Vol 1, Issue 14
Supplement to
VOL 65, NO 8
Funding for this newsletter series was provided by
Pulmonary Practice Pearls for Primary Care Physicians
14-part eNewsletter series
eNewsletter 14
Series Author

Barbara P. Yawn, MD, MSc, FAAFP
Director of Research,
Olmsted Medical Center,
Rochester, Minnesota

Dr. Yawn disclosed that she serves on advisory boards for Boehringer Ingelheim GmbH and Novartis Pharmaceuticals Corporation and has received grant support from AstraZeneca; Boehringer Ingelheim GmbH; Merck & Co., Inc.; and Novartis Pharmaceuticals Corporation.

Acknowledgments
The author thanks Dan Rigotti, PhD, of Scientific Connexions, an Ashfield Company, part of UDG Healthcare plc (Lyndhurst, NJ, USA) for medical writing support funded by AstraZeneca LP (Wilmington, DE, USA).




Primary care physicians routinely see patients with chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Although treatment guidelines are available, we still need practical information that translates guidelines and other evidence so that we can better diagnose and manage these diseases. Each issue in the Pulmonary Practice Pearls for Primary Care Physicians eNewsletter series focuses on a key topic in the management of COPD or asthma within the context of current national guidelines and clinical practice. Topics are brought to life through the presentation of hypothetical clinical cases, and an emphasis is placed on applying key learnings to clinical practice. Practice tools and links to additional information are featured in each issue.

Burden of COPD Exacerbations: Focus on Optimal Management and Prevention

Key Points
  • Exacerbations of COPD are associated with significant increases in hospitalizations, morbidity, and mortality; they tend to increase in frequency and severity as the severity of COPD escalates
  • COPD exacerbations are also associated with significant physical and psychological effects, which often manifest as a negative impact on activities of daily living (ADLs) and health-related quality of life (HRQoL), as well as anxiety and/or depression
  • Approaches to managing acute COPD exacerbations include pharmacologic (eg, systemic corticosteroids, short-acting bronchodilators, and antibiotics) and nonpharmacologic (eg, supplemental oxygen and ventilator support) modalities. Evaluation and treatment of comorbidities should be part of the management strategy
  • Preventing COPD exacerbations is of critical importance, and both pharmacologic and nonpharmacologic approaches can be used, including the following:
    • Inhaled corticosteroids (ICS) with one or more long-acting beta-agonist (LABA) or long-acting muscarinic antagonist (LAMA)
    • A phosphodiesterase-4 (PDE-4) inhibitor (roflumilast) can be considered in patients with severe COPD associated with chronic bronchitis and a history of exacerbations
    • Vaccinations against pneumococcal pneumonia and influenza are recommended
    • Pulmonary rehabilitation can be a valid adjunct to medication to increase exercise tolerance and HRQoL; it can also decrease hospital readmissions


Introduction

COPD is characterized by progressive airway limitation and is associated with enhanced inflammatory responses to certain environmental stimuli.1 The course of the disease is characterized by exacerbations, or periods during which symptoms become much worse. COPD exacerbations manifest as acute increases in, onset of, or worsening of more than one respiratory symptom (eg, cough, sputum, sputum purulence, wheezing, or dyspnea) lasting 3 or more days and requiring treatment with an antibiotic or a systemic corticosteroid. These episodes are often described as a worsening of symptoms beyond normal day-to-day variations.2-5

Exacerbations accelerate the loss of lung function (eg, decreased forced expiratory volume in one second [FEV1]), which results in poorer HRQoL.6 Exacerbations often initiate a cycle of subsequent exacerbations from the stable state, illustrated in Figure 1.5 There are treatment strategies that may mitigate some of the effects of exacerbations and prevent recurrence. This newsletter will address the prevalence, burden, and physical and psychological effects of COPD exacerbations, as well as management and prevention strategies.


Figure 1. The exacerbator phenotype and triggers of exacerbations5

Relationship between stable state and exacerbations in COPD. The exacerbator phenotype results from a cycle wherein periods of stable COPD are interrupted by exacerbations that are typically triggered by external stimuli (such as viruses or irritants). Each cycle leads to progressively slower resolution from exacerbation back to stable symptoms.

Abbreviations: CV, cardiovascular; FEV1, forced expiratory volume in 1 second.

Adapted from Wedzicha JA, Brill SA, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181.

Prevalence and Burden of COPD Exacerbations

Based on studies using patient diaries and questionnaires, the annual rate of COPD exacerbations has been estimated to range from 0.5 to 3.5 per patient.7 However, approximately 50% of COPD exacerbations are thought to be unreported and untreated.7 In general, exacerbations become more frequent and serious with increasing COPD severity6: exacerbation rates for patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 2 (moderate) COPD were 0.85 per person in the first year of follow-up, whereas patients with GOLD stage 4 (very severe) disease had a rate of 2.0 per person in the same follow-up period.6 Exacerbations are associated with worsening lung function, which is a hallmark of COPD.6

Acute COPD exacerbations create a burden of increased hospitalizations that is associated with poor prognoses and increased risk of death.1 Hospitalization rates may be as high as 2.4 per patient per year.7 Indeed, in 2011, there were more than 600,000 hospital discharges and more than 1.7 million emergency department visits attributed to COPD.8 In 2008, hospitalizations for acute COPD exacerbations accounted for 62.5% of all COPD-related hospital stays in the United States.9 Moreover, approximately 20% of patients hospitalized for COPD exacerbations were readmitted within 30 days of discharge.10

In the United States, overall deaths from COPD have been estimated at 110,000 per year11; exacerbations contribute to this number. The mortality risk increases along with exacerbation severity12 and the number of exacerbation recurrences (Figure 2).13 One study, which followed approximately 73,000 patients with a first hospitalization for COPD, found that the health status of patients with COPD with exacerbations declined rapidly after any subsequent exacerbation.13 Additionally, the risk of subsequent severe exacerbations increased threefold after the second severe exacerbation and 24-fold after the tenth severe exacerbation.13 Therefore, treatment aimed at delaying or preventing subsequent exacerbations should help reduce mortality and improve overall health status.13

Figure 2. Relationship between number of COPD exacerbations and mortality13
The crude and adjusted hazard ratios (HR; adjusted for age, sex, calendar time [cohort entry before 2000], and the modified chronic disease score divided by quartiles) are graphed as functions of subsequent exacerbations. For reference, the initial exacerbation is set to a hazard ratio of 1.0. The Cox proportional hazards model generated the data.

Case Study

Mary is a 69-year-old former long-time smoker with severe COPD who has experienced exacerbations 2 to 4 times a year. She spent 4 days in the hospital (1 in the intensive care unit [ICU]) for her most recent exacerbation and returned home 10 days ago. She was due in your office yesterday for a follow-up visit, but did not come. Your staff called to follow up and her granddaughter responded that Mary was too sick to come in.

Before her hospitalization, Mary was taking multiple medications for her COPD including an ICS/LABA and a LAMA. Together, these medications appeared to be reducing her rate of exacerbations, with no exacerbations occurring for more than 6 months. Besides COPD, Mary was being treated for hypertension, hyperlipidemia, congestive heart failure, and diabetes. Her Modified Medical Research Council score (Table 1)1 was 3 (shortness of breath with daily activities), but she was able to leave home several times per week, using her walker to shop, attend church, and go to quilting sessions with her friends. Mary did not require oxygen until her recent hospitalization. She has a history of depression that began with the onset of COPD that has improved since she began a pulmonary rehabilitation program.

During her most recent hospitalization, Mary’s lone ambulation was moving to a chair for one meal on the day of her discharge. She received some COPD education while in the ICU, was shown proper inhaler technique on discharge, and was sent home on most of her original medications (those for hyperlipidemia were overlooked). She also continued on oral corticosteroids (10 days total) and azithromycin (10 days total).

Note: This is a hypothetical case description for teaching purposes.
Table 1. Modified Medical Research Council questionnaire for assessing the severity of breathlessness1

Grade 0

I only get breathless with strenuous exercise.

Grade 1

I get short of breath when hurrying on the level or walking up a slight hill.

Grade 2

I walk slower than people of the same age on the level because of breathlessness, or I have to stop for breath when walking on my own pace on the level.

Grade 3

I stop for breath after walking about 100 meters or after a few minutes on the level.

Grade 4

I am too breathless to leave the house or I am breathless when dressing or undressing.
Reprinted with permission from Global Initiative for Chronic Obstructive Lung Disease (GOLD).

Physical Impact of COPD Exacerbations on ADLs

COPD exacerbations have negative effects on ADLs. In one study, nearly 90% of 125 patients with COPD reported that exacerbations impacted their ADLs, and approximately half of these patients needed additional help with certain tasks (including household chores, shopping, and cooking).14 For the same proportion (47.2%), an exacerbation meant cessation of all activities.14 Similarly, in another study of 1100 patients, up to 45% reported they had to remain recumbent all day during exacerbation episodes.15 The inability of patients with COPD to perform normal ADLs leads to reduced physical activity, with resultant negative consequences for muscle function and exercise tolerance (Figure 3).16 Physical inactivity also increases the risk for future exacerbations; in one study, as the distance patients could walk decreased (measured by 6-minute walk test), the risk of exacerbations increased.17 Moreover, physical inactivity has been shown to increase the risk of hospital admission for an exacerbation. Patients who walked 2500 steps/day fewer than 2 days/week had an increased rate of admission (hazard ratio 1.88; P = .048) compared with those who walked 2500 steps/day for 2 to 7 days/week.18 Furthermore, the Copenhagen City Heart Study of 2386 patients with COPD showed that regular physical activity reduced hospital admissions and all-cause mortality.19

Figure 3. Consequences of acute exacerbations lead to physical limitations16
Schematic overview of the systemic consequences of acute exacerbation, resulting in physical limitations due to inactivity.

Abbreviation: ADL, activities of daily living.

Reproduced with permission of the European Respiratory Society ©. Eur Respir J
Sep 2011, 38 (3) 702-712; DOI: 10.1183/09031936.00079111

 


COPD exacerbations also have effects on body composition and function. Acute exacerbation episodes have been shown to increase levels of circulating inflammatory mediators and oxidative stress.20-22 These processes induce muscle damage and deterioration and may result in negative outcomes including diaphragmatic weakness and weight loss; which in turn can promote the onset of future exacerbations (Figure 4).20-25 The effect of COPD exacerbations on muscle strength may have a relationship to mortality; in one study of 162 patients with COPD, the voluntary maximal contraction force of the quadriceps was second only to age as a predictor of mortality.26

Figure 4. The cycle of COPD exacerbations and muscle deterioration20-25
Acute exacerbation episodes are associated with increased inflammatory mediators (eg, alterations in circulating white blood cells and inflammatory cytokines, increased C-reactive protein levels in serum, and altered gene expression via NF-κB activation) and increased oxidative stress (eg, reactive oxygen species and subsequent lipid peroxidation, DNA damage, etc) The subsequent muscle damage and deterioration can result in diaphragm atrophy. A loss in body weight, in conjunction with physiological changes involving muscle breakdown, may contribute to future exacerbations.

Case Study (continued)

You ask the public health and/or home health nurses to pay Mary a visit. They each report that Mary is frustrated, discouraged, and too tired to cook any meals. Her granddaughter tries to help but is a college student juggling class and work schedules. Mary reports that she has continued to be too exhausted to move around the house and has not been outside at all. She mainly stays in bed, too tired to bathe or eat, and no longer pursues quilting, a hobby she loves. She does not want to burden her family and is thinking about moving into a nursing home.

The nurses report that Mary's blood pressure is elevated (150/96 mm Hg), as is her blood glucose (280 mg/dL on the home glucose monitor); they also report that Mary is “weak,” with difficulty walking from the bedroom to the living room with the aid of her walker.

Note: This is a hypothetical case description for teaching purposes.

Psychological Effects of COPD Exacerbations

Exacerbations have several negative psychological consequences for patients with COPD (Figure 5).27 Furthermore, there is an inverse relationship between repeated exacerbations and HRQoL.28 In a 2-year study of 441 patients, researchers found that HRQoL declines were more closely associated with frequency of exacerbations than severity of COPD: those with moderate COPD and frequent exacerbations had worse HRQoL scores than did those with severe COPD and infrequent exacerbations.29 In a 2006 study, patients reported that COPD exacerbation episodes had detrimental effects on their mood.14

Figure 5. The cycle of psychological effects of COPD exacerbations and hospital admissions and readmissions27
Republished with permission of DOVE Medical Press, from Examining the relationship between anxiety and depression and exacerbations of COPD which result in hospital admission: a systematic review, Pooler A, Beech R, 9, 2014; permission conveyed through Copyright Clearance Center, Inc.

COPD exacerbations are associated with negative patient perceptions of daily life. In a study by Miravitlles and colleagues, 17% of 1100 patients responded that they were afraid COPD would cripple or kill them; 54% responded they could not do things they enjoyed; and 52% reported sleep disturbances.15 The patients who feared COPD would cripple or kill them tended to be older with longer duration of disease than other patients.15 In another study, patients with COPD with frequent exacerbations reduced their time spent outdoors at a faster rate than those with less frequent exacerbations, and thus were at a greater risk of becoming housebound, which may contribute to underreporting of exacerbations to physicians.30

Patients with COPD may experience specific mental health issues such as anxiety and depression at times of exacerbation episodes, which may be serious enough to require management. Patients with frequent exacerbations had higher median baseline depression scores than those with infrequent exacerbations, and depression increased significantly from baseline to exacerbation episode.31 A meta-analysis of 380 published studies showed that both depression and anxiety correlated significantly with and were predictive of reduced HRQoL in COPD.32 Patients with anxiety and/or depression often have decreased self-esteem and increased loss of autonomy, which in turn may lead to impaired ability to cope with their COPD and comply with the treatment regimen.27 A quantitative review of 20 studies showed that the increased anxiety and depression among patients with COPD led to a statistically significant increase in hospitalizations.27 Thus, routine evaluation of anxiety and/or depression in patients with COPD is recommended to offer the proper treatment options.33 In addition, patients with COPD reported increased anger and hostility in general, with increased disability that resulted in them becoming less self-sufficient.34

Review of Case Report

Q: Is Mary’s posthospitalization experience what you would expect following a COPD exacerbation?
A: There are elements of Mary’s experience that are all too common among patients like her. Most patients report that exacerbations affect their ADLs, and for nearly half, an exacerbation is associated with cessation of all activities. Patients with frequent exacerbations also may experience more depression.

Q: Could any aspects of Mary’s posthospital condition have been prevented?
A: Maybe. Reconciliation should be completed so that all admission medications are resumed; especially those used to manage comorbidities appropriately. Comorbidities contribute to the decline in a patient’s health and therefore play a major role in the long-term prognosis for COPD patients. Many comorbidities (eg, hypertension) have symptoms in common with those associated with COPD; this can make it difficult to monitor and treat COPD progression over time. Moreover, it is important to consider potential impacts of COPD exacerbation therapy on other comorbidities (eg, the impact of high-dose steroids on diabetes).

Additionally, physical therapy could have been consulted to prevent deconditioning. In-hospital ambulation, early and often, even over short distances, may prevent loss of function, especially in the elderly.

Finally, a care coordinator would have proactively contacted the patient at home and coordinated many aspects of care, including medication reconciliation, social service needs, and specialty and primary care appointments.

Q: After Mary’s most recent hospitalization, what would have been your next steps?
A: Early home assessment might have identified Mary’s need for help, not only with ADLs like bathing and dressing, but also might have identified the need to provide meals on a short-term basis. With this type of help and simple support for ambulation, Mary might not have been as incapacitated in the weeks after her hospitalization. Exacerbations affect much more than respiratory function, especially in older adults with preexisting comorbidities.

Note: This is a hypothetical case description for teaching purposes.

Management of COPD Exacerbations: Treatment and Prevention

Both pharmacologic and nonpharmacologic approaches, including treatment of the associated comorbidities
(eg, diabetes, cardiovascular disease, dyslipidemia), can be implemented to manage acute exacerbations of COPD (Table 2).1 A comprehensive management plan should take into account all dimensions of the patient’s health and concomitant medications and conditions.1 Comorbidities affect the overall severity of COPD and are associated with poorer outcomes in patients with exacerbations.1

Table 2. Approaches for managing acute exacerbations of COPD1

Approach

Pharmacologic

Nonpharmacologic

Short-acting beta2-agonists

Supplemental oxygen to target saturation of 88% to 92%

Short-acting anticholinergics

Ventilatory support (noninvasive or invasive), if needed

Systemic corticosteroids

Antibiotics if:

  • Increased dyspnea, sputum volume, or sputum purulence (cardinal symptoms)
  • Increased sputum volume +1 other cardinal symptom
  • Mechanical ventilation

Adjunct therapies:

  • Counsel smoking cessationa
  • Treat comorbiditiesb
  • Maintain fluid balance
  • Maintain proper nutrition
  • Prevent thromboses as indicated
aIn counseling for smoking cessation, physicians should educate patients regarding all options, including pharmacologic aids.
bThe most current best practices should be used to treat comorbidities, as outlined in the GOLD guidelines.

Among these comorbid conditions, anxiety and depression in COPD may be managed through a collaborative care model. Nurses and physician assistants can provide follow-up, track outcomes with depression tools (such as the Patient Health Questionnaire), track adherence to antidepressant medication, and facilitate return visits to primary care physicians. A psychiatric consultation can provide clinical advice and decision support to primary care physicians for patients with persistent symptoms.35

Approaches for preventing future COPD exacerbations are summarized in Table 3.1,10 Pharmacologic approaches include ICS in combination with a LABA and/or LAMA.1,36 For patients with severe COPD, chronic bronchitis, and a history of exacerbations, the PDE-4 inhibitor roflumilast can be considered for reducing the risk of future exacerbations.1,36 Vaccination against pneumococcal pneumonia, in particular with the 23-valent vaccine, and against influenza is recommended.1,36

Table 3. Approaches for preventing acute exacerbations of COPD1,10

Approach

Pharmacologic

Nonpharmacologic

ICS plus LABA and/or LAMA

  • Teach proper inhaler technique, if necessary

Counsel on smoking cessationa

Phosphodiesterase-4 inhibitors, if needed

Pulmonary rehabilitation

  • Early pulmonary rehabilitation has been shown to reduce future exacerbations

Vaccinations

  • Influenza
  • Pneumococcus

Patients should be encouraged to:

  • Maintain physical activity
  • Discuss anxiety, depression, and social problems

Home care at time of discharge

  • Visiting nurse
  • Oxygen delivery
  • Help with chores, eg, meal preparation

Improve patient follow-up (eg, as organized by a care coordinator)

  • Schedule outpatient visits prior to discharge
  • Make reminder phone calls
  • Train patients regarding use of health care portals
    • These tools help patients manage appointments and prescription refills
aIn counseling for smoking cessation, physicians should educate patients regarding all options, including pharmacologic aids.
Abbreviations: ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist.

Nonpharmacologic approaches to COPD exacerbation prevention/reduction also are important. Pulmonary rehabilitation is a comprehensive intervention composed of patient-tailored therapies, including exercise training, education, and behavioral changes.37 It is recommended for patients who have been hospitalized within the previous 4 weeks,36,37 is generally safe, and often leads to significant improvement in exercise capacity and health status 3 months posthospitalization.38 It can also reduce the incidence of subsequent exacerbation episodes and hospitalizations.39 The latter is highly relevant in a patient population with a high readmission rate.16,39 It also improves exercise tolerance, reduces dyspnea, and improves HRQoL.40,41 For current smokers, counseling for cessation using best practices available to achieve this goal should be part of a comprehensive strategy.36

Patient follow-up is an essential component of preventing future exacerbations. Following treatment for an exacerbation, patients should be reassessed for proper inhaler technique and retrained if necessary before discharge; the importance of treatment adherence should be discussed as well.1 Among patients hospitalized for an exacerbation, posthospital follow-up within the first 2 weeks of discharge is important, because more than half of hospital readmissions occur within that period.10

Conclusions and Future Directions

COPD exacerbations are associated with significant increases in hospitalizations, morbidity, and mortality, and tend to increase in frequency and severity along with the severity of COPD. Patients with COPD exacerbations experience significant physical and psychological effects that negatively affect ADLs and HRQoL. Exacerbations are also part of a cycle of COPD progression, with more frequent exacerbations associated with accelerating loss of lung function.6 Pharmacologic and nonpharmacologic approaches are often used in acute COPD exacerbation management; comorbidities and concomitant medications also should be assessed and incorporated into any treatment approach.1 Given the profound consequences of COPD exacerbations, approaches aimed at preventing future exacerbations are critically important. Such pharmacologic approaches include treatment with an ICS administered concomitantly with a LABA and/or a LAMA. In patients with severe COPD associated with chronic bronchitis and a history of exacerbations, the PDE-4 inhibitor roflumilast may be beneficial.1,36 Pulmonary rehabilitation is an important patient-tailored, multifocal approach that can improve exercise capacity and reduce dyspnea in patients with COPD.42 Importantly, patients with exacerbations of COPD should be reassessed for treatment compliance and inhaler technique; for those hospitalized, follow-up within 2 weeks of discharge is recommended.

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