Strategies for Preventing COPD Exacerbations in Primary Care Settings

Chronic obstructive pulmonary disease (COPD) is a prevalent disease associated with high rates of morbidity and mortality. Although the underlying etiology of COPD can vary, the disease is marked by a triad of dyspnea, chronic cough, and sputum production.¹ The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recently changed the definition of COPD to reflect the heterogeneous nature of this condition, stating that it is characterized by chronic respiratory symptoms (dyspnea, cough, sputum production, exacerbations) caused by abnormalities of the airways (bronchitis, bronchiolitis) and/or alveoli (emphysema) that result in persistent, often progressive, airflow obstruction.¹

Although COPD is a persistent condition, patients often experience periods of increased local and systemic inflammation caused by infection, pollution, or other insults to the airways.¹ These episodes are termed exacerbations and are characterized by increased dyspnea and/or cough and sputum that worsens over less than 14 days.¹ Exacerbations of COPD range from mild to severe, with GOLD classifying exacerbations based on treatment requirements (Table 1).¹

Primary care providers are uniquely positioned to implement preventative strategies, considering the majority of exacerbations are treated in the outpatient setting. However, severe COPD exacerbations and subsequent hospitalizations account for 60% to 70% of the health care-associated COPD costs.² Unfortunately, severe exacerbations also have the greatest negative impact on a patient’s health status, disease course, and overall quality of life (QOL). As a result, proper exacerbation prevention is seen as a primary treatment goal in the COPD population.

Morbidity

Frequent exacerbations are associated with more rapid loss of lung function,^2,3 especially in patients with elevated blood eosinophil count (≥100 cell/µL) not treated with inhaled corticosteroids (ICS) therapy.³ Often, patients do not return to their baseline lung function following a severe exacerbation, which increases dyspnea and further limits functional capabilities.^2-4 Fortunately, multiple preventative therapies are proven to reduce exacerbation frequency. The potential to reduce exacerbation incidence and preserve lung function underlines the importance of implementing proper preventative therapy early in a patient’s disease course.

In addition, frequent and severe exacerbations correlate with more rapid cardiovascular decline. Cardiovascular comorbidities are common in the COPD population because of their common risk factors and coexistence within the cardiopulmonary system.⁵ As a result, worsening lung function is indicative of declining cardiovascular status. Thus, patients frequently present with signs of myocardial injury such as elevated troponin, electrocardiography changes, and/or chest pain during acute COPD exacerbations.⁶ A nearly 4-fold increase in major adverse cardiac events (acute MI, stroke, or cardiovascular death) occurs in the weeks following hospitalization for a COPD exacerbation.⁷ This increase is related at least in part to the additional stress put on the heart and/or an uncovering of previously unsuspected cardiac dysfunction.^2,6

Mortality

After hospitalization for an acute exacerbation, mortality risk peaks sharply within the first 10 days and declines gradually over the following 3 months.⁸ A recent Italian population-based study found a 3.1% to 7.6% increased risk of mortality in the first 10 days following admission for an acute COPD exacerbation.⁹ Other studies have found in-hospital mortality rates ranging from 4% to 25%.¹⁰ A 2018 longitudinal study in the Netherlands showed that the 5-, 10-, and 15-year survival rates following an initial exacerbation requiring hospitalization were 43.7%, 19.9%, and 7.3%, respectively.¹¹

These studies demonstrate the sharp decline in health status after a patient’s first clinical exacerbation and highlight the importance of preventing initial exacerbations. An understanding of the prognostic implications of these events helps clinicians better counsel patients and their families when discussing disease courses and QOL.

Quality of Life

A 2021 study compared the QOL in patients with COPD hospitalized for exacerbations with those treated in outpatient settings.¹² The findings showed that hospitalized patients have a poorer QOL at baseline, which did not improve with inpatient treatment.¹² By contrast, patients with less severe exacerbations reported clinical improvements with higher QOL scores over time.¹² Thus, patients experiencing COPD exacerbations not only face short-term declines in QOL but also long-term effects.

Variables contributing to poor QOL at baseline include worsening mental health and loss of functional capabilities. Specifically, COPD patients have a high prevalence of depression, with evidence suggesting that depression is an independent risk factor for acute exacerbations.^13,14 For example, studies have demonstrated that depressive symptoms are associated with increased dyspnea, increased exacerbation frequency, decreased physical activity, and higher rates of hospital readmission regardless of lung function and disease severity.^13-15 In one study, maintaining physical activity following a severe exacerbation was found to reduce hospital readmission by 28% (P =.033).¹⁶ Realizing the significance of mental health and physical activity is important so that providers can employ preventative strategies such as the use of antidepressants, cognitive behavioral therapy, pulmonary rehabilitation, and physical therapy. Addressing these potentially modifiable risk factors could lead to less frequent hospitalizations and improved outcomes for patients with mild to severe COPD.

Addressing Disparities

As with most chronic diseases, COPD disproportionately affects ethnic minorities and people with a low socioeconomic status (SES). Although tobacco smoking remains a primary risk factor for COPD in high-income countries, the 2023 GOLD Report also emphasizes the role of pollution (indoor and outdoor), occupational exposures (dust, vapors, fumes, gases, chemicals), and host factors such as genetics, prematurity, and childhood respiratory infections.¹ These primary risk factors for COPD are more common in low SES groups. Evidence suggests that people with low SES are 5 times more likely to smoke compared with college graduates.¹⁷ In addition, occupations with an increased risk of particle exposure (eg, mining, plastics, petroleum, construction) are more commonly performed by people with low SES.¹⁸

The disproportionate burden of COPD on people with low SES can be attributed to a variety of differences in socially acceptable behaviors, structural environmental exposures, sociopolitical factors, and health behaviors.¹⁸ While some of these systemic variables are beyond the scope of in-office risk reduction, primary care providers are distinctively positioned to counsel patients on smoking cessation and help implement effective environmental exposure interventions.

Unfortunately, research demonstrates disparities in tobacco cessation advice from health care providers across racial groups.¹⁹ A US study found that White smokers were two-thirds more likely to be counseled on smoking cessation compared with Black and Hispanic smokers.¹⁹ Thus, tremendous opportunity exists for primary care providers to take a more active role in meeting the unique needs of those at high risk for developing COPD.

Smoking cessation can be a difficult conversation to have with patients and use of the 5 As of smoking cessation may be helpful:

• Ask about use, history, and smoking habits
• Advise the patient to quit and discuss health risks
• Assess willingness to quit
• Assist with an action plan for quitting
• Arrange follow-up within 1 to 2 weeks

2023 Updates to COPD Diagnosis and Risk Factors

In addition to tobacco smoking, the GOLD Report now emphasizes the role of pollution, occupational exposures, and host factors.¹ The updated guidelines proposed a new taxonomy for COPD to expand classifications to include nonsmoking-related subtypes that can then lead to targeted treatment strategies¹:

• COPD-A: Disease in patients with comorbid asthma (particularly childhood asthma)
• COPD-P: Disease related to biomass and pollution exposure
• COPD-C: Disease related to tobacco smoke exposure (including in utero or via passive smoking), vaping or e-cigarette use, or cannabis use
• COPD-D: Disease related to abnormal lung development
• COPD-G: Genetically determined COPD
• COPD-I: COPD related to infections such as childhood infections, tuberculosis, or HIV

A postbronchodilator forced expiratory volume to forced vital capacity ratio (FEV₁/FVC) less than 0.7 on forced spirometry is now mandatory to establish a diagnosis of COPD.

Preventative Pharmacologic Therapies

Inhaled Bronchodilator Therapy

Inhaled bronchodilator therapy is the foundation of COPD treatment and subsequently exacerbation prevention. Numerous therapies are available, all of which can be divided into long- and short-acting β-agonists (LABA and SABA) and long- and short-acting muscarinic antagonists (LAMA and SAMA).¹ At a receptor level, β-agonists stimulate β₂-adrenergic receptors in the lungs to relax airway smooth muscle.¹ Muscarinic antagonists block M2/M3 receptors in airway smooth muscles and the receptors’ typical bronchoconstriction effect.¹ As a result, these agents are thought to decrease dyspnea by allowing mucus to clear, reducing lung hyperinflation, and improving lung ventilation capacity.^20,21 In comparison to long-acting agents, short-acting bronchodilators are not as effective in preventing exacerbations because of their frequent dosing, which results in poor adherence and less sustained symptom relief.²²

In 2023, the GOLD Report changed its recommendations for initial pharmacologic treatment and subsequent escalation. Previously, clinicians scaled pharmacologic treatment by placing patients in groups based on their symptoms and exacerbation risk. In this tiered approach, long-acting monotherapy was the cornerstone of treatment, and as exacerbations became more frequent, LAMA monotherapy was preferred over LABA monotherapy and/or combination therapy was implemented. Changes to the guidelines now reflect a new tiered escalation. These changes highlight the benefit of LABA+LAMA combination therapy and instruct clinicians to immediately escalate to a LABA+LAMA combination once patients no longer meet the criteria for the first-tier therapy (Figure).¹

These changes are also reflected in the GOLD exacerbation prevention recommendation that patients with persistent exacerbations on bronchodilator monotherapy (long-acting or short-acting agents) should be escalated to LABA+LAMA (Table 2).¹ Also, in patients with continued exacerbations despite combination therapy, the GOLD Report suggests using blood eosinophil count to guide therapy.¹

Addition of Inhaled Corticosteroid Therapy

Certain subsets of the COPD population demonstrate a greater reduction in exacerbations with the addition of ICS therapy. It is important to identify these groups before implementation of ICS because of an increased risk for pneumonia and fractures associated with treatment.²³ Therefore, clinicians must reflect on the patient’s full clinical picture and consider if the risk for morbidity and mortality outweighs any improvement in exacerbation frequency. Two subgroups seen to respond well to ICS are patients with elevated blood eosinophil counts and/or concomitant asthma diagnosis.^21,23 Current data indicate that patients with blood eosinophil count of 100 cells/µL or less have a low likelihood of treatment benefit whereas patients with 300 cells/µL or higher demonstrate the greatest benefit.¹

The 2023 GOLD Report recommends that patients with COPD exacerbations on bronchodilator monotherapy can escalate to LABA+LAMA; for those with a blood eosinophil count 300 cells/µL or greater, escalation to LABA+LAMA plus ICS may be considered. Patients on LABA+LAMA with blood eosinophil count 100 cells/µL or greater also can escalate to LABA+LAMA+ICS. Patients on LABA+LAMA with blood eosinophil count less than 100 cells/µL can add roflumilast (if they have an FEV₁ <50% predicted and chronic bronchitis) or a macrolide. Patients on LABA+LAMA+ICS also can add roflumilast (if they have an FEV₁ <50% predicted and chronic bronchitis) or a macrolide.¹

Of note, GOLD no longer encourages the use of LABA+ICS combination for COPD in the 2023 guideline. If a patient has an indication for ICS, use of LABA+LAMA+ICS is superior to LABA+ICS and is the preferred choice.¹

Phosphodiesterase-4 inhibitors

In 2011, roflumilast was the first phosphodiesterase-4 (PDE4) inhibitor approved by the FDA for treatment of COPD and the first novel COPD treatment in nearly 20 years.²⁴ Evidence suggests roflumilast works to reduce airway inflammation by inhibiting cyclic adenosine monophosphate (cAMP) breakdown intracellularly.^1,24 A recent review of relevant studies reported that patients treated with PDE4 inhibitors were 22% less likely to have an exacerbation.²⁵ Most subjects reviewed had moderate to severe COPD with a history of frequent exacerbations.²⁵ As a result, GOLD continues to recommend roflumilast as an add-on to optimized inhaled therapy. More specifically, roflumilast is recommended in patients with a history of frequent or hospitalized exacerbations and chronic bronchitis.¹ Side effects such as depression, diarrhea, nausea, sleep disturbances, and headache are common with this medication class. These side effects are seen more commonly with higher doses of roflumilast.^1,25

Antibiotic Prophylaxis

The GOLD Report recommends using long-term antibiotic therapy in patients with stable disease who are prone to exacerbations despite optimal inhaled treatments;¹ however, providers should be mindful of potential adverse effects such as hearing impairment, QT prolongation, gastrointestinal upset, and concerns about antibiotic resistance.^23,26,27 To help mitigate these adverse effects, low doses of azithromycin (250 mg/d or 500 mg 3 times a week) or erythromycin (250 mg 2 times per day) are suggested.¹ Patients must be closely monitored for side effects.

Macrolides have proven beneficial in preventing COPD exacerbations. With initial studies demonstrating decreased exacerbation frequency with long-term erythromycin use, supporting evidence from subsequent studies continues to grow.²³ A meta-analysis concluded that for every 10 subjects treated with a long-term low-dose macrolide, approximately 1.3 had an exacerbation prevented.²⁶ Azithromycin and erythromycin demonstrate the greatest reduction in exacerbation frequency because of the anti-inflammatory effects in addition to the antimicrobial activity of these agents.^26,27 Studies on use of these agents in COPD primarily included patients with moderate to severe COPD; little data exists on the efficacy and safety beyond 1 year.

Mucoregulators and Antioxidant Agents

Mucolytics such as erdosteine, carbocysteine, and N-acetylcysteine are available as prescriptions and sometimes over the counter. These medications work to thin mucus, thus aiding in airway clearance.²⁸ Also, they are known to have anti-inflammatory properties.^23,28 As a result, studies have found mucolytics reduce COPD exacerbations when taken at high doses and for longer durations.^28,29 This is especially true of patients with moderate disease and those not meeting ICS therapy requirements.^23,28,29 A recent pool of relevant studies found that mucolytics reduced the number of hospitalizations by 33% and reduced the exacerbation risk.²⁸ However, treatment did not demonstrate a significant improvement in symptoms, QOL, or mortality.²⁸ In addition, there was significant variability among populations studied in these trials with weak associations found at times.^1,28

As a result, GOLD does not identify a particular target population for mucolytic treatment.¹ Although more research is needed to support definitive preventative recommendations, is important to keep this medication class in mind especially because of its considerable safety profile and modest exacerbation impact.²⁸

Vaccinations

Considering that 64% of COPD exacerbations can be traced to viral causes,⁸ COVID-19, pneumococcal, and yearly influenza vaccinations are recommended for all COPD patients.¹ These vaccinations help reduce the risk of exacerbations³⁰ and hospitalizations.³¹ Patients should also be vaccinated against pertussis if they were not vaccinated in adolescence, and those older than 50 years of age should receive the shingles vaccine.¹

Summary

Chronic obstructive pulmonary disease is associated with periods of symptom exacerbation. These episodes have profound implications on patient health status, mortality risk, and QOL. As a result, exacerbation prevention has become a primary treatment goal for COPD. Many preventative treatments exist and require a personalized patient approach. Factors like frequency of exacerbations, blood eosinophil count, and side effect profile should all be considered. Primary care providers need to familiarize themselves with evidence-based preventative strategies because they are ideally positioned to implement treatments and ultimately improve COPD patient outcomes.

Caroline Fowler, PA-C, is currently working in emergency medicine in Augusta, GA; Amanda Breeden, MPA, PA-C, is an assistant professor at Augusta University Physician Assistant Program.

References

1. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, 2023 Report. Global Initiative for Chronic Obstructive Lung Disease.
2. Halpin DM, Miravitlles M, Metzdorf N, Celli B. Impact and prevention of severe exacerbations of COPD: a review of the evidence. Int J Chron Obstruct Pulmon Dis. 2017;12:2891-2908. doi:10.2147/COPD.S139470
3. Kerkhof M, Voorham J, Dorinsky P, et al. Association between COPD exacerbations and lung function decline during maintenance therapy. Thorax. 2020;75(9):744-753. doi:10.1136/thoraxjnl-2019-214457
4. Halpin DMG, Decramer M, Celli BR, Mueller A, Metzdorf N, Tashkin DP. Effect of a single exacerbation on decline in lung function in COPD. Respir Med. 2017;128:85-91. doi:10.1016/j.rmed.2017.04.013
5. Trinkmann F, Saur J, Borggrefe M, Akin I. Cardiovascular comorbidities in chronic obstructive pulmonary disease (COPD)-current considerations for clinical practice. J Clin Med. 2019;8(1)doi:10.3390/jcm8010069
6. MacDonald MI, Shafuddin E, King PT, Chang CL, Bardin PG, Hancox RJ. Cardiac dysfunction during exacerbations of chronic obstructive pulmonary disease. Lancet Respir Med. 2016;4(2):138-148. doi:10.1016/S2213-2600(15)00509-3
7. Reilev M, Pottegard A, Lykkegaard J, Sondergaard J, Ingebrigtsen TS, Hallas J. Increased risk of major adverse cardiac events following the onset of acute exacerbations of COPD. Respirology. 2019;24(12):1183-1190. doi:10.1111/resp.13620
8. Ritchie AI, Wedzicha JA. Definition, causes, pathogenesis, and consequences of chronic obstructive pulmonary disease exacerbations. Clin Chest Med. 2020;41(3):421-438. doi:10.1016/j.ccm.2020.06.007
9. Montagnani A, Mathieu G, Pomero F, et al. Hospitalization and mortality for acute exacerbation of chronic obstructive pulmonary disease (COPD): an Italian population-based study. Eur Rev Med Pharmacol Sci. 2020;24(12):6899-6907. doi:10.26355/eurrev_202006_21681
10. Ko FW, Chan KP, Hui DS, et al. Acute exacerbation of COPD. Respirology. 2016;21(7):1152-1165. doi:10.1111/resp.12780
11. van Hirtum PV, Sprooten RTM, van Noord JA, van Vliet M, de Kruif MD. Long term survival after admission for COPD exacerbation: a comparison with the general population. Respir Med. 2018;137:77-82. doi: 10.1016/j.rmed.2018.02.015
12. Camac ER, Voelker H, Criner GJ, Network CCR, the Canadian Institutes of Health R. Impact of COPD exacerbations leading to hospitalization on general and disease-specific quality of life. Respir Med. 2021;186:106526. doi:10.1016/j.rmed.2021.106526
13. Martínez-Gestoso S, García-Sanz M-T, Carreira J-M, et al. Impact of anxiety and depression on the prognosis of COPD exacerbations. BMC Pulm Med. 2022;22(1):169. doi:10.1186/s12890-022-01934-y
14. Iyer AS, Bhatt SP, Garner JJ, Wells JM, Trevor JL, Patel NM, Kirkpatrick d, Williams JC, Dransfield MT. Depression is associated with readmission for acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2016;13(2):197-203. doi:10.1513/AnnalsATS.201507-439OC
15. Blakemore A, Dickens C, Chew-Graham CA, et al. Depression predicts emergency care use in people with chronic obstructive pulmonary disease: a large cohort study in primary care. Int J Chron Obstruct Pulmon Dis. 2019;14:1343-1353. doi:10.2147/copd.S179109
16. Garcia-Aymerich J, Farrero E, Felez MA, et al. Risk factors of readmission to hospital for a COPD exacerbation: a prospective study. Thorax. 2003;58(2):100-105. doi:10.1136/thorax.58.2.100
17. Agaku IT, King BA, Dube SR. Current cigarette smoking among adults – United States, 2005-2012. MMWR Morb Mortal Wkly Rep. 2014;63(2):29-34.
18. Pleasants RA, Riley IL, Mannino DM. Defining and targeting health disparities in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2016;11:2475-2496. doi:10.2147/copd.S79077
19. Cokkinides VE, Halpern MT, Barbeau EM, Ward E, Thun MJ. Racial and ethnic disparities in smoking-cessation interventions: analysis of the 2005 National Health Interview Survey. Am J Prev Med. 2008;34(5):404-412. doi:10.1016/j.amepre.2008.02.003
20. O’Donnell DE, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J. 2004;23(6):832-840. doi:10.1183/09031936.04.00116004
21. Miravitlles M, Anzueto A, Jardim JR. Optimizing bronchodilation in the prevention of COPD exacerbations. Respir Res. 2017;18(1):125. doi:10.1186/s12931-017-0601-2
22. Burchette JE, Campbell GD, Geraci SA. Preventing hospitalizations from acute exacerbations of chronic obstructive pulmonary disease. Am J Med Sci. 2017;353(1):31-40. doi:10.1016/j.amjms.2016.06.006
23. MacLeod M, Papi A, Contoli M, et al. Chronic obstructive pulmonary disease exacerbation fundamentals: diagnosis, treatment, prevention and disease impact. Respirology. 2021;26(6):532-551. doi:10.1111/resp.14041
24. Baye J. Roflumilast (daliresp): a novel phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. P T. 2012;37(3):149-161.
25. Janjua S, Fortescue R, Poole P. Phosphodiesterase-4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2020;5(5):CD002309. doi:10.1002/14651858.CD002309.pub6
26. Janjua S, Mathioudakis AG, Fortescue R, et al. Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis. Cochrane Database Syst Rev. 2021;1(1):CD013198. doi:10.1002/14651858.CD013198.pub2
27. Herath SC, Normansell R, Maisey S, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2018;10(10):CD009764. doi:10.1002/14651858.CD009764.pub3
28. Poole P, Sathananthan K, Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2019;5(5):CD001287. doi:10.1002/14651858.CD001287.pub6
29. Zheng JP, Wen FQ, Bai CX, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014;2(3):187-194. doi:10.1016/s2213-2600(13)70286-8
30. Kopsaftis Z, Wood-Baker R, Poole P. Influenza vaccine for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2018;6(6):CD002733. doi:10.1002/14651858.CD002733.pub3
31. Gershon AS, Chung H, Porter J, et al. Influenza vaccine effectiveness in preventing hospitalizations in older patients with chronic obstructive pulmonary disease. J Infect Dis. 2020;221(1):42-52. doi:10.1093/infdis/jiz419

From the March/April 2023 Issue of Clinical Advisor