By Ralph J. Panos, MD, Chief of Medicine, Cincinnati Veteran Affairs Medical Center; Professor of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati
Peer Reviewer
Hemant Shah, MD, FACP, FCCP, DSM, Associate Professor of Medicine, Wright State University-Boonshoft School of Medicine; Medical Director, CCU, Kettering Medical Center; Medical Director, Respiratory Care, Kettering Medical Center, Kettering, OH
Statement of Financial Disclosure
To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, Dr. Panos (author) and Dr. Shah (peer reviewer) report no financial relationships relevant to this field of study.
Executive Summary
- Most individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction on spirometric testing and/or exhibit lung parenchymal and airway abnormalities on radiographic imaging.
- COPD has been classified as emphysema, chronic bronchitis, or a mixed process; more recent studies suggest that there are many more clinical groupings or phenotypes that may have prognostic and therapeutic implications.
- COPD is a multisystemic disorder with a myriad of nonpulmonary manifestations including cardiovascular, hematologic, endocrine, metabolic, and psychosocial derangements.
- Over the past decade, the treatment of COPD has migrated from therapeutic nihilism to multiple effective medications that reduce respiratory symptoms, improve quality of life, and prolong survival.
Chronic obstructive pulmonary disease (COPD) is a chronic, incurable but very treatable condition. Currently, COPD is the third leading cause of death in the United States and has been diagnosed in nearly 10% of adult Americans. This syndrome is identified by historical clues, clinical signs and symptoms, and physiologic and imaging abnormalities. There is no single diagnostic test for COPD.
Definition and Classification
COPD is a treatable, usually preventable, and, most frequently, insidiously progressive lung disease characterized by physiologic airflow limitation and/or radiographic imaging evidence of emphysema with pulmonary and systemic inflammation and a clinical course that is punctuated by exacerbations and episodes of worsening respiratory symptoms.1-4 Over the past decade, this definition of COPD has changed dramatically, as has the characterization and treatment of individuals with COPD. Multiple new therapies alter the course of this disease, reduce exacerbations, improve quality of life, and increase survival; previous nihilistic approaches to the management of COPD have been replaced by directed and effective pharmacologic and nonpharmacologic therapies. This update will review current approaches to the diagnosis and management of COPD and present the most recent evidence for the classification of COPD phenotypes and the implications of these categories for COPD treatment and prognosis.
Emphysema was recognized by 18th and 19th-century anatomists and pathologists who described voluminous lungs stuffed with air.5 Chronic bronchitis originally was described by Badham in 1814 as catarrh,6 and the current definition was codified in the American Thoracic Society Committee on Diagnostic Standards in 1962. The first use of the term COPD is ascribed to William Briscoe at the 9th Aspen Emphysema Conference in 1965.7 Because there is no single definitive diagnostic test for COPD and it may manifest in multiple different presentations, COPD is really a syndrome, a condition consistently associated with a group of symptoms. Traditionally, COPD has been considered an overlapping of two principle conditions: emphysema and chronic bronchitis. Emphysema is defined histopathologically or radiographically by the loss of lung parenchyma and abnormal enlargement of air spaces without associated fibrosis, whereas chronic bronchitis is defined clinically as the presence of a productive cough for at least three consecutive months in two consecutive years. Over the past decade, further refinements in the constellations of symptoms defining various groups of patients with COPD have been developed. These clinical groupings have been called COPD phenotypes and they are believed to assist with the prediction of clinical course and optimal therapies (see Table 1).
Table 1. COPD Phenotypes |
||||||
|
COPD Phenotype |
Treatment |
|||||
|
SABA |
LABA+/or LAMA |
ICS |
Mucolytic |
Macrolide |
PDE4 Inhibitor |
|
|
Overlap asthma/COPD |
+ |
+ |
+ |
|
|
|
|
Non- or infrequent exacerbator |
+ |
+ |
|
|
|
|
|
Frequent exacerbator |
|
|
|
|
|
|
|
Emphysema |
+ |
+ |
|
|
+ |
|
|
Phlegm- |
+ |
+ |
+ |
+ |
+ |
+ |
|
Use of COPD phenotypes to guide COPD treatment Abbreviations: SABA: short-acting beta-agonist; LABA: long-acting beta-agonist; LAMA: long-acting muscarinic antagonist; ICS: inhaled corticosteroid; PDE4: phosphodiesterase 4 |
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Epidemiology
Estimates of COPD’s prevalence range from 6.8% to 9.4% of the U.S. adult population and vary based on the criteria used to define COPD and the objective measurement of airflow limitation.8,9 Self-reported COPD diagnosis may significantly underestimate COPD prevalence, and the actual prevalence of airflow limitation may be two- to three-fold greater when spirometric testing is performed.10
In 2000, more women than men died from COPD in the United States,11 and by 2005, COPD was the primary cause of one in every 20 deaths in the United States.12 By 2008, lower respiratory diseases, including COPD, were the third-leading cause of death in the United States.13
In early COPD, the major causes of death are lung cancer and cardiac disease, whereas in more advanced COPD, respiratory failure is the major cause of mortality.14,15 During acute exacerbations of COPD, the leading causes of death are heart failure (37.2%), pneumonia (27.9%), pulmonary thromboembolism (20.9%), and respiratory failure (14%).16 Among individuals with COPD, pulmonary morbidity and mortality appear to be declining, possibly due to improvements in the pharmacologic and nonpharmacologic management of COPD. In contrast, the nonpulmonary morbidity and mortality associated with COPD are rising, suggesting that better and earlier identification of the extrapulmonary manifestations of COPD may be necessary to improve the survival and quality of life of individuals with COPD.
For every 10,000 patients in the U.S. population in 2010, there were 495 physician office visits, 72 emergency department visits, and 34 hospitalizations with a primary diagnosis of COPD.9 This health care utilization led to $32.1 billion in direct medical costs, which is projected to rise to $49 billion by 2020.17 The majority of health care costs are due to hospitalizations caused by acute COPD exacerbations. Indirect costs due to absenteeism, disability, or work reduction add nearly 10% to direct health care costs. Approximately two-thirds of individuals with COPD perceive diminished quality of life due to breathlessness.18 Medical and nonpharmacologic management of COPD can reduce health care costs, reduce mortality, and improve quality of life.
Risk Factors for COPD
The single most significant risk factor for the development of COPD is tobacco smoke inhalation. Factors that influence the development of COPD include the age of starting smoking, amount and type of tobacco product consumed, age of quitting, and length of smoking cessation.19 The prevalence of COPD has generally followed the prevalence of tobacco smoking, with a lag time of approximately 20-30 years. Whereas only 20-50% of all smokers develop COPD, approximately 75-90% of all individuals with COPD have been or are smokers. The processes leading to the increased predilection for the development of COPD within this subpopulation of tobacco smokers are currently unknown. Approximately one-quarter of individuals with COPD are never smokers.20,21 Other factors that may be associated with the development of COPD include indoor and outdoor air pollution; occupational exposures to gases, dusts, and fumes; and respiratory infections such as tuberculosis and human immunodeficiency virus.20,22-29 In the developing world, exposure to biomass smoke is a leading cause of COPD.30-32
Recent evidence suggests that submaximal lung development may be another factor predisposing to the development of airflow limitation in adults.34 Normally, maximal pulmonary physiologic function is achieved in the early 20s and is followed by a plateau or maximal maintenance phase that may last a decade (See figure A). Thereafter, airflow declines as a natural part of the aging process. If maximal lung function is not reached or if the duration of the plateau phase is reduced, symptomatic airflow obstruction may develop in individuals who experience a natural decline in lung function. Classically, COPD has been considered an increased rate of decline in airflow, but this course may only occur in about half of individuals with airflow limitation.34 These different routes to symptomatic airflow limitation have led to observations of variable rates of lung function decline and heterogeneous lung function among adults with COPD.35
Figure A. Lung Function and Age |
|
This figure illustrates the process of normal lung development, maintenance of maximal function during the plateau phase, and then gradual, natural functional decline with aging. From birth to maturity, alveoli increase first in number and then in size (solid green and blue lines). At maturity, lung function is maximal; the absolute maximal level of lung function varies and some individuals may achieve lower peak lung function (dotted blue line) than their peers (dotted green line). Maximal lung function is maintained throughout the plateau period which may vary in duration from person to person. Some individuals may begin to experience declining lung function once the apex is reached; others maintain maximal lung function for years before the decline starts. Individuals with normal or low plateau function may decline at a natural rate (purple, dashed blue, dashed green lines) or at an accelerated rate (red lines). As lung function declines, respiratory symptoms may develop. Accelerated pathologic airflow limitation may develop in individuals who reach either normal or reduced maximal lung function and then experience a greater rate of lung function decline. Middle aged individuals may develop pathologic airflow limitation by experiencing higher rates of lung function decline after achieving normal maximal and plateau lung function or normal rates of decline after abbreviated plateau phases or achievement of lower maximal lung function levels. For individuals with predicted maximal lung function and plateau phase duration with normal rates of functional decline, symptomatic airflow limitation would be predicted to occur at greater than 150 years of age. |
Clinical Manifestations
Pulmonary. Breathlessness, cough, and sputum production are the three major symptoms of COPD. Dyspnea is a subjective sensation of lack of air that is normally experienced by everyone during vigorous or strenuous activity; when shortness of breath impedes routine activity, it suggests a transition from a normal physiological response to a symptom of a pathologic process. Breathlessness may progress insidiously in individuals with COPD. Initially, there may be subtle changes such as an inability to maintain the pace when walking with peers or increased sensation of breathing while doing routine activities, which gradually progresses to impede routine daily activities. Cough is the forceful exhalation of air to clear the airways from irritating or obstructing material. Cough may be nonproductive or productive of phlegm. These symptoms of dyspnea, cough, and phlegm production are neither sensitive nor specific for the diagnosis of COPD and must be interpreted in conjunction with the clinical history and laboratory and radiographic findings.
The differential diagnosis of COPD includes other pulmonary processes, such as asthma, bronchiolitis, pulmonary infections, bronchiectasis, and cardiac disorders, including ischemic heart disease and congestive heart failure. In some patients it may not be possible to distinguish asthma and COPD despite extensive evaluation, and this undifferentiated group is now classified as the asthma COPD overlap syndrome (see Table 1). Many other disorders may occur concurrently with COPD and it may be difficult to discern which process is primary.
Extra-pulmonary Manifestations. Over the past decade, COPD has been recognized to be more than just a pulmonary disorder. The extra-pulmonary manifestations are truly protean and nearly every organ system is involved. Inflammation is postulated to be the pathophysiologic process linking pulmonary and nonpulmonary manifestations of COPD.36-44 This multisystemic involvement is believed to be due to inflammatory cytokines produced within the lungs and released into the circulation or inflammatory cells that are activated within the lungs and then enter the circulation for distribution throughout the body.45 These non-pulmonary manifestations include cardiac, cerebrovascular, oncologic, musculoskeletal, hematologic, endocrine, and psychologic disorders.
The prevalence of ischemic cardiovascular disease among individuals with COPD is more than twice the level found among smokers who do not have COPD.46,47 It is estimated that cardiovascular mortality increases by 28% for every 10% decline in forced expiratory volume in one second (FEV1).48 More than one-quarter of patients hospitalized with COPD exacerbations have elevations in serum markers of cardiac ischemia and approximately 8% have myocardial infarctions.49 This increased risk of cardiac ischemia may be due to elevated inflammatory cytokines that can increase the risk of plaque rupture, demand ischemia caused by an increased heart rate due to the underlying pulmonary disease, hypoxemia, and beta-agonist and anti-cholinergic medication effects.50,51
Between 9% and 52% of individuals with COPD have heart failure, and co-existent COPD and heart failure are associated with greater mortality than either process alone.52,53 Due to similarities in the clinical presentation of heart failure and COPD exacerbations, there may be a tendency to treat a patient for both processes simultaneously. However, mortality and hospitalizations are increased for patients with left ventricular heart failure but not COPD who are treated with beta-agonists.54 However, beta-blocker treatment for individuals with COPD and congestive heart failure should be continued during hospitalizations for COPD exacerbations and is considered to be safe chronically.55 Cardiac-pulmonary interactions in individuals with COPD and heart failure are just starting to be studied, and the optimal management of concurrent COPD and heart failure is under evaluation.52,53,56,57
Approximately one in four smokers with obstructive lung disease will develop lung cancer, whereas cancer is only predicted to occur in one of every 14 smokers who do not have airflow limitation.58 Radiographic evidence of emphysema increases the risk for lung cancer by 3.5-fold.59 In addition, concurrent COPD predicts a worse course for lung cancer patients.60 Based on this increased lung cancer prevalence and the 20% reduction in lung cancer mortality observed in the American National Lung Screening Trial, low-dose screening chest CTs may be beneficial for individuals with obstructive lung disease, especially those with mild-to-moderate airflow impairment.61-63
In contrast with popular belief, the most common hematologic manifestation of COPD is anemia (7.5-32.7%) and not polycythemia (6%).63-68 COPD-related anemia is usually associated with a normal to low mean corpuscular volume, low serum iron, and normal to increased ferritin.69 It is postulated to be caused by chronic inflammation (anemia of chronic disease). Patients with anemia generally have more breathlessness, decreased exercise capacity, lower quality of life, and increased health care utilization and cost.64,65-67,70-74
Approximately 24-69% of individuals with COPD have osteoporosis, 27-67% have osteopenia, and 24-63% have vertebral fractures.75-81 Vertebral fractures may cause kyphosis that further impairs lung function; for every vertebral fracture, the forced vital capacity (FVC) may be reduced by 9%.82 In addition, the presence of COPD predicts an increased risk of hip fracture, and nearly half of all individuals with hip fractures have COPD.83,84
In addition to osteoporosis, musculoskeletal instability, balance impairment, and falls contribute to an increased rate of hip fractures.85,86 Skeletal muscle dysfunction caused by muscle atrophy, disuse, systemic inflammation, malnutrition, and corticosteroids may contribute to musculoskeletal instability.87
Both the prevalence and risk of developing diabetes are increased in individuals with COPD.46,88,89 This increased prevalence and incidence of diabetes is greater than would be expected with corticosteroid use. Concurrent diabetes increases the risk for hospitalization and death among individuals with COPD.90-92
Nocturnal respiratory symptoms, intrinsic sleep disordered breathing, or a combination of both of these processes contribute to sleep disturbances in 32-78% of patients with COPD. A careful directed sleep history is often necessary to detect sleep disorders in patients with COPD. Obstructive sleep apnea (OSA) occurs in approximately 10% of individuals with COPD, and the concurrence of OSA and COPD is known as the overlap syndrome. Risk factors for the overlap syndrome include obesity and, possibly, more severe airflow limitation. The combined effects of OSA and COPD cause profound nocturnal desaturation, which may contribute to the development of severe pulmonary hypertension. Overlap syndrome management includes bronchodilators, supplemental oxygen, and noninvasive mechanical ventilation usually with continuous positive airway pressure (CPAP). CPAP is most beneficial in individuals with hypercarbia and relieves sleep symptoms, reduces COPD exacerbations, and increases survival.
Pulmonary vascular disorders occur frequently in individuals with COPD. Nearly 25% of patients hospitalized with COPD exacerbations have venous thromboembolism, which may increase morbidity and mortality and precipitate pulmonary hypertension. Demonstration of an enlarged pulmonary outflow tract on a chest CT scan, a radiographic sign of pulmonary hypertension, is associated with worse prognosis among individuals with COPD.93 Transient elevation of pulmonary artery pressures, especially during exertion, occurs commonly in COPD. Persistent pulmonary hypertension may lead to cor pulmonale and right heart failure due to progressive right ventricular dilation and dysfunction. Treatment of pulmonary hypertension includes optimal management of the underlying COPD, supplemental oxygen to prevent resting, exertional and nocturnal desaturation, and smoking cessation. Thus far, pharmacologic treatment of COPD-related pulmonary hypertension has not been effective.
COPD is associated with intense psychosocial derangements that profoundly affect an individual’s perception and response to respiratory symptoms and to their familial and social networks. The most common psychological disorders associated with COPD are anxiety, depression, and panic disorder. Anxiety and depression are associated with more morbidities, greater mortality, and higher health care utilization among individuals with COPD. Panic disorder may impair an individual’s ability to react to and manage a COPD exacerbation. Additionally, many patients with COPD suffer cognitive impairment that limits their functional ability, medication adherence and use, and interferes with social interactions. Many individuals with COPD experience constriction of their familial and social networks due to impaired mobility and socialization which fosters a sense of isolation and loneliness. Pulmonary rehabilitation reduces anxiety and depression and improves psychosocial functioning.
Thus, nonpulmonary processes cause significant morbidity and mortality in COPD. Increased awareness, detection, and management of these manifestations of COPD have the potential to improve survival, reverse morbidity, improve quality of life, and reduce healthcare utilization among patients with COPD. At present, there is no evidence that current pharmacologic treatments for COPD are effective treatments for COPD’s nonpulmonary manifestations.
Diagnostic Testing
Spirometry. Because COPD is a syndrome, there is not a single objective criterion for its diagnosis. Although pulmonary physiologic measurement of airflow limitation was previously required for the diagnosis of COPD and remains the most commonly applied diagnostic standard, recent evidence shows that some individuals with radiographic evidence of emphysema may not have demonstrable obstruction during spirometric testing.94 Therefore, physiologic demonstration of obstruction is a critical but not essential factor in the diagnosis of COPD, especially emphysema.
Spirometry is an effort-dependent test that measures the amount of air expelled from the lungs over time. Reproducibility and testing accuracy are dependent on well-trained personnel who are able to coach patients to provide maximal effort during testing. During testing, the patient breathes in maximally to total lung capacity and then quickly exhales down to residual volume, sustaining the exhalation for 6 seconds and the volume of air expelled from the lungs is measured.
The two key spirometric measurements are the amount of air expelled in the first second, FEV1, and the total amount of air exhaled, FVC. Additionally, the spirometer graphs the flow rate change over time to create the flow volume curve (see Table 2 and Figure 1). In individuals with COPD, the flow volume curve has a characteristic scooping of the expiratory limb that is caused by the obstruction to airflow during exhalation. The spirometer also calculates the FEV1:FVC ratio which is used to diagnosis airflow obstruction or limitation. Normally this ratio is approximately 80% (four-fifths of a vital capacity can be exhaled within the first second of exhalation). With obstruction, the FEV1:FVC ratio is reduced. The two most common thresholds are an absolute value of FEV1/FVC < 0.7 or the lower limit of normal, the fifth percentile of the distribution of the FEV1/FVC ratio in a nonsmoking population with no clinical evidence of lung disease. As individuals age, the ratio of FEV1:FVC decreases. Thus, the use of an absolute threshold of 0.7 may over-diagnose airflow obstruction in older individuals and under-diagnose younger people (see Figure 2).
Table 2. Spirometry |
|||||||
|
|
Pre-bronchodilator |
Post-bronchodilator |
|||||
|
Actual |
Pred |
% Pred |
LLN |
Actual |
% Change |
% Pred |
|
|
FVC (L) |
1.69 |
3.05 |
55 |
2.42 |
2.40 |
42 |
79 |
|
FEV1 (L) |
0.69 |
2.38 |
29 |
1.85 |
0.90 |
31 |
38 |
|
FEV1/FVC |
0.41 |
0.79 |
51 |
0.69 |
0.38 |
-7 |
38 |
|
FEF Max |
1.93 |
6.04 |
32 |
4.49 |
1.92 |
-1 |
32 |
|
FEF 25-72% |
0.24 |
2.35 |
10 |
1.23 |
0.52 |
112 |
22 |
|
Spirometry results for a 56-year-old woman who has smoked 1 pack per day for 40 years and is still smoking. This study shows severe airflow obstruction with a response to bronchodilators. The postbronchodilator FEV1/FVC is 0.38 and is less than the LLN, 0.69, and both the FEV1 and FVC increase by more than 12% and 200 mL after administration of a bronchodilator. The corresponding flow volume loop is shown in Figure 1. Abbreviations: FEV1: forced expiration in one second; FVC forced vital capacity; L: liters; FEF Max: maximal forced expiratory flow; FEF25-75%: forced expiratory flow between 25% and 75% of exhalation; Pred: predicted; LLN: lower limit of normal. |
|||||||
Figure 1. Flow Volume Loop |
|
This is the flow volume loop corresponding to the spirometry results presented in Table 2. The expiratory limb of the curve demonstrates decreased flow rates and the characteristic scooped appearance of airflow limitation. The dotted curves are pre-bronchodilator and the solid curves are post-bronchodilator. |
Figure 2. Effect of Different FEV1/FVC Thresholds for Airflow Limitation |
|
|
In addition, the FEV1 is often used to predict the severity of airflow limitation. The patient’s FEV1 is compared with the predicted FEV1 to calculate the FEV1 % predicted. A FEV1 % predicted of 50% suggests that an individual is only able to exhale half as much air in 1 second as a person with normal lung function. The FEV1 % predicted may be used to classify COPD severity into various categories (see Table 3).
Table 3. COPD Severity Based on FEV1 Percent Predicted |
|
|
FEV1 Percent |
COPD |
|
≥ 80% |
Mild |
|
< 80% and ≥ 50% |
Moderate |
|
< 50% and ≥ 30% |
Severe |
|
< 30% |
Very severe |
Previous COPD staging and treatment guidelines were based solely on the FEV1 % predicted. However, since FEV1 does not correlate well with disease course, clinical outcomes, health status, or disease management, the FEV1 % predicted has been augmented with other clinical variables to create multivariate classifications.95 Airflow severity, respiratory symptoms measured by the COPD Activity Test or mMRC (modified Medical Research Council) dyspnea scale, and the number of COPD exacerbations within the previous year are the three variables used in the current Global initiative for Obstructive Lung Disease (GOLD) staging classification scheme.1 Other multivariate classifications include BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity), ADO (Age, Dyspnea, and airflow Obstruction), and DOSE (Dyspnea, Obstruction, Smoking, and Exacerbation).73,95,96 These multivariable staging classifications provide a more comprehensive assessment of the patient with COPD extending beyond simple physiologic testing and may be useful in guiding management and predicting disease course.
Imaging. The most common imaging tests for the evaluation of COPD are the chest radiograph and computed tomography (CT) scan (see Figures 3, 4, and 5). Common chest radiographic manifestations of COPD include lung hyperinflation that manifests as enlarged lung fields, flattened diaphragms (best seen on the lateral view), increased retrosternal airspace, and caudal movement of the mediastinum with inferior displacement of the heart. Emphysema may cause effacement of the vascular markings and cause cysts or bullae. CT scans are more sensitive than chest radiographs for detecting the presence of emphysema and may be used to quantify lung parenchymal destruction, air trapping, and hyperinflation.97,98 CT scans are also useful in the diagnosis of bronchiectasis and, more recently, have been used to measure airway luminal diameter and wall thickness that may be increased in chronic bronchitis.99-101 CT scans may also detect other lung disorders associated with tobacco smoke inhalation such as desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, pulmonary Langerhans cell histiocytosis, and idiopathic pulmonary fibrosis. Newer advanced pulmonary imaging techniques such as X-ray CT, magnetic resonance imaging, and use of hyperpolarized noble gasses are in development and provide structural and functional pulmonary evaluations that may detect earlier and more subtle changes than can be measured by spirometry. Thus, as these newer lung imaging techniques are perfected and made more widely available, they may replace spirometry in the detection of the earliest pulmonary manifestations of COPD.
Figure 3. Posterior-anterior and Lateral Chest X-rays of
|
 |
Figure 4. Posterior-anterior and Lateral Chest X-rays of
|
 |
Figure 5. Chest Computed Tomography Scan (Upper, Middle, and Lower Lung Zones) |
|
This chest CT scan is from the same patient whose spirometry and flow volume loop are presented in Table 2 and Figure 1 and whose chest X-ray is presented in Figures 3 and 4. The chest CT shows diffuse empysema with loss of lung parenchyma. There is a calcified nodule in the posterior left lower lobe. |
|
|
Management
The goals of COPD treatment include reduction in respiratory symptoms, improved quality of life, preservation of lung function, reduced COPD-associated complications and comorbidities, decreased number and severity of COPD exacerbations, and improved survival.
In the past decade, multiple COPD treatments have been demonstrated to improve longevity (see Table 4). The principle clinical manifestation of COPD is breathlessness that initially occurs only with exertion and eventually progresses to interrupt daily activities. Causes of dyspnea may be multifactorial with contributions from bronchospasm, oxygen desaturation, secretions, and cough, but the major factor contributing to breathlessness is dynamic lung hyperinflation. Lung hyperinflation is caused by an increase in the volume of air remaining in the lungs at the end of a normal exhalation (end expiratory lung volume [EELV]) that causes excessive stretch and distension (loading) of the respiratory muscles, placing them at a mechanical disadvantage precipitating the sensation of breathlessness. In COPD, air is easily inhaled but exhalation is impaired; if less air is exhaled than is inhaled, hyperinflation occurs and EELV increases. With each breath, the EELV increases and eventually impairs the ability to inhale due to restriction of the inspiratory capacity and decreasing minute ventilation. The respiratory rate increases during exertion and there is less time in exhalation, which further worsens hyperinflation (see Figure 6). Bronchodilators may reduce dynamic hyperinflation but the best approach is to maintain a slow and steady respiratory pattern by inhaling through the nose and exhaling through the mouth with pursed lips. This technique, which is called pursed lip breathing, elevates the intra-airway pressure and maintains airway patency by reducing collapse due to reduced elastic recoil. By maintaining airway patency during exhalation, more air is expelled, less dynamic hyperinflation occurs, and breathlessness is alleviated.
Table 4. Evidence-based Interventions to Reduce Mortality in COPD |
|
COPD Treatments that Improve Survival |
|
Smoking cessation |
|
Oxygen for patients with resting hypoxemia |
|
Influenza vaccination |
|
Noninvasive ventilation for respiratory failure |
|
Pulmonary rehabilitation/exercise |
|
Tiotropium |
|
Lung volume reduction surgery in selected patients |
Figure 6. Dynamic Hyperinflation |
|
Dynamic hyperinflation is the major cause of breathlessness in individuals with COPD. In COPD, air is easily inhaled but exhalation is impeded by airflow limitation caused by increased resistance and reduced elastic recoil; if less air is exhaled than was inhaled, the lung begins to retain air, increasing the end expiratory lung volume (EELV). As EELV increases, the volume of air inhaled during subsequent breaths is decreased due to restriction of the inspiratory capacity. Thus, the lungs are unable to meet ventilatory and oxygenation demands. The increase in respiratory rate that occurs with exertion further augments hyperinflation by reducing expiratory time causing more air trapping and increase in the EELV. As hyperinflation increases, the respiratory muscles are stretched or loaded causing discomfort; the stretching also causes functional weakness by putting the muscles at a mechanical disadvantage. The discomfort caused by stretching and loading of respiratory muscles by dynamic hyperinflation is a significant factor contributing to the sensation of breathlessness. Both pharmacologic and nonpharmacologic treatments may help to ameliorate dynamic hyperinflation. Pursed lip breathing facilitates exhalation of air by creating an increased expiratory resistance that elevates the intra-airway pressure to maintain airway patency, reducing collapse due to diminished elastic recoil and increasing the amount of air expelled during exhalation. The improved expiratory airflow reduces air trapping and hyperinflation. Slow, deliberate, and controlled breathing utilizing pursed lip breathing helps to reduce the respiratory rate, which increases the exhalation time that may also reduce air trapping and hyperinflation. Control of anxiety, relaxation techniques, and better awareness of the perception of breathlessness may also help reduce the rate of breathing. |
Routine Management
The mainstays of COPD pharmacologic management are bronchodilators and inhaled corticosteroids. Short-acting beta-agonists are usually the initial bronchodilator and should be prescribed on an as-needed basis as a rescue inhaler. As with all inhalers, proper instruction is critical for patients to obtain maximal benefit from these medications. A spacer device improves delivery of medication to the lungs for all metered dose inhalers but should not be used for dry powder inhalers. The next level pharmacologic treatment is the addition of a long-acting anticholinergic or long-acting beta-agonist. Nebulizers are an alternative to metered dose inhalers when patients are unable to use metered dose inhalers properly or when they are hospitalized. There is no significant clinical therapeutic difference between medications delivered by a metered dose inhaler with a spacer and by nebulizer (see Table 5).
Table 5. Respiratory Medications Commonly Used to Treat COPD |
|||
|
Year Approved By the FDA |
|
|
|
|
1998 |
LABA |
Salmeterol |
Serevent Diskus |
|
1999 |
SABA |
Albuterol |
Proventil HFA |
|
2001 |
SABA |
Albuterol |
Ventolin HFA |
|
2001 |
SABA + SAch |
Albuterol + Ipratropium |
Duoneb |
|
2001 |
LABA |
Formoterol fumarate |
Foradil Aerolizer |
|
2003 |
LABA + ICS |
Salmeterol + Fluticasone furoate |
Advair Diskus |
|
2002 |
SABA |
Albuterol |
Xopenex |
|
2004 |
LAch |
Tiotropium bromide |
Spiriva HandiHaler |
|
2004 |
SAch |
Ipratroprium |
Atrovent HFA |
|
2006 |
LABA |
Arformoterol tartrate |
Brovana |
|
2009 |
LABA + ICS |
Formoterol + Budesonide |
Symbicort |
|
2011 |
LABA |
Indacaterol maleate |
Arcapta |
|
2011 |
PDE4 Inhibitor |
Roflumilast |
Daliresp |
|
2012 |
LAch |
Aclidinium bromide |
Tudorza Pressair |
|
2013 |
LACH + LABA |
Umeclidinium+ vilanterol |
Anoro Ellipta |
|
2013 |
LABA + ICS |
Vilanterol + Fluticasone furoate |
Breo Ellipta |
|
2014 |
LABA |
Olodaterol |
Stiverdi Respimat |
|
2014 |
LAch |
Umeclidinium |
Incruse Ellipta |
|
Abbreviations: SABA: short-acting beta-agonist; LABA: long-acting beta-agonist; ICS: inhaled corticosteroid; PDE4: phosphodiesterase 4 |
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Other medications for the treatment of COPD include phosphodiesterase inhibitors, macrolides, and mucolytics. Phosphodiesterase inhibitors include methylxanthines such as theophylline or aminophylline, which are rarely used due to their narrow therapeutic window and frequent side effects and medication interactions. The specific phosphodiesterase 4 inhibitor, roflumilast, is approved by the FDA for the reduction of COPD exacerbations in individuals with chronic bronchitis and frequent exacerbations.102 Macrolides such as erythromycin and azithromycin have anti-inflammatory properties in addition to antimicrobial effects. Recent studies have shown that either daily erythromycin or azithromycin decreases the frequency of COPD exacerbations in patients with a history of exacerbations.103-105 Although it remains unclear which subgroup of patients with COPD will benefit best from macrolide treatment and whether dosing should be daily or thrice weekly, current recommendations are to consider daily macrolide treatment in patients who, despite maximal standard bronchodilator therapy, have at least two exacerbations yearly.106 Potential adverse effects of prolonged macrolide use include development of bacterial resistance, cardiovascular events, and hearing loss. Mucolytics such as n-acetylcysteine and carbocysteine may reduce COPD exacerbations and improve health-related quality of life in patients with COPD.107 In one prospective study, n-acetylcysteine reduced hyperinflation.108 Mucolytics are used more frequently in Europe than in the United States.
Supplemental oxygen improves survival in patients with hypoxemia at rest (PaO2 < 55 torr or SpO2 < 88%; or PaO2 < 60 and > 55 torr with evidence of cor pulmonale).109,110 The mechanism(s) by which supplemental oxygen improves mortality is unknown. Oxygenation should be measured on room air at rest, with exertion, and during sleep after the administration of supplemental oxygen to ensure that desaturation is prevented. Even though there is no current evidence that supplemental oxygen during exercise or at night is beneficial in individuals with stable COPD and normoxemia at rest, Medicare and most insurers provide reimbursement for supplemental oxygen during exercise or at night with evidence of exercise or nocturnal desaturation.
Smoking cessation is the singularly most important intervention for the prevention and treatment of COPD. Even after quitting, many smokers return to smoking. Half of all individuals who are able to quit smoking for at least 6 months will resume smoking within 8 years of quitting.111 Thus, the process of smoking cessation is often a series of episodes of quitting and relapse before permanent abstinence is achieved. A commonly used smoking cessation guideline is the five A’s: ask, advise, assess, assist, and arrange.112 All patients should be asked about tobacco use at every encounter. Every smoker should be advised to quit. Nearly 10% of smokers will attempt to quit based upon their provider’s advice.113 The provider next assesses the patient’s readiness for change, motivates those who are not yet ready, and assists those who are prepared to stop smoking. Pharmacologic aids to smoking cessation include nicotine replacement therapy (gum, patch, lozenges, and sprays), buproprion, and varenicline. Lastly, the provider should arrange follow-up, which may be a subsequent visit or a phone call. Smoking cessation is usually a process that occurs across a series of attempts that finally culminate in permanent abstinence.
Most COPD management guidelines recommend both influenza and pneumococcal vaccination for individuals with COPD. Influenza vaccination reduces mortality, outpatient visits, hospitalizations, and exacerbations.114 Although pneumococcal vaccination reduces the incidence of invasive pneumococcal disease, it has not shown any significant effect on mortality, rates of pneumonia or exacerbations, lung function, or cost effectiveness.114,115 Vaccination against both influenza and pneumococcus may reduce COPD exacerbations more effectively than either vaccine alone.114
Pulmonary rehabilitation is a multidisciplinary program of education and exercise that provides COPD patients with information about their disease, its treatment, and mechanisms to cope with its consequences. Pulmonary rehabilitation is most effective when it is integrated into a comprehensive COPD management program that encourages behavior change and a shift from provider-initiated to patient self-directed care. Patients with COPD who maintain physical activity have less breathlessness with exertion, better health-related quality of life, improved long-term function and independence, and better psychological and physiological function.
Surgical or endoscopic lung volume reduction may also be effective in certain patients with COPD. Lung volume reduction surgery (LVRS) removes emphysematous lung parenchyma, which allows less deranged lung tissue to ventilate more normally, improving overall lung function. LVRS improves exercise tolerance, quality of life, and survival in selected patients with COPD.116 However, this surgery is only beneficial in patients with upper lobe emphysema and poor exercise tolerance and is detrimental in individuals with FEV1 < 20% of predicted, diffusing capacity < 20% of predicted, or diffusely distributed emphysema. Patients who are being considered for LVRS should be referred for pulmonary consultation. Endoscopic LVRS is a newer technique that may also benefit selected patients.
Because COPD is a multisystemic disorder with protean nonpulmonary manifestations, it is essential to evaluate and treat patients with COPD for conditions such as anemia, diabetes, lung cancer, and cardiovascular disease. At the present time, there is no evidence that current COPD management strategies affect the extra-pulmonary manifestations of COPD; therefore, treatments should be focused directly on these processes.
Exacerbations
The course of COPD is often marked by intermittent exacerbations and episodes of increased respiratory symptoms (especially cough, wheezing, phlegm production, and breathlessness) that vary in severity, frequency, duration, and consequence. A COPD exacerbation is defined as an acute event characterized by worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.1 Exacerbations are the major contributor to the socioeconomic and health-related burden of COPD. Risk factors for COPD exacerbations include age, worse quality of life, severity of airflow limitation (reduction in FEV1), chronic bronchitis, and comorbidities (especially gastroesophageal reflux disease).117 The best predictor of future exacerbations is a history of prior exacerbations.118 The treatment and prevention of COPD exacerbations are critical elements in COPD management and, over the past decade, multiple therapies have been demonstrated to reduce COPD exacerbation frequency.
Approximately half of all COPD exacerbations are not reported to health care providers and usually are not treated.119 Individuals with COPD may exhibit therapeutic paralysis, an attempt to “tough it out” during exacerbations, and often do not seek medical attention.120 Patients with COPD delay treatment initiation by a median duration of 3.7 days, even though each day without treatment prolongs the recovery time by nearly half a day.119 Additionally, those individuals who report exacerbations and are treated have a better quality of life compared with those who are not treated.119 Thus, although nearly half of all exacerbations are unreported and untreated, earlier recognition and treatment of COPD exacerbations may improve recovery and quality of life.
The annual frequency of COPD exacerbations ranges from approximately one-quarter to one-half of individuals with COPD, depending on the severity of their airflow limitation. The propensity toward frequent or infrequent exacerbations is stable over several years.118 Between 70-80% of COPD exacerbations are triggered by viral and bacterial respiratory infections and the majority of the rest are due to environmental exposures such as air pollution and medication non-adherence.121,122
The symptoms of a COPD exacerbation depend on its cause. Typical manifestations include cough, sputum production, dyspnea, tachypnea, wheezing, and a decrease in pulmonary function. Physical examination findings depend on the severity of the exacerbation and typically include tachypnea and wheezing. In more severe exacerbations, patients develop difficulty speaking, use accessory respiratory muscles, and exhibit paradoxical chest and abdominal wall movements due to asynchrony between the chest and abdomen during breathing. In very severe exacerbations, patients may develop hypoxemia and hypercapnia with lethargy and possibly obtundation.
Most COPD exacerbations can be treated in an ambulatory setting. Early recognition and management may be facilitated by providing instruction and a written action plan that describes the symptoms of an exacerbation. The action plan includes instruction on how to increase the use of short-acting beta-agonists (albuterol), utilization of relaxation exercises and breathing techniques, and the recognition of when to seek medical care. With the action plan, patients should be given prescriptions for antibiotics and steroids that they can fill preemptively to have the medications on hand and ready to take at the first sign of an exacerbation. If early, self-directed treatment is successful, patients should call their care provider to obtain refills. Rotation of antibiotic classes may reduce the risk of development of antibiotic-resistant organisms. Recovery duration after an exacerbation, quality of life, and breathlessness are improved with use of patient education and action plans.123,124 Self-management education reduces COPD hospitalizations by 43% with a number needed to treat of 8 for those at high risk of COPD hospitalization and 20 for those at low risk.124
If patients do not improve within 48 hours of starting their action plan, antibiotics, and steroids, they should seek medical attention. Similarly, worsening breathlessness, cough with increased phlegm production despite antibiotics, anxiety, confusion, or unrelenting constitutional symptoms would warrant escalation of the level of care to either an urgent office or emergency department visit.
Nearly half of all COPD exacerbations are associated with bacterial infections, and antibiotics are indicated for these patients. Clinical criteria (increased dyspnea, increased phlegm production, change in sputum quality) are usually sufficient to begin treatment with antibiotics, and sputum cultures are not usually obtained unless there is a clinical indication. Choice of antibiotic is usually empirical and trimethaprim-sulfamethoxazole, azithromycin, cefuroxime, or tetracycline is adequate for mild exacerbations. For more severe exacerbations, a broader-spectrum antibiotic such as moxifloxacin or levofloxacin that is effective against resistant strains of Haemophilus influenzae and Streptococcus pneumoniae is recommended. Patients with a more extensive infection such as pneumonia should be treated with a broad-spectrum antibiotic.
Several randomized, placebo-controlled trials have demonstrated that systemic corticosteroid therapy improves airflow, gas exchange, symptoms, and exacerbation resolution.125-130 Most exacerbations can be treated with 30-60 mg prednisone daily for 5-7 days1 and steroid therapy can be stopped without tapering if the duration of therapy is < 3 weeks.1,128 Longer durations of therapy have no added benefit and a higher risk of adverse effects, especially hyperglycemia. The REDUCE trial showed that 5 days was not inferior to 14 days of oral 40 mg prednisolone daily and time to the next exacerbation, mortality, lung function, and adverse events during the subsequent 6 months were equivalent.131 The current evidence for the use of corticosteroids is suggesting that lower doses (40 mg) for shorter periods (5 days) that do not require gradual tapers are as effective in treating COPD exacerbations as higher steroid doses for longer periods and are associated with fewer adverse events.
Although most patients resolve their respiratory symptoms within a week of a COPD exacerbation and physiologic function returns to baseline levels within 6 days, up to 14% of patients do not return to baseline within a month and many never regain full function.132 The rate of decline in pulmonary function is 2-8 mL/year greater in individuals with two or more exacerbations yearly compared with those with less frequent exacerbations.133,134 In addition, quality of life and health care encounters and cost are greater for those with more frequent exacerbations.135,136
Assessment of the patient with COPD who presents with worsening respiratory symptoms should begin with a broad differential diagnosis that includes congestive heart failure, myocardial infarction, bronchitis, pneumonia, pneumothorax, and pulmonary thromboembolism as well as COPD exacerbation. A complete medical history and thorough physical examination are critical in the refinement of this differential diagnosis. Other useful tests include pulse oximetry or arterial blood gas, chest radiograph, electrocardiogram, and complete blood count and metabolic panel. The decision to hospitalize an individual with a COPD exacerbation is individualized and based on the available hospital and community resources and the individual’s familial and social support network. Home care services such as hospital in home are able to provide equivalent outcomes as hospitalization for COPD exacerbation with significant cost savings.137
Hemodyamic or respiratory instability, alterations in mentation, cyanosis or new oxygen requirement, failure of outpatient management, severe airflow limitation, frequent exacerbations, significant comorbidities, and inadequate familial or social support network are potential indications for hospitalization. The next decision is whether a patient with a COPD exacerbation can be best managed on a medical ward or requires intensive care admission. Potential indications for critical care include life-threatening hemodynamic or respiratory instability, profound hypoxemia or hypercarbia associated with respiratory acidemia, requirement for ventilatory assistance with noninvasive ventilation or mechanical ventilation, and altered mentation.
For the hospitalized patient with a COPD exacerbation, the critical decision is the determination of the cause of the exacerbation. Most treatments for respiratory failure are supportive and maintain oxygenation and ventilation while the underlying process is treated. Airflow obstruction is treated with bronchodilators, including short-acting beta-adrenergic agonists, short-acting inhaled anticholinergic agents, and anti-inflammatory medications such as corticosteroids. Bronchodilators may be delivered either by metered dose inhalers with a spacer device or nebulizers. Although the clinical efficacy of these two delivery methods is equivalent, many providers prefer nebulized therapy.138 Short-acting beta-adrenergic agonists should be administered every 1 to 4 hours. The use of continuous nebulizer treatments does not improve their efficacy and may increase adverse events such as tachycardia and hypokalemia.139 Corticosteroids improve respiratory symptoms and reduce the length of stay for patients hospitalized with COPD exacerbations.128,140,141 Because steroids are nearly 100% bioavailable with enteral administration, oral prednisone is preferred unless the patient is unable to swallow or absorb oral medications. Compared with parenteral corticosteroids, enteral administration does not produce any differences in length of stay, treatment failure, respiratory symptoms, or physiologic function. Similar to corticosteroid dosing and duration during management of outpatient COPD exacerbations, treatment strategies are moving toward shorter duration and lower doses. A commonly used regimen is 40 mg of oral prednisone daily for 5 days with no tapering dose.131
Antibiotics are recommended for patients with increased phlegm production, for patients with clinical evidence of bronchitis or pneumonia, and for patients requiring ventilatory assistance. The success rate is similar for 5 days of antibiotics compared with 7-10 days.142 Serum procalcitonin is elevated in bacterial infection and may be used to guide the use of antibiotics during COPD exacerbations. The restriction of antibiotics to patients with elevated procalcitonin significantly reduces the cost of treatment and reduces the selection of antibiotic organisms but does not adversely affect mortality or treatment failure.143
For patients with COPD exacerbations and hypoxemic, hypercarbic, or mixed process respiratory failure, either noninvasive or invasive mechanical ventilation may be indicated. Noninvasive ventilation is the use of either CPAP or bilevel ventilation delivered through a facemask. Because bilevel ventilation augments minute ventilation, it is the preferred mode for individuals with hypercarbic or mixed respiratory failure. Use of noninvasive ventilation reduces mortality by 50% in individuals with COPD exacerbations and respiratory failure and decreases hospital and ICU length of stay and respiratory symptoms.144-147 Initiation and management of noninvasive ventilation usually requires pulmonary or critical care medicine consultation. Patients who are started on noninvasive ventilation should be evaluated carefully over the first 2 hours of treatment. If they are not improving within this period, intubation and mechanical ventilation should be initiated.
Pulmonary embolism may be diagnosed in up to one-quarter of patients hospitalized for COPD exacerbations who have persistent symptoms and no identifiable etiologic cause for their respiratory symptoms.148,149 CT with pulmonary angiography is the preferred diagnostic procedure because many of these patients have ventilatory abnormalities on ventilation-perfusion scans. Anticoagulation is the preferred treatment as long as there are no contraindications.
Hospitalized patients with COPD exacerbations are at increased risk of cardiovascular complications, especially myocardial ischemia and worsening of congestive heart failure.150 Beta-blockers are a mainstay of treatment for these cardiovascular complications but are not infrequently withheld due to concerns that they might worsen pulmonary bronchospasm. The evidence overwhelmingly supports the use of selective beta1-blockers in individuals with COPD and that their use reduces mortality in individuals with COPD exacerbations and myocardial infarction.55,151,152 Thus, beta-adrenergic blockade with selective beta1-blockers should be continued or initiated in patients with COPD exacerbations and evidence of myocardial ischemia.
COPD exacerbations have profound effects on patients’ well-being and are the leading contributors to COPD’s cost. Most exacerbations are never reported to health care providers. A history of prior exacerbations is the best predictor of future exacerbations. Most exacerbations can be self-managed by patients who are provided a care management plan, antibiotics, and corticosteroids. Early use of noninvasive ventilation in patients with severe respiratory failure may reduce the mortality of these episodes by half.
End of Life
Despite the availability of treatments to reduce COPD’s mortality and morbidity, COPD is a chronic, incurable disorder. Unlike many other chronic diseases, deaths due to COPD are rising and it is predicted to become the third leading cause of mortality and fourth leading cause of worldwide disability by 2020. Because the trajectory and natural history of COPD vary so greatly among individuals, it is very difficult to predict a patient’s future course. This uncertainty hampers many providers from discussing advanced care planning with patients with COPD and their families. Advanced care planning is the process of ongoing communication between providers and patients, their families, and other members of their social network to provide information about COPD, and its course and management, including medications and nonpharmaceutical interventions. Advanced care planning begins with a therapeutic approach and gradually evolves to more supportive and then palliative care as COPD progresses from diagnosis to chronic disease management, and, finally to death and bereavement. Palliative care emphasizes quality of life for patients and their families as they experience the chronic and unrelenting progression of COPD through careful management of all aspects of this disorder including psychosocial and spiritual care. End-of-life care occurs during the final stages of COPD and provides support for patients and their families and social network.
As COPD progresses, breathlessness and functional impairment worsen and patients enter a vicious downward spiral — their respiratory limitations impair their function, and they decrease their activity, losing physical conditioning, which further reduces their activity level. As they become more physically disabled, their social interactions decrease and they become more isolated and their social network constructs. In the last year of life, nearly half of patients with COPD are housebound and only leave home once a month.153 Nearly all of these individuals experience breathlessness, weakness, pain, and low mood that are inadequately treated.
Very few providers discuss the natural history of COPD with their patients. Impediments to these discussions include a preference for acute life-sustaining management rather than palliation, multiple providers and uncertainty as to which provider should initiate the dialogue, lack of certainty about the disease course, and disapproving attitudes toward a self-inflicted disorder.154-156
Advanced care planning can begin at the time of diagnosis. This discussion may include education about the management and natural history of COPD. As pharmacologic management progresses, discussion about advanced care directives, choice of health care decision surrogates, and familial discussion of future health care needs and provision may begin. As symptoms progress, the provider may begin to have conversations about advanced care directives, intubation and use of mechanical ventilation, and resuscitation status with the patient and family. These discussions can be difficult and are best conducted incrementally over time, with each conversation building on the prior discussions. Some providers may be more comfortable obtaining palliative care or hospice medicine consultation during this process.
As COPD progresses, the goals of treatment shift from cure to palliation. Breathlessness continues to be treated with bronchodilators and inhaled corticosteroids. Opioids may be added to improve quality of life and relieve dyspnea and may also alleviate caregivers’ anxiety. Benzodiazepines do not relieve breathlessness but may help with the anxiety associated with unrelenting dyspnea.157 Even though it is often prescribed, oxygen does not relieve breathlessness in individuals with COPD and normoxemia or mild hypoxemia.158,159
CONCLUSION
COPD is a chronic, incurable but very treatable condition that is currently the third leading cause of death in the United States. COPD is a syndrome composed of historical factors, clinical signs and symptoms, and physiologic and imaging abnormalities. Classically, COPD has been classified as emphysema, chronic bronchitis, or a mixed process; more recent studies suggest that there are many more clinical groupings or phenotypes that may have prognostic and therapeutic implications. Additionally, COPD is now recognized to be a multisystemic disorder with a myriad of nonpulmonary manifestations, including cardiovascular, hematologic, endocrine, metabolic, and psychosocial derangements. Although there is no single diagnostic test for COPD, most individuals with COPD have airflow obstruction on spirometric testing and exhibit lung parenchymal and airway abnormalities on radiographic imaging. Over the past decade, the treatment of COPD has migrated from therapeutic nihilism to multiple effective medications that reduce respiratory symptoms, improve quality of life, and improve survival. Early recognition, diagnosis, and treatment are key to improving outcomes for individuals with COPD.
REFERENCES
-
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: Revised 2014. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Available at: www.goldcopd.org.
-
World Health Organization. Chronic respiratory diseases. Available at: http://www.who.int/respiratory/copd/definition/en/.
-
American Thoracic Society. Standards for the Diagnosis and Management of Patients with COPD. Available at: http://www.thoracic.org/copd-guidelines/resources/copddoc.pdf.
-
Qaseem A, Wilt TJ, Weinberger SE,; American College of Physicians; American College of Chest Physicians; American Thoracic Society; European Respiratory Society. Diagnosis and management of stable chronic obstructive pulmonary disease: A clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med 2011;155:179-191.
-
Petty TL. The history of COPD. Int J Chron Obstruct Pulmon Dis 2006;1:3-14.
-
Badham C. An essay on bronchitis: with a supplement containing remarks on simple pulmonary abscess. 2nd ed. London: J Callow; 1814.
-
Briscoe WA, Nash ES. The slow space in chronic obstructive pulmonary disease. Ann N Y Acad Sci 1965;121:706-722.
-
Mannino DM, Gagnon RC, Petty TL, Lydick E. Obstructive lung disease and low lung function in adults in the United States: Data from the National Health and Nutrition Examination Survey, 1984-1994. Arch Intern Med 2000;160:1683-1689.
-
Ford ES, Croft JB, Mannino DM, et al. COPD surveillance — United States, 1999-2011. Chest 2013;144: 284-305.
-
Murphy DE, Chaudhry Z, Almoosa KF, Panos RJ. High prevalence of chronic obstructive pulmonary disease among veterans in the urban midwest. Mil Med 2011;176:552-560.
-
Arias E, Anderson RN, Hsiang-Ching K, et al. Deaths: Final data for 2001. National Vital Statistics Report 2003:52. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf.
-
Centers for Disease Control and Prevention. Deaths from chronic obstructive pulmonary disease--United States, 2000-2005. MMWR Morb Mortal Wkly Rep 2008;57:1229-1232.
-
Miniño AM, Xu JQ, Kochanek KD. Deaths: Preliminary data for 2008. National Vital Statistics Reports 2010;59. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdf.
-
Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: Role of comorbidities. Eur Respir J 2006;28:1245-1257.
-
Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: Findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med 2006;100:115-122.
-
Zvezdin B, Milutinov S, Kojicic M, et al. A postmortem analysis of major causes of early death in patients hospitalized with COPD exacerbation. Chest 2009;136: 376-380.
-
Ford ES, Murphy LB, Khavjou O, et al. Total and state-specific medical and absenteeism costs of chronic obstructive pulmonary disease among adults aged ≥ 18 years in the United States for 2010 and projections through 2020. Chest 2014;147:31-45.
-
Centers for Disease Control and Prevention (CDC). Chronic obstructive pulmonary disease among adults--United States, 2011. MMWR Morb Mortal Wkly Rep 2012;61: 938-943.
-
Forey BA, Thornton AJ, Lee PN. Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema. BMC Pulm Med 2011;11:36.
-
Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet 2009;374:733-743.
-
Zeng G, Sun B, Zhong N. Non-smoking-related chronic obstructive pulmonary disease: A neglected entity? Respirology 2012;17: 908-912.
-
Blanc PD, Iribarren C, Trupin L, et al. Occupational exposures and the risk of COPD: Dusty trades revisited. Thorax 2009;64:6-12.
-
Eisner MD, Anthonisen N, Coultas D, et al; Committee on Nonsmoking COPD, Environmental and Occupational Health Assembly. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010;182: 693-718.
-
Doney B, Hnizdo E, Syamlal G, et al. Prevalence of Chronic Obstructive Pulmonary Disease Among US Working Adults Aged 40 to 70 Years: National Health Interview Survey Data 2004 to 2011. J Occup Environ Med 2014;56:1088-1093.
-
Omland O, Würtz ET, Aasen TB, et al. Occupational chronic obstructive pulmonary disease: A systematic literature review. Scand J Work Environ Health 2014;40:19-35.
-
Allwood BW, Myer L, Bateman ED. A systematic review of the association between pulmonary tuberculosis and the development of chronic airflow obstruction in adults. Respiration 2013;86:76-85.
-
Ehrlich RI, Adams S, Baatjies R, Jeebhay MF. Chronic airflow obstruction and respiratory symptoms following tuberculosis: A review of South African studies. Int J Tuberc Lung Dis 2011;15: 886-891.
-
Raynaud C, Roche N, Chouaid C. Interactions between HIV infection and chronic obstructive pulmonary disease: Clinical and epidemiological aspects. Int J Chron Obstruct Pulmon Dis 2014;9:1145-1154.
-
Gingo MR, Morris A, Crothers K. Human immunodeficiency virus-associated obstructive lung diseases. Clin Chest Med 2013;34:273-282.
-
Regalado J, Perez-Padilla R, Sansores R, et al. The effect of biomass burning on respiratory symptoms and lung function in rural Mexican women. Am J Respir Crit Care Med 2006;174:901-905.
-
Rinne ST, Rodas EJ, Bender BS, et al. Relationship of pulmonary function among women and children to indoor air pollution from biomass use in rural Ecuador. Respir Med 2006;100:1208-1215.
-
Grigg J. Particulate matter exposure in children: Relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2009;6:564-569.
-
Lange P, Celli B, Agustí A, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373:111-122.
-
Vestbo J, Agusti A, Wouters EF, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints Study Investigators. Should we view chronic obstructive pulmonary disease differently after ECLIPSE? A clinical perspective from the study team. Am J Respir Crit Care Med 2014;189:1022-1030.
-
Cavaillès A, Brinchault-Rabin G, Dixmier A, et al. Comorbidities of COPD. Eur Respir Rev 2013;22:454-475.
-
Albu A, Fodor D, Poanta L, Man M. Markers of systemic involvement in chronic obstructive pulmonary disease. Rom J Intern Med 2012;250:129-134.
-
Huertas A, Palange P. COPD: A multifactorial systemic disease. Ther Adv Respir Dis 2011;5:217-224.
-
Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest 2011;139:165-173.
-
Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165-1185.
-
Decramer M, Rennard S, Troosters T, et al. COPD as a lung disease with systemic consequences — clinical impact, mechanisms, and potential for early intervention. COPD 2008;5:235-256.
-
Agustí A. Systemic effects of chronic obstructive pulmonary disease: What we know and what we don’t know (but should). Proc Am Thorac Soc 2007;4:522-525.
-
Agusti A, Soriano JB. COPD as a systemic disease. COPD 2008;5:133-138.
-
Fabbri LM, Luppi F, Beghé B, Rabe KF. Complex chronic comorbidities of COPD. Eur Respir J 2008;31:204-212.
-
Agustí A, Barberà JA, Wouters EF, et al. Lungs, bone marrow, and adipose tissue. A network approach to the pathobiology of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:1396-1406.
-
Mannino DM, Thorn D, Swensen A, Holquin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008;32:962-969.
-
Finkelstein J, Cha E, Scharf SM. Chronic obstructive pulmonary disease as an independent risk factor for cardiovascular morbidity. Int J Chron Obstruct Pulmon Dis 2009;4:337-349.
-
Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc 2005;2:8-11.
-
McAllister DA, Maclay JD, Mills NL, et al. Diagnosis of myocardial infarction following hospitalisation for exacerbation of COPD. Eur Respir J 2012;39:1097-1103.
-
Harvey KL, Hussain A, Maddock HL. Ipratropium bromide-mediated myocardial injury in in vitro models of myocardial ischaemia/reperfusion. Toxicol Sci 2014;138:457-467.
-
Visca D, Aiello M, Chetta A. Cardiovascular function in pulmonary emphysema. Biomed Res Int 2013;2013:184678.
-
Hawkins NM, Petrie MC, Jhund PS, et al. Heart failure and chronic obstructive pulmonary disease: Diagnostic pitfalls and epidemiology. Eur J Heart Fail 2009;11:130-139.
-
Hawkins NM, Virani S, Ceconi C. Heart failure and chronic obstructive pulmonary disease: The challenges facing physicians and health services. Eur Heart J 2013;34:2795-2803.
-
Au DH, Udris EM, Fan VS, et al. Risk of mortality and heart failure exacerbations associated with inhaled beta-adrenoceptor agonists among patients with known left ventricular systolic dysfunction. Chest 2003;123:1964-1969.
-
Stefan MS, Rothberg MB, Priya A, et al. Association between beta-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension. Thorax 2012;67:977-984.
-
Hawkins NM, Petrie MC, Macdonald MR, et al. Heart failure and chronic obstructive pulmonary disease: The quandary of beta-blockers and beta-agonists. J Am Coll Cardiol 2011;57:2127-2138.
-
Mentz RJ, Fiuzat M, Kraft M, et al. Bronchodilators in heart failure patients with COPD: Is it time for a clinical trial? J Card Fail 2012;18:413-422.
-
Young RP, Hopkins RJ, Christmas T, et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009;34:380-386.
-
Smith BM, Pinto L, Ezer N, et al. Emphysema detected on computed tomography and risk of lung cancer: A systematic review and meta-analysis. Lung Cancer 2012;77:58-63.
-
Kiri VA, Soriano J, Visick G, Fabbri L. Recent trends in lung cancer and its association with COPD: An analysis using the UK GP Research Database. Prim Care Respir J 2010;19:57-61.
-
The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.
-
Wender R, Fontham ET, Barrera E Jr, et al. American Cancer Society lung cancer screening guidelines. CA Cancer J Clin 2013;63:107-117.
-
Sekine Y, Katsura H, Koh E, et al. Early detection of COPD is important for lung cancer surveillance. Eur Respir J 2012;39:1230-1240.
-
Yohannes AM, Ershler WB. Anemia in COPD: A systematic review of the prevalence, quality of life, and mortality. Respir Care 2011;56:644-652.
-
Cote C, Zilberberg MD, Mody SH, et al. Haemoglobin level and its clinical impact in a cohort of patients with COPD. Eur Respir J 2007;29:923-929.
-
Chambellan A, Chailleux E, Similowski T. ANTADIR Observatory Group. Prognostic value of hematocrit in patients with severe COPD receiving long-term oxygen therapy. Chest 2005;128:1201-1208.
-
Shorr AF, Doyle J, Stern L, et al. Anemia in chronic obstructive pulmonary disease: Epidemiology and economic implications. Curr Med Res Opin 2008;24:1123-1130.
-
Nowinski A, Kaminski D, Korzybski D, et al. The impact of comorbidities on the length of hospital treatment in patients with chronic obstructive pulmonary disease. Pneumonol Alergol Pol 2011;79:388-396.
-
Portillo K, Martinez-Rivera C, Ruiz-Manzano J. Anaemia in chronic obstructive pulmonary disease. Does it really matter? Int J Clin Pract 2013;67:558-565.
-
Kollert F, Tippelt A, Müller C, et al. Hemoglobin levels above anemia thresholds are maximally predictive for long-term survival in COPD with chronic respiratory failure. Respir Care 2013;58:1204-1212.
-
Halpern MT, Zilberberg MD, Schmier JK, et al. Anemia, costs and mortality in chronic obstructive pulmonary disease. Cost Eff Resour Alloc 2006;4:17.
-
Barba R, de Casasola GG, Marco J, et al. Anemia in chronic obstructive pulmonary disease: A readmission prognosis factor. Curr Med Res Opin 2012;28:617-622.
-
Martinez-Rivera C, Portillo K, Munoz-Ferrer A, et al. Anemia is a mortality predictor in hospitalized patients for COPD exacerbation. COPD 2012;9:243-250.
-
Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004;350:1005-1012.
-
Boutou AK, Stanopoulos I, Pitsiou GG, et al. Anemia of chronic disease in chronic obstructive pulmonary disease: A case-control study of cardiopulmonary exercise responses. Respiration 2011;82:237-245.
-
Jorgensen NR, Schwarz P, Holme I, et al. The prevalence of osteoporosis in patients with chronic obstructive pulmonary disease: A cross sectional study. Respir Med 2007;101:177-185.
-
Nuti R, Siviero P, Maggi S, et al. Vertebral fractures in patients with chronic obstructive pulmonary disease: The EOLO Study. Osteoporos Int 2009;20:989-998.
-
Papaioannou A, Parkinson W, Ferko N, et al. Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada. Osteoporos Int 2003;14:913-917.
-
McEvoy CE, Ensrud KE, Bender E, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157(3 Pt 1):704-709.
-
Graat-Verboom L, Wouters EF, Smeenk FW, et al. Current status of research on osteoporosis in COPD: A systematic review. Eur Respir J 2009;34:209-218.
-
Lehouck A, Boonen S, Decramer M, Janssens W. COPD, bone metabolism, and osteoporosis. Chest 2011;139:648-657.
-
Rittayamai N, Chuaychoo B, Sriwijitkamol A. Prevalence of osteoporosis and osteopenia in Thai COPD patients. J Med Assoc Thai 2012;95:1021-1027.
-
Leech JA, Dulberg C, Kellie S, et al. Relationship of lung function to severity of osteoporosis in women. Am Rev Respir Dis 1990;141:68-71.
-
Regan EA, Radcliff TA, Henderson WG, et al. Improving hip fractures outcomes for COPD patients. COPD 2013;10:11-19.
-
Díez-Manglano J, López-García F, Barquero-Romero J, et al; en nombre de los investigadores del estudio ECCO y del Grupo de Enfermedad Pulmonar Obstructiva Crónica de la Sociedad Española de Medicina Interna. [Risk of osteoporotic fracture and hip fracture in patients with chronic obstructive pulmonary disease]. Rev Clin Esp 2011;211:443-449.
-
Beauchamp MK, Hill K, Goldstein RS, et al. Impairments in balance discriminate fallers from non-fallers in COPD. Respir Med 2009;103:1885-1891.
-
Hellström K, Vahlberg B, Urell C, Emtner M. Fear of falling, fall-related self-efficacy, anxiety and depression in individuals with chronic obstructive pulmonary disease. Clin Rehabil 2009;23:1136-1144.
-
Kim HC, Mofarrahi M, Hussain SN. Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2008;3:637-658.
-
Laghi F, Adiguzel N, Tobin MJ. Endocrinological derangements in COPD. Eur Respir J 2009;34:975-996.
-
Feary JR, Rodrigues LC, Smith CJ, et al. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: A comprehensive analysis using data from primary care. Thorax 2010;65:956-962.
-
Burt MG, Roberts GW, Aguilar-Loza NR, et al. Relationship between glycaemia and length of hospital stay during an acute exacerbation of chronic obstructive pulmonary disease. Intern Med J 2013;43:721-724.
-
Parappil A, Depczynski B, Collett P, Marks GB. Effect of comorbid diabetes on length of stay and risk of death in patients admitted with acute exacerbations of COPD. Respirology 2010;15: 918-922.
-
Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829-841.
-
Wells JM, Washko GR, Han MK, et al; COPDGene Investigators; ECLIPSE Study Investigators. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012;367:913-921.
-
Coxson HO, Leipsic J, Parraga G, Sin DD. Using pulmonary imaging to move chronic obstructive pulmonary disease beyond FEV1. Am J Respir Crit Care Med 2014;190:135-144.
-
Jones RC, Donaldson GC, Chavannes NH, et al. Derivation and validation of a composite index of severity in chronic obstructive pulmonary disease: The DOSE index. Am J Respir Crit Care Med 2009;180:1189-1195.
-
Puhan MA, Garcia-Aymerich J, Frey M, et al. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: The updated BODE index and the ADO index. Lancet 2009;374:704-711.
-
Friedman PJ. Imaging studies in emphysema. Proc Am Thorac Soc 2008;5:494-500.
-
Takahashi M, Fukuoka J, Nitta N, et al. Imaging of pulmonary emphysema: A pictorial review. Int J COPD 2008;3:193-204.
-
Nakano Y, Wong JC, de Jong PA, et al. The prediction of small airway dimensions using computed tomography. Am J Respir Crit Care Med 2005;171:142-146.
-
Patel BD, Coxson HO, Sreekumar GP, et al. Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;178:500-505.
-
Lutey BA, Conradi SH, Atkinson JJ, et al. Accurate measurement of small airways on low-dose thoracic CT scans in smokers. Chest 2013;143:1321-1329.
-
Reid DJ, Pham NT. Roflumilast: A novel treatment for chronic obstructive pulmonary disease. Ann Pharmacother 2012;46:521-529.
-
Martinez FJ, Curtis JL, Albert R. Role of macrolide therapy in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2008;3:331-350.
-
Seemungal TA, Wilkinson TM, Hurst JR, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;178:1139-1147.
-
Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689-698.
-
Mammen MJ, Sethi S. Macrolide therapy for the prevention of acute exacerbations in chronic obstructive pulmonary disease. Pol Arch Med Wewn 2012;122:54-59.
-
Decramer M, Janssens W. Mucoactive therapy in COPD. Eur Respir Rev 2010;19:134-140.
-
Stav D, Raz M. Effect of N-acetylcysteine on air trapping in COPD: A randomized placebo-controlled study. Chest 2009;136:381-386.
-
Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: A clinical trial. Ann Intern Med 1980;933:391-398.
-
Report of the Medical Research Council Working Party Report of the Medical Research Council Working Party. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1981;18222:681-686.
-
Yudkin P, Hey K, Roberts S, et al. Abstinence from smoking eight years after participation in randomized controlled trial of nicotine patch. BMJ 2003;327:28-29.
-
Fiore MC, Jason CR, Baker TB, et al. Treating Tobacco Use and Dependence. Update. Clinical Practice Guideline. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; May 2008.
-
Wilson DH, Wakefield MA, Steven ID, et al. Sick of smoking: Evaluation of a minimal smoking cessation intervention in general practice. Med J Aust 1990;152:518-521.
-
Varkey JB, Varkey AB, Varkey B. Prophylactic vaccinations in chronic obstructive pulmonary disease: Current status. Curr Opin Pulm Med 2009;15:90-99.
-
Walters JA, Smith S, Poole P, et al. Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2010;(11):CD001390.
-
Tidwell SL, Westfall E, Dransfield MT. Lung volume reduction for advanced emphysema: Surgical and bronchoscopic approaches. South Med J 2012;105:56-61.
-
Miravitlles M, Guerrero T, Mayordomo C, et al. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: A multiple logistic regression analysis. The EOLO study group. Respiration 2000;67:495-501.
-
Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. N Engl J Med 2010;363:1128-1138.
-
Wilkinson TM, Donaldson GC, Hurst JR, et al. Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004;169:1298-1303.
-
Mulhall AM, Lach LA, Krzywkowski-Mohn SM, et al. Therapeutic paralysis in veterans with COPD. Respir Med 2013;107:1547-1557.
-
Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008;359:2355-2365.
-
Ling SH, van Eeden SF. Particulate matter air pollution exposure: Role in the development and exacerbation of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2009;4:233-243.
-
Bischoff EW, Hamd DH, Sedeno M, et al. Effects of written action plan adherence on COPD exacerbation recovery. Thorax 2011;66:26-31.
-
Zwerink M, Brusse-Keizer M, van der Valk PD, et al. Self-management for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014;3:CD002990.
-
Albert RK, Martin TR, Lewis SW. Controlled clinical trial of methylprednisolone in patients with chronic bronchitis and acute respiratory insufficiency. Ann Intern Med 1980;92:753-758.
-
Thompson WH, Nielson CP, Carvalho P, et al. Controlled trial of oral prednisone in outpatients with acute COPD exacerbation. Am J Respir Crit Care Med 1996;154(2 Pt 1):407-412.
-
Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003;348:2618-2625.
-
Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999;340:1941-1947.
-
Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: A prospective randomised controlled trial. Lancet 1999;354:456-460.
-
Maltais F, Ostinelli J, Bourbeau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: A randomized controlled trial. Am J Respir Crit Care Med 2002;165:698-703.
-
Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: The REDUCE randomized clinical trial. JAMA 2013;309:2223-2231.
-
Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608-1613.
-
Donaldson G, Seemungal T, Bhowmik A, Wedzicha J. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847-852.
-
Vestbo J, Lisa D, Scanlon P, et al. Changes in forced expiratory volume in 1 second overtime in COPD. N Engl J Med 2011;365:1184-1192.
-
Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157(5 Pt 1):1418-1422.
-
Miravitlles M, Ferrer M, Pont A, et al. Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: A 2-year follow up study. Thorax 2004;59:387-395.
-
Ram FS, Picot J, Lightowler J, Wedzicha JA. Non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2004;3:CD004104.
-
Turner MO, Patel A, Ginsburg S, FitzGerald JM. Bronchodilator delivery in acute airflow obstruction. A meta-analysis. Arch Intern Med 1997;157:1736-1744.
-
Nair S, Thomas E, Pearson SB, Henry MT. A randomized controlled trial to assess the optimal dose and effect of nebulized albuterol in acute exacerbations of COPD. Chest 2005;128:48-54.
-
Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: A systematic review. Chest 2008;133-756-766.
-
de Jong YP, Uil SM, Grotjohan HP, et al. Oral or IV prednisolone in the treatment of COPD exacerbations: A randomized, controlled, double-blind study. Chest 2007;132:1741-1747.
-
Falagas ME, Avgeri SG., Matthaiou DK, et al. Short- versus long-duration antimicrobial treatment for exacerbations of chronic bronchitis: A meta-analysis. J Antimicrob Chemother 2008;62:442-450.
-
Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev 2012;9:CD007498.
-
Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1995;333:817-822.
-
Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: A multicentre randomised controlled trial. Lancet 2000;355:1931-1935.
-
Chandra D, Stamm JA, Taylor B, et al. Outcomes of noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the United States, 1998-2008. Am J Respir Crit Care Med 2012;185:152-159.
-
Conti G, Antonelli M, Navalesi P, et al. Noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: A randomized trial. Intensive Care Med 2002;28:1701-1707.
-
Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: Prevalence and risk factors. Ann Intern Med 2006;144:390-396.
-
Rizkallah J, Man SF, Sin DD. Prevalence of pulmonary embolism in acute exacerbations of COPD: A systematic review and metaanalysis. Chest 2009;135:786-793.
-
Donaldson GC, Hurst JR, Smith CJ, et al. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010;137:1091-1097.
-
Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;4:CD003566.
-
Quint JK, Herrett E, Bhaskaran K, et al. Effect of beta blockers on mortality after myocardial infarction in adults with COPD: Population based cohort study of UK electronic healthcare records. BMJ 2013;347:f6650.
-
Elkington H, White P, Addington-Hall J, et al. The healthcare needs of chronic obstructive pulmonary disease patients in the last year of life. Palliat Med 2005;19:485-491.
-
Knauft E, Nielsen EL, Engelberg RA, et al. Barriers and facilitators to end-of-life care communication for patients with COPD. Chest 2005;127:2188-2196.
-
Gott M, Gardiner C, Small N, et al. Barriers to advance care planning in chronic obstructive pulmonary disease. Palliat Med 2009;23:642-648.
-
Patel K, Janssen DJA, Curtis JR. Advance care planning in COPD. Respirology 2012;17:72-78.
-
Simon ST, Higginson IJ, Booth S, et al. Benzodiazepines for the relief of breathlessness in advanced malignant and non-malignant diseases in adults. Cochrane Database Syst Rev 2010;1:CD007354.
-
Davidson PM, Johnson MJ. Update on the role of palliative oxygen. Curr Opin Support Palliat Care 2011;5:87-91.
-
Abernethy AP, Currow DC, Frith P, Fazekas BS. Prescribing palliative oxygen: A clinician survey of expected benefit and patterns of use. Palliative Med 2005;19:168-170.
Over the past decade, this definition of COPD has changed dramatically, as has the characterization and treatment of individuals with COPD. Multiple new therapies alter the course of this disease, reduce exacerbations, improve quality of life, and increase survival; previous nihilistic approaches to the management of COPD have been replaced by directed and effective pharmacologic and nonpharmacologic therapies. This update will review current approaches to the diagnosis and management of COPD and present the most recent evidence for the classification of COPD phenotypes and the implications of these categories for COPD treatment and prognosis.
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