Chronic obstructive pulmonary disease (COPD) affects approximately 44 million persons worldwide and is the fourth leading cause of death. Patients characteristically have symptoms consistent with chronic bronchitis and emphysema, but the classic triad also includes asthma. New developments in recent decades have led to the increased use of spirometry, an acknowledgment of airflow obstruction as the central issue in determining susceptibility, and improved pathologic criteria and laboratory means for assessing emphysema and COPD. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition signifies a paradigm shift in the clinical approach to COPD; it proposes that the disease is both treatable and preventable. Therefore, it is important to educate patients with COPD about the disease and to encourage their operative sharing in therapy. This course is designed to present healthcare professionals with the information needed to keep up to date on the best practice clinical guidelines for COPD and to refresh the importance of patient education.

Education Category: Infection Control / Internal Medicine
Release Date: 11/01/2016
Expiration Date: 10/31/2019


This course is designed for physicians, primary care providers, nurses, respiratory therapists, and medical assistants involved in the care of patients with COPD.

Accreditations & Approvals

NetCE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NetCE is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE is accredited by the International Association for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU. This program has been pre-approved by The Commission for Case Manager Certification to provide continuing education credit to CCM® board certified case managers. The course is approved for 10 CE contact hour(s). Activity code: H00021046. Approval Number: 160001838. To claim these CEs, log into your CE Center account at www.ccmcertification.org.

Designations of Credit

NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 8 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. This home study course is approved by the Florida Board of Nursing Home Administrators for 5 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 10 hour(s) of continuing education credit - NHAP#1622010-5387/P. California NHAs may only obtain a maximum of 10 hours per course. NetCE is authorized by IACET to offer 1 CEU(s) for this program. AACN Synergy CERP Category A.

Individual State Nursing Approvals

In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through December 12, 2017); California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; Florida, Provider #50-2405; Iowa, Provider #295; Kentucky, Provider #7-0054 through 12/31/2017.

Special Approvals

This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.

Course Objective

The purpose of this course is to present healthcare professionals with the information needed to keep up to date on the best practice clinical guidelines for COPD and to refresh the importance of patient education.

Learning Objectives

Upon completion of this course, you should be able to:

  1. Define chronic obstructive pulmonary disease (COPD) and associated conditions.
  2. Identify risk factors and discuss the role of cigarette use, infection, and chronic inflammation in the pathogenesis and progression of COPD.
  3. Correlate pathologic changes in the lung with the clinical features of COPD.
  4. Describe the pathophysiology of airflow limitation and air trapping.
  5. Recognize and evaluate the clinical signs and symptoms of COPD.
  6. Analyze the various criteria and tests used in the diagnosis of COPD.
  7. Discuss the investigations used to assess the severity and to stage COPD.
  8. Identify interventions that may reduce the risk of developing COPD, including smoking cessation.
  9. Outline pharmacologic and nonpharmacologic options for the management of stable COPD.
  10. Use your knowledge of pathophysiology and options for therapy to devise a strategy for managing COPD exacerbations in the ambulatory setting or in the hospital.
  11. Describe the appropriate monitoring and assessment of COPD disease progression, as well as associated comorbidities.


John M. Leonard, MD, Professor of Medicine Emeritus, Vanderbilt University School of Medicine, completed his post-graduate clinical training at the Yale and Vanderbilt University Medical Centers before joining the Vanderbilt faculty in 1974. He is a clinician-educator and for many years served as director of residency training and student educational programs for the Vanderbilt University Department of Medicine. Over a career span of 40 years, Dr. Leonard conducted an active practice of general internal medicine and an inpatient consulting practice of infectious diseases.

Faculty Disclosure

Contributing faculty, John M. Leonard, MD, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planners

John V. Jurica, MD, MPH

Jane C. Norman, RN, MSN, CNE, PhD

Division Planners Disclosure

The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Table of Contents

Technical Requirements

Supported browsers for Windows include Microsoft Internet Explorer 9.0 and up, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Supported browsers for Macintosh include Safari, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Other operating systems and browsers that include complete implementations of ECMAScript edition 3 and CSS 2.0 may work, but are not supported.

#98811: COPD: An Overview of Pathophysiology and Treatment

  • Back to Course Home
  • Participation Instructions


Chronic obstructive pulmonary disease (COPD) is a diffuse inflammatory disorder of the pulmonary airways caused by the chronic inhalation of noxious gases and particles. Clinically, it is characterized by an insidious onset and progression of breathlessness, cough, and fatigue. COPD is a major cause of chronic morbidity and premature death, ranking fourth among causes of death worldwide [1]. In many parts of the world, the prevalence of COPD is increasing because of the widespread habit of smoking cigarettes and because of the extensive use of biomass fuels in developing countries [2]. The disorder is preventable and amenable to various therapeutic modalities. The degree of airflow obstruction and the pace of clinical change can be easily measured and monitored by simple pulmonary function tests [3].

In the nations of Europe, it is estimated that 44 million people are living with some degree of COPD. The World Health Organization estimates that, unless managed appropriately, COPD will become the third leading cause of death worldwide by 2030 [1]. In recent decades, the mortality rate for COPD has not declined as it has for other chronic diseases such as heart disease, cancer, and stroke.

COPD is a leading cause of morbidity and mortality in the United States. A nationwide prevalence survey conducted in 2010 by state health departments in collaboration with the Centers for Disease Control and Prevention (CDC) found that 6.3% of adults (an estimated 15 million) living in the United States had been told by a healthcare provider that they have COPD [4]. In this study, the prevalence of COPD increased from 3.2% among those 18 to 22 years of age to more than 11.6% among those older than 65 years of age.

In 2010, COPD accounted for nearly 700,000 hospitalizations, 10.3 million outpatient visits, and 1.5 million emergency department visits [5]. The total direct medical costs attributable to COPD and its sequelae were estimated at $32 billion, and the indirect (absenteeism) costs were $3.9 billion [5]. This cost burden is expected to increase through 2020.


The Global Initiative for Chronic Obstructive Lung Disease (GOLD), a project of the WHO, has defined COPD as a common preventable disease characterized by airflow limitation that is usually progressive and is associated with an abnormal inflammatory response in the airways and the lung to inhaled noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients [199]. Clinically and pathologically, COPD is comprised of two overlapping disease processes: chronic bronchitis and emphysema.

Chronic bronchitis is defined as a cough with sputum production on most days for at least three months of a year for two consecutive years [40]. Patients with chronic bronchitis have a characteristic hyperplasia and hypertrophy of the goblet cells and mucous glands of the airway, leading to excessive mucus secretion narrowing the airways, which results in repeated cough with sputum. The airway walls are infiltrated with inflammatory cells, and persistent inflammation results in thickening of the wall and airway narrowing. Progression of chronic bronchitis results in fibrosis and squamous metaplasia, which limits airflow [42]. Chronic bronchitis is a recurrent and irreversible condition, which differentiates it from acute bronchitis. Acute bronchitis is an inflammation of the large bronchi in the lungs typically caused by viruses or bacteria that may last several days or weeks [43].

Emphysema is an enlargement of the air spaces distal to the terminal bronchioles, with destruction of their walls [40]. The destruction of air space walls reduces elastic recoil and the surface area available for the exchange of oxygen and carbon dioxide during breathing. These airways can collapse, leading to further limitation in airflow. Emphysema can be classified by location as panacinar/panlobular and centriacinar/centrilobular [41].

Panacinar emphysema results in enlargement of respiratory bronchiole to alveoli and includes entire respiratory acini. It usually involves all lung fields, particularly the bases and anterior margins of the lungs. This type of emphysema is common in individuals with alpha-1 antitrypsin deficiency.

Centriacinar emphysema predominantly occurs in the upper lobes, resulting in enlargement of the respiratory bronchiole (i.e., the proximal and central part of the acinus); however, the distal acinus and alveoli are unaffected. This type of emphysema is common in smokers. Emphysema can also be classified as distal acinar emphysema, irregular emphysema, or congenital lobar emphysema (CLE). Distal acinar emphysema preferentially involves the distal airway structures, alveolar ducts, and alveolar sacs. CLE is a rare congenital disorder characterized by hyperinflation of one or more of the pulmonary lobes. Irregular emphysema is a fibrotic form of the disease that shows no consistent relationship to any portion of the acinus. Scarring is very common in patients with irregular emphysema.


In susceptible individuals, COPD develops gradually over years as the result of chronic inflammation induced by sustained inhalational exposure to cigarette smoke and other noxious (causative) agents, augmented by intercurrent infection of the bronchial tree and lower airways. Although cigarette smoking is the most common initiating factor, there are multiple other risk factors, often acting in concert, including genetic predisposition, occupational exposures, air pollution, and infection. (Table 1).


Genetic predisposition
Exposure to particles (e.g., tobacco smoke, organic and inorganic occupational dusts, outdoor air pollution, indoor air pollution from heating and cooking with biomass in poorly vented dwellings)
Poor lung growth and development
Oxidative stress
Female sex
Older age
Respiratory infections
Lower socioeconomic status
Poor nutrition


Cigarette smoking is the predominant and primary risk factor for COPD, and approximately 15% of all persons who smoke will develop clinically apparent COPD. Smokers of more than 40 pack-years exposure have a much higher likelihood of developing COPD than nonsmokers. The combined exposure to tobacco smoke and certain occupational dusts and chemicals magnifies the risk for COPD [6,7,8,9,10,11]. In developing countries, COPD has been attributed to chronic exposure to smoke from burning biomass fuels for indoor cooking and heating purposes. Smokers with pre-existing airway reactivity also have a greater susceptibility to developing COPD.

The mode of tobacco use appears to affect risk. The morbidity and mortality rates from COPD are higher for persons who smoke cigarettes than for those who smoke a pipe or cigars [6]. The level of risk in smokers is related to dose, age at initiation of smoking, total pack-years smoked, and current smoking status [6,7].


Occupational exposures to dusts, fumes, and chemicals also predispose to COPD [12]. The American Thoracic Society has concluded that occupational exposures account for 10% to 20% of symptoms or functional impairment consistent with COPD [13].


Biomass in the form of wood, animal dung, crop residues, or coal, each of which is typically burned in open fires or poorly functioning stoves, can result in significant indoor air pollution. Worldwide, approximately 40% of people use biomass and coal for cooking and heating, which increases their risk for developing COPD. This risk factor is responsible for the high prevalence of COPD among nonsmoking rural women in developing countries [14,15]. It is estimated that every year, 2 million women and children die due to indoor air pollution caused by from the burning of wood and other biomass fuels [16].


The role of outdoor air pollution in the development of COPD is still unclear, but it is considered to be of minor significance compared with that of cigarette smoking [75]. High levels of urban outdoor air pollution are known to be detrimental to the health of patients with pre-existing heart or lung disease. Studies on this point have demonstrated that decreases in pulmonary function measures can be directly related to increases in urban air pollution from fossil fuel combustion [17].


The airways of normal lungs are sterile, and pulmonary defense mechanisms (e.g., mucociliary clearance, alveolar macrophage phagocytosis) work in concert to maintain this sterility. Smoking cigarettes eventually leads to bronchial inflammation and disrupts host defense mechanisms to such an extent that "colonization" of the airways by microbial pathogens is established early in the course of many persons with COPD [23]. The pathogens most commonly implicated are adenovirus, Chlamydia, Haemophilus influenzae, Moraxella, and Streptococcus pneumoniae [23,24]. Bacterial colonization in this setting represents low-grade chronic infection, which, in combination with clinical exacerbations, augments airway inflammation and contributes to pathogenesis and disease progression. The airway inflammation associated with bacterial colonization is neutrophilic in character and mediated by interleukin-8 and other chemokines [25].

A study among older (mean age: 70 years) adults in Devonshire, England, found that men with a history of pneumonia in early childhood had a significantly greater prevalence of COPD in late life [26]. This association was not found in women, perhaps because men in that time and place were more likely to have had this predisposition unmasked by cigarette use and occupational exposures.


Individuals with poor lung growth are susceptible to developing COPD as they age. Some studies have confirmed a positive association between low birth weight and decreased forced expiratory volume (FEV1) in adulthood [18].


A higher risk for developing COPD has been attributed to conditions of imbalance between oxidants and antioxidants [19]. Antioxidant capacity in COPD is substantially reduced as a result of cigarette smoking and exacerbations, with oxidative stress persisting long after the cessation of cigarette smoking or exacerbation due to the continued production of reactive oxygen species from endogenous sources [187].


The role of an individual's biologic sex in determining COPD risk remains unclear [20]. Some studies have indicated that women are more susceptible to the harmful effects of tobacco smoke and more prone to develop COPD, as a consequence, than men [20,21,22].

It is believed that a variety of genes play an important role in COPD pathogenesis. A genetic disorder that causes alpha-1 antitrypsin deficiency is an important cause of emphysema in nonsmokers and increases susceptibility to disease in smokers. People with severe hereditary deficiency of alpha-1 antitrypsin are genetically predisposed to developing COPD. Alpha-1 antitrypsin stimulates neutrophil elastase activity, which leads to parenchymal destruction in the lungs and causes emphysema.


Experimental studies in animals have demonstrated a strong direct correlation between starvation and anabolic/catabolic status and the development of emphysema [30]. A study conducted in chronically malnourished women showed an increased propensity for emphysema-like changes in the lungs [31].


Studies have demonstrated that the risk of developing COPD increases in people of low socioeconomic status [27]. However, it is unclear to what extent this is related to excessive exposure to cigarette smoke, other pollutants, and harmful pathogens or to the prevalence of other risk factors, such as poor nutrition and infrequent healthcare contact [28,29].


Asthma may contribute to the development of COPD, although the available evidence is inconclusive. Some studies have shown that asthmatics have a higher risk for developing COPD over time compared to non-asthmatics, but more research is necessary before a definitive correlation can be established [32].


Although the defining pathologic changes of COPD are found in the lower airways of the tracheobronchial tree, the disease process also extends to the lung parenchyma and pulmonary vasculature (Table 2).


AreaInflammatory ChangesStructural Changes
Proximal airways (trachea, bronchi >2 mm internal diameter)
Increase in number of macrophages and CD8+ (cytotoxic) T-lymphocytes
Few neutrophils or eosinophils
Increase in goblet cells
Enlarged submucosal glands
Squamous metaplasia of epithelium
Peripheral airways (bronchioles <2 mm in diameter)
Increase in number of macrophages, T-lymphocytes (CD8+
Few neutrophils or eosinophils
Thickening of airway wall
Luminal inflammatory exudate
Peribronchial fibrosis
Airway narrowing
Increased inflammatory response and exudate correlated with disease severity
Lung parenchyma (respiratory bronchioles and alveoli)Increase in number of macrophages and CD8+ T-lymphocytes
Destruction of alveolar wall
Apoptosis of epithelial and endothelial cells
In centrilobular emphysema: Destruction and dilatation of respiratory bronchioles (frequently seen in smokers)
In panacinar emphysema: Destruction of alveolar sacs as well as respiratory bronchioles (frequently seen in alpha-1 antitrypsin deficiency)
Pulmonary vasculatureIncrease in number of macrophages and T-lymphocytes
Thickening of intima
Endothelial cell dysfunction
Smooth muscle pulmonary hypertension


COPD is characterized by a chronic, fixed limitation to airflow during the normal respiratory cycle and is caused by the combined effects of chronic inflammation, bronchial glandular hypertrophy, excess mucus production, and obstructive bronchiolitis. Airway inflammation plays the central role in pathogenesis and disease progression. Affected patients demonstrate an amplified inflammatory response within the airways to inhaled cigarette smoke, other noxious particles, and viral and bacterial infection. Chronic inflammation leads to structural changes, narrowing of the small airways, and loss of alveolar attachments to the small airways and impaired lung elasticity within the lung parenchyma. This in turn compromises the ability of lungs to remain open during expiration, further impeding airflow, trapping air, and diminishing gas exchange. Diagnosis is made by demonstrating the presence of airflow limitation, which can be done easily, accurately, and reliably by spirometry.

Inflammatory Cells

The chronic inflammatory process of COPD is mediated by a proliferation of inflammatory cells such as neutrophils, macrophages, B-cells, and CD8+ T-cells, particularly in the small airways (Table 3) [33,195]. The degree of inflammation mirrors the severity of disease.


Cell TypeCharacteristic Changes
NeutrophilsElevated levels of neutrophils in sputum of normal smokers, with greater levels in those with COPD related to disease severity. Few neutrophils are seen in tissue. They may be important in mucus hypersecretion and the release of proteases.
MacrophagesGreatly increased numbers of macrophages are seen in airway lumen, lung parenchyma, and bronchoalveolar lavage fluid. Derived from blood monocytes that differentiate within lung tissue, these cells produce increased inflammatory mediators and proteases in patients with COPD in response to cigarette smoke and may show defective phagocytosis.
T-lymphocytes (T-cells)Both CD4+ and CD8+ cells are increased in the airway wall and lung parenchyma, with an increased CD8+:CD4+ ratio. Greater numbers of CD8+ T-cells (Tc1) and T helper 1 (Th1) cells, which secrete interferon-γ and express the chemokine receptor CXCR39. CD8+ cells may be cytotoxic to alveolar cells, contributing to their destruction.
B-lymphocytes (B-cells)Elevated levels in peripheral airways and within lymphoid follicles, possibly as a response to chronic colonization and infection of the airways.
EosinophilsElevated levels of eosinophil proteins in sputum and increased eosinophils in airway wall during exacerbations.
Epithelial cellsMay be activated by cigarette smoke to produce inflammatory mediators.

It is suggested that neutrophils play a primary role in the generation of mucous metaplasia in chronic bronchitis and the destruction of lung tissue in emphysema. The neutrophilic inflammatory response appears to account for the excessive mucus secretion observed in response to an acute secretagogue and for augmentation of the bronchial mucus-producing apparatus observed in these patients [34,35]. There is a strong correlation between peripheral airway dysfunction in COPD and sputum neutrophil counts [36].

Macrophages are the predominant inflammatory cells present in lavage fluid in patients with COPD [37]. Numerous studies have demonstrated a direct correlation between the number of alveolar macrophage in the lung tissue and the severity of lung destruction [38].

In COPD, the total T-cell count is elevated. CD8+ cells are the predominant subtype [39].

Inflammatory Mediators

A number of inflammatory mediators are increased in patients with COPD (Table 4) [195]. These mediators function to attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors).


Cell TypeAction
Lipid mediators (e.g., leukotriene B4)Attract neutrophils and T-lymphocytes
Chemokines (e.g., interleukin-8)Attract neutrophils and monocytes
Proinflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-1ß, and interleukin-6)Amplify the inflammatory process and may contribute to some of the systemic effects of COPD
Growth factors (e.g., transforming growth factor-ß)May induce fibrosis in small airways


Oxidative stress plays an important role in both inflammation and emphysematous response to cigarette smoke exposure, and it also promotes mucus secretion and plasma exudation. Biomarkers of oxidative stress (e.g., hydrogen peroxide, 8-isoprostane) are elevated in patients with COPD. It is suspected that oxidative stress plays a key role in activating inflammatory genes and inactivating antiproteases.


The protease-antiprotease imbalance is suspected to be the culprit in the development of emphysema in smokers with severe alpha1-antitrypsin deficiency because of a deficient antiprotease protection against neutrophil elastase release in the lung. In addition, smoke exposure can inactivate endogenous antiproteases, contributing to this imbalance [191].


Research has resulted in a better understanding of the pathophysiology of the underlying disease process that results in the characteristic abnormalities and symptoms of COPD.


There is a direct correlation between degree of inflammation, fibrosis, and luminal exudates in small airways and the reduction in FEV1 and FEV1/forced vital capacity (FVC) ratio. The effect on airflow is pronounced in the smaller (<2 mm in diameter) conducting airways. The resultant peripheral airway obstruction produces alveolar hyperinflation and air trapping during expiration. Hyperinflation diminishes inspiratory capacity and increases functional residual capacity, which causes dyspnea and limitation of exercise capacity.


Inefficient and impaired gas exchange results in arterial oxygen deficiency (hypoxemia) and carbon dioxide (CO2) retention (hypercapnia). Gas exchange abnormalities worsen as the disease progresses. There is a strong relationship between the severity of emphysematous change and the degree of arterial oxygen deficit coupled with ventilation-perfusion (VA/Q) imbalance.

Patients with COPD often have respiratory muscle weakness and reduced respiratory muscle endurance. This further confounds the problem of ventilation and can result in serious hypercapnia during intercurrent illness, inadvertent sedation, and episodes of infectious bronchitis. The alveolar ventilation impairment and pulmonary vascular bed shrinkage leads to further deterioration of the VA/Q mismatch.


Excessive mucus secretion causes chronic productive cough in patients with chronic bronchitis. Ordinarily, this plays a minor role in airflow limitation but may become significant during episodes of infectious bronchitis. However, symptomatic mucus hypersecretion is not present in all patients with COPD. Many mediators and proteases can stimulate mucus hypersecretion by activating the epidermal growth factor receptor (EGFR).


Pulmonary hypertension develops late in the course of COPD, typically after the patient develops severe gas exchange impairments. Pulmonary hypertension supervenes in COPD because of vasoconstriction of small pulmonary arteries, endothelial cell dysfunction, and loss of the pulmonary capillary bed. This combination of events leads to progressive pulmonary hypertension, which causes right ventricular hypertrophy and ultimately cor pulmonale (right-side cardiac failure).


COPD is associated with systemic inflammation and skeletal muscle loss, especially in patients with a severe course. These systemic effects can lead to poor exercise capacity, cachexia, chronic anemia, osteoporosis, and depression. Inflammatory markers are typically elevated in COPD, and there is a direct correlation between elevated C-reactive protein (CRP) and risk of cardiovascular diseases [82].


The cardinal signs and symptoms of COPD are chronic cough, sputum production, breathlessness (shortness of breath and dyspnea), and limited exercise tolerance. Other common signs that may be present in COPD include:

  • Tachypnea

  • Pursed lips breathing

  • Prolonged expiration phase of breathing (compared with inspiration)

  • Active use of neck muscles during breathing

  • Increased resonance of the chest (by percussion) caused by hyperaeration and emphysematous change

  • Increased anteroposterior (A-P) diameter of the chest ("barrel chest")

In established and late-stage disease, systemic complications can develop, including skeletal muscle wasting and weakness, poor exercise capacity, weight loss, depression and anxiety, osteoporosis, cor pulmonale, and polycythemia.


Symptomatic COPD usually begins insidiously with a chronic cough, often intermittent and nonproductive, gradually becoming more frequent and productive of sputum as disease progresses. This productive cough may be more pronounced on arising in the morning, but eventually recurs throughout the day in advanced stages. In cases in which emphysema is the predominant form of COPD, patients may experience little or no cough despite progression to severe airflow limitation.

The prevalence of cough in patients with COPD increases with disease progression, age, and smoking status. Of 2,950 individuals with COPD who participated in a clinical survey, 55% reported chronic cough and 20% rated the cough as severe or extreme [83]. The high prevalence of cough may be related to increased mucus production, inefficient mucus clearing, and increased mucus retention. The number and severity of COPD exacerbations varies directly with the chronicity and severity of productive cough. Moreover, pervasive cough is fatiguing, interrupts sleep, and adversely affects overall health status and quality of life.


Sputum is a mucous substance produced from the lungs, usually expelled by coughing or clearing of the throat. Copious amounts of sputum can be associated with inflammation or infection of the respiratory tract and may be indicative of COPD. The color and consistency of sputum may be related to the type of COPD. Purulent sputum indicates an increase in inflammatory mediators such as interleukin (IL)-8, myeloperoxidase (MPO), and leukotriene B4 (LTB4) [44]. Presence of this type of sputum may signify the onset of an exacerbation [45].


Dyspnea, or severe and distressing shortness of breath, is the most common and characteristic symptom of COPD. Patients typically describe their dyspnea as air hunger, heaviness, difficulty breathing, or gasping. Dyspnea is usually first noticed during vigorous physical activity; however, as COPD progresses, dyspnea worsens and is felt even during a light physical activity. Eventually, it becomes constant even while resting.


Fatigue is the second most frequent symptom experienced by individuals with COPD. It is often poorly understood and frequently under-reported. Fatigue gradually impacts functional capabilities of patients with COPD, diminishing quality of life. Dyspnea and fatigue are the most predominant disabling symptoms in COPD.


Wheezing is caused by obstruction of the airways and is associated with labored breathing, while chest tightness is caused by an increased amount of mucus in the lungs and subsequent obstruction of the airways. Chest tightness can cause short, shallow respiration and is often present in patients with COPD. Severity of wheezing and chest tightness can fluctuate daily and over the course of a single day. These nonspecific symptoms may be present in early stages of COPD but are more characteristic of asthma or later stage COPD. Audible wheezes, or stridor, may be heard when retained sputum is present at the bronchial or laryngeal level. Bilateral, widespread inspiratory or expiratory wheezes can usually be heard on auscultation of the chest.


Hemoptysis is common in patients with COPD during periods of acute bronchitis or pneumonia. Though not a hallmark of the disease, hemoptysis may be present, and patients with more severe airflow obstruction tend to have more severe bleeding [193]. In some cases, angiographic embolization may be necessary.


Clubbing of the fingers may be present in patients with COPD, in part caused by chronic oxygen deprivation. However, it is relatively uncommon. Clubbing is more likely indicative of other chronic diseases such as congenital heart defect, bronchiectasis, infectious endocarditis, or cirrhosis of the liver.


A clinical diagnosis of COPD should be considered in the patient who presents with shortness of breath or dyspnea, chronic productive cough, and easy fatigue, especially if combined with a history of risk factor exposure (e.g., long-term exposure to tobacco or dust and chemicals, age, genetics). The diagnosis should then be confirmed by spirometry. The presence of a Tiffeneau index or postbronchodilator FEV1/FVC less than 0.70 and FEV1 less than 80% predicted confirms the presence of airflow limitation that is not fully reversible.

The possibility of COPD should be assessed in any individual older than 35 years of age who presents with any of the following key indicators:

  • Breathlessness that is persistent, progressive, and worsens with exertion. (It may be described by the patient as increased effort of breathing, heaviness, air hunger, or gasping.)

  • Chronic cough (may be intermittent and unproductive)

  • Chronic sputum production

  • Family history of COPD

  • History of exposure to risk factors, particularly tobacco smoke, smoke from home cooking and heating fuels, and/or occupational dusts and chemicals

Spirometry, which is simple and effective, is the preferred diagnostic study to confirm the diagnosis in such cases.

The COPD Assessment Test (CAT) is a patient-completed questionnaire that complements current approaches to assessing COPD [196]. The test consists of eight items evaluating the presence of COPD symptoms and the extent of their impact on activities of daily living. Each question is answered with a number from 0 to 5 depending on the level of impairment. The corresponding score is an indicator of impact of the disease on the patient's life. Patients periodically complete the CAT questionnaire to detect changes and trends in disease course.


Symptoms of COPD, with a few exceptions, usually arise in a particular pattern. The principal symptoms in mild COPD are chronic cough and sputum production. These symptoms are usually ignored, in some cases for years, and are often attributed to poor conditioning and old age. In moderate COPD, the airflow limitation worsens, leading to dyspnea and limiting the patient's daily activities [46]. This is the point at which the patient usually seeks medical care and may be diagnosed with COPD. However, some patients will not recognize COPD symptoms or seek medical help even at this stage. As the disease progresses, airflow limitation worsens. The symptoms of cough and sputum production persist, dyspnea worsens, and other systemic complications, such as cor pulmonale, weight loss, and respiratory failure, may supervene. The diagnosis is usually forthcoming when the patient with progressive breathlessness and exercise intolerance seeks medical help, or an episode of superimposed bronchitis or pneumonia leads to respiratory failure and the recognition of an acute-on-chronic pulmonary disorder.

There are also a number of nonspecific symptoms and signs that, if present, can help in diagnosis of COPD, including:

  • Weight loss

  • Exercise intolerance

  • Waking at night

  • Ankle swelling

  • Fatigue

  • Occupational hazards

  • Hemoptysis

  • Chest pain

Hemoptysis and chest pain are not common in COPD and should always prompt an evaluation for other related comorbidities, such as infection and malignancy.


The insidious onset and progression of dyspnea is so characteristic as to be a hallmark symptom of COPD. The majority of patients who seek medical opinion do so because of dyspnea and its associated disability and anxiety. As discussed, breathlessness is initially only noted on increased physical activity, such as running up a flight of stairs or walking. However, as the disease progresses and lung function worsens, breathlessness can be experienced even with slight physical effort. Finally, dyspnea will interfere with activities of daily living and even at rest. The degree of dyspnea varies from patient to patient, but it is usually not difficult to distinguish the dyspnea of COPD from that due to other causes. The Medical Research Council (MRC) Breathlessness Scale can be used to evaluate the impact of dyspnea on a patient's health status (Table 5) [197]. This questionnaire not only relates well to other measures of health status but also predicts future mortality risk.


GradeDegree of Breathlessness Related to Activities
1Not troubled by breathlessness except on strenuous exercise
2Short of breath when hurrying on the level or walking up a slight hill
3Walks slower than contemporaries on level ground because of breathlessness, stops after about a mile, or has to stop after 15 minutes when walking at own pace
4Stops for breath after walking about 100 yards or after a few minutes on level ground
5Too breathless to leave the house, or breathless when undressing


Chronic cough, usually the first symptom of COPD to develop, is often initially attributed to smoking or environmental exposures. In early stages, the cough usually comes and goes, but later it is present almost every day or even the entire day. Some patients have significant airflow limitation even in absence of cough. However, there are other possible causes of chronic cough, and chest x-ray and differential diagnosis is necessary (Table 6).


Bronchial asthma
Central bronchial carcinoma
Left heart failure
Interstitial lung disease
Cystic fibrosis
Gastroesophageal reflux disease (GERD)
Postnasal drip syndrome
Certain medications (e.g., angiotensin-converting enzyme [ACE] inhibitors)

Sputum Production

Individuals with COPD usually expectorate or swallow small quantities of sputum after coughing spells. Regular sputum production for three or more months in two consecutive years is indicative of chronic bronchitis. Patients producing copious amount of sputum may have underlying bronchiectasis.

Wheezing and Chest Tightness

As noted, wheezing and chest tightness are nonspecific symptoms of COPD. They may be present in the early stages of COPD, becoming more prominent in the later stages of the disease.

Additional Features in Severe Disease

Weight loss and anorexia are frequently present in advanced stages of COPD and are important prognostic markers. Therefore, these symptoms should be thoroughly investigated. In severe cases, coughing spells may cause patients to experience cough syncope (caused by rapid increases in intrathoracic pressure) or can cause rib fractures, especially in osteoporotic patients. Those persons with COPD who develop cor pulmonale usually develop ankle swelling.


As with any illness, a careful history is critical in determining the correct diagnosis. The goals of history taking are to identify possible causes of dyspnea and other symptoms and to screen for COPD risk factors. An inadequate history may result in misdiagnosis or delayed diagnosis, with ramifications on disease course. A comprehensive medical history of an individual presenting with COPD symptoms should include:

  • Long-term exposure to risk factors, such as smoking or occupational and environmental exposures

  • Past medical history, including asthma, allergy, respiratory infections in the past (especially in childhood), sinusitis or nasal polyps, and other respiratory illnesses

  • Family history of COPD or other chronic respiratory disease

  • Pattern of symptoms of COPD (e.g., development in adulthood, increasing dyspnea or breathlessness, frequent "winter colds," restricted social life)

  • History of previous hospitalizations or exacerbations for respiratory illnesses

  • Presence of comorbid conditions, such as chronic heart disease, malignancy, musculoskeletal disorders, or osteoporosis

  • Medical treatments

  • Impact of the disease on the patient's life, including restricted activity, absenteeism at work, financial impact, and depression or anxiety

  • Family and social support available

  • Possibilities for COPD risk factor reduction, particularly smoking cessation

This sample list may seem daunting, especially in the context of a brief office visit. However, it is critical that a detailed history be obtained. It may be more efficient to have a questionnaire available for patients to fill out while they are waiting or even prior to the office visit.

Language barriers can be a serious consideration when engaging a patient and elucidating possible causes of COPD symptoms. When a patient does not speak the same language as the clinician, a professional interpreter should be consulted to ensure accurate communication. Use of professional interpreters has been associated with improvements in communication (errors and comprehension), utilization, clinical outcomes, and satisfaction with care.


A physical examination is an important component of the diagnosis of COPD, but it is seldom diagnostic. Physical signs of airflow limitation are generally absent in the early stages of the disease, developing only later when there is a significant reduction in lung function [16,17]. Patients may have several physical signs indicative of COPD, but absence of these signs does not exclude diagnosis.


Shallow and rapid breathing with respiratory rate of more than 20 breaths per minute may be noted [17]. The presence of central cyanosis is hard to visualize in artificial light and in darker skinned patients, but it may be present in severe cases. Ankle or lower leg edema may be a sign of cor pulmonale.

Common chest wall abnormalities indicative of pulmonary hyperinflation (emphysema) may be seen in COPD, such as "barrel-shaped" chest, relatively horizontal ribs, and protruding abdomen. Flattening of the hemidiaphragms may be evident on percussion over the posterior chest or noted on chest x-ray.

Patients with advanced COPD/emphysema often show pursed-lip breathing, which slows expiratory flow and allows better lung emptying [18]. Patients in the later stages of COPD use accessory muscles (e.g., scalene and sternocleidomastoid muscles) to force breaths. Resting muscle activation while lying supine can also be seen in these patients.

Palpation and Percussion

Palpation and percussion are of limited value but may disclose a subtle degree of increased A-P diameter and increased resonance. Pulmonary hyperinflation will make the heart apex beat more difficult to detect. Hyperinflation also causes downward displacement of the liver, and it is easy to palpate this organ even with no enlargement.


Patients with COPD often have diminished breath sounds on auscultation [47]. The presence of wheezes during quiet breathing indicates airflow limitation. But, it is important to note that wheezing heard only after forced expiration is not diagnostic for COPD. Inspiratory crackles are also not diagnostically important in COPD.

In patients with pulmonary hypertension, the heart sounds may be distant and the pulmonary component of the second heart sound may be loud. Generally, heart sounds are best heard over the xiphoid area.


Every patient with known or suspected COPD should undergo spirometry in order to quantify the level of airflow obstruction. It is an important tool both for the diagnosis of COPD and to rule out conditions that may mimic COPD. Although spirometry does not provide a complete picture of the overall effect of COPD on a patient's health, it remains the gold standard for the diagnosis and periodic monitoring of the disease—it provides a standardized, reproducible, and objective measurement of airflow limitation (Table 7) [199].


Spirometers need calibration on a regular basis.
Spirometers should produce hard copy or have a digital display of the expiratory curve to permit detection of technical errors or have an automatic prompt to identify an unsatisfactory test and the reason for it.
The supervisor of the test needs training in its effective performance.
Maximal patient effort in performing the test is required to avoid underestimation of values and hence errors in diagnosis and management.
Possible dosage protocols are 400 mcg beta2-agonist, 160 mcg anticholinergic, or the two combined. FEV1 should be measured 10 to 15 minutes after a short-acting beta2-agonist is given, or 30 to 45 minutes after a short-acting anticholinergic or a combination.
Spirometry should be performed using techniques that meet published standards.
The expiratory volume/time traces should be smooth and free from irregularities.
The recording should go on long enough for a volume plateau to be reached, which may take more than 15 seconds in severe disease.
Both FVC and FEV1 should be the largest value obtained from any of three technically satisfactory curves, and the FVC and FEV1 values in these three curves should vary by no more than 5% or 150 mL, whichever is greater.
The FEV1/FVC ratio should be taken from the technically acceptable curve with the largest sum of FVC and FEV1.
Spirometry measurements are evaluated by comparison of the results with appropriate reference values based on age, height, sex, and race.
The presence of a postbronchodilator FEV1/FVC <0.70 confirms the presence of airflow limitation.

Spirometry accurately measures the volume of air forcibly exhaled from the point of maximal inspiration (FVC) and the volume of air exhaled during the first second of this maneuver (FEV1). The ratio of these two measurements is then calculated. Spirometry measurements are evaluated by comparison with reference values based on the individual's age, height, sex, and race. Patients with COPD typically show a reduction in both FEV1 and FVC, with the degree of abnormality correlated with disease severity [48]. The presence of airflow limitation is generally defined by a postbronchodilator FEV1/FVC ratio less than 0.70; however, it is important to note that there are no universally applicable reference values for FEV1 and FVC.

Spirometry should be performed after administrating short-acting inhaled bronchodilator (e.g., 400 mcg salbutamol) to minimize variability. Findings should be compared to age-related normal values in order to prevent overdiagnosis of COPD in the elderly [21]. Peak expiratory flow may also be used as a measure of airflow limitation. Data from the U.S. National Health and Nutrition Examination Survey suggest that peak expiratory flow is highly sensitive and can detect more than 90% of COPD cases. However, this measurement has poor specificity and should not be the only diagnostic test [49].

The role of screening spirometry for COPD is controversial. There are insufficient data to demonstrate the efficacy of screening spirometry in the general population [50].

Spirometry requires patients' cooperation, and therefore, it is unsuitable for patients who are unconscious, heavily sedated, or incapable of vigorous respiratory efforts. It is also not appropriate for children younger than 6 years of age.


A range of pulmonary and systemic conditions should be considered in the differential diagnosis of COPD (Table 8). Some patients are assumed to have coexisting asthma and COPD because a clear distinction between the two cannot be made using current methods and techniques. In such cases, management is similar to that of asthma. Other potential conditions are typically easier to distinguish from COPD and include heart failure, tuberculosis, and bronchiectasis. The differential diagnosis of these conditions and possible comorbidities may require additional testing.


DiagnosisSuggestive Featuresa
Onset in mid-life
Symptoms slowly progressive
Long history of tobacco smoking
Breathlessness or dyspnea during exercise
Largely irreversible airflow limitation
Early onset, often in childhood
Family history of asthma
Symptoms at night/early morning and vary from day to day
Presence of allergy, rhinitis, and/or eczema
Largely reversible airflow limitation
Copious amount of purulent sputum
Generally associated with bacterial infection
Coarse crackles or clubbing on auscultation
Bronchial dilation and thickening of bronchial wall on chest x-ray/CT
Congestive heart failure
Fine basilar crackles on auscultation
Dilated heart and pulmonary edema on chest x-ray
Pulmonary function tests show volume restriction with no airflow limitation
Onset all ages
Lung infiltrate visible on chest x-ray
Microbiologic confirmation of Mycobacterium tuberculosis
High local prevalence of tuberculosis
Diffuse panbronchiolitis
Majority of patients are men and nonsmokers
Chronic sinusitis
Diffuse small centrilobular nodular opacities and hyperinflation on chest x-ray and/or HRCT
Obliterative bronchiolitis
Onset in younger age, nonsmokers
May have history of rheumatoid arthritis or exposure to fumes
CT on expiration shows hypodense areas
aThese signs/symptoms/features tend to be characteristic of the respective diseases but are not present in every case.
CT = computed tomography, HRCT = high-resolution CT.


Assessment of COPD severity is based on the patient's level of symptoms, the degree of the spirometric abnormality, and the presence of complications such as respiratory failure, cor pulmonale, weight loss, and arterial hypoxemia. Spirometric classification of COPD categorizes the stage of disease progression based on postbronchodilator FEV1, FEV1/FVC ratio, and presence of respiratory failure (Table 9) [199].


GOLD StageSpirometric Finding
1 (mild)FEV1 ≥80% predicted
2 (moderate)50% ≤ FEV1 <80% predicted
3 (severe)30% ≤ FEV1 <50% predicted
4 (very severe)FEV1 <30% predicted
aIn patients with FEV1/FVC <0.70
FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, GOLD = Global Initiative for Chronic Obstructive Lung Disorder.

Presence of airflow limitation is crucial for assessing COPD severity, but it is not the only measure. Several studies have observed that individuals with early COPD experience at least one respiratory symptom (e.g., dyspnea, cough, sputum production, wheezing), even with relatively minor or no spirometric abnormality [51]. Presence of such respiratory symptoms can help in identifying high-risk individuals, but it is important to remember that not all individuals will go on to develop COPD [29]. When evaluating symptomatic patients, apart from severity of airflow obstruction, the severity of the patient's symptoms and the degree to which they affect activity of daily living are the major determinants of overall health status.

The severity of a patient's dyspnea is a reliable indicator of COPD severity and health status, particularly in the elderly, and this parameter can be determined using the mMRC or MRC scale. Objectively measured exercise intolerance or impairment, as assessed by a reduction in self-paced walking distance or during incremental exercise testing in a laboratory, is a powerful prognostic marker as well [30,52,53]. The ratio of inspiratory capacity to total lung capacity determined by plethysmograph may also be helpful in determining disease prognosis [54]. Patients experiencing weight loss and reduction in arterial oxygen tension are at increased risk for mortality [55,56]. Some have proposed using a combination of these variables when staging COPD and determining prognosis.

The BODE index is a multidimensional grading method used to assess clinical risk in patients with COPD based on four factors: body mass index (BMI), obstruction, dyspnea, and exercise (Table 10) [57]. It is a better prognostic marker of subsequent survival than any other component alone [57]. Each component of the BODE index is graded and a score out of 10 is obtained; higher scores are indicative of greater mortality risk. This method reflects the effect of both pulmonary and extrapulmonary factors on prognosis and survival in COPD.


VariablePoints on BODE Index
FEV1 (% of predicted)≥6550–6436–49≤35
Distance walked in six minutes≥350 m250–349 m150–249 m≤149 m
Modified Medical Research Council dyspnea scale score0–1234
Body mass index>21≤21
FEV1 = forced expiratory volume of air in one second.


For patients diagnosed with moderate (stage 2) COPD or more severe disease, other investigations should also be considered (Table 11) [201]. This includes bronchodilator reversibility testing, chest x-ray, arterial blood gas measurement, and alpha-1 antitrypsin deficiency screening.


Serial domiciliary peak flow measurementsTo rule out asthma if there is diagnostic doubt
Transfer factor for carbon monoxide (TLCO)To investigate symptoms that are disproportionate to the spirometric impairment
Alpha-1 antitrypsinIn case of early onset, minimal smoking history, or family history
Computed tomography (CT) scan of the thorax
To investigate symptoms that are disproportionate to the spirometric impairment
To investigate abnormalities present on a chest radiograph
To assess indication for surgery
ElectrocardiogramAssessment of cardiac status if features of cor pulmonale
Pulse oximetry
To assess oxygen therapy requirement
Presence of cyanosis, or cor pulmonale, or if FEV1 <50% predicted
EchocardiogramAssessment of cardiac status if features of cor pulmonale
Sputum cultureTo identify organisms if sputum is persistently present and purulent

Bronchodilator Reversibility Testing

Bronchodilator and oral corticosteroid reversibility testing are not accurate in predicting disease progression, whether indicated by decline in FEV1, worsening of health status, or number of exacerbations in persons with COPD [58,59]. However, minor deviation in initial airway caliber can lead to different classification of reversibility status depending on the day of testing, and the lower the prebronchodilator FEV1, the greater the chance of a patient being classified as reversible [59].


Abnormal findings detected on chest x-ray are often not definitive for diagnostic purposes. It is helpful in ruling out other conditions, such as lung carcinoma, and for confirming significant comorbidities, such as heart failure. Possible radiologic changes associated with COPD include:

  • Signs of hyperinflation (e.g., flattened diaphragm on the lateral chest film, an increase in the volume of the retrosternal air space)

  • Hyperlucency of the lung fields

  • Reduction in vascular markings

Computed tomography (CT) of the chest is also not routinely recommended, although high-resolution CT (HRCT) can be helpful in the differential diagnosis. Chest CT scan is essential in surgery involving lung volume reduction because the distribution of emphysema is one of the key indications for surgery [60].

Arterial Blood Gas Measurement

In patients with advanced COPD, analysis of arterial blood gases while the patient is breathing room air provides oxygenation status of the individual. The test should be undertaken in stable patients with FEV1 <50% predicted or in patients with suspected cor pulmonale or respiratory failure.

Screening for Alpha-1 Antitrypsin Deficiency

White patients who experience COPD at a young age (i.e., younger than 45 years) or who have a positive family history of COPD may be screened for alpha-1 antitrypsin deficiency. A serum concentration of alpha-1 antitrypsin less than 15% to 20% of the normal expected value indicates a high probability of homozygous alpha-1 antitrypsin deficiency.


The identification, reduction, and control of risk factors are essential for the prevention and management of COPD. As discussed, the prominent COPD risk factors are cigarette smoking and exposure to dust and/or all types of air pollutions and irritants. As the most important risk factor for COPD, tobacco smoking prevention and cessation programs should be implemented and encouraged universally. Exposure to all types of air pollutants should also be curtailed as much as possible.


A dramatic increase in public awareness concerning the dangers of secondhand smoke has corresponded to social demand for smoking restrictions. There is broad public support in the United States for smoking restrictions in many public places, including child care centers, hospitals, shopping malls, convenience stores, fast-food restaurants, and indoor sporting events [202].

Efforts to regulate tobacco products include the World Health Organization's Framework Convention on Tobacco Control. Additionally, legislation has been passed to give the FDA regulatory authority over tobacco. The main reason for these proposals is to minimize death and disease caused by tobacco smoke by reducing the prevalence of its use and the toxicity of its products. Based on scientific studies and tobacco industry documents, it is believed that tobacco products could be made less toxic if their design, content, emissions, and manufacturing were better controlled [203].

Nationwide polls reveal broad public support for increased taxing of tobacco [204]. Since 2002, the average state cigarette tax has increased from 43.4 cents to $1.65 per pack [205]. In February 2009, President Obama signed a 61.66-cent federal cigarette tax increase into law, bringing the federal cigarette tax to $1.01 [206]. As of 2014, the CDC reported an average national retail price of $6.28 per pack of cigarettes [207]. Increasing the cost of tobacco not only decreases tobacco use by creating a larger economic barrier to smoking, it also motivates people to try to quit.

The 2009 federal tax increase on the sale of cigarettes is expected to yield several health benefits. Projected benefits and cost savings include an increase in the number of children alive today who will not become smokers (1,992,000) and $493.3 million in five-year healthcare savings from fewer smoking-caused myocardial infarctions and strokes [206,208].

Though the state and local governments and employers provide protection from tobacco smoke at work, private homes are not subject to such regulation. Educational strategies are needed to increase awareness of personal and childhood tobacco exposure both in and out of the home. As with the business microenvironment, air quality cannot be maintained if smoking is allowed indoors, even with additional ventilation and air-cleaning devices.

Smoking Cessation

Behavioral Modifications

Behavioral interventions are nonpharmacologic treatments delivered directly to individual smokers [209]. The main disadvantage of this approach is that relatively few smokers (about 5%) are interested in attending specific classes at any given time [210]. Therefore, group sessions appear to be the most cost-effective approach to delivering smoking cessation interventions [211]. Although relatively few patients want to go to classes, healthcare professionals should still have a list of referral smoking cessation clinics in their area for those smokers who express an interest in attending them and for those who have failed to respond to other approaches. Simple computer-tailored cessation messages may also be an effective alternative for behavioral support, doubling the cessation rates. This concept has been incorporated into patient support programs provided by several manufacturers of smoking cessation products [210].

There are several behavioral interventions that have empirical support, such as multicomponent coping skills training (e.g., coping response therapy, problem-focused treatment, relapse prevention training, and cognitive-behavioral therapy). This training includes social support and didactic information about nicotine dependence, withdrawal symptoms, and situations that are risks for relapse (e.g., alcohol use, negative moods, or presence of other smokers) as well as training in the use of cognitive and behavioral responses to cope with urges to smoke that reduce the risk of relapse [212,213]. Aversive therapy for smoking cessation, known as rapid smoking, involves smokers in a controlled clinical setting who deeply inhale on cigarettes at six-second intervals. Up to nine cigarettes would be smoked per treatment session to produce strong aversive reactions to cigarettes [214]. Aversive cigarette use greatly declined after the introduction of nicotine-replacement therapies (NRTs), but it has been rediscovered and is being investigated as an aftercare strategy to reduce cravings and prevent relapse [215]. Another behavioral treatment, scheduled reduced smoking, involves three weeks of gradually reduced nicotine intake. In contrast with other smoking cessation strategies involving reduction of smoking, the patient does not control when and where smoking will occur. Rather, an algorithm is used to determine when each cigarette is to be smoked based on the passage of time [216].


The first-line pharmacologic interventions for smoking cessation are NRT, bupropion, and varenicline [217,218]. However, no pharmacotherapy has been approved for use among pregnant or nursing women. The five forms of NRT available are the patch, gum, lozenge, nasal spray, and inhaler.

The nicotine transdermal system, otherwise known as the patch, releases nicotine steadily during an extended period, with blood levels rising within the first 2 to 4 hours and then remaining relatively constant between 8 and 24 hours after application, depending on the product used [219]. Nicotine chewing gum is a type of NRT that may aid in smoking cessation and/or quitting smokeless tobacco. Chewing allows nicotine to be delivered quickly into the bloodstream. Typically available in either 2- or 4-mg doses, nicotine chewing gum is expected to last one to two hours.

The nicotine lozenge is similar to a hard candy. It slowly dissolves in the mouth (for 20 minutes or so) to release nicotine to the brain more quickly than the patch. A 2-mg sublingual nicotine tablet has shown efficacy in several studies and has been approved in Europe to manage nicotine withdrawal [220,221,222].

Nasal nicotine spray was approved by the FDA in 1997. Available by prescription, each spray contains 0.5 mg of nicotine, and a dose is defined as one spray in each nostril. In clinical trials, subjects were allowed to take up to five doses/hour, with a maximum of 40 doses/day (40 mg of nicotine). The cessation rates in trials with nicotine nasal spray at one year ranged from 15% to 25% [63,64,65].

The FDA also approved a nicotine inhalation system consisting of a mouthpiece and a nicotine-containing cartridge. Available with a prescription, each inhaler contains 10 mg of nicotine and 1 mg of menthol, of which 4 mg of nicotine can be extracted and 2 mg are systemically available. Shallow or deep puffing results in similar nicotine absorption.

Quitting smoking can be a difficult process, even with use of NRT. When subjects were given denicotinized cigarettes along with IV saline or nicotine, the variable most responsible for craving satisfaction, psychologic reward, and craving reduction was the denicotinized cigarette [66]. When ad libitum smoking of preferred brands was also allowed, the combination of nicotine-less cigarette and bolus IV nicotine were the most effective in lowering craving, negative affect, and total amount smoked [67]. Sensations in the tongue, nose, back of mouth, throat, windpipe, and chest showed strong correlation between nicotine-less cigarettes and the usual brand smoked by the subjects, perhaps explaining the strong effects on smoking suppression observed [66]. Therefore, it is important to recognize that while NRT is a key part of cessation therapy, it does not address all aspects of smoking behavior.

Bupropion is an atypical antidepressant that has both dopaminergic and adrenergic actions [68]. In 1998, the slow-release preparation of bupropion became available as a prescription item specifically for smoking cessation, with the trade name Zyban. This treatment could be appropriate for smokers who do not wish to use an NRT or for those whose treatment with NRT has failed. Unlike NRT, smokers begin bupropion treatment one week prior to cessation. The suggested dosage is 300 mg/day, and the duration of treatment is 7 to 12 weeks [69].

Another non-nicotine therapy for smoking cessation is varenicline tartrate (Chantix), a partial agonist selective for nicotine acetylcholine receptor subtypes. Released in 2006, varenicline is available in monthly dose packs (0.5-mg and 1-mg tablets) and is approved for a 12-week course of treatment [217].

The two second-line drugs for smoking cessation are clonidine and nortriptyline [218]. Clonidine is an antihypertensive medication that is administered orally or transdermally. It appears to increase the smoking cessation rate by approximately 11%; however, clonidine is known to produce such side effects as dry mouth, dizziness, sedation, and orthostatic hypotension [70]. Clonidine has not been approved by the FDA for smoking cessation but has been used with individuals who have failed NRT or bupropion. Nortriptyline is a tricyclic antidepressant that has been used to assist smoking cessation, although this is an unlabeled use [218].


In the United States, approximately 19% of COPD in smokers and up to 31% of COPD in nonsmokers is associated with exposure to occupational dust and fumes [76]. The COPD burden may be greater in regions where exposure to inhaled particles, fumes, and gases is more common. Many occupations, especially those involving exposure to chemical, mineral, and biologic fumes or dusts, have been linked with increased risk of developing COPD. The risks associated with these exposures may be reduced or controlled through a number of strategies, including [77,78,79]:

  • Proper implementation, monitoring, and enforcement of strict norms to control airborne exposure in the workplace

  • Adequate education for people who are directly or indirectly involved with occupational airborne exposure (e.g., workers, managers, physicians, legislators)

All employers, employees, and policy decision-makers should be aware of the harmful effects of cigarette smoking and airborne exposure to dust and fumes.

It should be stressed that primary prevention can easily be achieved by eliminating or reducing exposures to various substances in the workplace. Secondary prevention involves surveillance and early case detection. Both of these approaches are essential to prevent and control the risk of COPD from workplace exposures.


People are exposed to various indoor and outdoor environments throughout the day, and each environment has its own distinctive set of air contaminants and potentially harmful particulates. Exposure to air pollution can be decreased by the joint effort of individuals and society.

National and local governments establish air quality standards. Policies should be geared toward reducing pollution levels global and locally and protecting employees with occupational exposures (e.g., with personal protective equipment).

Proper and adequate ventilation should be provided in kitchens to reduce pollution. Face masks should be provided in workplaces with a high risk of exposure to toxic gases, fumes, and particles. Reducing workplace emissions and improving ventilation measures are also recommended in order to ensure cleaner and safer air quality in the workplace.

People with advanced COPD should avoid going outdoors when air pollution increases or air quality is poor. All patients should refrain from outdoor exercise during periods of increased air pollution.


The management of stable COPD is characterized by a stepwise increase in treatment guided by the overall health and clinical status of the patient and the severity of the disease (Table 12). Severity of long-term COPD is determined based on:

  • Severity and frequency of exacerbations

  • Degree of airflow limitation

  • Severity of symptoms

  • Presence of one or more complications

  • Presence of respiratory failure

  • Presence of comorbidities

  • Health status

  • Total number of medications required to manage COPD


Treatment StepStage 0 (At Risk)Stage 1 (Mild)

Stage 2 (Moderate)

Stage 3 (Severe)Stage 4 (Very Severe)
Step 1Avoidance of risk factors
Step 2 Add short-acting bronchodilator
Step 3 
Add regular treatment with one or more long-acting bronchodilators
Begin rehabilitation
Step 4 Add inhaled corticosteroids if repeated exacerbations
Step 5 
Add long-term oxygen if chronic respiratory failure
Consider surgery


Pharmacotherapy is used to both control and prevent COPD symptoms. Effective treatment will reduce the frequency and severity of COPD exacerbations, increase exercise capacity, and improve overall health status.

Currently, there is no medication for COPD that can prevent the long-term deterioration in lung function that is the hallmark of the disease. However, there are many drugs that can improve symptoms and provide relief to the patient (Table 13) [199].


DrugInhaler (mcg)Solution for Nebulizer (mg/mL)OralVials for Injection (mg)Duration of Action (hours)
Short-acting beta2-agonists
Fenoterol100–200 (MDI)10.05% (syrup)4–6
Levalbuterol45–90 (MDI)0.21, 0.426–8
Salbutamol (albuterol)100, 200 (MDI & DPI)55 mg (pill), 0.024% (syrup)0.1, 0.54–6
Terbutaline400, 500 (DPI)2.5 mg, 5 mg (pill)4–6
Long-acting beta2-agonists
Formoterol4.5–12 (MDI & DPI)0.0112
Indacaterol75–300 (DPI)24
Olodaterol5 (SMI)24
Salmeterol25–50 (MDI & DPI)12
Tulobuterol2 mg (transdermal)24
Short-acting muscarinic antagonists
Ipratropium bromide20, 40 (MDI)0.25–0.56–8
Oxitropium bromide100 (MDI)1.57–9
Long-acting muscarinic antagonists
Aclidinium bromide322 (DPI)12
Glycopyrronium bromide44 (DPI)24
Tiotropium18 (DPI), 5 (SMI)24
Umeclidinium62.5 (DPI)24
Combination short-acting beta2-agonist plus muscarinic antagonist in one inhaler
Fenoterol/ipratropium200/80 (MDI)1.25/0.56–8
Salbutamol/ipratropium100/20 (SMI)6–8
Combination long-acting beta2-agonist plus muscarinic antagonist in one inhaler
Formoterol/aclidinium12/340 (DPI)12
Indacaterol/glycopyrronium85/43 (DPI)24
Olodaterol/tiotropium5/5 (SMI)24
Vilanterol/umeclidinium25/62.5 (DPI)24
Aminophylline200–600 mg (pill)240Variable, up to 24
Theophylline (SR)100–600 mg (pill)Variable, up to 24
Inhaled corticosteroids
Beclomethasone50–400 (MDI & DPI)0.2–0.4
Budesonide100, 200, 400 (DPI)0.2, 0.25, 0.5
Fluticasone50–500 (MDI & DPI)
Combination long-acting beta2-agonist plus corticosteroid in one inhaler
Formoterol/beclometasone6/100 (MDI & DPI)
Formoterol/budesonide4.5/160 (MDI), 9/320 (DPI)
Formoterol/mometasone10/200, 10/400 (MDI)
Salmeterol/fluticasone50/100, 250, 500 (DPI)
Vilanterol/fluticasone furoate25/100 (DPI)
Systemic corticosteroids
Prednisone5–60 mg (pill)
Methylprednisolone4, 8, 16 mg (pill)
Phosphodiesterase-4 inhibitors
Roflumilast500 mcg (pill)24
MDI = metered-dose inhaler, DPI = dry-powder inhaler, SMI = soft-mist inhaler, SR = sustained release.

As noted, treatment usually increases in a step-up pattern and is cumulative, meaning the number of medications used increases as the patient's condition deteriorates. Regular treatment should be maintained at the same level for a long duration of time. Aggressive treatment is required only if significant side effects occur or COPD symptoms worsen.

Each individual responds differently to treatment and will experience a varying degree of side effects. Careful monitoring is required to ensure that the goal of treatment is met. If it is not, a step up is warranted [80].

The treatment regimen for the patient with COPD should be patient-specific. However, the step-up guidelines for therapy provide a useful framework for decisions to escalate treatment. Patients with mild (stage 1) COPD experiencing few or intermittent symptoms require a short-acting inhaled bronchodilator used as needed. Slow-release theophylline may be prescribed when inhaled bronchodilators are unavailable. Addition of a long-acting inhaled bronchodilator as needed is recommended for patients with stage 2–4 COPD who experience dyspnea refractory to treatment with short-acting bronchodilators. There is not enough data to support the use of one long-acting bronchodilator over the others. The addition of theophylline may help control symptoms in patients using a regular long-acting bronchodilator. Short-acting bronchodilators may be prescribed for stage 2–4 COPD in order to address exacerbations. Nebulized therapy is not suitable for stable patients unless it has more beneficial effects than standard dose therapy. Inhaled corticosteroid, used in combination with a long-acting beta2-agonist or a long-acting anticholinergic, is recommended for patients who have progressed to stage 3 or 4 (severe to very severe) COPD. This combination appears to reduce the risk of exacerbations and improve the overall health status in patients with advanced disease. Long-term treatment with oral corticosteroids is not recommended [199].


Bronchodilators are the cornerstone of treatment of COPD and are recommended as first-line therapy in patients with demonstrable airflow limitation or other symptoms. They are effective in significantly improving COPD symptoms and quality of life, predominantly by emptying trapped air through the dilatation of distal airways. However, bronchodilators offer symptomatic relief only and do not modify the disease process. They are prescribed on an as-needed basis for symptomatic relief (short-acting) or on a regular basis (long-acting) to reduce or prevent COPD symptoms. Short-acting bronchodilators often result in medical noncompliance due to the problems caused by multiple dosing. This has shifted the focus to the development of long-acting and ultra-long-acting bronchodilators that can induce sustained bronchodilation (12 to 24 hours). This once- or twice-daily dosing regimen improves compliance. As such, long-acting inhaled bronchodilators (i.e., beta2-agonists and muscarinic antagonists [LAMA]) now form the backbone of COPD management [176; 177; 178].

The side effects of bronchodilators are dose dependent and typically predictable. Adverse effects are more common in older patients and those with advanced COPD and comorbidities. However, they usually resolve promptly after medication withdrawal.

Bronchodilators increase FEV1 and affect other spirometric variables, usually by relaxing smooth muscle tone in the airway. They improve lung emptying, reduce dynamic hyperinflation at rest and during exercise, and increase exercise performance (Table 14). The degree of these changes, particularly in more advanced COPD, is difficult to predict from the improvement in FEV1. While these drugs reduce impedance to air flow and improve the efficiency of expiration, lung elastic recoil remains unchanged. Bronchodilators that act predominantly on the smooth muscles of the airway do not have a significant impact on the decline of lung function or disease prognosis.


Physiologic EffectsClinical Effects
Airway smooth muscle relaxation
Bronchodilation (improve FEV1, lung volumes)
Decreased air trapping and dynamic hyperinflation
Nonbronchodilator effects (e.g., stimulation of mucociliary transport)
↓Breathlessness (↓airway resistance, ↓hyperinflation)
↑Exercise tolerance (↓dynamic hyperinflation)
↑Sleep quality (↓nocturnal bronchospasm)
↑Health-related quality of life
↓Frequency of acute exacerbations

Inhaled bronchodilators require attention to training in inhaler technique for proper drug delivery. The choice of inhaler device and bronchodilator depends on:

  • Cost

  • Availability

  • Prescribing healthcare provider

  • Physical and mental condition of the patient

Inhaled bronchodilators are administered via metered-dose inhaler, dry powder inhaler, or nebulizer (jet or ultrasonic).

Metered-dose inhalers rely on a mixture of medication, preservatives, and liquid propellant gas to deliver medicine into the lungs in aerosol form. Some metered-dose inhalers discharge medication after a trigger is pressed, but newer versions are breath activated. For patients with poor coordination or impaired hand function, such as those with arthritis or with a history of stroke, breath-activated devices may improve medication delivery. The drawback of the breath-activated inhalers is that a lack of air may make device triggering difficult. Some patients require the assistance of a spacer when using an inhaler.

Breath-activated dry powder inhalers incorporate the same benefits as other breath-activated inhalers; patients are not required to coordinate inhaling with releasing medication. Some dry powder inhalers have a different delivery system involving the insertion of a capsule with medicated, fine powder into the canister. Depending upon the patient's ability to breathe in deeply, variable amounts of medication may be inhaled. Another concern involves the effect of humidity on dry powder, which may influence dose strength.

The nebulizer acts as a vaporizer or humidifier, delivering microdroplets of asthma medication in spray form and allowing a patient to breathe it in through a mouthpiece or face mask. Larger doses from nebulizers may increase the risk of side effects, and studies have shown metered-dose inhalers to be as effective as nebulizers in delivering medication to the lungs [71,72]. Wet nebulizers are usually not prescribed for regular treatment of COPD because they are more expensive and need regular maintenance [81].

Three classes of bronchodilators are available for the treatment of COPD and may be used alone or in combination: beta2-agonists, muscarinic antagonists (also referred to as anticholinergics), and methylxanthines. All classes of bronchodilators exhibit a similar effect on FEV1 with identical dose of medication. Toxicity with bronchodilators is dose dependent.


Beta2-agonists stimulate beta2-adrenergic receptors, resulting in increases in cyclic adenosine monophosphate and bronchodilation. Inhaled beta2-agonists produce a rapid bronchodilator effect, a response observed more quickly in asthma patients than those with COPD. Short-acting beta2-agonists produce bronchodilation for a duration of not more than 4 to 6 hours, while long-acting agents, such as salmeterol and formoterol, produce bronchodilation for more than 12 hours [87]. More recently, vilanterol and olodaterol were approved for use in the treatment of COPD. These novel beta2-agonists have 24-hour duration of action, allowing for once-daily dosing [86,226].

It has been observed that increasing the dose of either a beta 2-agonist or a muscarinic antagonist by an order of magnitude, particularly when given via wet nebulizer, offers subjective relief in acute episodes of COPD but is not necessarily beneficial in stable disease [199]. Rather than increasing dose for increased disease severity, another agent should be added to the treatment regimen.

In rare cases, inhaled beta2-agonists can cause resting sinus tachycardia and cardiac arrhythmias in patients with COPD [199]. At higher doses, these agents can cause exaggerated somatic tremor in the elderly. In fact, the risk of all adverse effects increases in a dose dependent manner, so the dose should be monitored carefully. Hypokalemia may occur, particularly when beta2-agonists are given together with a thiazide diuretic. Some patients experience a mild reduction in partial pressure of oxygen (PaO2) if short- and long-acting beta2-agonists are administered together. Despite the concerns raised related to beta2-agonists in the management of asthma, further detailed study has found no association between beta2-agonist use and an accelerated loss of lung function or increased mortality in COPD [199].

Muscarinic Antagonists

Muscarinic antagonists act to block acetylcholine's effect on M3 receptors. Short-acting muscarinic antagonists also alter neurotransmission at the pre-ganglionic junction and block M2 receptors. Tiotropium, a long-acting muscarinic antagonist, is M3- and M1-muscarinic receptor selective and is effective for more than 24 hours [88,89,90]. Short-acting inhaled anticholinergics produce bronchodilation for a longer duration than short-acting beta2-agonists, but their use is generally limited to the treatment of exacerbations.

Regular use of muscarinic antagonists, both short- and long-acting, improves overall clinical and health status, enhances the effectiveness of pulmonary rehabilitation, and reduces the rate of exacerbations [84,85]. These agents are often the preferred bronchodilators for COPD due to their greater efficacy and minimal cardiac stimulatory effects compared to those of beta2-agonists.

Muscarinic antagonists are comparatively safer to use and have fewer side effects than other available bronchodilators. The main side effects result from antimuscarinic activity and include xerostomia and a bitter, metallic taste. Studies indicate an increased risk for cardiovascular events, specifically heart failure, acute coronary syndrome, or dysrhythmias) associated with the muscarinic antagonist ipratropium bromide, making tiotropium the preferred agent [91]. Acute glaucoma has been observed in a few patients after wet nebulization with a face mask. These drugs do not have any effect on mucociliary clearance, and there is no increased risk of respiratory infection.


Methylxanthines have weak bronchodilator and respiratory stimulant properties. Both of the available methylxanthines (aminophylline and theophylline) are administered orally and have variable durations of action (up to 24 hours). The inhaled bronchodilators are preferred over these oral agents, as the latter tends to be less predictable and more toxic. Although useful for some patients, the methylxanthines are a third-line option in the treatment of stable COPD [199].

The therapeutic ratio of methylxanthines is small, meaning that near-toxic doses are often required to achieve efficacy. Side effects include nausea, headache, heartburn, insomnia, cardiac arrhythmias, and convulsions. The risk of overdose (accidental or intentional) is high with these agents. Several drugs and other factors affect the metabolism of methylxanthines, including anticonvulsants, quinolone antibiotics, alcohol, nicotine, and erythromycin [104].

Combination Bronchodilator Therapy

Combining bronchodilators can improve the impact of therapy with similar or fewer adverse effects. The combination of a beta2-agonist and a LAMA has been shown to be more effective than monotherapy with either agent [126,146,147,148,149,150,151,152]. This is believed to be related to the synergistic effect of combining the different mechanisms of action. One of the disadvantages of such an approach is delivery of LAMA and long-acting beta2-agonists at different locations in the lung, which results in a lowering of their synergistic potential.

Bronchodilator Research

The single molecule GSK961081 has dual properties of both antimuscarinic and beta2-agonist agents and is being investigated for its bronchodilator effect. This molecule can deliver the drugs to the same location, leading to optimum synergistic effect [180].

Discovery of novel classes of bronchodilator drugs has proved to be difficult. The focus has shifted to developing drugs that inhibit the contractile machinery in airway smooth muscle, including rho kinase inhibitors, myosin light chain kinase inhibitors, and direct smooth muscle myosin inhibitors. Even as research focuses on novel approaches to address the underlying pathophysiology of COPD, management of the disease remains largely palliative, with minimal impact on the inflammatory process that ultimately leads to a decline in lung function.


Corticosteroids, both oral and inhaled, have a limited role in the treatment of COPD except for exacerbations. Although used in the past to identify patients who would be more likely to respond to inhaled steroids, a number of studies have observed that improvement on a short course of oral corticosteroids is not a reliable predictor of the long-term response [199]. Therefore, it is difficult to recommend a therapeutic trial with oral corticosteroids in late stage (moderate to very severe) COPD.

Some retrospective studies have evaluated the effect of oral corticosteroids on long-term FEV1 changes in patients with moderate to very severe COPD [154,155]. However, long-term oral treatment is not recommended for patients with COPD because of numerous side effects and limited therapeutic benefit. Extended use of systemic corticosteroids can result in a variety of adverse effects, including steroid myopathy, respiratory failure, osteoporosis, and Cushing syndrome.

Although regular treatment with inhaled corticosteroids does not result in the long-term reduction of FEV1 in patients with COPD, it does reduce the frequency of exacerbations and positively impacts overall health status in certain patients [92,93,94,95]. Withdrawal from such treatment may result in COPD exacerbations in these patients [96]. Treatment with inhaled corticosteroids can be recommended for patients with advanced COPD (FEV1 <50%) with frequent exacerbations. Some pooled studies observed that this treatment reduces mortality, but this observation requires further evidence [97]. An inhaled corticosteroid in combination with a long-acting beta2-agonist has a higher efficacy than either drug alone [98,99].

Reversal of Corticosteroid Resistance

There is mounting evidence that resistance to corticosteroid treatment is the result of a reduction in histone deacetylase-2 (HDAC2) due to oxidative and nitrative stress [188]. Reversal of this corticosteroid resistance by increasing the expression and activity of HDAC2 may be beneficial in the treatment of COPD.

Animal studies have shown that low-dose oral theophylline may increase HDAC2 expression in alveolar macrophages and restore steroid responsiveness in patients with COPD [189]. Further studies may provide novel therapeutic strategies to restore corticosteroid responsiveness with fewer side effects and adverse effects.

Antioxidants. Patients with COPD have increased oxidative stress, especially during exacerbations. Oxidative stress lowers steroid responsiveness by reducing HDAC2 activity and expression, and antioxidants may reverse corticosteroid resistance and reduce inflammation. Glutathione-based antioxidants are weak and easily inactivated by oxidative stress; therefore, researchers are now focusing on more potent and stable antioxidants, such as superoxide dismutase mimics and nicotinamide adenine dinucleotide phosphate oxidase inhibitors [190].

Macrolides. The non-antibiotic macrolide EM-703, a derivative of erythromycin, reverses corticosteroid resistance by increasing HDAC2 activity [192]. Several nonantibiotic macrolides are now being studied and are in various developmental stages.

Alternative Anti-Inflammatory Treatments

Because inflammation in COPD lungs is predominantly corticosteroid-resistant, alternative anti-inflammatory treatment is often required [184,185]. The majority of broad-spectrum anti-inflammatory agents are systemic in nature, and there are doubts over the safety of such drugs. Therefore, an inhaled delivery may be the optimum mode to increase efficacy and decrease side effects.

Phosphodiesterase-4 (PDE4) is the principal PDE expressed in neutrophils, T-cells, and macrophages, indicating that PDE4 inhibitors would be effective in controlling inflammation in COPD [186]. Oral PDE4 inhibitors have good potential because there are fewer compliance issues and easy availability. Roflumilast, a selective PDE4 inhibitor that inhibits lung inflammation and emphysema, has been developed and approved for treatment of COPD. It is an orally administered drug found to marginally improve FEV1 compared to tiotropium [181]. For some patients, PDE4 inhibitors may be the optimum add-on therapy over LAMAs and beta2-agonists. However, PDE4 inhibitors have severe gastrointestinal side effects, such as nausea and diarrhea, which has driven researchers toward specific PDE4B and PDE7 inhibitors with fewer and milder side effects.



Influenza and pneumococcal vaccines are effective in preventing some of the infections that cause COPD exacerbations and should be administered to all patients with COPD. Annual vaccination against influenza reduces the incidence of serious illness and mortality [100]. Influenza vaccines containing killed or live, inactivated viruses have a greater efficacy in elderly patients with COPD and therefore are highly recommended. Because of antigenic drift, newly attuned vaccines are developed each year in order to assure appropriate efficacy; therefore, the patient with COPD should be immunized against influenza annually [101].

Pneumococcal vaccines have improved over time by broadening the coverage of serotypes in the vaccine to include those that cause the most common invasive infections. Prior to 2012, a single agent, the 23-valent pneumococcal polysaccharide vaccine (PPSV23), was available for use in selected adults with underlying disease (e.g., COPD) and for all adults older than 65 years of age. While the effectiveness of PPSV23 was initially demonstrated in elderly patients, a study designed to assess vaccine efficacy in patients with COPD found that anti-pneumococcal immunization reduced the incidence of community-acquired pneumonia in patients younger than 65 years of age with FEV1 <40% predicted [102].

At present, a second, highly effective conjugate vaccine (PCV 13) has been approved for use in combination with PPSV23. The CDC recommends PCV13 and PPSV23, in series, for adults with COPD, as well as those with other chronic conditions or age older than 65 years [103]. Only a single dose of PCV13 is necessary for adults, and no additional dose of PPSV23 is indicated for adults who have previously received this vaccine at or after age 65 years. Pneumococcal vaccine-naïve older adults, or those for whom the vaccine history is unknown, should first be immunized with PCV13, then in 6 to 12 months with PPSV23. Current information, schedules, and guidance for adult immunizations is maintained by the CDC at http://www.cdc.gov/vaccines/schedules.

Alpha-1 Antitrypsin Augmentation Therapy

Alpha-1 antitrypsin augmentation therapy (i.e., weekly infusion of alpha-1 antitrypsin protein from healthy donors) is suitable for young patients who have severe hereditary alpha-1 antitrypsin deficiency and emphysema [199]. However, this therapy is quite expensive and is available in only a few countries. It is not recommended for patients without alpha-1 antitrypsin deficiency.


Pulmonary rehabilitation is a multidisciplinary and comprehensive intervention that is individually tailored for patients with COPD. Its principal goals are to:

  • Reduce COPD symptoms

  • Optimize physical and emotional status

  • Reduce healthcare costs by controlling and reversing various dysfunctions (reducing the need for hospitalization)

  • Improve overall quality of life

  • Improve activities of daily living

Pulmonary rehabilitation can address nonpulmonary conditions that are not addressed by the medical management of COPD, including:

  • Muscle weakness and wasting

  • Exercise deconditioning

  • Depression

  • Relative social isolation

  • Weight loss

Addressing and treating such problems can disrupt the "vicious circle" in COPD, leading to overall improvement in all aspects of COPD. Patients involved in pulmonary rehabilitation experience an 11% increase in peak oxygen consumption, an 18% increase in peak workload, and an 87% increase in endurance time [105].

Exercise training programs are beneficial at all stages of COPD and can improve exercise tolerance and reduce symptoms of dyspnea and fatigue. Pulmonary rehabilitation requires a multidisciplinary approach involving a number of health professionals from different specialties and may be conducted in outpatient, inpatient, or home settings.

The following factors should be considered in choosing patients for pulmonary rehabilitation [199]:

  • Functional status: Overall benefits are observed in patients with a number of disabilities, although chair-bound patients with COPD seldom respond.

  • Motivation: Highly motivated patients perform well and are preferred in outpatient programs.

  • Severity of dyspnea: Grading of dyspnea with the aid of the MRC questionnaire can be helpful in identifying and selecting patients who can benefit from rehabilitation. Patients with MRC grade 4 dyspnea may not benefit from pulmonary rehabilitation.

  • Smoking status: There is no evidence that smokers benefit less than nonsmokers; however, continuing smokers have a greater likelihood of quitting pulmonary rehabilitation programs than nonsmokers.

Program Components

The components of pulmonary rehabilitation vary widely from program to program, but a comprehensive pulmonary rehabilitation program includes proper exercise training, nutrition counseling, and education.

Bicycle ergometry or treadmill exercise is usually the best option to evaluate exercise tolerance, with measurement of maximum heart rate, maximum work performed, and maximum oxygen consumption. Another simple approach is the self-paced, timed walking test (e.g., six-minute walking distance). These tests require at least one practice session before the interpretation of data. Shuttle walking tests are easier to perform than treadmill tests and provide more detailed information compared to a self-paced test. Exercise training lasts 10 to 45 minutes per session and can be performed daily or weekly. Severely disabled patients should use a simple wheeled walking aid, as it improves walking distance and dyspnea [107]. Other modes of improving outcomes include use of oxygen during exercise, exercising while breathing heliox gas mixtures, unloading the ventilatory muscles while exercising, or use of pursed lip breathing [108,109]. Anabolic steroids, specific strength training, and the use of neuromuscular electrical stimulation are also being investigated for their perceived benefits in COPD rehabilitation programs [106].

Studies have observed that programs involving less than 28 sessions demonstrate inferior results compared to those with longer treatment periods [199]. The minimum duration of an effective rehabilitation program is six weeks. But long-term beneficial effects are not usually maintained after cessation of rehabilitation regardless of program [110].

Patients who are not able to participate in a formal rehabilitation program should be encouraged to exercise on their own. The addition of upper limb exercises or other strength training to aerobic training is beneficial in improving strength; however, it has no beneficial effect on overall quality of life or exercise tolerance [199].

Nutritional status is a key determinant of morbidity and mortality, disability, symptom severity, and overall prognosis in an individual with COPD, and nutrition counseling is an important part of rehabilitation. Approximately 25% of patients with stage 2–4 (moderate to very severe) disease have a low BMI and fat-free mass. Reduced BMI is associated with increased mortality in patients with COPD. Healthcare providers should identify and correct the factors responsible for reduced calorie intake and take steps to improve overall nutrition status in such cases. Patients should be advised to take frequent, small meals, especially those who experience dyspnea while eating. Proper dental hygiene and correction of poor dentition is also vital.

Improvement in the nutritional status of patients with COPD leads to an increase in respiratory muscle strength. However, the cost-effectiveness of this treatment is controversial. Increased calorie intake and an exercise regimen can also be beneficial in patients with COPD without significant nutritional depletion [111]. Anabolic steroids increase body weight and lean body mass in patients with weight loss, but they are not effective in increasing exercise capacity [113,114].

As noted, the majority of pulmonary rehabilitation programs include an educational component. However, the benefits of continuing patient education have not been established.

Assessment and Follow-Up

Baseline and outcome evaluation should be assessed to quantify individual benefits and scope for improvement. This should include:

  • Detailed history

  • Physical examination

  • Evaluation by spirometry pre- and postbronchodilator drug

  • Assessment of overall health status and impact of dyspnea

  • Evaluation of exercise capacity

In patients with COPD who suffer from muscle wasting, lower limb strength and inspiratory and expiratory muscle strength should be evaluated. Patient history and physical examination are not useful in outcome assessment but are the principal criteria for baseline status and establishing entry suitability.

Several questionnaires are being used to aid in the assessment of health and mental health status, including questionnaires that are specifically designed for patients with COPD. The Medical Outcomes Study Short Form, the Dyspnea Management Questionnaire, and/or the Hospital Anxiety and Depression Scale (HADS) may be useful to improve identification and management of COPD symptoms [112,129,130].

Oxygen Therapy

Oxygen therapy is one of the main nonpharmacologic treatments for stage 4 COPD and can be administered as long-term continuous therapy, therapy during exercise, or therapy to relieve acute dyspnea.

The primary goal of oxygen therapy is to maintain or increase the baseline PaO2 to at least 8.0 kPa (60 mm Hg) at sea level and rest and/or to produce an oxygen saturation (SaO2) of at least 90%, which will protect vital organ function by ensuring sufficient delivery of oxygen. Long-term oxygen therapy (i.e., more than 15 hours per day) has been shown to improve survival in patients with chronic respiratory failure [199]. It also has a positive effect on lung function, hemodynamics, exercise tolerance, hematologic characteristics, and mental health [115]. Oxygen therapy may also prevent the progression of pulmonary hypertension.

Long-term oxygen therapy is usually indicated in stage 4 COPD for patients who have [199]:

  • PaO2 ≤7.3 kPa (55 mm Hg) or SaO2 ≤88%, with or without hypercapnia confirmed twice over a three-week period

  • PaO2 between 7.3 kPa (55 mm Hg) and 8.0 kPa (60 mm Hg) or SaO2 of 88%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive cardiac failure, or polycythemia (hematocrit >55%)

Oxygen is usually delivered by a facemask, with inspiratory flow rates ranging between 24% and 35%. During air travel, patients should be instructed to increase the flow by 1–2 L/min. The facemask allows appropriate and accurate titration of oxygen, which is especially beneficial in patients who are susceptible to CO2 retention. However, facemasks are readily dislodged and hinder eating and conversation, so many patients prefer nasal cannulae. Oxygen delivery by nasal cannulae necessitates additional blood gas monitoring.

More sophisticated and specialized methods of oxygen delivery are available but should only be used in specialized facilities. Long-term home oxygen therapy may be provided from a fixed oxygen concentrator with plastic piping, allowing the patient to use oxygen at home. Duration of treatment should be at least 15 hours per day, preferably longer.

An extra supply of oxygen should be given to allow patients to go outdoors for an appropriate period of time and to exercise while maintaining oxygen saturation greater than 90%. Oxygen therapy during exercise can increase endurance and/or reduce the degree of end-exercise dyspnea or breathlessness. However, studies have observed that ambulatory oxygen therapy has a poor compliance in patients with COPD [116].

Supplemental home oxygen is generally the most expensive component of outpatient therapy for patients who require it. Oxygen concentrator devices may be less expensive than cylinder delivery systems.

Ventilatory Support

Noninvasive ventilation, via the use of both negative and positive pressure ventilation devices, is extensively used to treat acute exacerbations of COPD. Noninvasive ventilation should be the treatment of choice for persistent hypercapnic ventilatory failure during COPD exacerbations in spite of optimal medical treatment [199]. Negative pressure ventilation is not recommended for the chronic management of stage 4 COPD with or without CO2 retention. Data do not support combination noninvasive intermittent positive pressure ventilation (NIPPV) with long-term oxygen therapy [117]. However, the addition of NIPPV can reduce CO2 retention and improve dyspnea in some patients [118].

Possible complications of NIPPV include nasal congestion, nasal bridge ulceration, and facial skin erythema. In addition, contraindications for NIPPV include:

  • Respiratory arrest

  • Unstable cardiovascular activity (e.g., cardiac arrhythmias, hypotension, myocardial infarction)

  • Impairment of mental status, increased somnolence, inability to cooperate

  • Copious and/or viscous secretions with high risk for aspiration

  • Recent history of facial or gastroesophageal surgery

  • Fixed nasopharyngeal abnormality and craniofacial trauma

  • Severe burns

  • Morbid obesity

Surgical Interventions

Surgery is recommended for patients with severe COPD that is uncontrolled (or not optimally managed) with medical intervention. Patient selection criteria vary by the surgical technique, but in general, patients who undergo surgical intervention have stage 4 COPD.

There is a limit beyond which it is inadvisable to perform surgery for high-risk patients, as the risks outweigh the perceived benefits. Patients undergoing pneumonectomy with a preoperative FEV1 <2 L or 50% predicted and/or a carbon monoxide diffusing capacity (DLCO) <50% predicted have a high risk of postoperative respiratory failure [119]. Patients with poor lung function should be thoroughly investigated for regional distribution of perfusion and exercise capacity [120]. Surgery should not be performed during COPD exacerbations.

Postoperative pulmonary complications are a principal element of the increased risk associated with surgery in patients with COPD. The main risk factors are smoking, age, poor health, obesity, and COPD severity. All COPD candidates for lung resection should undergo a number of tests prior to surgery, including:

  • Static lung volume

  • Forced spirometry with bronchodilator response

  • Arterial blood gases at rest

  • Diffusing capacity


Bullectomy is an older procedure that may be of use for patients with COPD and bullous emphysema. It involves the resection of a large, nonfunctional bulla that is compressing the adjacent lung parenchyma.

Thoracoscopic bullectomy is beneficial in reducing dyspnea and improving lung function [132]. It may also reduce hemoptysis, infection, and chest pain and facilitate re-expansion of a compressed lung region. A thoracic CT scan, arterial blood gas measurement, and comprehensive lung function tests are required before making a decision for bullectomy. Indications for this surgical intervention include the absence of significant hypoxemia, normal or near normal diffusing capacity, and evidence of regional reduction in perfusion with good perfusion in the remaining lung. Several other factors predict a positive or negative outcome with bullectomy (Table 15) [73].


Rapid progressive dyspnea despite maximal medical
Older age
Comorbid illness
Cardiac disease
Pulmonary hypertension
>10% weight loss
Frequent respiratory infections
Chronic bronchitis
Normal FVC or slightly reduced
FEV1 >40% of predicted
Little bronchoreversibility
High trapped lung volume
Normal or near normal DLCO
Normal PaO2 and PaCO2
FEV1 <35% of predicted
Low trapped gas volume
Decreased DLCO
Chest x-rayBulla >1/3 hemithorax
Vanishing lung syndrome
Poorly defined bullae
CT scanLarge and localized bulla with vascular crowding and normal pulmonary parenchyma around bullaMultiple ill-defined bullae in underlying lung
AngiographyVascular crowding with preserved distal vascular branchingVague bullae; disrupted vasculature elsewhere
Isotope scanWell-localized matching defect with normal uptake and washout for underlying lungAbsence of target zones, poor washout in remaining of lung
CT = computed tomography, DLCO = carbon dioxide diffusing capacity of the lung, FEV1 = forced expiratory volume in one second, FVC = forced vital capacity.

Lung Volume Reduction Surgery

Lung volume reduction surgery (LVRS) is a surgical procedure in which damaged parts of the lung are resected to reduce hyperinflation, thus improving efficacy of respiratory muscles. LVRS also improves expiratory flow rates by increasing the elastic recoil pressure of the lung. LVRS is considered for patients with bilateral emphysema on HRCT and severe obstruction with hyperinflation and air trapping [194]. As with bullectomy, certain characteristics may indicate the likelihood of a favorable or unfavorable outcome with LVRS (Table 16).


Age <75 years
Clinical picture consistent with emphysema
Not actively smoking (for at least three to six months)
Severe dyspnea despite maximal medical treatment including pulmonary rehabilitation
Requiring <20 mg prednisone a day
Comorbid illness which would increase surgical mortality
Clinically significant coronary artery disease
Pulmonary hypertension (PA systolic
Severe obesity or cachexia
Surgical constraints
Previous thoracic procedure
Chest wall deformity
FEV1 after bronchodilator <45% predicted
Hyperinflation (i.e., RV >150%, TLC >100% predicted)
PaO2 >6 kPa (45 mm Hg)
PaCO2<8 kPa (60 mm Hg)
Postrehabilitation six-minute walk >140 meters
Low post-rehabilitation maximal achieved cycle ergometry watts
FEV1 <20% predicted and DLCO <20% predicted
Decreased inspiratory conductance
High post-rehabilitation cycle ergometry maximal achieved wattage
ImagingHigh-resolution computed tomography confirming severe emphysema, ideally with upper lobe predominance
Homogeneous emphysema and FEV1 <20% predicted
Non-upper lobe predominant emphysema
DLCO = carbon dioxide diffusing capacity of the lung, FEV1 = forced expiratory volume in one second, PA = alveolar pressure, PaO2 = arterial oxygen tension, PaCO2 = arterial carbon dioxide tension, RV = residual volume, TLC = total lung capacity.

Lung Transplantation

Lung transplantation is a therapeutic option in appropriately selected patients with very advanced COPD. Criteria for referral for lung transplantation include COPD with a BODE index exceeding 5. Recommended criteria for listing include a BODE index of 7–10 and at least one of the following [199]:

  • History of exacerbation associated with acute hypercapnia (partial pressure of carbon dioxide [PaCO2] >6.7 kPa or 50 mm Hg)

  • Pulmonary hypertension, cor pulmonale, or both despite oxygen therapy

  • FEV1 <20% predicted with either DLCO <20% predicted or homogenous distribution of emphysema

Patients must remain symptomatic despite optimal medical treatment in order to be considered for transplant. In addition, prognosis should be assessed. Only patients with predicted disease-related survival equal to or less than the predicted survival after transplantation should be selected [194]. Transplantation improves lung function, exercise capacity, quality of life, and survival in patients with end-stage disease [133].

The number of lung transplantations performed is curtailed by a shortage of donor organs. To address this, specialized centers are adopting the single-lung technique. Common complications of this procedure include:

  • Acute rejection

  • Bronchiolitis obliterans

  • Cytomegalovirus infection

  • Fungal and bacterial infection

  • Operative mortality

  • Lymphoproliferative disease and lymphomas

Lung Regeneration

Despite making strides in understanding the mechanism and pathophysiology of COPD, treatment strategies have not changed significantly in the last few decades. However, the possibility of lung regeneration is offering a hope of cure. Lung regeneration has the potential to replace or repair nonfunctional tissue via restoration of functional alveoli and alveolar ducts. Advances made in the field of stem cells (embryonic and adult-derived)and the ability to differentiate them into chosen cell types offer a glimpse into the future of lung regeneration. Two main approaches are being evaluated for possible reversal of structural disease:

  • Extrinsic cell therapy: Exogenous stem cells, paracrine effects of stem cells, and ex vivo tissue engineering

  • Intrinsic cell therapy: Small molecules used to induce lung regeneration through actions on intrinsic populations of cells

Extrinsic Cell Therapy

Human exogenous stem cells can differentiate into type II pneumocytes and can possibly regenerate lung parenchyma, including alveoli. Sophisticated technologies and methods are being used to produce pure populations of exogenous stem cells, which is necessary to prevent the development of teratomas. However, there are two major hurdles for the development of this therapy. The first is an ethical issue, as stem cells are extracted from human embryos, which has been controversial in the United States. The second hurdle is risk of rejection, because the differentiated type II cells would not be autologous. The use of autologous adult stem cells can solve both these problems. Direct administration of differentiated type II cells is better than intravenous administration of mesenchymal stem cells [182].

Endogenous stem cell therapy avoids complications related to extrinsic cell therapy, particularly rejection. Tissue-specific stem cell populations have the capability to regenerate lung parenchyma. Research is being done to induce lung tissue regeneration without utilizing specific stem cell populations [182].

Retinoic Acid

Retinoic acid, particularly all-trans-retinoic acid (ATRA), plays an important role in fetal lung development and increases alveolar septation. ATRA also restores the normal lung structure in rats with emphysema. However, ATRA has not definitely shown beneficial effects in patients with emphysema [183].


A COPD exacerbation is an acute, persistent deterioration of a patient's symptoms from their usual baseline (beyond normal day-to-day variations) that requires a change in medication [121]. The characteristic clinical presentation is that of acute or subacute onset of breathlessness, cough, increased sputum volume, and a change in sputum color (purulence). Exacerbations may be classified according to clinical presentation based on the number of symptoms and/or healthcare resources utilized. Exacerbations have a major impact on patient health, and recovery often takes several weeks.

About 50% of COPD exacerbations can be attributed to intercurrent bronchial infection [122]. Ambient low-level colonization of the tracheobronchial tree by common respiratory bacterial pathogens (e.g., S. pneumoniae, H. influenzae) is common in patients with COPD. Studies have shown that exacerbations are associated with a new strain of one of these pathogens and an increase in the bacterial population of the lower airways as evidenced by quantitative cultures. Targeted antimicrobial therapy is known to speed clinical resolution [25].

Approximately 10% of patients admitted for a hypercarbic COPD exacerbation have a fatal outcome. Patients requiring mechanical support have a mortality rate of 40% after one year, and all-cause mortality following hospitalization for a COPD exacerbation jumps to 49% after three years [199].

COPD exacerbations lead to a more rapid decline in lung function, reduce quality of life, and impose a heavy socioeconomic cost burden because of subsequent hospitalizations. In one cost analysis, the annualized mean COPD-related cost of care ($12,765) for a patient with severe COPD exacerbations was nearly 10 times higher than that for a patient with COPD and no exacerbations ($1,425) [123]. Therefore, exacerbations should ideally be prevented or detected early and promptly treated in order to reduce adverse effects and minimize hospitalization risk. If hospitalization can be avoided with home care, this is best (Table 17).


FactorTreat at HomeTreat in Hospital
Able to cope at homeYesNo
General conditionGoodPoor/deteriorating
Level of activityGoodPoor/confined to bed
Worsening peripheral edemaNoYes
Level of consciousnessNormalImpaired
Already receiving long-term oxygen therapyNoYes
Social circumstancesGoodLiving alone/not coping
Acute confusion No Yes
Rate of onset Insidious or gradual Rapid
Significant comorbidity (particularly cardiac disease and insulin-dependent diabetes) No Yes
SaO2 <90% No Yes
Changes on chest radiograph No Present
Arterial pH level≥7.35<7.35
Arterial PaO2≥7 kPa<7 kPa
PaO2 = partial pressure of oxygen, SaO2 = oxygen saturation.


The principal symptom of an exacerbation is increased breathlessness, often accompanied by chest tightness, wheezing, increased cough and sputum production, and change of the color and/or tenacity of sputum. Certain nonspecific symptoms are common, including malaise, worsening fatigue, decreased exercise tolerance, palpitations, somnolence, and mild confusion. An increase in sputum volume and shift toward purulence is indicative of bacterial infectious bronchitis. Prominent fever or shaking chills should raise suspicion of pneumonia.

The severity of an exacerbation is assessed on the basis of a patient's medical history prior to exacerbation, physical examination, symptoms, pre-existing comorbidities, arterial blood gas measurements, and other laboratory tests [198]. Key indicators for assessing severity of an exacerbation include:

  • Severity and frequency of attacks of breathlessness and cough

  • Volume and color of the sputum

  • Limitation of activities of daily living

Acute changes in arterial blood gas measurements during and prior to an exacerbation are also important indicators. Altered mental status during an exacerbation in stage 4 COPD requires urgent assessment in the hospital.


Patients experiencing an exacerbation of COPD may have difficulty performing even a simple pulmonary function test such as spirometry. Spirometric measurements are not reliable during an acute exacerbation and thus are not recommended.

Pulse Oximetry and Arterial Blood Gas Measurement

Pulse oximetry is helpful in determining a patient's need for supplemental oxygen therapy during exacerbations. Accurate arterial blood gas measurement is also crucial to assess the severity of an exacerbation, especially in patients requiring hospitalization for their COPD. Respiratory failure is characterized by a PaO2 <8.0 kPa (60 mm Hg) and/or SaO2 <90% with or without PaCO2 >6.7 kPa (50 mm Hg) when breathing room air. Mechanical ventilation is indicated when there is moderate-to-severe respiratory acidosis (pH ≤7.35) plus hypercapnia (PaCO2 >6–8 kPa or 45–60 mm Hg) in a patient with COPD and severe dyspnea with clinical signs suggestive of respiratory muscle fatigue, increased work of breathing, or both, such as use of respiratory accessory muscles, paradoxical motion of the abdomen, or retraction of the intercostal spaces [199].

Pulmonary embolism (without infarction) has a similar clinical presentation to an exacerbation of COPD, and it may be difficult to distinguish between the two, particularly in patients with advanced COPD who may already have developed clinical, radiographic, and electrocardiographic (ECG) signs of right heart strain. A history of transient syncope, hypotension, or an inability to increase PaO2 greater than 8.0 kPa (60 mm Hg) despite high-flow oxygen should raise suspicion for pulmonary embolism. The two conditions are not mutually exclusive; in fact, cor pulmonale is a risk factor for pulmonary embolism. Treatment for both, at least initially, may be the best option when pulmonary embolism is suspected and the diagnosis is unclear.

Chest X-Ray and ECG

Chest radiographs with posterior/anterior and lateral views, combined with ECG, are helpful in differentiating other diseases that can mimic COPD exacerbations. These include cardiac arrhythmias, right ventricular hypertrophy, and myocardial ischemia.

Other Laboratory Tests

A complete blood count may detect polycythemia (i.e., hematocrit >55%) or bleeding, but white blood cell counts do not provide any concrete information regarding exacerbations. Antibiotic treatment should be initiated promptly if there is fever or purulent sputum. Bacterial infections with S. pneumoniae, H. influenzae, or Moraxella catarrhalis are most frequently involved in COPD exacerbations. A sputum culture and an antibiogram are required when antibiotic treatment is ineffective against a COPD exacerbation.

Abnormal biochemical test results can be linked to COPD exacerbations and comorbid conditions. Common test abnormalities include metabolic acid-base disorder, electrolyte disturbance, and poor glucose control.


Approximately 10% to 30% of patients considered to have an acute exacerbation of COPD have atypical clinical features or are refractory to treatment. Such cases require a thorough re-evaluation for other medical disease or conditions that can worsen symptoms or imitate COPD exacerbation. As an example, one study reported that 49 of 197 patients (25%) admitted to the hospital with an initial diagnosis of COPD exacerbation were subsequently found to have sustained an acute pulmonary embolism [227]. Common differential diagnosis considerations include:

  • Congestive heart failure

  • Pneumothorax

  • Pneumonia

  • Cardiac arrhythmia

  • Pleural effusion

  • Pulmonary embolism

Elevated serum levels of brain-type natriuretic peptide together with other clinical indications can help detect patients with acute dyspnea secondary to congestive heart failure [124]. Noncompliance with prescribed medications can also result in increased symptoms that may be confused with a true COPD exacerbation.


Patients with early mild-to-moderate COPD exacerbation can often be managed in the outpatient setting. The goals of therapy are to control infection, reduce inflammation and airway trapping, and restore overall respiratory compensation. The usual strategy is to combine antibiotic and enhanced bronchodilator therapy with a brief course of corticosteroids for 7 to 10 days.

Patients and their relatives are increasingly interested in home care for end-stage COPD, although studies of the cost-effectiveness of this approach have produced mixed results [223]. Nurse-administered home care (hospital-at-home care) has been found to be an effective alternative to hospitalization in select patients with exacerbations without acidotic respiratory failure. However, the exact criteria for home management as opposed to hospital treatment remain unclear, and vary according to healthcare setting.

Bronchodilator Therapy

Beta2-agonists are highly effective in the home management of COPD exacerbations. Increasing the dose and/or frequency of beta2-agonists is beneficial in such cases. There is insufficient data to compare efficacy of different classes of short-acting bronchodilators; bronchodilator therapy delivered by metered-dose inhaler with a spacer and by hand-held nebulizer yield similar clinical responses.


For patients experiencing an exacerbation, systemic corticosteroids act by improving lung function, shortening recovery time, improving hypoxemia, and reducing the risk of early relapse, treatment failure, and duration of hospital stay. If the patient's baseline FEV1 is less than 50% predicted corticosteroids may be added to the bronchodilator(s) to improve the response to treatment. A regimen commonly used is prednisone 30–40 mg daily for 7 to 10 days. There is little reason to taper the dosage as exogenous steroids administered for less than 10 to 14 days rarely causes significant adrenal suppression.


Antimicrobial therapy is indicated for patients who present with all the cardinal features of a COPD exacerbation, but if there is little change in sputum volume and no shift toward purulence, then, absent fever, antibiotics are unlikely to be of benefit. Sputum culture requires 48 to 72 hours for meaningful results and thus is of limited usefulness in outpatient management of COPD. The selection of a specific antimicrobial should be made in consideration of the patient's age, severity of airway obstruction, comorbidities, and anticipated respiratory bacterial pathogens [25]. Amoxicillin/clavulanate or trimethoprim/sulfamethoxazole is a good choice for many patients; a macrolide or tetracycline has the advantage of covering atypical pathogens such as mycoplasma and Chlamydia species. A respiratory fluoroquinolone is preferred in patients with comorbidities, recent hospital discharge, or recent use of other antimicrobials.


The patient with COPD exacerbation usually presents to the emergency department or physician's office. The first priority is to assess the degree of respiratory failure and need for supplemental oxygen and support of ventilation. The mortality risk from COPD exacerbation is closely linked to the development of respiratory acidosis, the presence of significant comorbidities, and the need for intermittent or continuous mechanical ventilation. Features that indicate a need for hospital assessment/admission include:

  • Severe underlying COPD

  • Marked increase in intensity of symptoms

  • Onset of new physical signs such as cyanosis or peripheral edema

  • Exacerbation refractory to initial medical treatment

  • Frequent exacerbations

  • Significant comorbidities

  • Uncertain diagnosis

  • Newly occurring cardiac arrhythmias

  • Older age

  • Inadequate home support

Immediate admission to an intensive care unit (ICU) is indicated for the patient who exhibits any of the following:

  • Severe dyspnea or breathlessness that does not respond adequately to initial emergency treatment

  • Persistent or worsening hypoxemia (PaO2 <5.3 kPa or <40 mm Hg), severe or worsening hypercapnia (PaCO2 >8.0 kPa or >60 mm Hg), and/or severe or worsening respiratory acidosis (pH <7.25) despite supplemental oxygen and noninvasive ventilation

  • Altered mental status (e.g., coma, confusion, lethargy)

  • Need for invasive mechanical ventilation

  • Hemodynamic instability (i.e., need for vasopressors)

Most patients with a COPD exacerbation who present to a hospital emergency department will require some degree of supplemental oxygen therapy. If clinical and laboratory features indicate that the exacerbation is life threatening, the patient should be admitted to the ICU immediately. Otherwise, patients with moderate-to-severe COPD may be managed initially in the emergency department to assess response to treatment and determine the need for hospitalization. In addition to treatment with bronchodilators, corticosteroid, antimicrobials, and supplemental oxygen, emergency department- and hospital-based care often includes the following adjunctive measures:

  • Adequate and accurate fluid administration with monitoring of fluid balance

  • Proper nutrition with supplementation as required

  • Prophylaxis of deep vein thrombosis

  • Respiratory therapy to facilitate clearance of bronchial secretions (pulmonary toilet)

Mechanical chest percussion and postural drainage may be helpful in patients producing more than 25 mL sputum per day or who present with lobar atelectasis.

Controlled Oxygen Therapy

Controlled oxygen therapy is a main component of the hospital treatment of acute COPD exacerbations. Careful titration of supplemental oxygen is essential to improve the patient's hypoxemia. Safer levels of oxygenation (PaO2 >8.0 kPa/60 mm Hg or SaO2 >90%) can be easily attained in uncomplicated COPD exacerbations; however, there is a danger of CO2 retention that can develop insidiously. Arterial blood gases should be measured 30 to 60 minutes after the initiation of oxygen therapy to ensure adequate levels of oxygenation without acidosis or CO2 retention. Compared to nasal prongs, Venturi masks provide more accurate delivery of controlled oxygen but are less well tolerated by patients.

Bronchodilator Therapy

A short-acting inhaled beta2-agonist administered by nebulizer every one to four hours is usually the bronchodilator of choice for initial treatment of COPD exacerbations. The addition of a muscarinic antagonist is recommended if prompt relief is not provided by the beta2-agonist. Methylxanthines may be considered as second-line intravenous therapy when there is insufficient response to short-acting bronchodilators [199].


Corticosteroid, administered orally or intravenously, is recommended for moderate-to-severe acute exacerbations [199]. A dose equivalent to 30–40 mg prednisone daily is commonly used for a 7- to 10-day period, then rapidly tapered over the ensuing 5 to 7 days [104,199]. Corticosteroid therapy for longer than two weeks is rarely necessary, and extended use increases the risk of adverse effects.


As noted, acute exacerbations frequently occur in association with viral and/or bacterial upper respiratory infections. As a practical matter, most patients receive empirical antimicrobial therapy, and studies have observed a small beneficial effect of antibiotics on lung function in COPD exacerbations [199]. One clinical trial demonstrated a significant beneficial effect of antibiotics in patients who presented with increased breathlessness, sputum volume, and sputum purulence [199].

Based on the available evidence, antibiotics should be prescribed for patients with cough accompanied by increased sputum volume and purulence, increased dyspnea, and/or fever. Patients experiencing COPD exacerbation that necessitates mechanical ventilation (invasive or noninvasive) should also receive antibiotics.

The bacterial pathogens most commonly associated with COPD exacerbations are H. influenzae, S. pneumoniae, and M. catarrhalis. Atypical pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, have also been detected in patients with COPD exacerbations. As FEV1 declines and patients have more frequent exacerbations and/or comorbid diseases, infections with H. influenzae and M. catarrhalis become more frequent. Pseudomonas aeruginosa is a consideration in patients with severe airway limitation or history of bronchiectasis [199].

The mode of administration depends on the ability of the patient to eat and the pharmacokinetics of the antibiotic. The oral route is the preferred mode of administration, but hospitalized patients should be treated parenterally, switching to the oral route when clinical stabilization permits. The initial selection of therapy, pending results of sputum culture, should address the most likely pathogens, taking into account local antimicrobial resistance patterns.

Respiratory Stimulants

Respiratory stimulants are not prescribed for patients with COPD and acute respiratory failure. However, doxapram, a nonspecific but relatively safe respiratory stimulant, may be used only in cases when noninvasive intermittent ventilation (NIV) is not available or not recommended [125]. For these patients, doxapram can increase tidal volume and respiratory rate.

Ventilatory Support

COPD exacerbations cause bronchoconstriction, airway inflammation, increased mucus production, and loss of elastic recoil, all of which reduce passive functional residual capacity at the end of expiration, shrink dynamic hyperinflation, and increase breathing effort [128]. These deficits may be managed with ventilator support in certain patients. The principal goals of ventilatory support are to reduce breathing load and to encourage efficient gas exchange and alveolar ventilation, which in turn decreases mortality and morbidity and relieves symptoms.

Ventilatory support can be categorized as:

  • NIV: Uses either negative or positive pressure devices

  • Invasive mechanical ventilation: Provided by orotracheal tube or tracheostomy

Noninvasive Intermittent Ventilation

NIV is indicated for persistent hypercapnic ventilatory failure during exacerbations refractory to medical treatment. It should be provided only by specialized staff experienced and educated in this field.

Several clinical studies have successfully demonstrated the efficacy of NIV in acute respiratory failure, with success rates of 80% to 85% [126]. NIV decreases the rate of respiration, incidence of respiratory acidosis, severity of dyspnea or breathlessness, duration of hospitalization, and mortality and intubation rates [127]. NIV is not preferred for patients whose primary diagnosis is cardiac failure or pneumonia; however, it may be indicated in patients with these complications if escalation to intubation and ventilation is perceived to be inappropriate.

The selection criteria for NIV are based on clinical observations and gas exchange measurements. Patients with moderate-to-severe dyspnea with signs of increased breathing load (i.e., use of accessory muscles and paradoxical abdominal motion) and tachypnea (>25 breaths per minute) as well as moderate-to-severe acidosis (pH ≤7.35) and/or hypercapnia (PaCO2 >6.0 kPa OR 45 mm Hg) are considered candidates for NIV [199]. Relative contraindications include [199]:

  • Respiratory arrest

  • Life-threatening hypoxemia

  • Unstable cardiovascular status (e.g., cardiac arrhythmias, myocardial infarction, hypotension)

  • Altered mental status or inability to cooperate (e.g., low Glasgow coma score)

  • High aspiration risk, vomiting

  • Viscous or copious secretions

  • Recent history of facial or gastroesophageal surgery

  • Craniofacial trauma

  • Bowel obstruction

  • Fixed nasopharyngeal abnormalities

  • Severe burns

  • Morbid obesity

Certain factors are useful predictors of failure of NIV. These include:

  • Hypercapnic respiratory failure

  • No overall improvement or worsening pH within one to two hours of effective NIV therapy

  • Minimal improvement in oxygenation after one to two hours of effective NIV therapy

  • Multi-organ failure

  • Lack of response or cooperation

  • Hypoxemia

  • Respiratory failure

  • Older age

Invasive Mechanical Ventilation

With the advent of better and more sophisticated technology, a number of indications for invasive mechanical ventilation are now being effectively treated with NIV. However, some patients will require more intensive ventilatory support. The indications for initiating invasive mechanical ventilation during exacerbations of COPD include:

  • Unable to tolerate NIV or NIV failure (or exclusion criteria)

  • Severe dyspnea with use of accessory muscles and paradoxical abdominal motion

  • Tachypnea (>35 breaths per minute)

  • Life-threatening hypoxemia

  • Severe acidosis (pH <7.25) and/or hypercapnia (PaCO2 >8.0 kPa or 60 mm Hg)

  • Respiratory arrest

  • Somnolence or altered mental status

  • Cardiovascular complications (e.g., hypotension, shock)

  • Other complications (e.g., sepsis, metabolic impairments, pneumonia, massive pleural effusion, pulmonary embolism)

The choice of whether or not to initiate invasive ventilation may also be influenced by non-medical factors. Cultural and psychologic aspects should be considered, as should any financial limitations. The major risks associated with mechanical ventilation are increased susceptibility to ventilator-acquired pneumonia (particularly when multidrug-resistant organisms are present), pulmonary barotrauma, and failure to wean to spontaneous ventilation [199]. However, ventilator-associated fatalities among patients with COPD and respiratory failure are comparatively fewer than among patients ventilated for non-COPD causes.

Weaning off mechanical ventilation can be difficult and potentially dangerous in patients with COPD. The key determinant of mechanical ventilatory dependency is the balance between the respiratory load and the ability of the respiratory muscles to deal with this load. The best method to wean patients from ventilator still remains unclear.

Hospital Discharge and Follow-Up

There are no clear guidelines for the optimal duration of hospitalization for patients with COPD exacerbation. Patients may be considered for discharge if they meet the following criteria:

  • Inhaled beta2-agonist therapy required less often than every four hours

  • Able to eat and sleep without frequent awakening by dyspnea

  • Able to walk across room (if previously ambulatory)

  • Clinically stable for 12 to 24 hours

  • Arterial blood gases stable for 12 to 24 hours

  • Patient (or home caregiver) fully understands correct use of medications

  • Follow-up and home care arrangements made (e.g., visiting nurse, oxygen delivery, meal provisions)

  • Able to manage successfully at home

Patients hospitalized with COPD exacerbations may be discharged earlier if visits by a home nurse are ensured. In patients who experience hypoxemia during a COPD exacerbation, arterial blood gas measurements and/or pulse oximetry should be conducted before discharge and in the following three months. Long-term supplemental oxygen therapy may be necessary in hypoxemic patients. Strategies to prevent future exacerbations should be evaluated before hospital discharge, with greater emphasis on smoking cessation, vaccination, medical compliance, inhaler technique, and recognition of exacerbation symptoms.

Patients should be scheduled for follow-up four to six weeks after discharge. Follow-up should include an assessment of the patient's ability to manage in his or her usual environment, FEV, inhaler technique, and understanding of the recommended treatment plan. Patients with stage 4 COPD should be assessed for the need for long-term oxygen therapy and/or home nebulizer.

The use of long-acting inhaled bronchodilators, inhaled corticosteroids, and combination inhalers should be specifically considered. Long-acting inhaled bronchodilators reduce the number of exacerbations and hospitalizations and delay the time of first/next hospitalization. Early outpatient pulmonary rehabilitation immediately following discharge is a safe and effective way to improve exercise capacity and health status. Social problems should be identified and discussed in detail if the patient experiences persisting disability.


COPD is a progressive disease, and lung function will deteriorate over time even with the best available medical care. Airflow limitation, together with symptoms and objective measures, should be monitored periodically to guide modification of treatment and identification of any complications that may arise during the course of the disease. Comorbidities are frequently present in COPD and often complicate COPD management and vice versa.

The number of visits required for monitoring increases with disease progression. Ongoing or periodic monitoring and assessment in COPD guarantees that the goals of treatment are being achieved and should include evaluation and assessment of:

  • Risk factors (particularly tobacco smoking)

  • COPD progression and complications

  • Response and adherence to drug therapy and other medical treatments

  • History of exacerbation(s)

  • Comorbidities


After a diagnosis of COPD has been established, follow-up visits should include a physical examination and discussion of symptoms, particularly development of any new symptoms or worsening of previous symptoms. Periodic spirometry measurements are necessary to monitor the patient's decline in lung function, although it should not be done more than once a year unless there is a significant increase in symptoms or a complication. Other pulmonary function tests, such as flow-volume loops, inspiratory capacity, DLCO measurements, and measurement of lung volumes are usually not required in a routine assessment. However, these tests may provide information about the overall impact of the disease and may be beneficial in electing patients for surgery and in resolving diagnostic doubts. A number of exercise tests, such as treadmill and cycle ergometry and six-minute and shuttle walking tests, can be conducted to assess exercise capacity, but these are mainly conducted concurrently with pulmonary rehabilitation programs.

Only patients with respiratory failure require assessment of pulmonary artery pressure; otherwise, its measurement is not recommended. The development of respiratory failure is indicated by a PaO2 less than 8.0 kPa (60 mm Hg) with or without PaCO2 greater than 6.7 kPa (50 mm Hg) in arterial blood gas measurements while breathing air at sea level. Patients may be screened with pulse oximetry and arterial blood gases if SaO2 is less than 92%.

Measurement of inspiratory muscle force is helpful in evaluating patients when dyspnea or hypercapnia cannot be explained by LFTs or in suspected cases of peripheral muscle weakness. Individuals with COPD may have increased inspiratory muscle force when other assessments of lung mechanics are equivocal.

Cor Pulmonale

Pitting ankle edema and elevated jugular venous pressure are the most common findings in patients with COPD and cor pulmonale. Because fluctuations in intrathoracic pressure are common, it is usually difficult to evaluate jugular venous pressure in patients with COPD. Several other studies, such as MRI, echocardiography, electrocardiography, and radionucleotide scintigraphy, are crucial for diagnosing cor pulmonale in these patients. Sleep studies may be necessary if cor pulmonale or hypoxemia develops with relatively mild airflow limitation or when sleep apnea is suspected.


Anemia affects approximately 25% of patients with COPD [61]. Smokers usually develop polycythemia in the presence of arterial hypoxemia, which is indicated by increase in hematocrit of more than 55%. However, a low hematocrit signifies a poor prognosis in patients receiving long-term oxygen therapy [62].


Each follow-up visit should include a thorough discussion of the current treatment plan in order to adjust the treatment appropriately with disease progression. Careful monitoring of drug dosage, compliance, appropriate inhaler technique, and safety and efficacy of the treatment is essential in patients with COPD. Adherence to prescribed pharmacotherapy can be improved with thorough patient education, optimized pharmacotherapy choices (e.g., longer acting agents), and regular monitoring of treatment effectiveness.


Each COPD exacerbation should be recorded during periodic assessments, including the severity, frequency, and possible causes. Documentation of symptoms indicative of exacerbation (e.g., increased sputum volume, purulent sputum, acutely worsening dyspnea) is of utmost importance. The severity of a COPD exacerbation can be gauged by the greater need for bronchodilator therapy, steroids, and antibiotics. All emergency or unscheduled visits to healthcare providers and telephone calls for assistance should also be noted. A note should be made in case intubation or any other emergency care was provided to the patient during hospitalization. Proper documentation of all the hospital summaries should also be done.


Comorbidities are common in COPD, and include bronchial carcinoma, ischemic heart disease, and osteoporosis. Some comorbidities will develop independently, but the majority develop in the presence of COPD. Other conditions, such as diabetes and arthritis, become more prevalent as the patient ages. Comorbidities are difficult to treat in presence of COPD, because it can increase the degree of disability and polypharmacy may result in untoward drug-drug interactions. It is imperative that comorbidities be identified and treated according to evidence-based guidelines.


For years, the role and significance of comorbidities in COPD was not properly understood. However, studies have increasingly demonstrated the relationship of comorbidities and COPD severity and outcomes. It is yet to be ascertained if nonpulmonary interventions targeting systemic inflammatory burden, osteoporosis, cardiovascular disease, anemia, or malnutrition can change the natural course of COPD. In addition, more research is necessary to better understand the influence of COPD and different COPD management strategies on these comorbidities.

Comorbidities commonly seen in patients with COPD include pulmonary hypertension, cardiac disease, lung cancer, diabetes, osteoporosis, metabolic syndrome, and psychologic disorders (Table 18) [74]. Tobacco smoking is a predominant risk factor for COPD and many of its comorbidities, which makes the relationship complicated. Studies have confirmed a strong independent relationship between COPD and its comorbidities, especially with cardiovascular disease [135,136,137]. It has also been observed that systemic inflammation plays a key role in many chronic medical diseases, which may indicate a shared etiology [136]. A number of such comorbidities are now regarded as part of the nonpulmonary sequelae of COPD and are crucial in comprehending the real burden of COPD and developing more effective management strategies.


Comorbidity Prevalence by Source
van Manen et al. (n=1,145) Mapel et al. (n=200) Soriano et al. (n=2,699) Sidney et al. (n=45,966) Walsh and Thomashow (n=3,000)
Psychiatric disorders9%17%10%38%


Cardiovascular disease is a common cause of death and hospitalization in patients with COPD and is observed even in mild cases of COPD. Both diseases have the common risk factors of cigarette smoking, advanced age, low socioeconomic status, and sedentary lifestyle.

Patients with COPD carry an increased burden of cardiovascular disease, cardiac arrhythmia, and cardiac failure when compared to the general population. In a cross-sectional analysis, COPD was associated with increased risks of cardiovascular disease and diabetes as well as an increased rate of myocardial ischemia and stroke. Curkendall et al. observed that the prevalence of all cardiovascular diseases was greater in patients with COPD compared with control subjects and that the risk of hospitalization and mortality due to cardiovascular causes was increased in patients with COPD [131].

Patients with COPD and cardiac disease have been found to have worse lung function, poorer quality of life, and a need for more medications and more health resources with greater expenditure compared to patients without heart disease [140].

Approximately 20% to 32% of patients with COPD have coexisting cardiac failure [138]. Cardiac failure is often difficult to diagnose in patients with COPD due to the similar symptomatology and decreased efficacy of echocardiography. Assessment of the natriuretic peptides is generally helpful in detecting cardiac failure in patients with acute dyspnea; however, they have a vague diagnostic role in stable disease and cannot exclude comorbid COPD.

Possible contributing factors include systemic inflammation, hypoxia, acidosis, autonomic dysfunction, and hemodynamic impairments. Impaired lung function is a major risk factor for cardiac arrhythmia and cardiovascular disease, and patients with COPD have increased arterial stiffness [162].

Medications commonly used in the treatment of COPD can also increase cardiac morbidity and mortality. In addition, some patients with COPD on beta-blockers will experience deterioration of lung function, but avoidance of beta-blockers may lead to increased cardiovascular events, particularly in high-risk individuals [199]. In contrast, bronchodilators may cause tachyarrhythmia. Analysis from the TOwards a Revolution in COPD Health (TORCH) study did not indicate increased cardiovascular risk from use of the bronchodilator salmeterol at the standard dose [139]. However, further investigation must be done before reaching any conclusion.

Data from a multicenter, prospective, cross-sectional study of cardiovascular disease observed a direct relationship between the extent of emphysema and impairment of left ventricle filling, stroke volume reduction, and lowering of cardiac output in healthy individuals [156]. In COPD, cardiac failure has an adverse effect on morbidity and prognosis. A cohort study observed that comorbid heart failure was a strong predictor of all-cause mortality over long-term follow-up [141]. It was also a major risk factor for death from respiratory failure and for respiratory admissions.



Beta-blockers are effective in helping to control hypertension and coronary artery disease, but practice guidelines generally indicate that these agents are contraindicated in patients with COPD [199]. This was based primarily on case reports of acute bronchospasm precipitated by high doses of noncardioselective beta-blockers, but evidence increasingly supports the use of cardioselective beta-blockers for the management of cardiovascular comorbidities in patients with COPD [161]. A Cochrane review found that cardioselective beta-blockers were safe and effective in patients with COPD with cardiac failure and should not be withheld, even in the presence of severe airflow limitation [142]. Short et al. observed a reduction in all-cause mortality in patients with COPD being treated with beta-blockers [143]. Beta-blocker use was also not associated with a decline in lung function. Among study participants, use of beta-blockers reduced the risk of cardiac death, respiratory death, oral corticosteroid use, and respiratory-related hospitalizations.


Statins have the beneficial effect of lowering lipid levels in patients with COPD with cardiovascular disease. Statins have been shown to reduce all-cause mortality, COPD-related mortality, and the need for respiratory-related urgent care [163]. Several single studies have observed a reduction in the number of exacerbations, exertional dyspnea, and inflammation and a minimal decline in lung function [163].


As with cardiac failure, overlapping symptoms may make pulmonary embolism difficult to diagnose in patients with COPD. Experts suggest that pulmonary embolism should be suspected in patients with COPD who present with acute exacerbation with no evident cause. Because it is a potentially fatal condition with high mortality, early detection and classification is vital to initiating the optimum treatment.

Clinical features that favor a diagnosis of pulmonary embolism (over COPD exacerbation) include sudden-onset dyspnea, tachypnea, pleuritic chest pain, an absence of fever or sputum change, and new-onset hemoptysis. Patients with large or recurrent pulmonary embolism may have cyanosis, circulatory instability, and in some cases, respiratory failure. Physical examination may be of limited utility in differentiating between COPD and pulmonary embolism in patients with acute respiratory distress. A pleural friction rub may be heard on auscultation over the affected part of the lung when embolism is accompanied by infarction. The past history may provide useful clues to the possibility of pulmonary embolism (e.g., previous deep vein thrombosis or pulmonary embolism, recent unilateral leg swelling or discomfort, and/or underlying malignancy). Laboratory and imaging findings, such as spiral CT and ventilation/perfusion scans, in combination with clinical symptoms and signs provide the best means for reaching the diagnosis. The decision to pursue diagnostic imaging studies, which can be expensive and time consuming, requires some clinical judgment of pretest probability. Clinical assessment tools have been devised to assist clinicians in this decision process. Two such tools are the Wells Scoring System and the Revised Geneva Scoring System [170,171]. These systems assess a combination of clinical symptoms/signs and risk factors to determine likelihood of pulmonary embolism.


Anticoagulation is the mainstay of pulmonary embolism treatment in all cases. This involves the administration of anticoagulants such as unfractionated heparin, low-molecular-weight heparin, or fondaparinux. Warfarin, acenocoumarol, or phenprocoumon therapy is started within several days of this initial treatment.

Systemic thrombolysis is highly effective in treating pulmonary embolism, especially massive and submassive pulmonary embolisms. Commonly used fibrinolytic drugs to address thrombolysis include streptokinase, urokinase, and recombinant tissue plasminogen activators such as alteplase, reteplase, and tenecteplase. Surgical or catheter embolectomy is indicated when fibrinolytic drugs fail to induce improvement, thrombolysis is contraindicated, or persistent pulmonary vascular obstruction is present.


Pneumonia is the most common comorbid condition in patients with COPD. Pneumonia can present as a part or a trigger of COPD exacerbations; however, there are important clinical differences between pneumonia and acute COPD exacerbations without pneumonia. COPD exacerbation with pneumonia has a more rapid onset of symptoms, more severe illness, longer length of hospital stay, and higher rate of ICU admission and mortality compared to an exacerbation without pneumonia [144].

It is crucial to differentiate COPD exacerbations from pneumonia in order to initiate proper management. Prompt initiation of antibiotic therapy provides significant benefits in patients with pneumonia. Corticosteroids are the mainstay for acute exacerbations of COPD; however, their role in the management of patients with COPD with pneumonia is not clearly defined [146,147]. Treatment with salmeterol and fluticasone to manage COPD exacerbations may increase the risk of pneumonia [145].


Lung cancer and COPD are thought to be interlinked by the pathobiology of COPD rather than the shared risk factor of exposure to smoking. Although COPD and lung cancer are closely associated to smoking, patients with airway obstruction are more susceptible to developing lung cancer regardless of degree of smoking [148]. The incidence of lung cancer in the presence of moderate-to-severe airway obstruction does not differ significantly among ex-smokers and current smokers.


Musculoskeletal dysfunction limits exercise tolerance and increases disability in patients with COPD. Research indicates that patients with COPD have a decreased capacity to sustain repetitive muscular contractions, with rapid onset of muscle fatigue [149]. Patients with COPD have muscle fiber atrophy and decreased activity of aerobic enzymes. Some studies have observed lower survival rates in underweight patients with COPD, while other studies have indicated that loss of fat-free mass may be a more accurate measure of functional debilitation than other indicators, such as BMI [150]. The increased incidence of musculoskeletal dysfunction is attributed to multiple factors, including:

  • Corticosteroid use

  • Longer periods of reduced activity

  • Malnutrition

  • Oxidative stress

  • Systemic inflammation

Prolonged bed rest results in loss of muscle strength at a rate of 1% to 1.5% per day, and some patients with COPD may become cachectic or malnourished [172]. Ongoing systemic inflammation and oxidative stress can ultimately lead to muscle wasting and reduced exercise capacity. In one study, CRP levels were elevated in patients with COPD and correlated inversely with six-minute walk distance [151]. Another study revealed that elevated CRP levels were associated with inferior quality of life and limited exercise capacity in patients with severe COPD [152].

Management of musculoskeletal dysfunction involves preventing or minimizing deconditioning and avoiding systemic corticosteroid treatment. Other possible interventions include:

  • Pulmonary rehabilitation

  • Nutritional supplementation (e.g., dietary supplements, vitamins)

  • Hormone replacement (experimental with no proven efficacy)


Several factors make patients with COPD prone to osteoporosis, including old age, smoking, restricted physical activity, low BMI, undernutrition, hypogonadism, and prolonged use of corticosteroids. Systemic corticosteroids are the most common cause of drug-related osteoporosis, and long-term use of systemic corticosteroids may lead to osteoporosis, hypertension, diabetes, muscle dysfunction, and adrenal insufficiency [134]. However, some studies have observed a significant association between COPD and osteoporosis/osteopenia regardless of corticosteroid use, and the risk for osteoporosis appears to increase with COPD disease severity [173,174,175]. Daily calcium and vitamin D supplementation (1,000–1,500 mg and 400–800 IU, respectively) and lifestyle modification with pulmonary rehabilitation may be beneficial in the management of osteoporosis in patients with COPD.

People with a smoking history or advanced COPD and those being treated with continuous high-dose inhaled corticosteroids or low-to-medium dose inhaled corticosteroids with frequent courses of oral corticosteroids are considered at high risk for osteoporosis and should be screened. Risedronate (5 mg/d) or alendronate (5–10 mg/d) is the recommended first-line therapy for the prevention and treatment of osteopenia and osteoporosis [104]. Screening for metabolic abnormalities and hormonal deficiencies should be considered.


There is an increased prevalence of gastroesophageal reflux disease (GERD) and other esophageal disorders in patients with COPD, and GERD symptoms are more frequent in patients with COPD compared to control subjects [153]. Severity of COPD is also correlated to severity of GERD symptoms [153]. Still, there is not enough evidence to establish the exact nature and significance of the relationship between COPD and GERD. It is believed that Helicobacter pylori may play an important role in increasing airway inflammation [154].

The most common symptoms of GERD are heartburn, dysphagia, and regurgitation; less frequent symptoms include odynophagia (sore throat), increased salivation, chest pain, and nausea. Symptoms may be controlled by avoiding food two hours before bedtime and elevating the head of the bed. Sleeping on the left side also reduces nighttime reflux episodes [155]. In terms of pharmacotherapy, proton pump inhibitors are the most effective in treating in GERD. Other agents that can help are gastric H2-receptor blockers, antacids, sucralfate, and prokinetics. In severe cases, surgery may be necessary, and Nissen fundoplication is the standard surgical option.


Approximately 2% to 16% of patients with COPD have comorbid diabetes [74]. Studies have found that a reduction in lung function is a risk factor for developing diabetes [157,158]. In addition, CRP and inflammatory cytokines (e.g., tumor necrosis factor-alpha [TNF-a], interleukin-6), are elevated in COPD and in diabetes, indicating a possible joint etiology. One study found that patients with poor glycemic control who were hospitalized for acute COPD exacerbation had a significantly higher mortality than those with normal blood glucose levels [159]. Even after hospital discharge, diabetes remains a risk factor for mortality in these patients [160]. It is not clear whether tighter glucose control would improve COPD outcomes.


Hematopoietic suppression in COPD, similar to other chronic inflammatory diseases, is probably mediated by three different mechanisms:

  • Shortened life span of red blood cells

  • Bone marrow erythropoietin resistance

  • Impairment of iron homeostasis

Smoking, malnutrition, and systemic inflammation likely play an important role in inducing these mechanisms. Systemic inflammation in COPD is characterized by elevated levels of interleukin-6, interleukin-8, CRP, and TNF-a, with the latter two probably playing a crucial role in the mechanisms implicated in anemia.

Anemia is common in patients with COPD and is linked to greater mortality, comorbidity, and health expenditures [165]. Studies indicate that anemia is present in 8% to 33% of patients with COPD. A study by John et al. revealed significantly elevated CRP and erythropoietin levels in anemic compared with nonanemic patients with COPD [164]. Risk factors for anemia in patients with COPD include:

  • More severe airway obstruction

  • Lower BMI

  • Older age

  • Other comorbidities

Treating anemia with blood transfusion has a positive impact on clinical and physiologic parameters in patients with COPD [179]. However, the role of pharmacotherapy in the treatment of anemia in patients with COPD is not clear.


Aspiration of food and/or liquids can lead to recurrent exacerbations and complications in patients with COPD. Some patients experience impaired breathing-swallowing coordination and are at risk of aspiration, which in turn increases the risk of COPD exacerbation.

Diagnosis of aspiration can easily be made with an adequate history from the patient and his or her carer(s). Treatment generally involves training in safe and proper swallowing techniques. Patients should be advised to:

  • Sit upright, especially when eating

  • Take a small quantity of food at a time

  • Avoid talking when eating

  • Chew adequately

  • Drink thickened fluids

  • Drink with dry foods

  • Use a straw


COPD has become a global health problem and is increasing worldwide, especially in underdeveloped and developing countries [166]. This chronic debilitating disease is now one of the leading causes of mortality and disability, with a prevalence of approximately 10% in individuals older than 40 years of age in most countries [167]. COPD also leads to significant economic burden on people and society.

Despite making rapid strides in understanding the pathophysiology of COPD, the natural history of this condition and its treatment strategies have not changed significantly in recent decades. There are no drug therapies capable of preventing disease progression or reducing mortality. However, researchers now have a better understanding of COPD, which is resulting in identification of novel targets for new drugs and treatments [168,169].

Works Cited

1. World Health Organization. COPD Predicted to be Third Leading Cause of Death in 2030. Available at http://www.who.int/gard/news_events/World_Health_Statistics_2008/en/index.html. Last accessed October 14, 2016.

2. Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J. 2006;27(2):397-412.

3. Nathell L, Nathell M, Malmberg P, Larsson K. COPD diagnosis related to different guidelines and spirometry techniques. Respir Res. 2007;4(8):89.

4. Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR. 2012;61(46):938-943.

5. Ford ES, Murphy LB, Khaviou O, Giles WH, et al. Total and state-specific medical and absenteeism costs of COPD among adults aged ≥18 years In the United States for 2010 and projections through 2020. Chest. 2015;147(1):31-45.

6. U.S. Surgeon General. The Health Consequences of Smoking: Chronic Obstructive Pulmonary Disease. Washington, DC: U.S. Department of Health and Human Services; 1984.

7. Burrows B, Knudson RJ, Cline MG, Lebowitz MD. Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis. 1977;115(2):195-205.

8. Becklake MR. Occupational exposures: evidence for a causal association with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1989;140(3 Pt 2):S85-S91.

9. Trupin L, Earnest G, San Pedro M, et al. The occupational burden of chronic obstructive pulmonary disease. Eur Respir J. 2003;22(3):462-469.

10. Matheson MC, Benke G, Raven J, et al. Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease. Thorax. 2005;60(8):645-651.

11. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Association between chronic obstructive pulmonary disease and employment by industry and occupation in the US population: a study of data from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2002;156(8):738-746.

12. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Airflow obstruction attributable to work in industry and occupation among U.S. race/ethnic groups: a study of NHANES III data. Am J Ind Med. 2004;46(2):126-135.

13. Balmes J, Becklake M, Blanc P, et al. American Thoracic Society Statement: Occupational contribution to the burden of airway disease. Am J Respir Crit Care Med. 2003;167(5):787-797.

14. Smith KR. Inaugural article: national burden of disease in India from indoor air pollution. Proc Natl Acad Sci USA. 2000;97(24):13286-13293.

15. Chan-Yeung M, Ait-Khaled N, White N, Ip MS, Tan WC. The burden and impact of COPD in Asia and Africa. Int J Tuberc Lung Dis. 2004;8(1):2-14.

16. Smith KR. Indoor air pollution. Pollut Manage Focus. 1999;8(4).

17. Abbey DE, Burchette RJ, Knutsen SF, McDonnell WF, Lebowitz MD, Enright PL. Long-term particulate and other air pollutants and lung function in nonsmokers. Am J Respir Crit Care Med. 1998;158(1):289-298.

18. Lawlor DA, Ebrahim S, Davey Smith G. Association of birth weight with adult lung function: findings from the British Women's Heart and Health Study and a meta-analysis. Thorax. 2005;60(10):851-858.

19. MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(1):50-60.

20. Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur Respir J. 1994;7(6):1056-1061.

21. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA. 1994;272(19):1497-1505.

22. Silverman EK, Weiss ST, Drazen JM, et al. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;162(6):2152-2158.

23. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173:991-998.

24. Retamales I, Elliott WM, Meshi B, et al. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med. 2001;164:469-473.

25. Sethi S, Murphy T. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359:2355-2365.

26. Shaheen SO, Barker DJ, Shiell AW, Crocker FJ, Wield GA, Holgate ST. The relationship between pneumonia in early childhood and impaired lung function in late adult life. Am J Respir Crit Care Med. 1994;149(3 Pt 1):616-619.

27. Prescott E, Lange P, Vestbo J. Socioeconomic status, lung function and admission to hospital for COPD: results from the Copenhagen City Heart Study. Eur Respir J. 1999;13(5):1109-1114.

28. Tao X, Hong CJ, Yu S, Chen B, Zhu H, Yang M. Priority among air pollution factors for preventing chronic obstructive pulmonary disease in Shanghai. Sci Total Environ. 1992;127(1-2):57-67.

29. U.S. Centers for Disease Control and Prevention. Criteria for a Recommended Standard: Occupational Exposure to Respirable Coal Mine Dust. Washington, DC: National Institute of Occupational Safety and Health; 1995.

30. Sahebjami H, Vassallo CL. Influence of starvation on enzyme induced emphysema. J Appl Physiol. 1980;48(2):284-288.

31. Coxson HO, Chan IH, Mayo JR, Hlynsky J, Nakano Y, Birmingham CL. Early emphysema in patients with anorexia nervosa.Am J Respir Crit Care Med. 2004;170(7):748-752.

32. Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest. 2004;126(1):59-65.

33. Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364(9435):709-721.

34. Breuer R, Christensen TG, Lucey EC, et al. An ultrastructural morphometric analysis of elastase-treated hamster bronchi shows discharge followed by progressive accumulation of secretory granules. Am Rev Respir Dis. 1987;136(3):698-703.

35. Nadel JA. Role of mast cell and neutrophil proteases in airway secretion. Am Rev Respir Dis. 1991;144(3 Pt 2):548-551.

36. O'Donnell RA, Peebles C, Ward JA, et al. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax. 2004;59(10):837-843.

37. Kuschner WG, D'Alessandro A, Wong H, Blanc PB. Dose-dependent cigarette smoking-related inflammatory responses in healthy adults. Eur Respir J. 1996;9(10)1989-1994.

38. Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med. 1995;152(5 Pt 1):1665-1672.

39. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema.Eur Respir J. 2001;17(5):946-953.

40. Longmore JM, Wilkinson I, Rajagopalan SR. Oxford Handbook of Clinical Medicine. Oxford: Oxford University Press; 2004.

41. Lodish H, Berk A, Matsudaira P, et al. Molecular Cell Biology. 5th ed. New York, NY: WH Freeman; 2000.

42. Kumar P, Clark M. Clinical Medicine. 6th ed. Edinburgh: Elsevier Saunders; 2005.

43. Wenzel RP, Fowler AA. Clinical practice: acute bronchitis. N Engl J Med. 2006;355(20):2125-2130.

44. Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis.Am J Respir Crit Care Med. 1999;160(3):893-898.

45. Stockley RA, O'Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient management of acute exacerbation. Chest. 2000;117(6)1638-1645.

46. Mannino DM, Ford ES, Redd SC. Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination. Am J Med. 2003;114(9):758-762.

47. Badgett RG, Tanaka DJ, Hunt DK, et al. Can moderate chronic obstructive pulmonary disease be diagnosed by historical and physical findings alone? Am J Med. 1993;94(2):188-196.

48. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26(5):948-968.

49. Jackson H, Hubbard R. Detecting chronic obstructive pulmonary disease using peak flow rate: cross sectional survey. BMJ. 2003;327(7416):653-654.

50. Wilt TJ, Niewoehner D, Kim C, et al. Use of spirometry for case finding, diagnosis, and management of chronic obstructive pulmonary disease (COPD). Evid Rep Technol Assess (Summ). 2005;(121):1-7.

51. Kanner RE, Connett JE, Williams DE, Buist AS. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med. 1999;106(4):410-416.

52. Pinto-Plata VM, Cote C, Cabral H, Taylor J, Celli BR. The 6-min walk distance: change over time and value as a predictor of survival in severe COPD. Eur Respir J. 2004;23(1):28-33.

53. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T. Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med. 2003;167(4):544-549.

54. Casanova C, Cote C, de Torres JP, et al. Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171(6):591-597.

55. Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party. Lancet. 1981;1(8222):681-686.

56. Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive disease. Am J Clin Nutr. 2005;82(1):53-59.

57. 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(10):1005-1012.

58. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA. Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study. Thorax. 2003;58(8):654-658.

59. Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW. Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax. 2003;58(8):659-664.

60. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volumereduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348(21):2059-2073.

61. John M, Lange A, Hoernig S, Witt C, Anker SD. Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases. Int J Cardiol. 2006;111(3):365-370.

62. Chambellan A, Chailleux E, Similowski T. Prognostic value of the hematocrit in patients with severe COPD receiving longterm oxygen therapy. Chest. 2005;128(3):1201-1208.

63. Hjalmarson A, Franzon M, Westin A, Wiklund O. Effect of nicotine nasal spray on smoking cessation: a randomized, placebo-controlled, double-blind study. Arch Intern Med. 1994;154(22):2567-2572.

64. Schneider NG, Olmstead R, Mody FV, et al. Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial. Addiction. 1995;90(12):1671-1682.

65. Sutherland G, Stapleton JA, Russell MA, et al. Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet. 1992;340(8815):324-329.

66. Rose JE, Behm FM, Westman EC, Johnson M. Dissociating nicotine and nonnicotine components of cigarette smoking. Pharmacol Biochem Behav. 2000;67(1):71-81.

67. Rose JE, Behm FM, Westman EC, Bates JE, Salley A. Pharmacologic and sensorimotor components of satiation in cigarette smoking. Pharmacol Biochem Behav. 2003;76(2):243-250.

68. Ascher JA, Cole JO, Colin JN, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry. 1995;56(9):395-401.

69. Hughes JR, Goldstein MG, Hurt RD, Shiffman S. Recent advances in the pharmacotherapy of smoking. JAMA. 1999;281(1):72-76.

70. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2004;(3):CD000058.

71. Batra V, Sethi GR, Sachdev HPS. Comparative efficacy of jet nebulizer and metered dose inhaler with spacer device in the treatment of acute asthma. Indian Pediatr. 1997;34(6):497-503.

72. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines. Chest. 2005;127(1):335-371.

73. Martinez FJ. Surgical therapy for chronic obstructive pulmonary disease: conventional bullectomy and lung volume reduction surgery in the absence of giant bullae. Semin Respir Crit Care Med. 1999;20:351-364.

74. Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4):549-555.

75. Liu Y, Lee K, Perez-Padilla R, Hudson NL, Mannino DM. Outdoor and indoor air pollution and COPD-related diseases in high- and low-income countries. Int J Tuberc Lung Dis. 2008;12(2):115-127.

76. Celli BR, Halbert RJ, Nordyke RJ, Schan B. Airway obstruction in never smokers: results from the Third National Health and Nutrition Examination Survey. Am J Med. 2005;118(12):1364-1372.

77. Chapman RS, Xingzhou H, Blair AE, Lan Q. Improvement in household stoves and risk of chronic obstructive pulmonary disease in Xuanwei, China: retrospective cohort study. BMJ. 2005;331:1050.

78. Ghambarian MH, Feenstra TL, Zwanikken P, Kalinina AM. Can prevention be improved? Proposal for an integrated intervention strategy. Prev Med. 2004;39(2):337-343.

79. Nichter M. Introducing tobacco cessation in developing countries: an overview of Quit Tobacco International. Tob Control. 2006;15(Suppl 1):12-17.

80. Vestbo J, Pauwels R, Anderson JA, Jones P, Calverley P. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease. Thorax. 2005;60(4):301-304.

81. Boe J, Dennis JH, O'Driscoll BR, et al. European Respiratory Society Guidelines on the use of nebulizers. Eur Respir J. 2001;18(1):228-242.

82. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250-255.

83. Calverley PMA. Cough in chronic obstructive pulmonary disease: is it important and what are the effects of treatment? Cough. 2013;9:17.

84. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143(5):317-326.

85. Casaburi R, Kukafka D, Cooper CB, Witek TJJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005;127(3):809-817.

86. U.S. Food and Drug Administration. FDA Approves Breo Ellipta to Treat Chronic Obstructive Pulmonary Disease. Available at http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm351664.htm. Last accessed October 14, 2016.

87. Rossi A, Kristufek P, Levine BE, et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest. 2002;121(4):1058-1069.

88. Kato M, Komamura K, Kitakaze M. Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure. Circ J. 2006;70(12):1658-1660.

89. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. Thorax. 2000;55(4):289-294.

90. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19(2):217-224.

91. Rabe KF. Anticholinergic drugs for the treatment of COPD are safe…are they? Chest. 2010;137(1):1-3.

92. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166(8):1084-1091.

93. Jones PW, Willits LR, Burge PS, Calverley PM. Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations. Eur Respir J. 2003;21(1):68-73.

94. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet. 2003;361(9356):449-456.

95. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21(1):74-81.

96. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med. 2002;166(10):1358-1363.

97. Sin DD, Wu L, Anderson JA, et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax. 2005;60(12):992-997.

98. Hanania NA, Darken P, Horstman D, Reisner C, Lee B, Davis S, Shah T. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003;124(3):834-843.

99. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22(6):912-919.

100. Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest. 2004;125(6):2011-2020.

101. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections. Eur Respir J. 2005;26(6):1138-1180.

102. Alfageme I, Vazquez R, Reyes N, et al. Clinical efficiacy of anti-pneumococcal vaccination in patients with COPD. Thorax. 2006;61:189-195.

103. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged >/= 65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2014;63(37):822-825.

104. LexiComp Online. Available at http://online.lexi.com. Last accessed October 14, 2016.

105. Troosters T, Casaburi R, Gosselink R, Decramer M. Pulmonary rehabilitation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;172(1):19-38.

106. Wijkstra PJ, Wempe JB. New tools in pulmonary rehabilitation. Eur Respir J. 2011;38(6):1468-1474.

107. Yohannes AM, Connolly MJ. Early mobilization with walking aids following hospital admission with acute exacerbation of chronic obstructive pulmonary disease. Clin Rehabil. 2003;17(5):465-471.

108. Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R. Benefits of supplemental oxygen in exercise training in nonhypoxemic chronic obstructive pulmonary disease patients. Am J Respir Crit Care Med. 2003;168(9):1034-1042.

109. Palange P, Valli G, Onorati P, et al. Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients. J Appl Physiol. 2004;97(5):1637-1642.

110. Ries AL, Kaplan RM, Myers R, Prewitt LM. Maintenance after pulmonary rehabilitation in chronic lung disease: a randomized trial. Am J Respir Crit Care Med. 2003;167(6):880-888.

111. Steiner MC, Barton RL, Singh SJ, Morgan MD. Nutritional enhancement of exercise performance in chronic obstructive pulmonary disease: a randomised controlled trial. Thorax. 2003;58(9):745-751.

112. Migliore Norweg A, Whiteson J, Demetis S, Rey M. A new functional status outcome measure of dyspnea and anxiety for adults with lung disease: the dyspnea management questionnaire. J Cardiopulm Rehabil. 2006;26(6):395-404.

113. Yeh SS, DeGuzman B, Kramer T. Reversal of COPD-associated weight loss using the anabolic agent oxandrolone. Chest. 2002;122(2):421-428.

114. Weisberg J, Wanger J, Olson J, et al. Megestrol acetate stimulates weight gain and ventilation in underweight COPD patients. Chest. 2002;121(4):1070-1078.

115. Tarpy SP, Celli BR. Long-term oxygen therapy. N Engl J Med. 1995;333(11):710-714.

116. Lacasse Y, Lecours R, Pelletier C, Begin R, Maltais F. Randomised trial of ambulatory oxygen in oxygen-dependent COPD. Eur Respir J. 2005;25(6):1032-1038.

117. Elliott MW. Noninvasive ventilation in chronic ventilatory failure due to chronic obstructive pulmonary disease. Eur Respir J. 2002;20(3):511-514.

118. Clini E, Sturani C, Rossi A, et al. The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients. Eur Respir J. 2002;20(3):529-538

119. Schuurmans MM, Diacon AH, Bolliger CT. Functional evaluation before lung resection. Clin Chest Med. 2002;23(1):159-172.

120. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932-946.

121. Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J. 2003;41:46s-53s.

122. White AJ, Gompertz S, Stockley RA. Chronic obstructive pulmonary disease. 6: the aetiology of exacerbations of chronic obstructive pulmonary disease. Thorax. 2003;58(1):73-80.

123. Pasquale MK, Sun SX, Song F, et al. Impact of exacerbations on health care cost and resource utilization in chronic obstructive pulmonary disease patients with chronic bronchitis from a predominately Medicare population. Int J Chron Obstruct Pulmon Dis. 2012;7:757-764.

124. Mueller C, Laule-Kiliam K, Frana B, et al. The use of B-natriuretic peptide in the management of elderly patients with acute dyspnea. J Intern Med. 2005;258(1):77-85.

125. Greenstone M, Lasserson TJ. Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2003;(1):CD000223

126. Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003;326(7382):185.

127. 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(9219):1931-1935.

128. Parker CM, Voduc N, Aaron SD, Webb KA, O'Donnell DE. Physiological changes during symptom recovery from moderate exacerbations of COPD. Eur Respir J. 2005;26(3):420-428.

129. Puhan MA, Frey M, Büchi S, Schünemann HJ. The minimal important difference of the hospital anxiety and depression scale in patients with chronic obstructive pulmonary disease. Health Qual Life Outcomes. 2008;6:46.

130. Stewart AL, Greenfield S, Hays RD, et al. Functional status and well-being of patients with chronic conditions. JAMA. 1989;262:907-913.

131. Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan, Canada cardiovascular disease in COPD patients. Ann Epidemiol. 2006;16(1):63-70.

132. Schipper PH, Meyers BF, et al. Outcomes after resection of giant emphysematous bullae. Ann Thorac Surg. 2004;78:976-982.

133. Lahzami S, Bridevaux PO, Soccal PM, et al. Survival impact of lung transplantation for COPD. Eur Respir J. 2010;36(1):74-80.

134. Barr RG, Celli BR, Martinez FJ, et al. Physician and patient perceptions in COPD: the COPD Resource Network Needs Assessment Survey. Am J Med. 2005;118:1415.

135. Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest. 2005;127(6):1952-1959.

136. Agusti A. Thomas A. Neff lecture. Chronic obstructive pulmonary disease: a systemic disease. Proc Am Thorac Soc. 2006;3(6): 478-481.

137. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59(7):574-580.

138. Ukena C, Mahfoud F, Kindermann M, et al. The cardiopulmonary continuum systemic inflammation as "common soil" of heart and lung disease. Int J Cardiol. 2010;145:172-176.

139. Calverley PM, Anderson JA, Celli B, et al. Cardiovascular events in patients with COPD: TORCH study results. Thorax. 2010;65(8):719-725.

140. De Miguel-Diez J, Carrasco-Garrido P, Rejas-Gutierrez J, et al. The influence of heart disease on characteristics, quality of life, use of health resources, and costs of COPD in primary care settings. BMC Cardiovasc Disord. 2010;10:8.

141. Boudestein LC, Rutten FH, Cramer MJ, Lammers JW, Hoes AW. The impact of concurrent heart failure on prognosis in patients with chronic obstructive pulmonary disease. Eur J Heart Fail. 2009;11(12):1182-1188.

142. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;(4):CD003566.

143. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ. 2011;342:d2549.

144. Lieberman D, Lieberman D, Gelfer Y, et al. Pneumonic vs. nonpneumonic acute exacerbations of COPD. Chest. 2002;122(4):1264-1270.

145. Calverley PM, Anderson JA, Celli B, et al. TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789.

146. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care. 2007;176(6):532-555.

147. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Respir Crit Care Med. 2005;171(3):242-248.

148. Wasswa-Kintu S, Gan WQ, Man SF, Pare PD, Sin DD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax. 2005;60(7):570-575

149. Coronell C, Orozco-Levi M, Mendez R, Ramirez-Sarmiento A, Galdiz JB, Gea J. Relevance of assessing quadriceps endurance in patients with COPD. Eur Respir J. 2004;24(1):129-136.

150. Vestbo J, Prescott E, Almdal T, et al. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study. Am J Respir Crit Care Med. 2006;173(1):79-83.

151. Pinto-Plata VM, Mullerova H, Toso JF, et al. C-reactive protein in patients with COPD, control smokers and non-smokers. Thorax. 2006;61(1):23-28.

152. Broekhuizen R, Wouters EF, Creutzberg EC, Schols AM. Raised CRP levels mark metabolic and functional impairment in advanced COPD. Thorax. 2006;61(1):17-22.

153. Mokhlesi B, Morris AL, Huang CF, Curcio AJ, Barrett TA, Kamp DW. Increased prevalence of gastroesophageal reflux symptoms in patients with COPD. Chest. 2001;119(4):1043-1048.

154. Roussos A, Philippou N, Krietsepi V, et al. Helicobacter pylori seroprevalence in patients with chronic obstructive pulmonary disease. Respir Med. 2005;99(3):279-284.

155. Khoury RM, Camacho-Lobato L, Katz PO, Mohiuddin MA, Castell DO. Influence of spontaneous sleep positions on nighttime recumbent reflux in patients with gastroesophageal reflux disease. Am J Gastroenterol. 1999;94(8):2069-2073.

156. Barr RG, Bluemke DA, Ahmed FS, et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N Engl J Med. 2010;362:217-227.

157. Engstrom G, Janzon L. Risk of developing diabetes is inversely related to lung function: a population-based cohort study. Diabet Med. 2002;19(2):167-170.

158. Engstrom G, Hedblad B, Nilsson P, Wollmer P, Berglund G, Janzon L. Lung function, insulin resistance and incidence of cardiovascular disease: a longitudinal cohort study. J Intern Med. 2003;253(5):574-581.

159. Baker EH, Janaway CH, Philips BJ, et al. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax. 2006;61(4):284-289.

160. Gudmundsson G, Gislason T, Lindberg E, et al. Mortality in COPD patients discharged from hospital: the role of treatment and comorbidity. Respir Res. 2006;7(1):109.

161. Etminan M, Jafari S, Carleton B, FitzGerald JM. Beta-blocker use and COPD mortality: a systematic review and meta-analysis. BMC Pulm Med. 2012;12:48.

162. Sin DD, Man SF. Chronic obstructive pulmonary disease as a risk factor for cardiovascular morbidity and mortality. Proc Am Thorac Soc. 2005;2(1):8-11.

163. Dobler CC, Wong KK, Marks GB. Associations between statins and COPD: a systematic review. BMC Pulm Med. 2009;9:32.

164. John M, Hoernig S, Doehner W, Okonko DD, Witt C, Anker SD. Anemia and inflammation in COPD. Chest. 2005;127(3):825-829.

165. Halpern MT, Zilberberg MD, Schmier JK, Lau EC, Shorr AF. Anemia, costs and mortality in chronic obstructive pulmonary disease. Cost Eff Resour Alloc. 2006;4:17.

166. Barnes PJ. Chronic obstructive pulmonary disease: a growing but neglected epidemic. PLoS Med. 2007;4(5):e112.

167. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007;370(9589):765-773.

168. Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. 2003;22(4):672-688.

169. Barnes PJ. Emerging pharmacotherapies for COPD. Chest. 2008;134(6):1278-1286.

170. Wells PS, Ginsberg JS, Anderson DR, et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med. 1998;129(12):997-1005.

171. Le Gal G, Righini M, Roy PM, et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med. 2006;144(3):165-171.

172. Topp R, Ditmyer M, King K, Doherty K, Hornyak J 3rd. The effect of bed rest and potential of prehabilitation on patients in the intensive care unit. AACN Clin Issues. 2002;13(2):263-276.

173. Iqbal F, Michaelson J, Thaler L, et al. Declining bone mass in men with chronic pulmonary disease: contribution of glucocorticoid treatment, body mass index, and gonadal function. Chest. 1999;116:1616-1624.

174. Praet JP, Peretz A, Rozenberg S, et al. Risk of osteoporosis in men with chronic bronchitis. Osteoporos Int. 1992;2:257-261.

175. Vrieze A, de Greef MH, Wijkstra PJ, Wempe JB. Low bone mineral density in COPD patients related to worse lung function, low weight and decreased fat-free mass. Osteoporos Int. 2007;18:1197-1202.

176. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of COPD—2006 update.Am J Respir Crit Care Med. 2007;176(6):532-555.

177. Cazzola M, Matera MG. Novel long-acting bronchodilators for COPD and asthma. Br J Pharmacol. 2008;155(3):291-299.

178. Forest Laboratories. Forest Laboratories and Almirall Announce FDA Approval of Tudorza Pressair for the Long-Term Maintenance Treatment of COPD. Available at http://www.businesswire.com/news/home/20120723006370/en/Forest-Laboratories-Almirall-Announce-FDA-Approval-Tudorza%E2%84%A2. Last accessed October 14, 2016.

179. Schonhofer B, Wenzel M, Geibel M, Kohler D. Blood transfusion and lung function in chronically anemic patients with severe chronic obstructive pulmonary disease. Crit Care Med. 1998;26:1824-1828.

180. Bateman ED, Kornmann O, Ambery C, Norris V. Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther. 2013;26(5):581-587.

181. U.S. Food and Drug Administration. FDA Approves New Drug to Treat Chronic Obstructive Pulmonary Disease. Available at http://www.fda.gov/NewsEvents/newsroom/PressAnnouncements/ucm244989.htm. Last accessed October 14, 2016.

182. Hind M, Maden M. Is a regenerative approach viable for the treatment of COPD? Br J Pharmacol. 2011;163(1):106-115.

183. Mallia P, Johnston SL. COPD: new treatment strategies. Future Prescriber. 2013;14(1):13-16.

184. Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373(9678):1905-1917.

185. Suissa S, Barnes PJ. Inhaled corticosteroids in COPD: the case against. Eur Respir J. 2009;34:13-16.

186. Giembycz MA. Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?Br J Pharmacol. 2008;155(3):288-290.

187. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144(1):266-273.

188. Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 2009;71:451-464.

189. Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004;200(5):689-695.

190. Kirkham P, Rahman I. Oxidative stress in asthma and COPD: antioxidants as a therapeutic strategy. Pharmacol Ther. 2006;111(2):476-494.

191. Fischer BM, Pavlisko E, Voynow JA. Pathogenic triad in COPD: oxidative stress, protease-antiprotease imbalance, and inflammation. Int J Chron Obstruct Pulmon Dis. 2011;6:413-421.

192. Charron C, Sumakuza T, Oomura S, Ito K. EM-703, a non-antibacterial erythromycin derivative, restores HDAC2 activation diminished by hypoxia and oxidative stress. Proc Am Thorac Soc. 2007;175:A640.

193. Delage A, Tillie-Leblond I, Cavestri B, Wallaert B, Marquette CH. Cryptogenic hemoptysis in chronic obstructive pulmonary disease: characteristics and outcome. Respiration. 2010;80(5):387-392.

194. Patel N, DeCamp M, Criner GJ. Lung transplantation and lung volume reduction surgery versus transplantation in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4):447-453.

195. Alldredge BK, Corelli RL, Ernst ME, et al. (eds). Koda-Kimble and Young's Applied Therapeutics: The Clinical Use of Drugs. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.

196. Glaxo Kline Smith. Health Professional User Guide: COPD Assessment Test. Available at http://www.catestonline.org/images/UserGuides/CATHCPUser%20guideEn.pdf. Last accessed October 14, 2016.

197. Stenton C. The MRC breathlessness scale. Occup Med (Lond). 2008;58(3):226-227.

198. Todd DC, McIvor RA, Pugsley SO, Cox G. Approach to chronic obstructive pulmonary disease in primary care. Can Fam Physician. 2008;54(5):706-711.

199. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of COPD, 2016. Available at http://goldcopd.org/global-strategy-diagnosis-management-prevention-copd-2016. Last accessed October 14, 2016.

200. Breathe California. Managing Chronic Obstructive Pulmonary Disease (COPD): Differential Diagnosis of COPD. Available at http://www.ggbreathe.org/wp-content/uploads/2014/08/Differential-Diagnosis-of-COPD.pdf. Last accessed October 14, 2016.

201. Chronic obstructive pulmonary disease: national clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax. 2004;59(Suppl I):1-232.

202. Proctor RN. The Nazi war on tobacco: ideology, evidence, and possible cancer consequences. Bull Hist Med. 1997;71(3):435-488.

203. Henningfield JE, Benowitz NL, Connolly GN, et al. Reducing tobacco addiction through tobacco product regulation. Tob Control. 2004;13(2):132-135.

204. Campaign for Tobacco-Free Kids. Voters Across the Country Support Significant Increases in Cigarette Taxes. Available at http://www.tobaccofreekids.org/research/factsheets/pdf/0026.pdf. Last accessed October 14, 2016.

205. Campaign for Tobacco-Free Kids. Map of State Cigarette Tax Rates. Available at http://www.tobaccofreekids.org/research/factsheets/pdf/0222.pdf. Last accessed October 14, 2016.

206. Lindblom E. Campaign for Tobacco-Free Kids. Public Health Benefits and Healthcare Cost Savings from the Federal Cigarette Tax Increase. Available at http://www.tobaccofreekids.org/research/factsheets/pdf/0375.pdf. Last accessed October 14, 2016.

207. Centers for Disease Control and Prevention. Trends in State and Federal Cigarette Tax and Retail Price—United States, 1970–2014. Available at https://www.cdc.gov/tobacco/infographics/economics/index.htm. Last accessed October 14, 2016.

208. Eriksen MP, Gottlieb NH. A review of the health impact of smoking control at the workplace. Am J Health Promot. 1998;13(2): 83-104.

209. Brandon TH. Behavioral tobacco cessation treatments: yesterday's news or tomorrow's headlines? J Clin Oncol. 2001;19(18 Suppl):64S-68S.

210. Thompson RS, Michnich ME, Friedlander L, Gilson B, Grothaus LC, Storer B. Effectiveness of smoking cessation interventions integrated into primary care practice. Med Care. 1988;26(1):62-76.

211. Cromwell J, Bartosch WJ, Fiore MC, Hasselblad V, Baker T. Cost-effectiveness of the clinical practice recommendations in the AHCPR guideline for smoking cessation. JAMA. 1997;278(21):1759-1766.

212. Hall S, Rugg D, Tunstall C, Jones RT. Preventing relapse to cigarette smoking by behavioral skill training. J Consult Clin Psychol. 1984;52(3):372-382.

213. Stevens VJ, Hollis JF. Preventing smoking relapse using an individually tailored skills-training technique. J Consult Clin Psychol. 1989;57(3):420-424.

214. Tiffany ST, Martin EM, Baker TB. Treatments for cigarette smoking: An evaluation of the contributions of aversion and counseling procedures. Behav Res Ther. 1986;24(4):437-452.

215. Houtsmuller EJ, Stitzer ML. Manipulation of cigarette craving through rapid smoking: efficacy and effects on smoking behavior. Psychopharmacology (Berl). 1999;142(2):149-157.

216. Cinciripini PM, Lapitsky LG, Wallfisch A, Mace R, Nezami E, Van Vunakis H. An evaluation of a multicomponent treatment program involving scheduled smoking and relapse prevention procedures: initial findings. Addict Behav. 1994;19(1):13-22.

217. Pfizer Inc. Chantix (Varenicline) Tablets. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021928s008lbl.pdf. Last accessed October 14, 2016.

218. Marlow SP, Stoller JK. Smoking cessation. Respir Care. 2003;48(12):1238-1256.

219. Gorsline J, Okerholm RA, Rolf CN, Moos CD, Hwang SS. Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites. J Clin Pharmacol. 1992;32(6):576-581.

220. Hurt RD. New medications for nicotine dependence treatment. Nicotine Tob Res. 1999;1(Suppl 2):S175-S179; discussion S207-S210.

221. Molander L, Lunell E, Fagerström KO. Reduction of tobacco withdrawal symptoms with a sublingual nicotine tablet: a placebo controlled study. Nicotine Tob Res. 2000;2(2):187-191.

222. Tønnesen P, Mikkelsen K, Bremann L. Nurse-conducted smoking cessation in patients with COPD using nicotine sublingual tablets and behavioral support. Chest. 2006;130(2):334-342.

223. Spathis A, Booth S. End of life care in chronic obstructive pulmonary disease: in search of a good death. Int J Chron Obstruct Pulmon Dis. 2008;3(1):11-29.

224. Global Initiative for Chronic Obstructive Pulmonary Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (Updated 2016). Available at http://goldcopd.org/global-strategy-diagnosis-management-prevention-copd-2016/. Last accessed October 14, 2016.

225. U.S. Food and Drug Administration. FDA Approves Anora Ellipta to Treat Chronic Obstructive Pulmonary Disease. Available at http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm379057.htm. Last accessed October 14, 2016.

226. U.S. Food and Drug Administration. FDA Approves Striverdi Respimat to Treat Chronic Obstructive Pulmonary Disease. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm407465.htm. Last accessed October 14, 2016.

227. 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 Int Med. 2006;144(6):390-396.

Evidence-Based Practice Recommendations Citations

1. Qaseem A, Wilt TJ, Weinberger SE, et al. 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(3):179-191. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/34205. Last accessed October 21, 2016.

2. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147(4):894-942. Summary retrieved from National Guideline Clearinghouse at https://www.guideline.gov/summaries/summary/49133. Last accessed October 21, 2016.

Copyright © 2016 NetCE, P.O. Box 997571, Sacramento, CA 95899-7571
Mention of commercial products does not indicate endorsement.