priming doses if they are new or not recently used.

β-Agonists relax bronchial smooth muscle and increase mucociliary clearance. Albuterol aerosol, 2 puffs (90 to 100 mcg/puff) inhaled from a metered-dose inhaler 4 to 6 times/day prn, is usually the drug of choice because of low cost. Long-acting β-agonists are preferable for patients with nocturnal symptoms or for those who find frequent dosing inconvenient. Options include salmeterol powder, 1 puff (50 mcg) inhaled bid, indacaterol 1 puff (75 mcg) inhaled once/day (150 mcg once/day in Europe), and formoterol powder, 1 puff (12 mcg) inhaled bid. The dry-powder formulations may be more effective for patients who have trouble coordinating use of a metered-dose inhaler. Patients should be taught the difference between short-acting and long-acting drugs, because long-acting drugs that are used as needed or more than twice/day increase the risk of cardiac arrhythmias. Adverse effects commonly result from use of any β-agonist and include tremor, anxiety, tachycardia, and mild, temporary hypokalemia.

Anticholinergics (antimuscarinics) relax bronchial smooth muscle through competitive inhibition of muscarinic receptors (M1, M2, and M3). Ipratropium is a short-acting anticholinergic; dose is 2 to 4 puffs (18 mcg/puff) from a metered-dose inhaler q 4 to 6 h. Ipratropium has a slower onset of action (within 30 min; peak effect in 1 to 2 h), so a β2-agonist is often prescribed with it in a single combination inhaler or as a separate as-needed rescue drug. Tiotropium is a long-acting quaternary anticholinergic inhaled as a powder formulation. Dose is 1 puff (18 mcg) once/day. Aclidinium bromide is available as a multidose dry-powder inhaler. Dose is 1 puff (400 mcg/puff) bid. Umeclidinium can be used as a once/day combination with vilanterol (a long-acting beta-agonist) in a dry-powder inhaler. Adverse effects of all anticholinergics are pupillary dilation (and risk of triggering or worsening acute angle closure glaucoma), urinary retention, and dry mouth.

Corticosteroids are often part of treatment. Inhaled corticosteroids seem to reduce airway inflammation, reverse β-receptor down-regulation, and inhibit leukotriene and cytokine production. They do not alter the course of pulmonary function decline in patients with COPD who continue to smoke, but they do relieve symptoms and improve short-term pulmonary function in some patients, are additive to the effect of bronchodilators, and may diminish the frequency of COPD exacerbations. They are indicated for patients who have repeated exacerbations or symptoms despite optimal bronchodilator therapy. Dose depends on the drug; examples include fluticasone 500 to 1000 mcg/day and beclomethasone 400 to 2000 mcg/day. The long-term risks of inhaled corticosteroids in elderly people are not proved but probably include osteoporosis, cataract formation, and an increased risk of nonfatal pneumonia. Long-term users therefore should undergo periodic ophthalmologic and bone densitometry screening and should possibly receive supplemental calcium, vitamin D, and a bisphosphonate as indicated.

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

Oral or systemic corticosteroids should usually not be used to treat chronic stable COPD.

Theophylline plays only a small role in the treatment of chronic stable COPD now that safer, more effective drugs are available. Theophylline decreases smooth muscle spasm, enhances mucociliary clearance, improves right ventricular function, and decreases pulmonary vascular resistance and arterial pressure. Its mode of action is poorly understood but appears to differ from that of β2-agonists and anticholinergics. Its role in improving diaphragmatic function and dyspnea during exercise is controversial. Low-dose oral theophylline (300 to 400 mg/day) has anti-inflammatory properties and may enhance the effects of inhaled corticosteroids.

Theophylline can be used for patients who have not adequately responded to inhaled drugs and who have shown symptomatic benefit from a trial of the drug. Serum levels need not be monitored unless the patient does not respond to the drug, develops symptoms of toxicity, or is questionably adherent; slowly absorbed oral theophylline preparations, which require less frequent dosing, enhance adherence. Toxicity is common and includes sleeplessness and GI upset, even at low blood levels. More serious adverse effects, such as supraventricular and ventricular arrhythmias and seizures, tend to occur at blood levels > 20 mg/L. Hepatic metabolism of theophylline varies greatly and is influenced by genetic factors, age, cigarette smoking, hepatic dysfunction, and some drugs, such as macrolide and fluoroquinolone antibiotics and nonsedating histamine2blockers.

Phosphodiesterase-4 inhibitors are more specific than theophylline for pulmonary phosphodiesterase and have fewer adverse effects. They have anti-inflammatory properties and are mild bronchodilators. Phosphodiesterase-4 inhibitors include roflumilast and cilomilast, but roflumilast is the only one in routine clinical use. It can be used in addition to other bronchodilators for reduction of exacerbations in patients with COPD. The dose is 500 mcg po once/day. Common adverse effects include nausea, headache, and weight loss, but these effects may subside with continued use.

O 2 therapy

Long-term O2 therapy prolongs life in patients with COPD whose Pao2is chronically < 55 mm Hg. Continual 24-h use is more effective than a 12-h nocturnal regimen. O2 therapy brings Hct toward normal levels; improves neuropsychologic factors, possibly by facilitating sleep; and ameliorates pulmonary hemodynamic abnormalities. O2 therapy also increases exercise tolerance in many patients.

O2 saturation should be measured during exercise and while at rest. Similarly, a sleep study should be considered for patients with advanced COPD who do not meet the criteria for long-term O2 therapy while they are awake (see Table: Indications for Long-Term O2 Therapy in COPD) but whose clinical assessment suggests pulmonary hypertension in the absence of daytime hypoxemia. Nocturnal O2 may be prescribed if a sleep study shows episodic desaturation to 88%. Such treatment prevents progression of pulmonary hypertension, but its effects on survival are unknown.

O2 is administered by nasal cannula at a flow rate sufficient to achieve a Pao2 > 60 mm Hg (Sao2>90%), usually 3 L/min at rest. O2 is supplied by electrically driven O2 concentrators, liquid O2 systems, or cylinders of compressed gas. Concentrators, which limit mobility but are the least expensive, are preferable for patients who spend most of their time at home. Such patients require small O2 tanks for backup in case of an electrical failure and for portable use.

A liquid system is preferable for patients who spend much time out of their home. Portable canisters of liquid O2are easier to carry and have more capacity than portable cylinders of compressed gas. Large compressed-air cylinders are the most expensive way of providing O2 and should be used only if no other source is available. All patients must be taught the dangers of smoking during O2 use.

Various O2-conserving devices can reduce the amount of O2 used by the patient, either by using a reservoir system or by permitting O2 flow only during inspiration. Systems with these devices correct hypoxemia as effectively as do continuous flow systems.

Some patients need supplemental O2 during air travel, because flight cabin pressure in commercial airliners is below sea level air pressure (often equivalent to 1830 to 2400 m [6000 to 8000 ft]). Eucapnic COPD patients who have a Pao2 > 68 mm Hg at sea level generally have an in-flight Pao2 > 50 mm Hg and do not require supplemental O2. All patients with COPD with a Pao2 68 mm Hg at sea level, hypercapnia, significant anemia (Hct < 30), or a coexisting heart or cerebrovascular disorder should use supplemental O2during long flights and should notify the airline when making their reservation. Airlines can provide supplemental O2, and most require a minimum notice of 24 h, a physician’s statement of necessity, and an O2 prescription before the flight. Patients should bring their own nasal cannulas, because some airlines provide only face masks. Patients are not permitted to transport or use their own liquid O2, but many airlines now permit use of portable battery-operated O2 concentrators, which also provide a suitable O2 source on arrival.

Indications for Long-Term O2 Therapy in COPD

Pao2 55 mm Hg or Sao2 88%* in patients receiving optimal medical regimen for at least 30 days

Pao2= 55 to 59 mm Hg or Sao2 89%* for patients with cor pulmonale or erythrocytosis (Hct > 55%)

Can be considered for Pao2 60 mm Hg or Sao2 90%* for patients whose room-air Pao2is 55 mm Hg or Sao2 88% during exercise or sleep

*Arterial O2levels are measured at rest during air breathing.

Patients who are recovering from an acute respiratory illness and who meet the listed criteria should be given O2 and rechecked while breathing room air after 60 to 90 days.

Smoking cessation

Smoking cessation (see Tobacco Use) is both extremely difficult and extremely important; it slows but does not halt the rate of FEV1 decline (see Figure: Changes in lung function (percentage of predicted FEV1) in patients who quit smoking compared with those who continue.). Simultaneous use of multiple strategies is most effective: establishment of a quit date, behavior modification techniques, group sessions, nicotine replacement therapy (by gum, transdermal patch, inhaler, lozenge, or nasal spray), varenicline or bupropion, and physician encouragement. Quit rates > 50% at 1 yr have not been demonstrated even with the most effective interventions, such as use of bupropion combined with nicotine replacement or use of varenicline alone.

Changes in lung function (percentage of predicted FEV1) in patients who quit smoking compared with those who continue.

During the first year, lung function improved in patients who quit smoking and declined in those who continued. Subsequently, the rate of decline in those who continued was twice that of those who quit. Function declined in those who relapsed and improved in those who quit regardless of when the change occurred. Based on data from Scanlon PD et al: Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease; the Lung Health Study. American Journal of Respiratory and Critical Care Medicine 161:381–390, 2000.


All patients with COPD should be given annual influenza vaccinations. If a patient is unable to receive a vaccination or if the prevailing influenza strain is not included in the annual vaccine formulation, prophylactic treatment with a neuraminidase inhibitor (oseltamivir or zanamivir) is sometimes used if there is close exposure to influenza-infected people. Treatment with a neuraminidase inhibitor should be started at the first sign of an influenza-like illness. Pneumococcal polysaccharide vaccine, although of unproven efficacy in COPD, has minimal adverse effects and should probably also be given.


COPD patients are at risk of weight loss and nutritional deficiencies because of a higher energy cost of daily activities; reduced caloric intake relative to need because of dyspnea; and the catabolic effect of inflammatory cytokines such as TNF-α. Generalized muscle strength and efficiency of O2 use are impaired. Patients with poorer nutritional status have a worse prognosis, so it is prudent to recommend a balanced diet with adequate caloric intake in conjunction with exercise to prevent or reverse undernutrition and muscle atrophy. However, excessive weight gain should be avoided, and obese patients should strive to gradually reduce body fat. Studies of nutritional supplementation alone have not shown improvement in pulmonary function or exercise capacity. Trials of appetite stimulants, anabolic steroids, growth hormone supplementation, and TNF antagonists in reversing undernutrition and improving functional status and prognosis in COPD have been disappointing.

Pulmonary rehabilitation

Pulmonary rehabilitation programs serve as adjuncts to drug treatment to improve physical function (see also Pulmonary Rehabilitation); many hospitals and health care organizations offer formal multidisciplinary rehabilitation programs. Pulmonary rehabilitation includes exercise, education, and behavioral interventions. Treatment should be individualized; patients and family members are taught about COPD and medical treatments, and patients are encouraged to take as much responsibility for personal care as possible. The benefits of rehabilitation are greater independence and improved quality of life and exercise capacity. Pulmonary rehabilitation typically does not improve pulmonary function. A carefully integrated rehabilitation program helps patients with severe COPD accommodate to physiologic limitations while providing realistic expectations for improvement. Patients with severe disease require a minimum of 3 mo of rehabilitation to benefit and should continue with maintenance programs.

An exercise program can be helpful in the home, in the hospital, or in institutional settings. Graded exercise can ameliorate skeletal muscle deconditioning resulting from inactivity or prolonged hospitalization for respiratory failure. Specific training of respiratory muscles is less helpful than general aerobic conditioning.

A typical training program begins with slow walking on a treadmill or unloaded cycling on an ergometer for a few minutes. Duration and exercise load are progressively increased over 4 to 6 wk until the patient can exercise for 20 to 30 min nonstop with manageable dyspnea. Patients with very severe COPD can usually achieve an exercise regimen of walking for 30 min at 1 to 2 mph. Maintenance exercise should be done 3 to 4 times/wk to maintain fitness levels. O2 saturation is monitored, and supplemental O2 is provided as needed.

Upper extremity resistance training helps the patient in doing daily tasks (eg, bathing, dressing, house cleaning). The usual benefits of exercise are modest increases in lower extremity strength, endurance, and maximum O2 consumption.

Patients should be taught ways to conserve energy during activities of daily living and to pace their activities. Difficulties in sexual function should be discussed and advice should be given on using energy-conserving techniques for sexual gratification.


Surgical options for treatment of severe COPD include lung volume reduction and transplantation.

Lung volume reduction surgery consists of resecting nonfunctioning emphysematous areas. The procedure improves lung function, exercise tolerance, and quality of life in patients with severe, predominantly upper-lung emphysema who have low baseline exercise capacity after pulmonary rehabilitation. Mortality is increased in the first 90 days after lung volume reduction surgery, but survival is higher at 5 yr. The effect on ABGs is variable and not predictable, but most patients who require O2 before surgery continue to need it. Improvement is less than that with lung transplantation. The mechanism of improvement is believed to be enhanced lung recoil and improved diaphragmatic function. Operative mortality is about 5%. The best candidates for lung volume reduction surgery are patients with an FEV1 20 to 40% of predicted, a DLCO> 20% of predicted, significantly impaired exercise capacity, heterogeneous pulmonary disease on CT with an upper-lobe predominance, Paco2< 50 mm Hg, and absence of severe pulmonary hypertension and coronary artery disease.

Rarely, patients have extremely large bullae that compress the functional lung. These patients can be helped by surgical resection of these bullae, with resulting relief of symptoms and improved pulmonary function. Generally, resection is most beneficial for patients with bullae affecting more than one third of a hemithorax and an FEV1 about half of the predicted normal value. Improved pulmonary function is related to the amount of normal or minimally diseased lung tissue that was compressed by the resected bullae. Serial chest x-rays and CT scans are the most useful procedures for determining whether a patient’s functional status is due to compression of viable lung by bullae or to generalized emphysema. A markedly reduced DLCO (< 40% predicted) indicates widespread emphysema and suggests a poorer outcome from surgical resection.

Lung transplantation (see Lung and Heart-Lung Transplantation) can be single or double. Perioperative complications tend to be lower with single-lung transplantation, but some evidence shows that survival time is increased with double-lung transplantation. Candidates for transplantation are patients < 65 yr with an FEV1< 25% predicted after bronchodilator therapy or with severe pulmonary hypertension. The goal of lung transplantation is to improve quality of life, because survival time is not necessarily increased. The 5-yr survival after transplantation for emphysema is 45 to 60%. Lifelong immunosuppression is required, with the attendant risk of opportunistic infections.

Treatment of Acute COPD Exacerbation

  • O2 supplementation

  • Bronchodilators

  • Corticosteroids

  • Antibiotics

  • Sometimes ventilatory assistance

The immediate objectives are to ensure adequate oxygenation and near-normal blood pH, reverse airway obstruction, and treat any cause.

The cause of an acute exacerbation is usually unknown, although some acute exacerbations result from bacterial or viral infections. Smoking, irritative inhalational exposure, and high levels of air pollution also contribute. Mild exacerbations often can be treated on an outpatient basis in patients with adequate home support. Elderly, frail patients and patients with comorbidities, a history of respiratory failure, or acute changes in ABG measurements are admitted to the hospital for observation and treatment. Patients with life-threatening exacerbations manifested by uncorrected moderate to severe acute hypoxemia, acute respiratory acidosis, new arrhythmias, or deteriorating respiratory function despite hospital treatment should be admitted to the ICU and their respiratory status monitored frequently.

O 2

Most patients require O2 supplementation, even those who do not need it chronically. Hypercapnia may worsen in patients given O2. This worsening has traditionally been thought to result from an attenuation of hypoxic respiratory drive. However, increased V/Q mismatch probably is a more important factor. Before O2administration, pulmonary vasoconstriction minimizes V/Q mismatch by decreasing perfusion of the most poorly ventilated areas of the lungs. Increased V/Q mismatch occurs because O2administration attenuates this hypoxic pulmonary vasoconstriction. The Haldane effect may also contribute to worsening hypercapnia, although this theory is controversial. The Haldane effect is a decrease in Hb’s affinity for CO2, which results in increased amounts of CO2 dissolved in plasma. O2 administration, even though it may worsen hypercapnia, is recommended; many patients with COPD have chronic as well as acute hypercapnia and thus severe CNS depression is unlikely unless Paco2 is >85 mm Hg. The target level for Pao2 is about 60 mm Hg; higher levels offer little advantage and increase the risk of hypercapnia. O2 is given via Venturi mask so it can be closely regulated, and the patient is closely monitored. Patients whose condition deteriorates with O2 therapy (eg, those with severe acidemia or CNS depression) require ventilatory assistance.

Many patients who require home O2for the first time when they are discharged from the hospital after an exacerbation improve within 30 days and no longer require O2. Thus, the need for home O2should be reassessed 60 to 90 days after discharge.

Ventilatory assistance

Noninvasive positive-pressure ventilation (eg, pressure support or bilevel positive airway pressure ventilation by face mask—see Noninvasive positive pressure ventilation (NIPPV)) is an alternative to full mechanical ventilation. Noninvasive ventilation appears to decrease the need for intubation, reduce hospital stay, and reduce mortality in patients with severe exacerbations (defined as a pH < 7.30 in hemodynamically stable patients not at immediate risk of respiratory arrest). Noninvasive ventilation appears to have no effect in patients with less severe exacerbation. However, it may be indicated for patients with less severe exacerbations whose ABGs worsen despite initial drug or O2 therapy or who appear to be imminent candidates for full mechanical ventilation but who do not require intubation for control of the airway or sedation for agitation. Patients who have severe dyspnea, hyperinflation, and use of accessory muscles of respiration may also gain relief from positive airway pressure. Deterioration while receiving noninvasive ventilation necessitates invasive mechanical ventilation.

Deteriorating ABG values and mental status and progressive respiratory fatigue are indications for endotracheal intubation and mechanical ventilation. Ventilator settings, management strategies, and complications are discussed elsewhere (see Respiratory Failure and Mechanical Ventilation). Risk factors for ventilatory dependence include an FEV1< 0.5 L, stable ABGs with a Pao2 < 50 mm Hg, or a Paco2 > 60 mm Hg, severe exercise limitation, and poor nutritional status. Therefore, if patients are at high risk, discussion of their wishes regarding intubation and mechanical ventilation should be initiated and documented (see Advance Directives) while they are stable outpatients. However, overconcern about possible ventilator dependence should not delay management of acute respiratory failure; many patients who require mechanical ventilation can return to their pre-exacerbation level of health.

In patients who require prolonged intubation (eg, > 2 wk), a tracheostomy is indicated to facilitate comfort, communication, and eating. With a good multidisciplinary rehabilitation program, including nutritional and psychologic support (see Pulmonary Rehabilitation), many patients who require prolonged mechanical ventilation can be successfully liberated and can return to their former level of function. Specialized programs are available for patients who remain ventilator-dependent after acute respiratory failure. Some patients can remain off the ventilator during the day. For patients with adequate home support, training of family members can permit some patients to be sent home with ventilators.

Pearls & Pitfalls

  • Overconcern about possible ventilator dependence should not delay management of acute respiratory failure; many patients who require mechanical ventilation can return to their pre-exacerbation level of health.

Drug therapy

β-Agonists and anticholinergics, with or without corticosteroids, should be started concurrently with O2 therapy (regardless of how O2 is administered) with the aim of reversing airway obstruction. Methylxanthines, once considered essential to treatment of acute COPD exacerbations, are no longer used; toxicities exceed benefits.

Short-acting β-agonists are the cornerstone of drug therapy for acute exacerbations. The most widely used drug is albuterol 2.5 mg by nebulizer or 2 to 4 puffs (100 mcg/puff) by metered-dose inhaler q 2 to 6 h. Inhalation using a metered-dose inhaler causes rapid bronchodilation; there are no data indicating that doses taken with nebulizers are more effective than the same doses correctly taken with metered-dose inhalers. In life-threatening exacerbations, risks of the exacerbation usually exceed those of high-dose β-agonists; thus, β-agonists may be given continuously via nebulizer until improvement occurs.

Ipratropium, an anticholinergic, is effective in acute COPD exacerbations and should be given concurrently or alternating with β-agonists. Dosage is 0.25 to 0.5 mg by nebulizer or 2 to 4 inhalations (17 to 18 mcg of drug delivered per puff) by metered-dose inhaler q 4 to 6 h. Ipratropium generally provides bronchodilating effect similar to that of usual recommended doses of β-agonists. The role of the longer-acting anticholinergic tiotropium in treating acute exacerbations has not been defined.

Corticosteroids should be begun immediately for all but mild exacerbations. Options include prednisone 30 to 60 mg po once/day for 5 days or tapered over 7 to 14 days and methylprednisolone 60 to 500 mg IV once/day for 3 days and then tapered over 7 to 14 days. Alternatively, a 5-day course of 40 mg of prednisone appears to be equally effective. These drugs are equivalent in their acute effects; inhaled corticosteroids have no role in the treatment of acute exacerbations.

Antibiotics are recommended for exacerbations in patients with purulent sputum. Some physicians give antibiotics empirically for change in sputum color or for nonspecific chest x-ray abnormalities. Routine cultures and Gram stains are not necessary before treatment unless an unusual or resistant organism is suspected (eg, in hospitalized, institutionalized, or immunosuppressed patients). Drugs directed against oral flora are indicated. Trimethoprim/sulfamethoxazole 160 mg/800 mg po bid, amoxicillin 250 to 500 mg po tid, tetracycline 250 mg po qid, and doxycycline 50 to 100 mg po bid given for 7 to 14 days are all effective and inexpensive. Choice of drug is dictated by local patterns of bacterial sensitivity and patient history. If the patient is seriously ill or if clinical evidence suggests that the infectious organisms are resistant, broader spectrum 2nd-line drugs can be used. These drugs include amoxicillin/clavulanate 250 to 500 mg po tid, fluoroquinolones (eg, ciprofloxacin, levofloxacin), 2nd-generation cephalosporins (eg, cefuroxime, cefaclor), and extended-spectrum macrolides (eg, azithromycin, clarithromycin). These drugs are effective against β-lactamase–producing strains of H. influenzae and M. catarrhalis but have not been shown to be more effective than first-line drugs for most patients. Patients can be taught to recognize a change in sputum from normal to purulent as a sign of impending exacerbation and to start a 10- to 14-day course of antibiotic therapy. Long-term antibiotic prophylaxis is recommended only for patients with underlying structural changes in the lung, such as bronchiectasis or infected bullae. In patients with frequent exacerbations, long-term macrolide use reduces exacerbation frequency but may have adverse effects.

Antitussives, such as dextromethorphan and benzonatate, have little role.

Opioids (eg, codeine, hydrocodone, oxycodone) should be used judiciously for relief of symptoms (eg, severe coughing paroxysms, pain) insofar as these drugs may suppress a productive cough, impair mental status, and cause constipation.

End-of-life care

With very severe disease, particularly when death is imminent, exercise is unwarranted and activities of daily living are arranged to minimize energy expenditure. For example, patients may arrange to live on one floor of the house, have several small meals rather than fewer large meals, and avoid wearing shoes that must be tied. End-of-life care should be discussed, including whether to pursue mechanical ventilation, the use of palliative sedation, and appointment of a surrogate medical decision-maker in the event of the patient’s incapacitation.

Key Points

  • Cigarette smoking in genetically predisposed people is the major cause of COPD in the developed world.

  • Diagnose COPD and differentiate it from disorders that have similar characteristics (eg, asthma, heart failure) primarily by routine clinical information, such as symptoms (particularly time course), age at onset, risk factors, and results of routine tests (eg, chest x-ray, pulmonary function tests).

  • Reductions of FEV1, FVC, and the ratio of FEV1/FVC are characteristic findings.

  • Categorize patients based on FEV1 and symptoms into one of 4 groups and use that category to guide drug treatment.

  • Relieve symptoms rapidly with primarily short-acting beta-adrenergic drugs and decrease exacerbations with inhaled corticosteroids, long-acting beta-adrenergic drugs, long-acting anticholinergic drugs, or a combination.

  • Encourage smoking cessation using multiple interventions.(eg, behavior modification, support groups, nicotine replacement, drug therapy).

  • Optimize use of supportive treatments (eg, nutrition, pulmonary rehabilitation, self-directed exercise).

  • Use antibiotics if patients have acute exacerbations and purulent sputum.

  • For patients with end stage COPD, address end-of-life care proactively, including preferences regarding mechanical ventilation and palliative sedation.

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