Cleveland Clinic Journal of Medicine

Contents

Introduction
Barbara P. Yawn, MD, MSc, FAAFP

Dyspnea and Hyperinflation in Chronic Obstructive Pulmonary Disease: Impact on Physical Activity
Nathaniel Marchetti, DO, and Alan Kaplan, MD

Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management
Abebaw Mengistu Yohannes, PhD; Alan Kaplan, MD; and Nicola A. Hanania, MD, MS

Considerations for Optimal Inhaler Device Selection in Chronic Obstructive Pulmonary Disease
Rajiv Dhand, MD; Tricia Cavanaugh, MD; and Neil Skolnik, MD

Treatment Options for Stable Chronic Obstructive Pulmonary Disease: Current Recommendations and Unmet Needs
Barbara Yawn, DM, MSc, FAAFP; and Victor Kim, MD

Contents

Introduction
Barbara P. Yawn, MD, MSc, FAAFP

Dyspnea and Hyperinflation in Chronic Obstructive Pulmonary Disease: Impact on Physical Activity
Nathaniel Marchetti, DO, and Alan Kaplan, MD

Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management
Abebaw Mengistu Yohannes, PhD; Alan Kaplan, MD; and Nicola A. Hanania, MD, MS

Considerations for Optimal Inhaler Device Selection in Chronic Obstructive Pulmonary Disease
Rajiv Dhand, MD; Tricia Cavanaugh, MD; and Neil Skolnik, MD

Treatment Options for Stable Chronic Obstructive Pulmonary Disease: Current Recommendations and Unmet Needs
Barbara Yawn, DM, MSc, FAAFP; and Victor Kim, MD

Contents

Introduction
Barbara P. Yawn, MD, MSc, FAAFP

Dyspnea and Hyperinflation in Chronic Obstructive Pulmonary Disease: Impact on Physical Activity
Nathaniel Marchetti, DO, and Alan Kaplan, MD

Anxiety and Depression in Chronic Obstructive Pulmonary Disease: Recognition and Management
Abebaw Mengistu Yohannes, PhD; Alan Kaplan, MD; and Nicola A. Hanania, MD, MS

Considerations for Optimal Inhaler Device Selection in Chronic Obstructive Pulmonary Disease
Rajiv Dhand, MD; Tricia Cavanaugh, MD; and Neil Skolnik, MD

Treatment Options for Stable Chronic Obstructive Pulmonary Disease: Current Recommendations and Unmet Needs
Barbara Yawn, DM, MSc, FAAFP; and Victor Kim, MD

More than 13 million people in the United States have been diagnosed with chronic obstructive pulmonary disease (COPD),¹ a complex, heterogeneous respiratory condition characterized by persistent, and usually progressive, airflow limitation.^2,3 The prevalence of COPD is rising: It has been declared the third leading cause of death in the United States,⁴ and the World Health Organization has predicted that it will become the third leading cause of death worldwide by 2030.⁵ This increase is driven by an aging population, and tobacco smoking, which is the primary risk factor for COPD in high-income countries.⁶

Symptoms of COPD, as well as the severity of these symptoms, can vary, but patients typically present with dyspnea, chronic cough, and sputum production.² These symptoms are often underreported by patients with COPD,² but have a significant impact on patients’ day-to-day lives, adversely affecting their quality of life and their ability to engage in physical activity, further contributing to disease progression.^7,8

Comorbidities are common in patients with COPD, and can pose significant challenges to the diagnosis and management of the condition. Some of these comorbidities, such as lung cancer and ischemic heart disease, share a common etiologic pathway with COPD—smoking; while others, such as anxiety and depression, appear to be unrelated to COPD pathogenesis, although they may share a systemic inflammatory basis, and are highly prevalent in patients with COPD.⁹

Primary care physicians are the key point of contact for most patients with COPD,¹⁰ and play a critical role in diagnosis, drug and device selection, and long-term disease management of COPD and associated comorbidities. A number of pharmacologic and nonpharmacologic treatment options are available to manage COPD symptoms, which can confer considerable benefits to patients. Selection of pharmacologic treatment should be based on an individual patient’s symptom burden and their exacerbation history, and it is important that physicians are aware of when therapy should be escalated, and indeed stopped if no longer required.²

Proper device selection is an important part of choosing treatments for patients with COPD. A variety of inhaler devices are available for COPD medications, and it is important that devices are matched to patients’ needs and preferences based on device characteristics and individual patient capabilities.

The aim of this supplement is to provide readers with an introduction to 4 key topics critical to the effective management of COPD in primary care, highlighting best practices to optimize patient care and outcomes. In the first article, Dr. Marchetti and Dr. Kaplan review physical activity in COPD, discussing its inter-relationship with dyspnea and hyperinflation, and its importance in modifying disease progression.

The second article examines anxiety and depression in COPD. Prof. Yohannes, Dr. Kaplan, and Dr. Hanania review the prevalence, mechanisms, and impact of the 2 often overlooked and undertreated psychologic comorbidities in patients with COPD. The authors provide guidance on how anxiety and depression can be detected and managed in patients with COPD in a primary care setting.

The third article is authored by Dr. Dhand, Dr. Cavanaugh, and Dr. Skolnik, and reviews the device options available for COPD pharmacologic therapy. It summarizes the key features of each respective inhaler device, discusses considerations for patient-device matching, and emphasizes the importance of training in correct device use.

Finally, Dr. Victor Kim and I assess different COPD treatment options in the supplement’s fourth article. We review the latest updates in recommendations from both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the COPD Foundation, discuss the importance of personalized treatment goals for patients, and review how to address current unmet needs in patient management.

More than 13 million people in the United States have been diagnosed with chronic obstructive pulmonary disease (COPD),¹ a complex, heterogeneous respiratory condition characterized by persistent, and usually progressive, airflow limitation.^2,3 The prevalence of COPD is rising: It has been declared the third leading cause of death in the United States,⁴ and the World Health Organization has predicted that it will become the third leading cause of death worldwide by 2030.⁵ This increase is driven by an aging population, and tobacco smoking, which is the primary risk factor for COPD in high-income countries.⁶

Symptoms of COPD, as well as the severity of these symptoms, can vary, but patients typically present with dyspnea, chronic cough, and sputum production.² These symptoms are often underreported by patients with COPD,² but have a significant impact on patients’ day-to-day lives, adversely affecting their quality of life and their ability to engage in physical activity, further contributing to disease progression.^7,8

Comorbidities are common in patients with COPD, and can pose significant challenges to the diagnosis and management of the condition. Some of these comorbidities, such as lung cancer and ischemic heart disease, share a common etiologic pathway with COPD—smoking; while others, such as anxiety and depression, appear to be unrelated to COPD pathogenesis, although they may share a systemic inflammatory basis, and are highly prevalent in patients with COPD.⁹

Primary care physicians are the key point of contact for most patients with COPD,¹⁰ and play a critical role in diagnosis, drug and device selection, and long-term disease management of COPD and associated comorbidities. A number of pharmacologic and nonpharmacologic treatment options are available to manage COPD symptoms, which can confer considerable benefits to patients. Selection of pharmacologic treatment should be based on an individual patient’s symptom burden and their exacerbation history, and it is important that physicians are aware of when therapy should be escalated, and indeed stopped if no longer required.²

Proper device selection is an important part of choosing treatments for patients with COPD. A variety of inhaler devices are available for COPD medications, and it is important that devices are matched to patients’ needs and preferences based on device characteristics and individual patient capabilities.

The aim of this supplement is to provide readers with an introduction to 4 key topics critical to the effective management of COPD in primary care, highlighting best practices to optimize patient care and outcomes. In the first article, Dr. Marchetti and Dr. Kaplan review physical activity in COPD, discussing its inter-relationship with dyspnea and hyperinflation, and its importance in modifying disease progression.

The second article examines anxiety and depression in COPD. Prof. Yohannes, Dr. Kaplan, and Dr. Hanania review the prevalence, mechanisms, and impact of the 2 often overlooked and undertreated psychologic comorbidities in patients with COPD. The authors provide guidance on how anxiety and depression can be detected and managed in patients with COPD in a primary care setting.

The third article is authored by Dr. Dhand, Dr. Cavanaugh, and Dr. Skolnik, and reviews the device options available for COPD pharmacologic therapy. It summarizes the key features of each respective inhaler device, discusses considerations for patient-device matching, and emphasizes the importance of training in correct device use.

Finally, Dr. Victor Kim and I assess different COPD treatment options in the supplement’s fourth article. We review the latest updates in recommendations from both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the COPD Foundation, discuss the importance of personalized treatment goals for patients, and review how to address current unmet needs in patient management.

More than 13 million people in the United States have been diagnosed with chronic obstructive pulmonary disease (COPD),¹ a complex, heterogeneous respiratory condition characterized by persistent, and usually progressive, airflow limitation.^2,3 The prevalence of COPD is rising: It has been declared the third leading cause of death in the United States,⁴ and the World Health Organization has predicted that it will become the third leading cause of death worldwide by 2030.⁵ This increase is driven by an aging population, and tobacco smoking, which is the primary risk factor for COPD in high-income countries.⁶

Symptoms of COPD, as well as the severity of these symptoms, can vary, but patients typically present with dyspnea, chronic cough, and sputum production.² These symptoms are often underreported by patients with COPD,² but have a significant impact on patients’ day-to-day lives, adversely affecting their quality of life and their ability to engage in physical activity, further contributing to disease progression.^7,8

Comorbidities are common in patients with COPD, and can pose significant challenges to the diagnosis and management of the condition. Some of these comorbidities, such as lung cancer and ischemic heart disease, share a common etiologic pathway with COPD—smoking; while others, such as anxiety and depression, appear to be unrelated to COPD pathogenesis, although they may share a systemic inflammatory basis, and are highly prevalent in patients with COPD.⁹

Primary care physicians are the key point of contact for most patients with COPD,¹⁰ and play a critical role in diagnosis, drug and device selection, and long-term disease management of COPD and associated comorbidities. A number of pharmacologic and nonpharmacologic treatment options are available to manage COPD symptoms, which can confer considerable benefits to patients. Selection of pharmacologic treatment should be based on an individual patient’s symptom burden and their exacerbation history, and it is important that physicians are aware of when therapy should be escalated, and indeed stopped if no longer required.²

Proper device selection is an important part of choosing treatments for patients with COPD. A variety of inhaler devices are available for COPD medications, and it is important that devices are matched to patients’ needs and preferences based on device characteristics and individual patient capabilities.

The aim of this supplement is to provide readers with an introduction to 4 key topics critical to the effective management of COPD in primary care, highlighting best practices to optimize patient care and outcomes. In the first article, Dr. Marchetti and Dr. Kaplan review physical activity in COPD, discussing its inter-relationship with dyspnea and hyperinflation, and its importance in modifying disease progression.

The second article examines anxiety and depression in COPD. Prof. Yohannes, Dr. Kaplan, and Dr. Hanania review the prevalence, mechanisms, and impact of the 2 often overlooked and undertreated psychologic comorbidities in patients with COPD. The authors provide guidance on how anxiety and depression can be detected and managed in patients with COPD in a primary care setting.

The third article is authored by Dr. Dhand, Dr. Cavanaugh, and Dr. Skolnik, and reviews the device options available for COPD pharmacologic therapy. It summarizes the key features of each respective inhaler device, discusses considerations for patient-device matching, and emphasizes the importance of training in correct device use.

Finally, Dr. Victor Kim and I assess different COPD treatment options in the supplement’s fourth article. We review the latest updates in recommendations from both the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the COPD Foundation, discuss the importance of personalized treatment goals for patients, and review how to address current unmet needs in patient management.

Introduction

Dyspnea, the sensation of difficult or labored breathing, is the most common symptom in chronic obstructive pulmonary disease (COPD) and the primary symptom that limits physical activity in more advanced disease.¹ According to the American Thoracic Society, dyspnea may be measured according to 3 domains²:

• what breathing feels like for the patient
• how distressed the patient feels when breathing
• how dyspnea affects functional ability, employment, health-related quality of life, or health status.

As disease severity increases, breathlessness becomes more disabling at lower activity levels. These changes further impact the quality of life of patients, and can lead to anxiety and depression.¹¹

Physical inactivity is often considered to be a major contributor to the progression of COPD,⁶ and is linked to hospitalizations and increased all-cause mortality.¹² There is therefore a need to recognize symptoms early and treat them accordingly.

CASE STUDY: 

KD, a 64-year-old woman, presented to her primary care physician’s office for a routine visit. Upon assessment, KD revealed that she used to enjoy going on walks with her neighbor, but she cannot walk up the hills in her neighborhood anymore without feeling “incredibly breathless.” She has become increasingly concerned that she is “having trouble getting a full breath.” KD informed her doctor that these symptoms had worsened since her last visit, and so she had stopped going on neighborhood walks. She was diagnosed with COPD 4 years ago, and is currently using a long-acting muscarinic antagonist (LAMA) bronchodilator. KD has a 40 pack-year smoking history, and has previously been advised to stop smoking, but has relapsed several times. She has a medical history of hypertension and depression, and a notable family history of emphysema, breast cancer, and diabetes.

The relationship between lung hyperinflation and dyspnea in COPD

In COPD, pathologic changes give rise to physiologic abnormalities such as mucus hypersecretion and ciliary dysfunction, gas exchange abnormalities, pulmonary hypertension, and airflow limitation and lung hyperinflation.¹³ Lung hyperinflation, an increase in resting functional residual volume above a normal level, represents a mechanical link between the characteristic expiratory airflow impairment, dyspnea, and physical activity limitation in COPD.¹

Although patients can compensate for several of the negative consequences of hyperinflation (eg, altering the chest wall due to overdistended lungs), such compensatory mechanisms are unable to cope with large increases in ventilation, such as those that occur during exercise.¹ Air trapping, together with ineffectiveness of respiratory muscle function, leads to increased ventilation requirements and dynamic pulmonary hyperinflation, resulting in dyspnea.¹

Patients with COPD describe a sensation of “air hunger,” reporting “unsatisfied” or “unrewarded” inhalation, “shallow breathing,” and a feeling that they “cannot get a deep breath,”¹⁸ whereas, in fact, they are limited in their ability to fully exhale. Verbal descriptors (eg, “air hunger” or “chest tightness”) are important tools in understanding a patient’s experience with dyspnea, and a patient’s choice of descriptor may be related to dyspnea severity, and the level of distress that dyspnea causes a given patient.¹⁹ Air hunger in turn encourages faster breathing, leading to further shortness of breath and more dynamic hyperinflation.^1,20

To deflate the lungs of patients with COPD, physiologic, pharmacologic, and possibly surgical interventions are required:

• Controlled breathing techniques (eg, purse-lipped breathing) that encourage slow and deep breathing can correct abnormal chest wall motion, decrease the work of breathing, increase breathing efficiency, and improve the distribution of ventilation to empty the lungs.²¹
• Bronchodilators can help to achieve lung deflation by improving ventilatory mechanics, as shown by increases in inspiratory capacity and vital capacity.²²
• Lung volume reduction surgery can also be considered to treat severe hyperinflation in emphysematous patients⁵; bronchoscopic interventions that lower lung volumes are also in development.²³ 

The impact of lung hyperinflation and dyspnea on physical activity in COPD

Dyspnea and hyperinflation are closely interrelated with physical activity limitation,^16,29,30 and so can be viewed as significant contributors to patient disability. During an acute exacerbation, patients with COPD will experience worsening airway obstruction, dynamic hyperinflation, and dyspnea.³¹ Patients with a greater number of comorbid conditions may also have greater shortness of breath.³² In addition, patients with COPD and hyperinflation perform less physical activity than individuals without hyperinflation, regardless of COPD severity, as assessed using the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe) and BODE (Body-mass index, airflow Obstruction, Dyspnea, and Exercise) index.³³ These patients also exhibit increases in dyspnea perception during commonly performed ADLs, which may limit physical activity and worsen lung hyperinflation.³³ More limited physical activity also contributes to higher dyspnea scores during ADLs.⁸

Furthermore, the ability to perform typical ADLs may be significantly altered or eliminated altogether in patients with COPD.¹¹ Leisure activities are often the first to be dropped by patients, as they generally require greater effort than simpler tasks, and are not critical to daily life.¹¹ Eventually, these activities become progressively more difficult, and most patients with moderate or severe COPD can struggle to complete even the most basic daily activities.¹¹

In addition to the morbidity burden and impact on ADLs, lower levels of physical activity in patients with COPD have also been shown to increase the risk of mortality and exacerbations, and elevate the risk of comorbidities such as heart disease and metabolic disease.³⁴ In light of these observations, improving exercise capacity should be a key goal in COPD management.

Assessment and measurement of dyspnea and hyperinflation

Reducing hyperinflation and dyspnea is essential for improving physical activity endurance and overall physical activity in patients with COPD; therefore, measuring the degree of impairment is important.²² Clinicians should be aware that some patients may have relief of dyspnea due to improvements in hyperinflation, despite relatively mild changes in FEV₁.³⁵ Lung volume measures, including total lung capacity, residual volume and functional residual capacity, are valuable tools in the assessment of lung hyperinflation in COPD, and therefore constitute a key component of pulmonary function testing.³⁶ However, expanded pulmonary function testing may be required for patients with severe dyspnea that does not correspond to spirometric findings, or cases in which diagnosis is uncertain.³⁷

Lung volumes are evaluated primarily by body plethysmography, during which a patient sits inside an airtight “body box” equipped to measure pressure and volume changes.^14,38 Helium dilution and nitrogen washing can also be used to measure functional residual capacity in patients with COPD,¹⁴ but body plethysmography is considered to be a more accurate method of lung volume evaluation in patients with severe airflow obstruction.^14,38 Radiographic techniques can also be used, but due to a lack of standardization, they are not typically utilized in clinical practice.¹⁴ Measurement of IC may complement other lung volume measures as part of assessment of hyperinflation.¹⁶ This can be measured using either spirometry or body plethysmography.^39,40

In addition to evaluating hyperinflation, ADLs, physical activity, exercise capacity, and dyspnea should all be assessed in patients with COPD in primary care. It is known that patients may self-limit ADLs to avoid symptoms of COPD; in doing so, worsening symptoms may be underappreciated, and subsequently underreported, by the patient. Thus, it is essential that physicians ask patients with COPD, as well as individuals at risk of COPD, questions about changes in their physical activity or ability to perform common tasks. There are a number of methods to measure functional performance, but for a simple assessment of ADLs, clinicians can ask the patient or caregiver questions related to basic daily tasks.¹¹ In early COPD, patients who experience mild dyspnea during exercise should be able to perform most productive activities. Patients with stable COPD and moderate dyspnea during exercise should be able to carry out most of the higher functioning ADLs, whereas patients with severe COPD may struggle to complete basic ADLs without assistance.¹¹ It should be noted, however, that patients may experience dyspnea with fairly routine activities, and even reduce physical activity at relatively early stages of airflow limitation.^41,42

Other tests may be useful in assessing the impact of an intervention, be it pharmacologic or nonpharmacologic, on dyspnea severity. For example, increases in the 6-minute-walk distance (6MWD) have been shown to correlate with improvements in dyspnea.⁴⁶ The 6MWD has also been shown to be an important predictor of hospitalization and mortality in patients with COPD.⁴⁷ However, it is important to note that improvements in 6MWD show only a very weak correlation with patient-reported outcomes,⁴⁸ and may be a less sensitive measure for patients with less disability than those with more profound functional limitation.⁴⁹ Moreover, 6MWD can be affected by a patient’s psychologic motivation,^6,50 as well as other comorbidities observed in patients with COPD, such as osteoporosis, heart failure, and peripheral vascular disease.^46,51 Although not used for COPD diagnosis or evaluation of dyspnea or physical activity limitation, a chest X-ray can also be a useful tool for excluding alternative diagnoses, as well as for detecting significant comorbidities in patients with COPD, such as concomitant respiratory, cardiac, and skeletal diseases.⁵

Pulmonary rehabilitation is a tailored intervention that encompasses exercise training, education, and self-management support for people with chronic respiratory disease, based on detailed assessment of their exercise capacity and symptoms.⁵² Pulmonary rehabilitation is as important as medication in COPD management, providing a cost-effective intervention with minimal adverse effects.⁵³ Moreover, pulmonary rehabilitation has been shown to benefit patients with mild to severe dyspnea (as classified according to the Medical Research Council dyspnea scale), demonstrating the value of successful execution of these programs in patients with COPD, irrespective of disease severity.⁵⁴ Although the most significant improvements in patient quality of life are observed when a multimodality approach is used, exercise and proper pulmonary rehabilitation programs have been shown to improve quality of life more than medication alone.^5,55 Notably, there are few supporting data for the use of supplemental oxygen in patients experiencing dyspnea without hypoxemia. Oxygen supplementation is only of minimal benefit to relieving the sensation of dyspnea.^56,57

The relationship between the impact of pulmonary rehabilitation in patients with COPD and frailty scores has also been evaluated. Frailty scores are calculated based on an individual’s level of physical activity, and other key criteria that are indicative of their ability to self-manage their medical condition.⁵⁸ These scores are particularly relevant in the context of COPD, given the high prevalence of the condition in older people.⁵⁸ Although frailty is a strong independent predictor of noncompletion of pulmonary rehabilitation, completion of a pulmonary rehabilitation program in patients who are frail has been shown to reverse their frailty in the short term.⁵⁸ It is therefore important that physicians guide and encourage these patients for the duration of a pulmonary rehabilitation program, from initiation through to completion, to ensure that those who are likely to derive the greatest benefit from pulmonary rehabilitation are supported to do so.

In addition to pulmonary rehabilitation, other nonpharmacologic interventions have emerged in recent years that may help to relieve dyspnea in patients with COPD. Airway clearance devices, such as acapella (Smiths Medical; Minneapolis, MN), Flutter (Allergan; Dublin, Ireland), Lung Flute (Medical Acoustics; Buffalo, NY), Quake (Thayer Medical; Tucson, AZ), and Aerobika (Monaghan Medical; Plattsburgh, NY) promote the clearance of sputum through the application of positive expiratory pressure, possibly allowing medicines to penetrate the lungs more effectively, and improving diffuse airflow obstruction.^59-61 Incorporating an airway clearance device into a bronchodilator therapy regimen has been shown to improve dyspnea scores, both before and after exercise, compared with bronchodilator therapy combined with a nonfunctional control device in patients with severe COPD.⁵⁹ In addition, noninvasive forms of ventilation, such as continuous positive airway pressure and bi-level positive airway pressure (BiPAP), have been shown to effectively reduce dyspnea in patients with COPD.^62,63 In a 24-month study in patients with severe COPD, resting dyspnea improved significantly in patients using the BiPAP Auto-Trak (Philips Respironics, Best, The Netherlands) in conjunction with their regular bronchodilator therapy, compared with those receiving long-term oxygen therapy in addition to their typical therapeutic regimen.⁶³ Further studies are required to establish the impact of these devices in the management of dyspnea and other symptoms of COPD.

These nonpharmacologic interventions can be supplemented with pharmacologic treatments to help patients achieve their treatment goals of improved dyspnea and increased exercise performance. Bronchodilators, which form the basis of various COPD treatment options, include⁵:

• short-acting muscarinic antagonists (SAMAs), such as ipratropium
• short-acting β₂-agonists (SABAs), such as albuterol, levalbuterol, and terbutaline
• SAMA/SABA combinations
• LAMAs, such as aclidinium, glycopyrrolate, tiotropium, and umeclidinium
• long-acting β ₂-agonists (LABAs), such as arformoterol, indacaterol, formoterol, olodaterol, salmeterol, and vilanterol
• LAMA/LABA combinations (umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, glycopyrrolate/indacaterol)

Inhaled corticosteroids can also be used in a fixed-dose combination with a LABA, which can be combined with a LAMA, in select patients⁵; however, these combination products may have minimal value in treating dyspnea unless asthma is concomitantly present.^5,64 Further discussion of the different treatment options available for patients with COPD can be found in the final article of this supplement.

In addition to improving quality of life, long-acting bronchodilators, such as LAMAs, LABAs, and LAMA/LABA combinations, increase expiratory flow, reduce dynamic hyperinflation, and improve exercise capacity of patients.^65-67 As disease severity worsens, physicians may opt for long-acting bronchodilator options that have twice-daily dosing, which may confer a benefit in improving night-time symptom control.⁶⁸

As well as active pharmacologic and nonpharmacologic interventions, physicians should always encourage smoking cessation in patients with COPD, as this has the greatest capacity to influence the natural course of the disease.⁵ It is essential that health care providers continually deliver smoking cessation messages to patients with COPD; patients can also be supported to stop smoking by using nicotine replacement therapy, pharmacologic interventions, attending smoking cessation programs, and counseling.⁵

Lung volume reduction surgery may also be considered as a strategy for the management of dyspnea in severe, refractory COPD.⁶⁹ Similarly, nonsurgical bronchoscopic interventions are being developed that look to achieve similar results to lung volume reduction surgery, including endobronchial one-way valves, lung volume reduction coils, airway bypasses, adhesives, and vapor therapy.²³ 

CASE STUDY:

The primary care physician assessed KD’s dyspnea using the CAT and ordered a chest X-ray to identify any significant comorbidities, such as concomitant respiratory, skeletal, or cardiac diseases. As KD’s CAT score was 17, and her symptoms were uncontrolled on LAMA monotherapy, her physician prescribed a long-acting LAMA/LABA combination, along with pulmonary rehabilitation. The physician also counseled KD on the importance of smoking cessation, and referred her to a local smoking cessation program.

Conclusions

Dyspnea, the most common symptom of COPD and the primary consequence of the condition’s characteristic lung hyperinflation, is a heavy burden on the lives of patients. The impact of dyspnea is perhaps most apparent in the context of physical activity, with activity limitation observed frequently in patients with COPD, regardless of disease stage. This can affect patients’ quality of life significantly, and has long-term consequences on disease progression. Improving dyspnea and increasing exercise endurance should therefore be a key goal for COPD management, which should encompass both nonpharmacologic interventions, such as pulmonary rehabilitation, and pharmacologic interventions, such as use of bronchodilator therapy.

Introduction

Dyspnea, the sensation of difficult or labored breathing, is the most common symptom in chronic obstructive pulmonary disease (COPD) and the primary symptom that limits physical activity in more advanced disease.¹ According to the American Thoracic Society, dyspnea may be measured according to 3 domains²:

• what breathing feels like for the patient
• how distressed the patient feels when breathing
• how dyspnea affects functional ability, employment, health-related quality of life, or health status.

As disease severity increases, breathlessness becomes more disabling at lower activity levels. These changes further impact the quality of life of patients, and can lead to anxiety and depression.¹¹

Physical inactivity is often considered to be a major contributor to the progression of COPD,⁶ and is linked to hospitalizations and increased all-cause mortality.¹² There is therefore a need to recognize symptoms early and treat them accordingly.

CASE STUDY: 

KD, a 64-year-old woman, presented to her primary care physician’s office for a routine visit. Upon assessment, KD revealed that she used to enjoy going on walks with her neighbor, but she cannot walk up the hills in her neighborhood anymore without feeling “incredibly breathless.” She has become increasingly concerned that she is “having trouble getting a full breath.” KD informed her doctor that these symptoms had worsened since her last visit, and so she had stopped going on neighborhood walks. She was diagnosed with COPD 4 years ago, and is currently using a long-acting muscarinic antagonist (LAMA) bronchodilator. KD has a 40 pack-year smoking history, and has previously been advised to stop smoking, but has relapsed several times. She has a medical history of hypertension and depression, and a notable family history of emphysema, breast cancer, and diabetes.

The relationship between lung hyperinflation and dyspnea in COPD

In COPD, pathologic changes give rise to physiologic abnormalities such as mucus hypersecretion and ciliary dysfunction, gas exchange abnormalities, pulmonary hypertension, and airflow limitation and lung hyperinflation.¹³ Lung hyperinflation, an increase in resting functional residual volume above a normal level, represents a mechanical link between the characteristic expiratory airflow impairment, dyspnea, and physical activity limitation in COPD.¹

Although patients can compensate for several of the negative consequences of hyperinflation (eg, altering the chest wall due to overdistended lungs), such compensatory mechanisms are unable to cope with large increases in ventilation, such as those that occur during exercise.¹ Air trapping, together with ineffectiveness of respiratory muscle function, leads to increased ventilation requirements and dynamic pulmonary hyperinflation, resulting in dyspnea.¹

Patients with COPD describe a sensation of “air hunger,” reporting “unsatisfied” or “unrewarded” inhalation, “shallow breathing,” and a feeling that they “cannot get a deep breath,”¹⁸ whereas, in fact, they are limited in their ability to fully exhale. Verbal descriptors (eg, “air hunger” or “chest tightness”) are important tools in understanding a patient’s experience with dyspnea, and a patient’s choice of descriptor may be related to dyspnea severity, and the level of distress that dyspnea causes a given patient.¹⁹ Air hunger in turn encourages faster breathing, leading to further shortness of breath and more dynamic hyperinflation.^1,20

To deflate the lungs of patients with COPD, physiologic, pharmacologic, and possibly surgical interventions are required:

• Controlled breathing techniques (eg, purse-lipped breathing) that encourage slow and deep breathing can correct abnormal chest wall motion, decrease the work of breathing, increase breathing efficiency, and improve the distribution of ventilation to empty the lungs.²¹
• Bronchodilators can help to achieve lung deflation by improving ventilatory mechanics, as shown by increases in inspiratory capacity and vital capacity.²²
• Lung volume reduction surgery can also be considered to treat severe hyperinflation in emphysematous patients⁵; bronchoscopic interventions that lower lung volumes are also in development.²³ 

The impact of lung hyperinflation and dyspnea on physical activity in COPD

Dyspnea and hyperinflation are closely interrelated with physical activity limitation,^16,29,30 and so can be viewed as significant contributors to patient disability. During an acute exacerbation, patients with COPD will experience worsening airway obstruction, dynamic hyperinflation, and dyspnea.³¹ Patients with a greater number of comorbid conditions may also have greater shortness of breath.³² In addition, patients with COPD and hyperinflation perform less physical activity than individuals without hyperinflation, regardless of COPD severity, as assessed using the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe) and BODE (Body-mass index, airflow Obstruction, Dyspnea, and Exercise) index.³³ These patients also exhibit increases in dyspnea perception during commonly performed ADLs, which may limit physical activity and worsen lung hyperinflation.³³ More limited physical activity also contributes to higher dyspnea scores during ADLs.⁸

Furthermore, the ability to perform typical ADLs may be significantly altered or eliminated altogether in patients with COPD.¹¹ Leisure activities are often the first to be dropped by patients, as they generally require greater effort than simpler tasks, and are not critical to daily life.¹¹ Eventually, these activities become progressively more difficult, and most patients with moderate or severe COPD can struggle to complete even the most basic daily activities.¹¹

In addition to the morbidity burden and impact on ADLs, lower levels of physical activity in patients with COPD have also been shown to increase the risk of mortality and exacerbations, and elevate the risk of comorbidities such as heart disease and metabolic disease.³⁴ In light of these observations, improving exercise capacity should be a key goal in COPD management.

Assessment and measurement of dyspnea and hyperinflation

Reducing hyperinflation and dyspnea is essential for improving physical activity endurance and overall physical activity in patients with COPD; therefore, measuring the degree of impairment is important.²² Clinicians should be aware that some patients may have relief of dyspnea due to improvements in hyperinflation, despite relatively mild changes in FEV₁.³⁵ Lung volume measures, including total lung capacity, residual volume and functional residual capacity, are valuable tools in the assessment of lung hyperinflation in COPD, and therefore constitute a key component of pulmonary function testing.³⁶ However, expanded pulmonary function testing may be required for patients with severe dyspnea that does not correspond to spirometric findings, or cases in which diagnosis is uncertain.³⁷

Lung volumes are evaluated primarily by body plethysmography, during which a patient sits inside an airtight “body box” equipped to measure pressure and volume changes.^14,38 Helium dilution and nitrogen washing can also be used to measure functional residual capacity in patients with COPD,¹⁴ but body plethysmography is considered to be a more accurate method of lung volume evaluation in patients with severe airflow obstruction.^14,38 Radiographic techniques can also be used, but due to a lack of standardization, they are not typically utilized in clinical practice.¹⁴ Measurement of IC may complement other lung volume measures as part of assessment of hyperinflation.¹⁶ This can be measured using either spirometry or body plethysmography.^39,40

In addition to evaluating hyperinflation, ADLs, physical activity, exercise capacity, and dyspnea should all be assessed in patients with COPD in primary care. It is known that patients may self-limit ADLs to avoid symptoms of COPD; in doing so, worsening symptoms may be underappreciated, and subsequently underreported, by the patient. Thus, it is essential that physicians ask patients with COPD, as well as individuals at risk of COPD, questions about changes in their physical activity or ability to perform common tasks. There are a number of methods to measure functional performance, but for a simple assessment of ADLs, clinicians can ask the patient or caregiver questions related to basic daily tasks.¹¹ In early COPD, patients who experience mild dyspnea during exercise should be able to perform most productive activities. Patients with stable COPD and moderate dyspnea during exercise should be able to carry out most of the higher functioning ADLs, whereas patients with severe COPD may struggle to complete basic ADLs without assistance.¹¹ It should be noted, however, that patients may experience dyspnea with fairly routine activities, and even reduce physical activity at relatively early stages of airflow limitation.^41,42

Other tests may be useful in assessing the impact of an intervention, be it pharmacologic or nonpharmacologic, on dyspnea severity. For example, increases in the 6-minute-walk distance (6MWD) have been shown to correlate with improvements in dyspnea.⁴⁶ The 6MWD has also been shown to be an important predictor of hospitalization and mortality in patients with COPD.⁴⁷ However, it is important to note that improvements in 6MWD show only a very weak correlation with patient-reported outcomes,⁴⁸ and may be a less sensitive measure for patients with less disability than those with more profound functional limitation.⁴⁹ Moreover, 6MWD can be affected by a patient’s psychologic motivation,^6,50 as well as other comorbidities observed in patients with COPD, such as osteoporosis, heart failure, and peripheral vascular disease.^46,51 Although not used for COPD diagnosis or evaluation of dyspnea or physical activity limitation, a chest X-ray can also be a useful tool for excluding alternative diagnoses, as well as for detecting significant comorbidities in patients with COPD, such as concomitant respiratory, cardiac, and skeletal diseases.⁵

Pulmonary rehabilitation is a tailored intervention that encompasses exercise training, education, and self-management support for people with chronic respiratory disease, based on detailed assessment of their exercise capacity and symptoms.⁵² Pulmonary rehabilitation is as important as medication in COPD management, providing a cost-effective intervention with minimal adverse effects.⁵³ Moreover, pulmonary rehabilitation has been shown to benefit patients with mild to severe dyspnea (as classified according to the Medical Research Council dyspnea scale), demonstrating the value of successful execution of these programs in patients with COPD, irrespective of disease severity.⁵⁴ Although the most significant improvements in patient quality of life are observed when a multimodality approach is used, exercise and proper pulmonary rehabilitation programs have been shown to improve quality of life more than medication alone.^5,55 Notably, there are few supporting data for the use of supplemental oxygen in patients experiencing dyspnea without hypoxemia. Oxygen supplementation is only of minimal benefit to relieving the sensation of dyspnea.^56,57

The relationship between the impact of pulmonary rehabilitation in patients with COPD and frailty scores has also been evaluated. Frailty scores are calculated based on an individual’s level of physical activity, and other key criteria that are indicative of their ability to self-manage their medical condition.⁵⁸ These scores are particularly relevant in the context of COPD, given the high prevalence of the condition in older people.⁵⁸ Although frailty is a strong independent predictor of noncompletion of pulmonary rehabilitation, completion of a pulmonary rehabilitation program in patients who are frail has been shown to reverse their frailty in the short term.⁵⁸ It is therefore important that physicians guide and encourage these patients for the duration of a pulmonary rehabilitation program, from initiation through to completion, to ensure that those who are likely to derive the greatest benefit from pulmonary rehabilitation are supported to do so.

In addition to pulmonary rehabilitation, other nonpharmacologic interventions have emerged in recent years that may help to relieve dyspnea in patients with COPD. Airway clearance devices, such as acapella (Smiths Medical; Minneapolis, MN), Flutter (Allergan; Dublin, Ireland), Lung Flute (Medical Acoustics; Buffalo, NY), Quake (Thayer Medical; Tucson, AZ), and Aerobika (Monaghan Medical; Plattsburgh, NY) promote the clearance of sputum through the application of positive expiratory pressure, possibly allowing medicines to penetrate the lungs more effectively, and improving diffuse airflow obstruction.^59-61 Incorporating an airway clearance device into a bronchodilator therapy regimen has been shown to improve dyspnea scores, both before and after exercise, compared with bronchodilator therapy combined with a nonfunctional control device in patients with severe COPD.⁵⁹ In addition, noninvasive forms of ventilation, such as continuous positive airway pressure and bi-level positive airway pressure (BiPAP), have been shown to effectively reduce dyspnea in patients with COPD.^62,63 In a 24-month study in patients with severe COPD, resting dyspnea improved significantly in patients using the BiPAP Auto-Trak (Philips Respironics, Best, The Netherlands) in conjunction with their regular bronchodilator therapy, compared with those receiving long-term oxygen therapy in addition to their typical therapeutic regimen.⁶³ Further studies are required to establish the impact of these devices in the management of dyspnea and other symptoms of COPD.

These nonpharmacologic interventions can be supplemented with pharmacologic treatments to help patients achieve their treatment goals of improved dyspnea and increased exercise performance. Bronchodilators, which form the basis of various COPD treatment options, include⁵:

• short-acting muscarinic antagonists (SAMAs), such as ipratropium
• short-acting β₂-agonists (SABAs), such as albuterol, levalbuterol, and terbutaline
• SAMA/SABA combinations
• LAMAs, such as aclidinium, glycopyrrolate, tiotropium, and umeclidinium
• long-acting β ₂-agonists (LABAs), such as arformoterol, indacaterol, formoterol, olodaterol, salmeterol, and vilanterol
• LAMA/LABA combinations (umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, glycopyrrolate/indacaterol)

Inhaled corticosteroids can also be used in a fixed-dose combination with a LABA, which can be combined with a LAMA, in select patients⁵; however, these combination products may have minimal value in treating dyspnea unless asthma is concomitantly present.^5,64 Further discussion of the different treatment options available for patients with COPD can be found in the final article of this supplement.

In addition to improving quality of life, long-acting bronchodilators, such as LAMAs, LABAs, and LAMA/LABA combinations, increase expiratory flow, reduce dynamic hyperinflation, and improve exercise capacity of patients.^65-67 As disease severity worsens, physicians may opt for long-acting bronchodilator options that have twice-daily dosing, which may confer a benefit in improving night-time symptom control.⁶⁸

As well as active pharmacologic and nonpharmacologic interventions, physicians should always encourage smoking cessation in patients with COPD, as this has the greatest capacity to influence the natural course of the disease.⁵ It is essential that health care providers continually deliver smoking cessation messages to patients with COPD; patients can also be supported to stop smoking by using nicotine replacement therapy, pharmacologic interventions, attending smoking cessation programs, and counseling.⁵

Lung volume reduction surgery may also be considered as a strategy for the management of dyspnea in severe, refractory COPD.⁶⁹ Similarly, nonsurgical bronchoscopic interventions are being developed that look to achieve similar results to lung volume reduction surgery, including endobronchial one-way valves, lung volume reduction coils, airway bypasses, adhesives, and vapor therapy.²³ 

CASE STUDY:

The primary care physician assessed KD’s dyspnea using the CAT and ordered a chest X-ray to identify any significant comorbidities, such as concomitant respiratory, skeletal, or cardiac diseases. As KD’s CAT score was 17, and her symptoms were uncontrolled on LAMA monotherapy, her physician prescribed a long-acting LAMA/LABA combination, along with pulmonary rehabilitation. The physician also counseled KD on the importance of smoking cessation, and referred her to a local smoking cessation program.

Conclusions

Dyspnea, the most common symptom of COPD and the primary consequence of the condition’s characteristic lung hyperinflation, is a heavy burden on the lives of patients. The impact of dyspnea is perhaps most apparent in the context of physical activity, with activity limitation observed frequently in patients with COPD, regardless of disease stage. This can affect patients’ quality of life significantly, and has long-term consequences on disease progression. Improving dyspnea and increasing exercise endurance should therefore be a key goal for COPD management, which should encompass both nonpharmacologic interventions, such as pulmonary rehabilitation, and pharmacologic interventions, such as use of bronchodilator therapy.

Introduction

Dyspnea, the sensation of difficult or labored breathing, is the most common symptom in chronic obstructive pulmonary disease (COPD) and the primary symptom that limits physical activity in more advanced disease.¹ According to the American Thoracic Society, dyspnea may be measured according to 3 domains²:

• what breathing feels like for the patient
• how distressed the patient feels when breathing
• how dyspnea affects functional ability, employment, health-related quality of life, or health status.

As disease severity increases, breathlessness becomes more disabling at lower activity levels. These changes further impact the quality of life of patients, and can lead to anxiety and depression.¹¹

Physical inactivity is often considered to be a major contributor to the progression of COPD,⁶ and is linked to hospitalizations and increased all-cause mortality.¹² There is therefore a need to recognize symptoms early and treat them accordingly.

CASE STUDY: 

KD, a 64-year-old woman, presented to her primary care physician’s office for a routine visit. Upon assessment, KD revealed that she used to enjoy going on walks with her neighbor, but she cannot walk up the hills in her neighborhood anymore without feeling “incredibly breathless.” She has become increasingly concerned that she is “having trouble getting a full breath.” KD informed her doctor that these symptoms had worsened since her last visit, and so she had stopped going on neighborhood walks. She was diagnosed with COPD 4 years ago, and is currently using a long-acting muscarinic antagonist (LAMA) bronchodilator. KD has a 40 pack-year smoking history, and has previously been advised to stop smoking, but has relapsed several times. She has a medical history of hypertension and depression, and a notable family history of emphysema, breast cancer, and diabetes.

The relationship between lung hyperinflation and dyspnea in COPD

In COPD, pathologic changes give rise to physiologic abnormalities such as mucus hypersecretion and ciliary dysfunction, gas exchange abnormalities, pulmonary hypertension, and airflow limitation and lung hyperinflation.¹³ Lung hyperinflation, an increase in resting functional residual volume above a normal level, represents a mechanical link between the characteristic expiratory airflow impairment, dyspnea, and physical activity limitation in COPD.¹

Although patients can compensate for several of the negative consequences of hyperinflation (eg, altering the chest wall due to overdistended lungs), such compensatory mechanisms are unable to cope with large increases in ventilation, such as those that occur during exercise.¹ Air trapping, together with ineffectiveness of respiratory muscle function, leads to increased ventilation requirements and dynamic pulmonary hyperinflation, resulting in dyspnea.¹

Patients with COPD describe a sensation of “air hunger,” reporting “unsatisfied” or “unrewarded” inhalation, “shallow breathing,” and a feeling that they “cannot get a deep breath,”¹⁸ whereas, in fact, they are limited in their ability to fully exhale. Verbal descriptors (eg, “air hunger” or “chest tightness”) are important tools in understanding a patient’s experience with dyspnea, and a patient’s choice of descriptor may be related to dyspnea severity, and the level of distress that dyspnea causes a given patient.¹⁹ Air hunger in turn encourages faster breathing, leading to further shortness of breath and more dynamic hyperinflation.^1,20

To deflate the lungs of patients with COPD, physiologic, pharmacologic, and possibly surgical interventions are required:

• Controlled breathing techniques (eg, purse-lipped breathing) that encourage slow and deep breathing can correct abnormal chest wall motion, decrease the work of breathing, increase breathing efficiency, and improve the distribution of ventilation to empty the lungs.²¹
• Bronchodilators can help to achieve lung deflation by improving ventilatory mechanics, as shown by increases in inspiratory capacity and vital capacity.²²
• Lung volume reduction surgery can also be considered to treat severe hyperinflation in emphysematous patients⁵; bronchoscopic interventions that lower lung volumes are also in development.²³ 

The impact of lung hyperinflation and dyspnea on physical activity in COPD

Dyspnea and hyperinflation are closely interrelated with physical activity limitation,^16,29,30 and so can be viewed as significant contributors to patient disability. During an acute exacerbation, patients with COPD will experience worsening airway obstruction, dynamic hyperinflation, and dyspnea.³¹ Patients with a greater number of comorbid conditions may also have greater shortness of breath.³² In addition, patients with COPD and hyperinflation perform less physical activity than individuals without hyperinflation, regardless of COPD severity, as assessed using the 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging (stage I, mild; stage II, moderate; stage III, severe; stage IV, very severe) and BODE (Body-mass index, airflow Obstruction, Dyspnea, and Exercise) index.³³ These patients also exhibit increases in dyspnea perception during commonly performed ADLs, which may limit physical activity and worsen lung hyperinflation.³³ More limited physical activity also contributes to higher dyspnea scores during ADLs.⁸

Furthermore, the ability to perform typical ADLs may be significantly altered or eliminated altogether in patients with COPD.¹¹ Leisure activities are often the first to be dropped by patients, as they generally require greater effort than simpler tasks, and are not critical to daily life.¹¹ Eventually, these activities become progressively more difficult, and most patients with moderate or severe COPD can struggle to complete even the most basic daily activities.¹¹

In addition to the morbidity burden and impact on ADLs, lower levels of physical activity in patients with COPD have also been shown to increase the risk of mortality and exacerbations, and elevate the risk of comorbidities such as heart disease and metabolic disease.³⁴ In light of these observations, improving exercise capacity should be a key goal in COPD management.

Assessment and measurement of dyspnea and hyperinflation

Reducing hyperinflation and dyspnea is essential for improving physical activity endurance and overall physical activity in patients with COPD; therefore, measuring the degree of impairment is important.²² Clinicians should be aware that some patients may have relief of dyspnea due to improvements in hyperinflation, despite relatively mild changes in FEV₁.³⁵ Lung volume measures, including total lung capacity, residual volume and functional residual capacity, are valuable tools in the assessment of lung hyperinflation in COPD, and therefore constitute a key component of pulmonary function testing.³⁶ However, expanded pulmonary function testing may be required for patients with severe dyspnea that does not correspond to spirometric findings, or cases in which diagnosis is uncertain.³⁷

Lung volumes are evaluated primarily by body plethysmography, during which a patient sits inside an airtight “body box” equipped to measure pressure and volume changes.^14,38 Helium dilution and nitrogen washing can also be used to measure functional residual capacity in patients with COPD,¹⁴ but body plethysmography is considered to be a more accurate method of lung volume evaluation in patients with severe airflow obstruction.^14,38 Radiographic techniques can also be used, but due to a lack of standardization, they are not typically utilized in clinical practice.¹⁴ Measurement of IC may complement other lung volume measures as part of assessment of hyperinflation.¹⁶ This can be measured using either spirometry or body plethysmography.^39,40

In addition to evaluating hyperinflation, ADLs, physical activity, exercise capacity, and dyspnea should all be assessed in patients with COPD in primary care. It is known that patients may self-limit ADLs to avoid symptoms of COPD; in doing so, worsening symptoms may be underappreciated, and subsequently underreported, by the patient. Thus, it is essential that physicians ask patients with COPD, as well as individuals at risk of COPD, questions about changes in their physical activity or ability to perform common tasks. There are a number of methods to measure functional performance, but for a simple assessment of ADLs, clinicians can ask the patient or caregiver questions related to basic daily tasks.¹¹ In early COPD, patients who experience mild dyspnea during exercise should be able to perform most productive activities. Patients with stable COPD and moderate dyspnea during exercise should be able to carry out most of the higher functioning ADLs, whereas patients with severe COPD may struggle to complete basic ADLs without assistance.¹¹ It should be noted, however, that patients may experience dyspnea with fairly routine activities, and even reduce physical activity at relatively early stages of airflow limitation.^41,42

Other tests may be useful in assessing the impact of an intervention, be it pharmacologic or nonpharmacologic, on dyspnea severity. For example, increases in the 6-minute-walk distance (6MWD) have been shown to correlate with improvements in dyspnea.⁴⁶ The 6MWD has also been shown to be an important predictor of hospitalization and mortality in patients with COPD.⁴⁷ However, it is important to note that improvements in 6MWD show only a very weak correlation with patient-reported outcomes,⁴⁸ and may be a less sensitive measure for patients with less disability than those with more profound functional limitation.⁴⁹ Moreover, 6MWD can be affected by a patient’s psychologic motivation,^6,50 as well as other comorbidities observed in patients with COPD, such as osteoporosis, heart failure, and peripheral vascular disease.^46,51 Although not used for COPD diagnosis or evaluation of dyspnea or physical activity limitation, a chest X-ray can also be a useful tool for excluding alternative diagnoses, as well as for detecting significant comorbidities in patients with COPD, such as concomitant respiratory, cardiac, and skeletal diseases.⁵

Pulmonary rehabilitation is a tailored intervention that encompasses exercise training, education, and self-management support for people with chronic respiratory disease, based on detailed assessment of their exercise capacity and symptoms.⁵² Pulmonary rehabilitation is as important as medication in COPD management, providing a cost-effective intervention with minimal adverse effects.⁵³ Moreover, pulmonary rehabilitation has been shown to benefit patients with mild to severe dyspnea (as classified according to the Medical Research Council dyspnea scale), demonstrating the value of successful execution of these programs in patients with COPD, irrespective of disease severity.⁵⁴ Although the most significant improvements in patient quality of life are observed when a multimodality approach is used, exercise and proper pulmonary rehabilitation programs have been shown to improve quality of life more than medication alone.^5,55 Notably, there are few supporting data for the use of supplemental oxygen in patients experiencing dyspnea without hypoxemia. Oxygen supplementation is only of minimal benefit to relieving the sensation of dyspnea.^56,57

The relationship between the impact of pulmonary rehabilitation in patients with COPD and frailty scores has also been evaluated. Frailty scores are calculated based on an individual’s level of physical activity, and other key criteria that are indicative of their ability to self-manage their medical condition.⁵⁸ These scores are particularly relevant in the context of COPD, given the high prevalence of the condition in older people.⁵⁸ Although frailty is a strong independent predictor of noncompletion of pulmonary rehabilitation, completion of a pulmonary rehabilitation program in patients who are frail has been shown to reverse their frailty in the short term.⁵⁸ It is therefore important that physicians guide and encourage these patients for the duration of a pulmonary rehabilitation program, from initiation through to completion, to ensure that those who are likely to derive the greatest benefit from pulmonary rehabilitation are supported to do so.

In addition to pulmonary rehabilitation, other nonpharmacologic interventions have emerged in recent years that may help to relieve dyspnea in patients with COPD. Airway clearance devices, such as acapella (Smiths Medical; Minneapolis, MN), Flutter (Allergan; Dublin, Ireland), Lung Flute (Medical Acoustics; Buffalo, NY), Quake (Thayer Medical; Tucson, AZ), and Aerobika (Monaghan Medical; Plattsburgh, NY) promote the clearance of sputum through the application of positive expiratory pressure, possibly allowing medicines to penetrate the lungs more effectively, and improving diffuse airflow obstruction.^59-61 Incorporating an airway clearance device into a bronchodilator therapy regimen has been shown to improve dyspnea scores, both before and after exercise, compared with bronchodilator therapy combined with a nonfunctional control device in patients with severe COPD.⁵⁹ In addition, noninvasive forms of ventilation, such as continuous positive airway pressure and bi-level positive airway pressure (BiPAP), have been shown to effectively reduce dyspnea in patients with COPD.^62,63 In a 24-month study in patients with severe COPD, resting dyspnea improved significantly in patients using the BiPAP Auto-Trak (Philips Respironics, Best, The Netherlands) in conjunction with their regular bronchodilator therapy, compared with those receiving long-term oxygen therapy in addition to their typical therapeutic regimen.⁶³ Further studies are required to establish the impact of these devices in the management of dyspnea and other symptoms of COPD.

These nonpharmacologic interventions can be supplemented with pharmacologic treatments to help patients achieve their treatment goals of improved dyspnea and increased exercise performance. Bronchodilators, which form the basis of various COPD treatment options, include⁵:

• short-acting muscarinic antagonists (SAMAs), such as ipratropium
• short-acting β₂-agonists (SABAs), such as albuterol, levalbuterol, and terbutaline
• SAMA/SABA combinations
• LAMAs, such as aclidinium, glycopyrrolate, tiotropium, and umeclidinium
• long-acting β ₂-agonists (LABAs), such as arformoterol, indacaterol, formoterol, olodaterol, salmeterol, and vilanterol
• LAMA/LABA combinations (umeclidinium/vilanterol, tiotropium/olodaterol, glycopyrrolate/formoterol, glycopyrrolate/indacaterol)

Inhaled corticosteroids can also be used in a fixed-dose combination with a LABA, which can be combined with a LAMA, in select patients⁵; however, these combination products may have minimal value in treating dyspnea unless asthma is concomitantly present.^5,64 Further discussion of the different treatment options available for patients with COPD can be found in the final article of this supplement.

In addition to improving quality of life, long-acting bronchodilators, such as LAMAs, LABAs, and LAMA/LABA combinations, increase expiratory flow, reduce dynamic hyperinflation, and improve exercise capacity of patients.^65-67 As disease severity worsens, physicians may opt for long-acting bronchodilator options that have twice-daily dosing, which may confer a benefit in improving night-time symptom control.⁶⁸

As well as active pharmacologic and nonpharmacologic interventions, physicians should always encourage smoking cessation in patients with COPD, as this has the greatest capacity to influence the natural course of the disease.⁵ It is essential that health care providers continually deliver smoking cessation messages to patients with COPD; patients can also be supported to stop smoking by using nicotine replacement therapy, pharmacologic interventions, attending smoking cessation programs, and counseling.⁵

Lung volume reduction surgery may also be considered as a strategy for the management of dyspnea in severe, refractory COPD.⁶⁹ Similarly, nonsurgical bronchoscopic interventions are being developed that look to achieve similar results to lung volume reduction surgery, including endobronchial one-way valves, lung volume reduction coils, airway bypasses, adhesives, and vapor therapy.²³ 

CASE STUDY:

The primary care physician assessed KD’s dyspnea using the CAT and ordered a chest X-ray to identify any significant comorbidities, such as concomitant respiratory, skeletal, or cardiac diseases. As KD’s CAT score was 17, and her symptoms were uncontrolled on LAMA monotherapy, her physician prescribed a long-acting LAMA/LABA combination, along with pulmonary rehabilitation. The physician also counseled KD on the importance of smoking cessation, and referred her to a local smoking cessation program.

Conclusions

Dyspnea, the most common symptom of COPD and the primary consequence of the condition’s characteristic lung hyperinflation, is a heavy burden on the lives of patients. The impact of dyspnea is perhaps most apparent in the context of physical activity, with activity limitation observed frequently in patients with COPD, regardless of disease stage. This can affect patients’ quality of life significantly, and has long-term consequences on disease progression. Improving dyspnea and increasing exercise endurance should therefore be a key goal for COPD management, which should encompass both nonpharmacologic interventions, such as pulmonary rehabilitation, and pharmacologic interventions, such as use of bronchodilator therapy.

Introduction

Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), occurring more frequently than in the general population^1-4 or patients with other chronic diseases such as hypertension, diabetes, cancer, or musculoskeletal disorders.^5,6 Their presence is associated with worse outcomes of COPD, and increased morbidity, mortality, disability, and health care expenditure.^6-8 In spite of this, both anxiety and depression are frequently overlooked and undertreated in patients with COPD,⁹ and symptoms of anxiety and depression can overlap significantly, as well as overlap with COPD symptoms.^7,10 

Comorbid depressive disorders that may occur in patients with COPD include major depressive disorder, dysthymias (chronic depressive symptoms of mild severity), and minor depression.¹¹ Depressive disorders are characterized by feelings of sadness, emptiness, and/or irritability, along with cognitive and somatic symptoms, which have a detrimental effect on the patient’s ability to function.¹¹ Anxiety disorders include generalized anxiety disorder (GAD), phobias, and panic disorders.¹¹ The main features of anxiety disorders, such as excessive fear and anxiety, may be accompanied by behavioral disturbances related to these symptoms, such as panic attacks and avoidance.^11,12

The reported prevalence of depression in COPD varies widely between studies, owing to differences in sampling methods and degrees of illness severity used in assessment of depression⁶; rates have been reported to range from 10% to 42% in patients with stable COPD,^6,13 and from 10% to 86% in patients with acute COPD exacerbation.¹⁴ Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD.¹⁰

Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients. GAD, panic disorders, and specific phobias are reported most frequently.¹⁵ Patients with COPD are 85% more likely to develop anxiety disorders compared with matched controls without COPD,⁴ and panic disorder is reported with a prevalence that is up to 10-fold higher than in the general population.¹⁶

Global prevalence rates of anxiety and depression are 1.8- and 1.4-fold higher in women than men, respectively¹⁷; the same gender difference is observed in patients with COPD.⁶ The higher prevalence rates of anxiety and depression in women are thought to be a result of sex differences in brain structure, function, and stress responses, as well as differences in exposure to reproductive hormones, social constraints, and experiences between women and men.¹⁸ However, psychologic comorbidity is an issue for both men and women with COPD, so it is important that clinicians are vigilant in recognizing anxiety and depression in both sexes, and are careful not to underestimate the burden in the male patient population.

It is also important to note that depression and anxiety often occur simultaneously in patients with COPD, with prevalence estimates of 26% to 43%.^9,19,20 COPD patients with both depression and anxiety are at a heightened risk of suicidal ideation, increased physical disability, and chronic depressive symptoms versus those with either disorder alone.^10,15 It is therefore important that comorbid anxiety and depression is not overlooked in patients with COPD.

Ensuring that anxiety and depression are recognized and treated effectively in patients with COPD is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD.

Potential mechanisms of anxiety and depression in COPD

Growing evidence suggests that the relationship between mood disorders—particularly depression—and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression.²¹ For example, in a study of
60 stable patients with COPD, elevated dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with the condition.²² In addition, the risk of new-onset depression was increased in COPD patients with moderate-to-severe dyspnea in a 3-year follow-up study.²³ Conversely, depression has been shown to be a significant risk factor for disabling dyspnea (modified Medical Research Council score ≥2) in patients with COPD.²⁴

COPD can lead to feelings of hopelessness, social isolation, reduced physical functioning, and sedentary lifestyle, all of which are associated with an increased level of depressive symptoms.²⁵ Similarly, inadequate social support increases the risk of anxiety in patients with COPD.²⁶ Therefore, ensuring that patients with COPD have high-quality support is very important for reducing anxiety and depressive symptoms.²⁷

The exact mechanisms for the association between mood disorders and COPD remain unclear.^7,10 Research to date indicates that the relationship between depression and impaired pulmonary function may be partly mediated by chronic inflammation^7,10; systemic inflammation has been associated with other comorbidities of COPD (eg, muscle wasting and osteoporosis),²⁸ and emerging data appear to show that proinflammatory cytokines partly mediate the association between depressive symptoms and pulmonary function.²⁹ Smoking and hypoxemia may also influence the prevalence of depression in COPD, but symptom severity and impaired quality of life remain the most important determinants.^6,30

Clinical studies have demonstrated that a number of patient-related factors, including female gender, younger age, current smoking, greater severity of airflow limitation, and lower socioeconomic status, are associated with a higher prevalence and/or increased risk of depression and/or anxiety in COPD.^3,4,30,31 Frequent episodes of rehospitalization, and comorbidities such as hypertension, arthritis, cancer, and heart disease, have been found to increase the risk of anxiety and depression in patients with COPD.^3,32 Risk of anxiety has been shown to increase with greater dyspnea severity.⁴ Pain, a frequently overlooked symptom in COPD, has been shown to be associated with symptoms of both anxiety and depression in patients with COPD.³³ This is driven by worsened quality of life and sleep quality, decreased physical activity, and an increased fear of movement that occur as a result of pain.³⁴

The impact of anxiety and depression in COPD

Comorbid anxiety and depression have a significant detrimental impact on morbidity and mortality in patients with COPD. Both disorders have been associated with an increased risk of death in COPD.^13,35-37 Indeed, of 12 comorbidities proposed to be predictors of mortality in a cohort of 187 female outpatients with COPD, anxiety was associated with the highest risk of death.^35,36

In addition, patients with COPD and anxiety and/or depression have a higher risk of COPD exacerbations,^{4,8,23,36,38-40} hospitalization,^41,42 rehospitalization,^14,36,43 longer hospital stays,^37,41,44 and mortality after exacerbations,^14,36,41 compared with patients without these comorbidities. Patients with COPD who have elevated anxiety symptoms also often experience their first hospitalization earlier in the natural course of COPD than those without anxiety.³⁶

Psychologic comorbidities are also associated with worse lung function, dyspnea, and respiratory symptom burden in patients with COPD.^37,40 Patients with COPD and anxiety are more likely to experience greater dyspnea at an earlier stage of disease than those without anxiety.³⁶ Persistent smoking at 6 months after hospitalization for an acute exacerbation of COPD is also more likely to be seen in patients with depression.³⁷

Patient-centered outcomes are worse in COPD patients with mood disorders. Both anxiety and depression have been shown to correlate with significantly reduced health-related quality of life (HRQoL), poorer physical health status, functional limitations, and reduced exercise capacity.^{4,23,37,40,45} The presence of either anxiety or depression at baseline has been shown to correlate with reduced HRQoL at 1-year follow-up, but depression appears to be the stronger predictor of low future HRQoL than anxiety.⁴⁵

Additionally, mood disorders—particularly depression—reduce physical activity in patients with COPD.^46,47 Emotional responses to COPD symptoms, such as dyspnea, can further decrease activity and worsen deconditioning, resulting in a downward spiral of reduced inactivity, social isolation, fear, anxiety, and depression.⁴⁸

COPD patients with any comorbidity exhibit lower rates of medication adherence than those without comorbidities.^49-51 Clinical studies have demonstrated that anxiety and depression are significant predictors of poor adherence to COPD interventions, including pulmonary rehabilitation (PR).^51-55 Nonadherence to COPD therapies is associated with poor clinical outcomes, including higher hospitalization rates and increased emergency department visits, and increased costs.^56,57 Health care expenditure, in terms of both specific COPD-related costs and general “all-cause” costs, is significantly higher in COPD patients with anxiety and/or depression than in those without.⁸

The underdiagnosis and undertreatment of anxiety and depression in this population is common and can adversely affect patient outcomes.^6,7,9,10,58 Hence, it is crucial that anxiety and depression are identified and more effectively managed in clinical practice.¹⁰

Primary care practitioners are the main point of contact for many patients with COPD,^6,59,60 and so can play a key role in screening for and early identification of anxiety and depression. However, detection of mood disorders by primary care practitioners is challenging for several reasons. These include the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),⁶ as well as factors associated with time constraints, such as competing agendas, duration of visits, and high patient load.^6,61 Furthermore, system-level barriers, such as lack of electronic medical records and adequate health insurance, as well as any communication gaps between primary care and mental health care, may hinder the detection and management of anxiety and depression.⁶ In addition, patients themselves may have a limited understanding of these comorbidities, or may be hesitant to discuss symptoms of anxiety or depression with their primary care practitioner owing to stigma around mental illness.⁶ 

Patients with COPD should be screened and assessed for anxiety and depression, and the United States Preventive Services Task Force recommends that clinicians screen for depression in all adults.^6,62 There are several validated screening tools suitable for clinical use:

• Anxiety Inventory for Respiratory (AIR) Disease scale: a brief, easy-to-use tool for screening and measuring anxiety in COPD.^63,64 It is a self-administered scale, and takes approximately 2 minutes to complete. The AIR scale is responsive to PR.⁶⁴
• COPD Anxiety Questionnaire (CAF): a reliable tool for early identification of COPD-related anxiety.⁶⁵
• Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ; available at: http://www.phqscreeners.com/select-screener/): the PRIME-MD comprises 26 yes/no questions on the 5 most common psychiatric disorders, including depression and anxiety.^66,67 This is not a diagnostic tool, but a high number of positive responses from a patient in any given module indicates that they require further clinical evaluation.
• PHQ-2 and PHQ-9 (Table 1; PHQ-9 available at http://www.phqscreeners.com/select-screener/): widely-used self-administered 2- and 9-item versions of the PRIME-MD, specific to depression; similarly, the 3-item PHQ-3 is available for anxiety assessment (Table 2).^6,67,68 In a study investigating tools used by family physicians in England to assess depression, over 75% used PHQ-9.⁶⁹
• 
  
  Generalized Anxiety Disorder 7-item (GAD-7) scale: an efficient, self-report scale that scores 7 common anxiety symptoms and can be used for screening and severity assessment of GAD in clinical practice.⁷⁰
• Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire-version 20 (GHQ-20): both can be used to screen for psychologic distress in patients with COPD.⁷¹
• The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI): two 21-item self-report questionnaires that are widely used in the United States to evaluate anxiety and depression.⁷²

In addition to specific anxiety and depression questionnaires (Tables 1 and 2), more general COPD assessments tools, such as the COPD Assessment Test and the COPD Clinical Questionnaire, also incorporate questions that may be indicative of symptoms of these comorbidities in patients with COPD.⁷³

Management of anxiety and depression in COPD

Even though anxiety and depression are among the most common and burdensome comorbid conditions in COPD, less than one-third of patients with these comorbidities receive effective intervention.^6,10 Primary care providers have an excellent opportunity to impact this care gap.

As in non-COPD patients, comorbid depression and anxiety may be treated with nonpharmacologic and/or pharmacologic interventions (Figure 1).⁷⁶

Evidence to date suggests that nonpharmacologic interventions such as behavioral therapy are as effective as antidepressants, and may be preferred by patients with mood disorders.¹²

Cognitive behavioral therapy (CBT), which is typically administered by psychologists/psychiatrists, may be effective in treating COPD-related anxiety and depression, especially in conjunction with exercise and education.^12,76,77 Individualized or group CBT is the treatment of choice for addressing thinking patterns that contribute to anxiety and depression to change a patient’s behavior and emotional state.⁷⁶ PR programs involve several components, including aerobic exercise, lung function training, and psycho-education.^62,76 PR is suitable for most patients with COPD, and provides multiple benefits, including reduced hospitalizations in patients who have had a recent exacerbation, and improved dyspnea, exercise tolerance, and health status in patients with stable disease,⁶² as well as clinically and statistically significant improvements in depression and anxiety, irrespective of age.^7,78,79 Exercise-based forms of PR appear to be the most effective for reducing mood symptoms,^12,76 and incorporating psychotherapy may also improve psychologic outcomes.⁸⁰ Stress reduction (relaxation) therapy aims to reduce anxiety-related physiologic changes, and includes a variety of techniques (eg, breathing exercises, sequential muscle relaxation, hypnosis, mindfulness meditation), some of which may be included in PR or used alongside other treatments (eg, CBT).⁷⁶ Limited data indicate that such therapy may be beneficial for reducing anxiety and depression, as well as respiratory symptoms and dyspnea, in patients with COPD.^12,76

Self-management techniques improve clinical outcomes in patients with COPD, but data on the management of depression or anxiety are inconclusive.^7,12 A minimal, home-based, nurse-led, psycho-educational intervention was designed to encourage more open-ended, descriptive discussions of thoughts, emotions, behaviors, and bodily sensations in patients with COPD.⁸¹ The intervention, which involved nurses attending a 1-hour face-to-face session in the patients’ homes with a 15-minute telephone “booster” session 2 weeks later, helped patients with advanced COPD to self-manage their condition and provide relief from anxiety.^81,82 However, it should be noted that there is currently a lack of high-quality data evaluating psychologic interventions in the COPD population.⁸³

In addition, it is important that caregivers are supported in the management of patients with COPD and comorbid anxiety and/or depression; areas in which caregivers can be assisted in their role may include disease education and counseling, where appropriate.⁸⁴

Given that smoking cessation is a key recommendation for patients with COPD,^44,62 practitioners should be aware that patients with comorbid depression and anxiety may experience greater difficulty in smoking cessation, and worsened mood during nicotine withdrawal.⁴⁴ Clinicians should therefore carefully monitor current smokers with COPD and comorbid depression/anxiety (using the tools described previously^63,68,70,71) when they are attempting to quit smoking.

Pharmacologic interventions

Pharmacologic therapy of anxiety and depression has so far only been investigated in patients with COPD in small studies.⁷⁶ However, the available evidence does not indicate that COPD patients with anxiety and depression should be managed any differently from individuals without COPD.⁶² As such, pharmacologic interventions are particularly important for patients with acute or severe anxiety or depression.

Antidepressant agents are categorized according to their mechanism of action, and most commonly include selective serotonin-reuptake inhibitors (SSRIs), selective norepinephrine-reuptake inhibitors, bupropion (a norepinephrine- and dopamine-reuptake inhibitor; also approved for smoking cessation⁸⁵), and mirtazapine (a norepinephrine and serotonin modulator), among others.⁸⁶ SSRIs are the current firstline drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date.⁷⁶ However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy.⁸⁷ In addition to antidepressants, atypical antipsychotics have also been shown to be useful for treating anxiety, either as monotherapy or combination therapy, and possibly as an adjunctive therapy for the management of depression.^88,89

Primary care practitioners can refer to existing guidelines on the management of anxiety and depression in patients with COPD,^86,90 while taking certain factors into consideration. Any pharmacologic management strategy for the treatment of COPD may increase the risk of drug–drug or drug–disease interactions.⁷⁶ For example, it is important to avoid medications that cause respiratory depression (eg, benzodiazepines [unless used with extreme caution], particularly in patients who are already CO₂ retainers) or sedation; chosen drugs should have minimal other adverse effects.⁷⁶ Moreover, SSRIs may also be associated with troublesome adverse effects during treatment initiation, such as gastrointestinal upset, headache, tremor, psychomotor activation, and sedation⁷⁶; in addition, dry mouth is an adverse effect associated with both SSRI treatment and several inhaled therapies, so may be particularly problematic in patients with COPD.^91,92 Currently, data are particularly scarce for the management of anxiety in patients with COPD, with inconclusive or contradictory findings reported for SSRIs, azapirones (including buspirone), and tricyclic antidepressants.⁷⁶

In addition to monitoring adherence to COPD therapies, primary care practitioners should carefully monitor patients treated with antidepressants and anxiolytics for adherence. A meta-analysis of 18,245 individuals with chronic diseases showed that depressed patients had a 76% significantly higher risk of nonadherence to medication compared with those without depressive symptoms.⁹³

Targeting dyspnea is key to the management of anxiety and depression in COPD, as breathlessness is frequently associated with the onset of both comorbidities.^21,22 Therapeutic approaches to alleviating dyspnea include PR, optimizing respiratory mechanics and muscle function (with bronchodilator therapy), and reducing central neural drive to respiratory muscles with supplemental oxygen or opioid medication.⁹⁴

Although bronchodilator therapy for COPD has not been shown to have significant direct effects on depression or anxiety,⁹⁵ it can be assumed that the beneficial effects on dyspnea are likely to alleviate associated emotional and mood symptoms.

Further research into effective screening, diagnosis, and management of comorbid anxiety and depressive disorders in COPD is warranted, including evaluation of a broad range of nonpharmacologic and drug-based interventions, alone and in combination.⁷⁶

Conclusions

Anxiety and depression are common, yet frequently overlooked, comorbidities in COPD. The impact of these psychologic comorbidities is significant; their consequences are evident in morbidity and mortality data, as well as in patient-reported outcomes. As key points of contact for patients with COPD, it is essential that primary care practitioners are vigilant in monitoring for anxiety and depression in their patients with COPD, making the most of the available tools that can support them in doing so, and maintain an ongoing line of communication with other members of the multidisciplinary team. Treatment of anxiety and depression in COPD should adopt a holistic approach that incorporates both nonpharmacologic and pharmacologic interventions. However, the impact of effective screening, diagnosis, and management of anxiety and depression on COPD burden in patients requires further investigation.

Introduction

Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), occurring more frequently than in the general population^1-4 or patients with other chronic diseases such as hypertension, diabetes, cancer, or musculoskeletal disorders.^5,6 Their presence is associated with worse outcomes of COPD, and increased morbidity, mortality, disability, and health care expenditure.^6-8 In spite of this, both anxiety and depression are frequently overlooked and undertreated in patients with COPD,⁹ and symptoms of anxiety and depression can overlap significantly, as well as overlap with COPD symptoms.^7,10 

Comorbid depressive disorders that may occur in patients with COPD include major depressive disorder, dysthymias (chronic depressive symptoms of mild severity), and minor depression.¹¹ Depressive disorders are characterized by feelings of sadness, emptiness, and/or irritability, along with cognitive and somatic symptoms, which have a detrimental effect on the patient’s ability to function.¹¹ Anxiety disorders include generalized anxiety disorder (GAD), phobias, and panic disorders.¹¹ The main features of anxiety disorders, such as excessive fear and anxiety, may be accompanied by behavioral disturbances related to these symptoms, such as panic attacks and avoidance.^11,12

The reported prevalence of depression in COPD varies widely between studies, owing to differences in sampling methods and degrees of illness severity used in assessment of depression⁶; rates have been reported to range from 10% to 42% in patients with stable COPD,^6,13 and from 10% to 86% in patients with acute COPD exacerbation.¹⁴ Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD.¹⁰

Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients. GAD, panic disorders, and specific phobias are reported most frequently.¹⁵ Patients with COPD are 85% more likely to develop anxiety disorders compared with matched controls without COPD,⁴ and panic disorder is reported with a prevalence that is up to 10-fold higher than in the general population.¹⁶

Global prevalence rates of anxiety and depression are 1.8- and 1.4-fold higher in women than men, respectively¹⁷; the same gender difference is observed in patients with COPD.⁶ The higher prevalence rates of anxiety and depression in women are thought to be a result of sex differences in brain structure, function, and stress responses, as well as differences in exposure to reproductive hormones, social constraints, and experiences between women and men.¹⁸ However, psychologic comorbidity is an issue for both men and women with COPD, so it is important that clinicians are vigilant in recognizing anxiety and depression in both sexes, and are careful not to underestimate the burden in the male patient population.

It is also important to note that depression and anxiety often occur simultaneously in patients with COPD, with prevalence estimates of 26% to 43%.^9,19,20 COPD patients with both depression and anxiety are at a heightened risk of suicidal ideation, increased physical disability, and chronic depressive symptoms versus those with either disorder alone.^10,15 It is therefore important that comorbid anxiety and depression is not overlooked in patients with COPD.

Ensuring that anxiety and depression are recognized and treated effectively in patients with COPD is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD.

Potential mechanisms of anxiety and depression in COPD

Growing evidence suggests that the relationship between mood disorders—particularly depression—and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression.²¹ For example, in a study of
60 stable patients with COPD, elevated dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with the condition.²² In addition, the risk of new-onset depression was increased in COPD patients with moderate-to-severe dyspnea in a 3-year follow-up study.²³ Conversely, depression has been shown to be a significant risk factor for disabling dyspnea (modified Medical Research Council score ≥2) in patients with COPD.²⁴

COPD can lead to feelings of hopelessness, social isolation, reduced physical functioning, and sedentary lifestyle, all of which are associated with an increased level of depressive symptoms.²⁵ Similarly, inadequate social support increases the risk of anxiety in patients with COPD.²⁶ Therefore, ensuring that patients with COPD have high-quality support is very important for reducing anxiety and depressive symptoms.²⁷

The exact mechanisms for the association between mood disorders and COPD remain unclear.^7,10 Research to date indicates that the relationship between depression and impaired pulmonary function may be partly mediated by chronic inflammation^7,10; systemic inflammation has been associated with other comorbidities of COPD (eg, muscle wasting and osteoporosis),²⁸ and emerging data appear to show that proinflammatory cytokines partly mediate the association between depressive symptoms and pulmonary function.²⁹ Smoking and hypoxemia may also influence the prevalence of depression in COPD, but symptom severity and impaired quality of life remain the most important determinants.^6,30

Clinical studies have demonstrated that a number of patient-related factors, including female gender, younger age, current smoking, greater severity of airflow limitation, and lower socioeconomic status, are associated with a higher prevalence and/or increased risk of depression and/or anxiety in COPD.^3,4,30,31 Frequent episodes of rehospitalization, and comorbidities such as hypertension, arthritis, cancer, and heart disease, have been found to increase the risk of anxiety and depression in patients with COPD.^3,32 Risk of anxiety has been shown to increase with greater dyspnea severity.⁴ Pain, a frequently overlooked symptom in COPD, has been shown to be associated with symptoms of both anxiety and depression in patients with COPD.³³ This is driven by worsened quality of life and sleep quality, decreased physical activity, and an increased fear of movement that occur as a result of pain.³⁴

The impact of anxiety and depression in COPD

Comorbid anxiety and depression have a significant detrimental impact on morbidity and mortality in patients with COPD. Both disorders have been associated with an increased risk of death in COPD.^13,35-37 Indeed, of 12 comorbidities proposed to be predictors of mortality in a cohort of 187 female outpatients with COPD, anxiety was associated with the highest risk of death.^35,36

In addition, patients with COPD and anxiety and/or depression have a higher risk of COPD exacerbations,^{4,8,23,36,38-40} hospitalization,^41,42 rehospitalization,^14,36,43 longer hospital stays,^37,41,44 and mortality after exacerbations,^14,36,41 compared with patients without these comorbidities. Patients with COPD who have elevated anxiety symptoms also often experience their first hospitalization earlier in the natural course of COPD than those without anxiety.³⁶

Psychologic comorbidities are also associated with worse lung function, dyspnea, and respiratory symptom burden in patients with COPD.^37,40 Patients with COPD and anxiety are more likely to experience greater dyspnea at an earlier stage of disease than those without anxiety.³⁶ Persistent smoking at 6 months after hospitalization for an acute exacerbation of COPD is also more likely to be seen in patients with depression.³⁷

Patient-centered outcomes are worse in COPD patients with mood disorders. Both anxiety and depression have been shown to correlate with significantly reduced health-related quality of life (HRQoL), poorer physical health status, functional limitations, and reduced exercise capacity.^{4,23,37,40,45} The presence of either anxiety or depression at baseline has been shown to correlate with reduced HRQoL at 1-year follow-up, but depression appears to be the stronger predictor of low future HRQoL than anxiety.⁴⁵

Additionally, mood disorders—particularly depression—reduce physical activity in patients with COPD.^46,47 Emotional responses to COPD symptoms, such as dyspnea, can further decrease activity and worsen deconditioning, resulting in a downward spiral of reduced inactivity, social isolation, fear, anxiety, and depression.⁴⁸

COPD patients with any comorbidity exhibit lower rates of medication adherence than those without comorbidities.^49-51 Clinical studies have demonstrated that anxiety and depression are significant predictors of poor adherence to COPD interventions, including pulmonary rehabilitation (PR).^51-55 Nonadherence to COPD therapies is associated with poor clinical outcomes, including higher hospitalization rates and increased emergency department visits, and increased costs.^56,57 Health care expenditure, in terms of both specific COPD-related costs and general “all-cause” costs, is significantly higher in COPD patients with anxiety and/or depression than in those without.⁸

The underdiagnosis and undertreatment of anxiety and depression in this population is common and can adversely affect patient outcomes.^6,7,9,10,58 Hence, it is crucial that anxiety and depression are identified and more effectively managed in clinical practice.¹⁰

Primary care practitioners are the main point of contact for many patients with COPD,^6,59,60 and so can play a key role in screening for and early identification of anxiety and depression. However, detection of mood disorders by primary care practitioners is challenging for several reasons. These include the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),⁶ as well as factors associated with time constraints, such as competing agendas, duration of visits, and high patient load.^6,61 Furthermore, system-level barriers, such as lack of electronic medical records and adequate health insurance, as well as any communication gaps between primary care and mental health care, may hinder the detection and management of anxiety and depression.⁶ In addition, patients themselves may have a limited understanding of these comorbidities, or may be hesitant to discuss symptoms of anxiety or depression with their primary care practitioner owing to stigma around mental illness.⁶ 

Patients with COPD should be screened and assessed for anxiety and depression, and the United States Preventive Services Task Force recommends that clinicians screen for depression in all adults.^6,62 There are several validated screening tools suitable for clinical use:

• Anxiety Inventory for Respiratory (AIR) Disease scale: a brief, easy-to-use tool for screening and measuring anxiety in COPD.^63,64 It is a self-administered scale, and takes approximately 2 minutes to complete. The AIR scale is responsive to PR.⁶⁴
• COPD Anxiety Questionnaire (CAF): a reliable tool for early identification of COPD-related anxiety.⁶⁵
• Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ; available at: http://www.phqscreeners.com/select-screener/): the PRIME-MD comprises 26 yes/no questions on the 5 most common psychiatric disorders, including depression and anxiety.^66,67 This is not a diagnostic tool, but a high number of positive responses from a patient in any given module indicates that they require further clinical evaluation.
• PHQ-2 and PHQ-9 (Table 1; PHQ-9 available at http://www.phqscreeners.com/select-screener/): widely-used self-administered 2- and 9-item versions of the PRIME-MD, specific to depression; similarly, the 3-item PHQ-3 is available for anxiety assessment (Table 2).^6,67,68 In a study investigating tools used by family physicians in England to assess depression, over 75% used PHQ-9.⁶⁹
• 
  
  Generalized Anxiety Disorder 7-item (GAD-7) scale: an efficient, self-report scale that scores 7 common anxiety symptoms and can be used for screening and severity assessment of GAD in clinical practice.⁷⁰
• Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire-version 20 (GHQ-20): both can be used to screen for psychologic distress in patients with COPD.⁷¹
• The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI): two 21-item self-report questionnaires that are widely used in the United States to evaluate anxiety and depression.⁷²

In addition to specific anxiety and depression questionnaires (Tables 1 and 2), more general COPD assessments tools, such as the COPD Assessment Test and the COPD Clinical Questionnaire, also incorporate questions that may be indicative of symptoms of these comorbidities in patients with COPD.⁷³

Management of anxiety and depression in COPD

Even though anxiety and depression are among the most common and burdensome comorbid conditions in COPD, less than one-third of patients with these comorbidities receive effective intervention.^6,10 Primary care providers have an excellent opportunity to impact this care gap.

As in non-COPD patients, comorbid depression and anxiety may be treated with nonpharmacologic and/or pharmacologic interventions (Figure 1).⁷⁶

Evidence to date suggests that nonpharmacologic interventions such as behavioral therapy are as effective as antidepressants, and may be preferred by patients with mood disorders.¹²

Cognitive behavioral therapy (CBT), which is typically administered by psychologists/psychiatrists, may be effective in treating COPD-related anxiety and depression, especially in conjunction with exercise and education.^12,76,77 Individualized or group CBT is the treatment of choice for addressing thinking patterns that contribute to anxiety and depression to change a patient’s behavior and emotional state.⁷⁶ PR programs involve several components, including aerobic exercise, lung function training, and psycho-education.^62,76 PR is suitable for most patients with COPD, and provides multiple benefits, including reduced hospitalizations in patients who have had a recent exacerbation, and improved dyspnea, exercise tolerance, and health status in patients with stable disease,⁶² as well as clinically and statistically significant improvements in depression and anxiety, irrespective of age.^7,78,79 Exercise-based forms of PR appear to be the most effective for reducing mood symptoms,^12,76 and incorporating psychotherapy may also improve psychologic outcomes.⁸⁰ Stress reduction (relaxation) therapy aims to reduce anxiety-related physiologic changes, and includes a variety of techniques (eg, breathing exercises, sequential muscle relaxation, hypnosis, mindfulness meditation), some of which may be included in PR or used alongside other treatments (eg, CBT).⁷⁶ Limited data indicate that such therapy may be beneficial for reducing anxiety and depression, as well as respiratory symptoms and dyspnea, in patients with COPD.^12,76

Self-management techniques improve clinical outcomes in patients with COPD, but data on the management of depression or anxiety are inconclusive.^7,12 A minimal, home-based, nurse-led, psycho-educational intervention was designed to encourage more open-ended, descriptive discussions of thoughts, emotions, behaviors, and bodily sensations in patients with COPD.⁸¹ The intervention, which involved nurses attending a 1-hour face-to-face session in the patients’ homes with a 15-minute telephone “booster” session 2 weeks later, helped patients with advanced COPD to self-manage their condition and provide relief from anxiety.^81,82 However, it should be noted that there is currently a lack of high-quality data evaluating psychologic interventions in the COPD population.⁸³

In addition, it is important that caregivers are supported in the management of patients with COPD and comorbid anxiety and/or depression; areas in which caregivers can be assisted in their role may include disease education and counseling, where appropriate.⁸⁴

Given that smoking cessation is a key recommendation for patients with COPD,^44,62 practitioners should be aware that patients with comorbid depression and anxiety may experience greater difficulty in smoking cessation, and worsened mood during nicotine withdrawal.⁴⁴ Clinicians should therefore carefully monitor current smokers with COPD and comorbid depression/anxiety (using the tools described previously^63,68,70,71) when they are attempting to quit smoking.

Pharmacologic interventions

Pharmacologic therapy of anxiety and depression has so far only been investigated in patients with COPD in small studies.⁷⁶ However, the available evidence does not indicate that COPD patients with anxiety and depression should be managed any differently from individuals without COPD.⁶² As such, pharmacologic interventions are particularly important for patients with acute or severe anxiety or depression.

Antidepressant agents are categorized according to their mechanism of action, and most commonly include selective serotonin-reuptake inhibitors (SSRIs), selective norepinephrine-reuptake inhibitors, bupropion (a norepinephrine- and dopamine-reuptake inhibitor; also approved for smoking cessation⁸⁵), and mirtazapine (a norepinephrine and serotonin modulator), among others.⁸⁶ SSRIs are the current firstline drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date.⁷⁶ However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy.⁸⁷ In addition to antidepressants, atypical antipsychotics have also been shown to be useful for treating anxiety, either as monotherapy or combination therapy, and possibly as an adjunctive therapy for the management of depression.^88,89

Primary care practitioners can refer to existing guidelines on the management of anxiety and depression in patients with COPD,^86,90 while taking certain factors into consideration. Any pharmacologic management strategy for the treatment of COPD may increase the risk of drug–drug or drug–disease interactions.⁷⁶ For example, it is important to avoid medications that cause respiratory depression (eg, benzodiazepines [unless used with extreme caution], particularly in patients who are already CO₂ retainers) or sedation; chosen drugs should have minimal other adverse effects.⁷⁶ Moreover, SSRIs may also be associated with troublesome adverse effects during treatment initiation, such as gastrointestinal upset, headache, tremor, psychomotor activation, and sedation⁷⁶; in addition, dry mouth is an adverse effect associated with both SSRI treatment and several inhaled therapies, so may be particularly problematic in patients with COPD.^91,92 Currently, data are particularly scarce for the management of anxiety in patients with COPD, with inconclusive or contradictory findings reported for SSRIs, azapirones (including buspirone), and tricyclic antidepressants.⁷⁶

In addition to monitoring adherence to COPD therapies, primary care practitioners should carefully monitor patients treated with antidepressants and anxiolytics for adherence. A meta-analysis of 18,245 individuals with chronic diseases showed that depressed patients had a 76% significantly higher risk of nonadherence to medication compared with those without depressive symptoms.⁹³

Targeting dyspnea is key to the management of anxiety and depression in COPD, as breathlessness is frequently associated with the onset of both comorbidities.^21,22 Therapeutic approaches to alleviating dyspnea include PR, optimizing respiratory mechanics and muscle function (with bronchodilator therapy), and reducing central neural drive to respiratory muscles with supplemental oxygen or opioid medication.⁹⁴

Although bronchodilator therapy for COPD has not been shown to have significant direct effects on depression or anxiety,⁹⁵ it can be assumed that the beneficial effects on dyspnea are likely to alleviate associated emotional and mood symptoms.

Further research into effective screening, diagnosis, and management of comorbid anxiety and depressive disorders in COPD is warranted, including evaluation of a broad range of nonpharmacologic and drug-based interventions, alone and in combination.⁷⁶

Conclusions

Anxiety and depression are common, yet frequently overlooked, comorbidities in COPD. The impact of these psychologic comorbidities is significant; their consequences are evident in morbidity and mortality data, as well as in patient-reported outcomes. As key points of contact for patients with COPD, it is essential that primary care practitioners are vigilant in monitoring for anxiety and depression in their patients with COPD, making the most of the available tools that can support them in doing so, and maintain an ongoing line of communication with other members of the multidisciplinary team. Treatment of anxiety and depression in COPD should adopt a holistic approach that incorporates both nonpharmacologic and pharmacologic interventions. However, the impact of effective screening, diagnosis, and management of anxiety and depression on COPD burden in patients requires further investigation.

Introduction

Anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), occurring more frequently than in the general population^1-4 or patients with other chronic diseases such as hypertension, diabetes, cancer, or musculoskeletal disorders.^5,6 Their presence is associated with worse outcomes of COPD, and increased morbidity, mortality, disability, and health care expenditure.^6-8 In spite of this, both anxiety and depression are frequently overlooked and undertreated in patients with COPD,⁹ and symptoms of anxiety and depression can overlap significantly, as well as overlap with COPD symptoms.^7,10 

Comorbid depressive disorders that may occur in patients with COPD include major depressive disorder, dysthymias (chronic depressive symptoms of mild severity), and minor depression.¹¹ Depressive disorders are characterized by feelings of sadness, emptiness, and/or irritability, along with cognitive and somatic symptoms, which have a detrimental effect on the patient’s ability to function.¹¹ Anxiety disorders include generalized anxiety disorder (GAD), phobias, and panic disorders.¹¹ The main features of anxiety disorders, such as excessive fear and anxiety, may be accompanied by behavioral disturbances related to these symptoms, such as panic attacks and avoidance.^11,12

The reported prevalence of depression in COPD varies widely between studies, owing to differences in sampling methods and degrees of illness severity used in assessment of depression⁶; rates have been reported to range from 10% to 42% in patients with stable COPD,^6,13 and from 10% to 86% in patients with acute COPD exacerbation.¹⁴ Individuals with severe COPD are twice as likely to develop depression than patients with mild COPD.¹⁰

Prevalence rates for clinical anxiety in COPD range from 13% to 46% in outpatients and 10% to 55% among inpatients. GAD, panic disorders, and specific phobias are reported most frequently.¹⁵ Patients with COPD are 85% more likely to develop anxiety disorders compared with matched controls without COPD,⁴ and panic disorder is reported with a prevalence that is up to 10-fold higher than in the general population.¹⁶

Global prevalence rates of anxiety and depression are 1.8- and 1.4-fold higher in women than men, respectively¹⁷; the same gender difference is observed in patients with COPD.⁶ The higher prevalence rates of anxiety and depression in women are thought to be a result of sex differences in brain structure, function, and stress responses, as well as differences in exposure to reproductive hormones, social constraints, and experiences between women and men.¹⁸ However, psychologic comorbidity is an issue for both men and women with COPD, so it is important that clinicians are vigilant in recognizing anxiety and depression in both sexes, and are careful not to underestimate the burden in the male patient population.

It is also important to note that depression and anxiety often occur simultaneously in patients with COPD, with prevalence estimates of 26% to 43%.^9,19,20 COPD patients with both depression and anxiety are at a heightened risk of suicidal ideation, increased physical disability, and chronic depressive symptoms versus those with either disorder alone.^10,15 It is therefore important that comorbid anxiety and depression is not overlooked in patients with COPD.

Ensuring that anxiety and depression are recognized and treated effectively in patients with COPD is essential for optimizing outcomes. Primary care practitioners are well placed to diagnose anxiety and depression, and to ensure these conditions are suitably managed alongside treatments of COPD.

Potential mechanisms of anxiety and depression in COPD

Growing evidence suggests that the relationship between mood disorders—particularly depression—and COPD is bidirectional, meaning that mood disorders adversely impact prognosis in COPD, whereas COPD increases the risk of developing depression.²¹ For example, in a study of
60 stable patients with COPD, elevated dyspnea and reduced exercise capacity were the predominant mechanisms leading to anxiety and depression symptoms associated with the condition.²² In addition, the risk of new-onset depression was increased in COPD patients with moderate-to-severe dyspnea in a 3-year follow-up study.²³ Conversely, depression has been shown to be a significant risk factor for disabling dyspnea (modified Medical Research Council score ≥2) in patients with COPD.²⁴

COPD can lead to feelings of hopelessness, social isolation, reduced physical functioning, and sedentary lifestyle, all of which are associated with an increased level of depressive symptoms.²⁵ Similarly, inadequate social support increases the risk of anxiety in patients with COPD.²⁶ Therefore, ensuring that patients with COPD have high-quality support is very important for reducing anxiety and depressive symptoms.²⁷

The exact mechanisms for the association between mood disorders and COPD remain unclear.^7,10 Research to date indicates that the relationship between depression and impaired pulmonary function may be partly mediated by chronic inflammation^7,10; systemic inflammation has been associated with other comorbidities of COPD (eg, muscle wasting and osteoporosis),²⁸ and emerging data appear to show that proinflammatory cytokines partly mediate the association between depressive symptoms and pulmonary function.²⁹ Smoking and hypoxemia may also influence the prevalence of depression in COPD, but symptom severity and impaired quality of life remain the most important determinants.^6,30

Clinical studies have demonstrated that a number of patient-related factors, including female gender, younger age, current smoking, greater severity of airflow limitation, and lower socioeconomic status, are associated with a higher prevalence and/or increased risk of depression and/or anxiety in COPD.^3,4,30,31 Frequent episodes of rehospitalization, and comorbidities such as hypertension, arthritis, cancer, and heart disease, have been found to increase the risk of anxiety and depression in patients with COPD.^3,32 Risk of anxiety has been shown to increase with greater dyspnea severity.⁴ Pain, a frequently overlooked symptom in COPD, has been shown to be associated with symptoms of both anxiety and depression in patients with COPD.³³ This is driven by worsened quality of life and sleep quality, decreased physical activity, and an increased fear of movement that occur as a result of pain.³⁴

The impact of anxiety and depression in COPD

Comorbid anxiety and depression have a significant detrimental impact on morbidity and mortality in patients with COPD. Both disorders have been associated with an increased risk of death in COPD.^13,35-37 Indeed, of 12 comorbidities proposed to be predictors of mortality in a cohort of 187 female outpatients with COPD, anxiety was associated with the highest risk of death.^35,36

In addition, patients with COPD and anxiety and/or depression have a higher risk of COPD exacerbations,^{4,8,23,36,38-40} hospitalization,^41,42 rehospitalization,^14,36,43 longer hospital stays,^37,41,44 and mortality after exacerbations,^14,36,41 compared with patients without these comorbidities. Patients with COPD who have elevated anxiety symptoms also often experience their first hospitalization earlier in the natural course of COPD than those without anxiety.³⁶

Psychologic comorbidities are also associated with worse lung function, dyspnea, and respiratory symptom burden in patients with COPD.^37,40 Patients with COPD and anxiety are more likely to experience greater dyspnea at an earlier stage of disease than those without anxiety.³⁶ Persistent smoking at 6 months after hospitalization for an acute exacerbation of COPD is also more likely to be seen in patients with depression.³⁷

Patient-centered outcomes are worse in COPD patients with mood disorders. Both anxiety and depression have been shown to correlate with significantly reduced health-related quality of life (HRQoL), poorer physical health status, functional limitations, and reduced exercise capacity.^{4,23,37,40,45} The presence of either anxiety or depression at baseline has been shown to correlate with reduced HRQoL at 1-year follow-up, but depression appears to be the stronger predictor of low future HRQoL than anxiety.⁴⁵

Additionally, mood disorders—particularly depression—reduce physical activity in patients with COPD.^46,47 Emotional responses to COPD symptoms, such as dyspnea, can further decrease activity and worsen deconditioning, resulting in a downward spiral of reduced inactivity, social isolation, fear, anxiety, and depression.⁴⁸

COPD patients with any comorbidity exhibit lower rates of medication adherence than those without comorbidities.^49-51 Clinical studies have demonstrated that anxiety and depression are significant predictors of poor adherence to COPD interventions, including pulmonary rehabilitation (PR).^51-55 Nonadherence to COPD therapies is associated with poor clinical outcomes, including higher hospitalization rates and increased emergency department visits, and increased costs.^56,57 Health care expenditure, in terms of both specific COPD-related costs and general “all-cause” costs, is significantly higher in COPD patients with anxiety and/or depression than in those without.⁸

The underdiagnosis and undertreatment of anxiety and depression in this population is common and can adversely affect patient outcomes.^6,7,9,10,58 Hence, it is crucial that anxiety and depression are identified and more effectively managed in clinical practice.¹⁰

Primary care practitioners are the main point of contact for many patients with COPD,^6,59,60 and so can play a key role in screening for and early identification of anxiety and depression. However, detection of mood disorders by primary care practitioners is challenging for several reasons. These include the lack of a standardized approach in diagnosis, and inadequate knowledge or confidence in assessing psychological status (particularly given the number of strategies available for screening patients for mood disorders),⁶ as well as factors associated with time constraints, such as competing agendas, duration of visits, and high patient load.^6,61 Furthermore, system-level barriers, such as lack of electronic medical records and adequate health insurance, as well as any communication gaps between primary care and mental health care, may hinder the detection and management of anxiety and depression.⁶ In addition, patients themselves may have a limited understanding of these comorbidities, or may be hesitant to discuss symptoms of anxiety or depression with their primary care practitioner owing to stigma around mental illness.⁶ 

Patients with COPD should be screened and assessed for anxiety and depression, and the United States Preventive Services Task Force recommends that clinicians screen for depression in all adults.^6,62 There are several validated screening tools suitable for clinical use:

• Anxiety Inventory for Respiratory (AIR) Disease scale: a brief, easy-to-use tool for screening and measuring anxiety in COPD.^63,64 It is a self-administered scale, and takes approximately 2 minutes to complete. The AIR scale is responsive to PR.⁶⁴
• COPD Anxiety Questionnaire (CAF): a reliable tool for early identification of COPD-related anxiety.⁶⁵
• Primary Care Evaluation of Mental Disorders (PRIME-MD) Patient Health Questionnaire (PHQ; available at: http://www.phqscreeners.com/select-screener/): the PRIME-MD comprises 26 yes/no questions on the 5 most common psychiatric disorders, including depression and anxiety.^66,67 This is not a diagnostic tool, but a high number of positive responses from a patient in any given module indicates that they require further clinical evaluation.
• PHQ-2 and PHQ-9 (Table 1; PHQ-9 available at http://www.phqscreeners.com/select-screener/): widely-used self-administered 2- and 9-item versions of the PRIME-MD, specific to depression; similarly, the 3-item PHQ-3 is available for anxiety assessment (Table 2).^6,67,68 In a study investigating tools used by family physicians in England to assess depression, over 75% used PHQ-9.⁶⁹
• 
  
  Generalized Anxiety Disorder 7-item (GAD-7) scale: an efficient, self-report scale that scores 7 common anxiety symptoms and can be used for screening and severity assessment of GAD in clinical practice.⁷⁰
• Hospital Anxiety and Depression Scale (HADS) and General Health Questionnaire-version 20 (GHQ-20): both can be used to screen for psychologic distress in patients with COPD.⁷¹
• The Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI): two 21-item self-report questionnaires that are widely used in the United States to evaluate anxiety and depression.⁷²

In addition to specific anxiety and depression questionnaires (Tables 1 and 2), more general COPD assessments tools, such as the COPD Assessment Test and the COPD Clinical Questionnaire, also incorporate questions that may be indicative of symptoms of these comorbidities in patients with COPD.⁷³

Management of anxiety and depression in COPD

Even though anxiety and depression are among the most common and burdensome comorbid conditions in COPD, less than one-third of patients with these comorbidities receive effective intervention.^6,10 Primary care providers have an excellent opportunity to impact this care gap.

As in non-COPD patients, comorbid depression and anxiety may be treated with nonpharmacologic and/or pharmacologic interventions (Figure 1).⁷⁶

Evidence to date suggests that nonpharmacologic interventions such as behavioral therapy are as effective as antidepressants, and may be preferred by patients with mood disorders.¹²

Cognitive behavioral therapy (CBT), which is typically administered by psychologists/psychiatrists, may be effective in treating COPD-related anxiety and depression, especially in conjunction with exercise and education.^12,76,77 Individualized or group CBT is the treatment of choice for addressing thinking patterns that contribute to anxiety and depression to change a patient’s behavior and emotional state.⁷⁶ PR programs involve several components, including aerobic exercise, lung function training, and psycho-education.^62,76 PR is suitable for most patients with COPD, and provides multiple benefits, including reduced hospitalizations in patients who have had a recent exacerbation, and improved dyspnea, exercise tolerance, and health status in patients with stable disease,⁶² as well as clinically and statistically significant improvements in depression and anxiety, irrespective of age.^7,78,79 Exercise-based forms of PR appear to be the most effective for reducing mood symptoms,^12,76 and incorporating psychotherapy may also improve psychologic outcomes.⁸⁰ Stress reduction (relaxation) therapy aims to reduce anxiety-related physiologic changes, and includes a variety of techniques (eg, breathing exercises, sequential muscle relaxation, hypnosis, mindfulness meditation), some of which may be included in PR or used alongside other treatments (eg, CBT).⁷⁶ Limited data indicate that such therapy may be beneficial for reducing anxiety and depression, as well as respiratory symptoms and dyspnea, in patients with COPD.^12,76

Self-management techniques improve clinical outcomes in patients with COPD, but data on the management of depression or anxiety are inconclusive.^7,12 A minimal, home-based, nurse-led, psycho-educational intervention was designed to encourage more open-ended, descriptive discussions of thoughts, emotions, behaviors, and bodily sensations in patients with COPD.⁸¹ The intervention, which involved nurses attending a 1-hour face-to-face session in the patients’ homes with a 15-minute telephone “booster” session 2 weeks later, helped patients with advanced COPD to self-manage their condition and provide relief from anxiety.^81,82 However, it should be noted that there is currently a lack of high-quality data evaluating psychologic interventions in the COPD population.⁸³

In addition, it is important that caregivers are supported in the management of patients with COPD and comorbid anxiety and/or depression; areas in which caregivers can be assisted in their role may include disease education and counseling, where appropriate.⁸⁴

Given that smoking cessation is a key recommendation for patients with COPD,^44,62 practitioners should be aware that patients with comorbid depression and anxiety may experience greater difficulty in smoking cessation, and worsened mood during nicotine withdrawal.⁴⁴ Clinicians should therefore carefully monitor current smokers with COPD and comorbid depression/anxiety (using the tools described previously^63,68,70,71) when they are attempting to quit smoking.

Pharmacologic interventions

Pharmacologic therapy of anxiety and depression has so far only been investigated in patients with COPD in small studies.⁷⁶ However, the available evidence does not indicate that COPD patients with anxiety and depression should be managed any differently from individuals without COPD.⁶² As such, pharmacologic interventions are particularly important for patients with acute or severe anxiety or depression.

Antidepressant agents are categorized according to their mechanism of action, and most commonly include selective serotonin-reuptake inhibitors (SSRIs), selective norepinephrine-reuptake inhibitors, bupropion (a norepinephrine- and dopamine-reuptake inhibitor; also approved for smoking cessation⁸⁵), and mirtazapine (a norepinephrine and serotonin modulator), among others.⁸⁶ SSRIs are the current firstline drug treatment for depression, and have been shown to significantly improve depression and anxiety in patients with COPD in some, but not all, trials published to date.⁷⁶ However, it is important to note that a diagnosis of bipolar disorder must be ruled out before initiating standard antidepressant therapy.⁸⁷ In addition to antidepressants, atypical antipsychotics have also been shown to be useful for treating anxiety, either as monotherapy or combination therapy, and possibly as an adjunctive therapy for the management of depression.^88,89

Primary care practitioners can refer to existing guidelines on the management of anxiety and depression in patients with COPD,^86,90 while taking certain factors into consideration. Any pharmacologic management strategy for the treatment of COPD may increase the risk of drug–drug or drug–disease interactions.⁷⁶ For example, it is important to avoid medications that cause respiratory depression (eg, benzodiazepines [unless used with extreme caution], particularly in patients who are already CO₂ retainers) or sedation; chosen drugs should have minimal other adverse effects.⁷⁶ Moreover, SSRIs may also be associated with troublesome adverse effects during treatment initiation, such as gastrointestinal upset, headache, tremor, psychomotor activation, and sedation⁷⁶; in addition, dry mouth is an adverse effect associated with both SSRI treatment and several inhaled therapies, so may be particularly problematic in patients with COPD.^91,92 Currently, data are particularly scarce for the management of anxiety in patients with COPD, with inconclusive or contradictory findings reported for SSRIs, azapirones (including buspirone), and tricyclic antidepressants.⁷⁶

In addition to monitoring adherence to COPD therapies, primary care practitioners should carefully monitor patients treated with antidepressants and anxiolytics for adherence. A meta-analysis of 18,245 individuals with chronic diseases showed that depressed patients had a 76% significantly higher risk of nonadherence to medication compared with those without depressive symptoms.⁹³

Targeting dyspnea is key to the management of anxiety and depression in COPD, as breathlessness is frequently associated with the onset of both comorbidities.^21,22 Therapeutic approaches to alleviating dyspnea include PR, optimizing respiratory mechanics and muscle function (with bronchodilator therapy), and reducing central neural drive to respiratory muscles with supplemental oxygen or opioid medication.⁹⁴

Although bronchodilator therapy for COPD has not been shown to have significant direct effects on depression or anxiety,⁹⁵ it can be assumed that the beneficial effects on dyspnea are likely to alleviate associated emotional and mood symptoms.

Further research into effective screening, diagnosis, and management of comorbid anxiety and depressive disorders in COPD is warranted, including evaluation of a broad range of nonpharmacologic and drug-based interventions, alone and in combination.⁷⁶

Conclusions

Anxiety and depression are common, yet frequently overlooked, comorbidities in COPD. The impact of these psychologic comorbidities is significant; their consequences are evident in morbidity and mortality data, as well as in patient-reported outcomes. As key points of contact for patients with COPD, it is essential that primary care practitioners are vigilant in monitoring for anxiety and depression in their patients with COPD, making the most of the available tools that can support them in doing so, and maintain an ongoing line of communication with other members of the multidisciplinary team. Treatment of anxiety and depression in COPD should adopt a holistic approach that incorporates both nonpharmacologic and pharmacologic interventions. However, the impact of effective screening, diagnosis, and management of anxiety and depression on COPD burden in patients requires further investigation.

Device considerations

The SMI delivers the aerosol as a fine mist with slow velocity lasting >1 second, which is considerably slower than spray delivery with pMDIs.¹⁴ The aim of this design is to make it easier for patients to coordinate actuation with inhalation, but it is important to note that some coordination is still required for SMI devices to function correctly.¹⁴ In addition, the SMI is not dependent on a patient’s ability to generate sufficient PIF for effective drug delivery. A limitation of the SMI is the need to assemble the device, as patients with poor manual dexterity may encounter difficulty when attempting to load the drug cartridge.¹⁵

Nebulizers deliver aerosolized drug in a fine mist. Newer-generation portable vibrating mesh nebulizers can deliver a dose over a period of ~2 minutes, compared with 10 minutes for conventional pneumatic devices.¹⁶ Patients find them effective and easy to use, and the newer generation devices overcome problems with portability and length of treatment, which may be an issue during the daytime for ambulatory patients, along with the requirement for cleaning after each dose.^4,8 However, drug delivery may be somewhat compromised with nebulizers compared with other inhalation devices, as medication can be dispersed into the atmosphere and lost, rather than inhaled.⁷ An additional point to consider is medication availability; some medications, particularly fixed-dose combination maintenance therapies, are currently unavailable in a nebulized format.¹⁶

The most important device-related factors influencing the site of deposition within the lungs are aerosol velocity and particle size of the inhaled drug.^3,7,17 To maximize clinical effectiveness, adequate distribution throughout the lung is required to reach target sites of action for β₂-agonists, anticholinergics, and corticosteroids.¹⁷ Particle size differs between inhaler device types, but all available devices generate drug particles sufficient for deposition throughout the lower airways and lung periphery, ie, within the range of 1–5 microns.^3,18-21 Extra fine particles of <1 micron (or “submicron particles”) can be deposited deeper in the pulmonary acinus, but a higher fraction of such particles may be exhaled compared with particles 1–5 microns in size.^3,20,22 In contrast, particles >5 microns deposit in the oropharynx and may be swallowed, potentially leading to systemic adverse effects.^3,20,22

When more than one drug is required, it may be preferable to deliver them via a single device where possible to facilitate patient compliance with correct technique, and decrease confusion about how to use different inhalers.²³ The inhaler device ideally serves as a platform on which many treatments are available; the greater the number of devices employed by the patient, the greater the likelihood of making an error with the usage of each device.²⁴

Errors relating to device handling are common in patients with COPD. The results of a meta-analysis by Chrystyn et al reported that overall error rates were high across all devices in patients with COPD and asthma, ranging from 50%–100%²⁵; the reported frequencies of patients with at least one error were 86.8% and 60.9% for pMDIs and DPIs, respectively. However, the authors note that heterogeneity between the studies used in the analysis was high, and suggest that future investigations should look to use a more standardized approach in assessment of inhaler device errors.²⁵ Moreover, further studies to investigate the frequency of errors in SMI devices, and to establish the relationship between critical errors in device handling and device efficacy, are warranted.

Handling errors are directly linked to compromised drug delivery and reduced treatment efficacy.³ This may lead to more frequent or inappropriate medication use that, in turn, could result in unnecessary dose increases by the physician due to perceived lack of efficacy, and subsequently more adverse effects.^3,26-28 However, these errors can be addressed through proper training and demonstration.^29-32

Common device-handling errors include^{4,26,27,32,33}:

• pMDIs: not shaking the inhaler (for suspensions), not exhaling fully before actuation, inhaling too forcefully, and not holding their breath for long enough after inhalation.
• DPIs: exhaling into the device mouthpiece, not exhaling fully before inhalation, not inhaling deeply or forcefully enough, and not holding their breath after inhalation.
• SMIs: not rotating the inhaler with mouth cap facing upwards, rotating the inhaler while looking into the spray nozzle with the cap open (before inhalation), and not maintaining inhalation with drug spray.