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Case Presentation
A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m2. He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.
What is the significance of acute exacerbations of COPD?
Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.3 Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.4 Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.
How is AECOPD defined?
COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.5 Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.6 Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.7
What is the underlying pathophysiology?
AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.2 With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.1 Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.6
How do acute exacerbations affect the course of the disease?
In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.8 Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV1) per lower respiratory tract infection per year,9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.11
What are the triggers for COPD exacerbation?
Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.2 Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.12 Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.6
What are the pharmacologic options available for prevention of AECOPD?
In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society5 have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.
Roflumilast
Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.13 In 2 large clinical trials,14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV1 < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.
Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.
Of note, earlier trials with roflumilast included patients with ICS and LAMA use.14,16 These trials were focused on FEV1 improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.17 While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.4 This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.
Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.18 Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.6 Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.5
N-acetylcysteine
N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.19 Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,20-22 although the largest clinical trial to date was reported in 2014.23 Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV1/forced vital capacity ratio < 0.7, and FEV1 < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.
Macrolides
Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.5 One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.26 In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).27 Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.28 Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.5 The prescribing clinician also needs to consider potential of prolongation of the QT interval.26
Immunostimulants
Immunostimulants have also been reported to reduce frequency of AECOPD.29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.6 Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD31 found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.6
β-Blockers
Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.32 Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.33
Proton Pump Inhibitors
Gastroesophageal reflux disease is an independent risk factor for exacerbations.34 Two small, single-center studies,35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,6 which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.37 Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.
1. Wedzicha JA, Singh R, Mackay AJ. Acute COPD exacerbations. Clin Chest Med. 2014;35:157-163.
2. Wedzicha JA, Seemungal TAR. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796.
3. Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23:698-702.
4. Blanchette CM, Gross NJ, Altman P. Rising costs of COPD and the potential for maintenance therapy to slow the trend. Am Health Drug Benef. 2014;7:98.
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894-942.
6. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 report. Respirology. 2017;22:575-601.
7. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181.
8. Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418-1422.
9. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1995;122:823-832.
10. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164:358-364.
11. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-852.
12. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173:1114-1121.
13. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163:53-67.
14. Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694.
15. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695-703.
16. Lee S, Hui DSC, Mahayiddin AA, et al. Roflumilast in Asian patients with COPD: a randomized placebo-controlled trial. Respirology. 2011;16:1249-1257.
17. Calverley PM, Martinez FJ, Fabbri LM, et al. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Obstruct Pulmon Dis. 2012;7:375-382.
18. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013(11):CD002309.
19. Sheffner AL, Medler EM, Jacobs LW, Sarett HP. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. Am Rev Respir Dis. 1964;90:721-729.
20. Boman G, Bäcker U, Larsson S, et al. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis. 1983;64:405-415.
21. Grassi C, Morandini GC. A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis. Eur J Clin Pharmacol. 1976;9:393-396.
22. Hansen NCG, Skriver A, Brorsen-Riis L, et al. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med. 1994;88:531-535.
23. 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;2:187-194.
24. Francis RS, Spicer CC. Chemotherapy in chronic bronchitis: Influence of daily penicillin and tetracycline on exacerbations and their cost: A report to the research committee of the British Tuberculosis Association by Their Chronic Bronchitis Subcommittee. BMJ. 1960;1:297-303.
25. Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis. BMJ. 1961;2:979.
26. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.
27. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.
28. Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:361-368.
29. Collet JP, Shapiro S, Ernst P, et al. Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997;156:1719-1724.
30. Jing LI. Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary. Age. 2004;67:828-834.
31. Braido F, Tarantini F, Ghiglione V, et al. Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory recurrent infections. Int J Chron Obstruct Pulmon Dis. 2007;2:335.
32. Bhatt SP, Wells JM, Kinney GL, et al. β-Blockers are associated with a reduction in COPD exacerbations. Thorax. 2016;71:8-14.
33. Bhatt SP, Connett JE, Voelker H, et al. β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol. BMJ Open. 2016;6:e012292.
34. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128-1138.
35. Sasaki T, Nakayama K, Yasuda H, et al. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57:1453-1457.
36. Xiong W, Zhang Qs, Zhao W, et al. A 12-month follow-up study on the preventive effect of oral lansoprazole on acute exacerbation of chronic obstructive pulmonary disease. Int J Exper Pathol. 2016;97:107-113.
37. Baumeler L, Papakonstantinou E, Milenkovic B, et al. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD. Respirology. 2016;21:883-890.
Case Presentation
A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m2. He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.
What is the significance of acute exacerbations of COPD?
Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.3 Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.4 Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.
How is AECOPD defined?
COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.5 Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.6 Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.7
What is the underlying pathophysiology?
AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.2 With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.1 Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.6
How do acute exacerbations affect the course of the disease?
In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.8 Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV1) per lower respiratory tract infection per year,9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.11
What are the triggers for COPD exacerbation?
Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.2 Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.12 Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.6
What are the pharmacologic options available for prevention of AECOPD?
In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society5 have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.
Roflumilast
Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.13 In 2 large clinical trials,14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV1 < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.
Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.
Of note, earlier trials with roflumilast included patients with ICS and LAMA use.14,16 These trials were focused on FEV1 improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.17 While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.4 This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.
Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.18 Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.6 Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.5
N-acetylcysteine
N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.19 Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,20-22 although the largest clinical trial to date was reported in 2014.23 Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV1/forced vital capacity ratio < 0.7, and FEV1 < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.
Macrolides
Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.5 One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.26 In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).27 Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.28 Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.5 The prescribing clinician also needs to consider potential of prolongation of the QT interval.26
Immunostimulants
Immunostimulants have also been reported to reduce frequency of AECOPD.29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.6 Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD31 found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.6
β-Blockers
Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.32 Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.33
Proton Pump Inhibitors
Gastroesophageal reflux disease is an independent risk factor for exacerbations.34 Two small, single-center studies,35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,6 which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.37 Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.
Case Presentation
A 70-year-old man with severe chronic obstructive pulmonary disease (COPD) on oxygen therapy and obstructive sleep apnea treated with nocturnal continuous positive airway pressure was seen in the pulmonary clinic for evaluation of his dyspnea. He was symptomatic with minimal activity and had chronic cough with some sputum production. He had been hospitalized 3 times over the past 12 months and had been to the emergency department (ED) the same number of times for dyspnea. Pertinent medications included as-needed albuterol inhaler, inhaled steroids, and tiotropium 18 mcg inhaled daily. He demonstrated good inhaler technique. On examination, his vital signs were pulse 99 beats/min, oxygen saturation 94% on 2 L/min of oxygen by nasal cannula, blood pressure 126/72 mm Hg, respiratory rate 15 breaths/min, and body mass index 35 kg/m2. He appeared chronically ill but in no acute distress. No wheezing or rales were heard. He had no lower extremity edema. The remainder of the exam was within normal limits. His last pulmonary function test demonstrated moderate obstruction with significant bronchodilator response to 2 puffs of albuterol. The side effects of chronic steroid therapy were impressed upon the patient and 500 mg of roflumilast was started daily. Over the course of the next 3 months, he had no further exacerbations. Roflumilast was continued. He has not required any further hospitalizations, ED visits, or oral steroid use since the last clinic visit.
What is the significance of acute exacerbations of COPD?
Acute exacerbation of COPD (AECOPD) is a frequently observed complication for many patients with COPD.1,2 AECOPD is associated with accelerated disease progression, augmented decline in health status and quality of life, and increased mortality.3 Exacerbations account for most of the costs associated with COPD. Estimates suggest that the aggregate costs associated with the treatment of AECOPD are between $3.2 and $3.8 billion, and that annual health care costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations.4 Hence, any intervention that could potentially minimize or prevent this complication will have far-reaching benefits to patients with COPD as well as provide significant cost saving.
How is AECOPD defined?
COPD exacerbation is defined as a baseline change of the patient’s dyspnea, cough, and/or sputum that is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD.5 Exacerbation in clinical trials has been defined on the basis of whether an increase in the level of care beyond regular care is required primarily in the hospital or ED.6 Frequent exacerbations are defined as 3 symptom-defined exacerbations per year or 2 per year if defined by the need for therapy with corticosteroids, antibiotics, or both.7
What is the underlying pathophysiology?
AECOPD is associated with enhanced upper and lower airway and systemic inflammation. The bronchial mucosa of stable COPD patients have increased numbers of CD8+ lymphocytes and macrophages. In mild AECOPD, eosinophils are increased in the bronchial mucosa and modest elevation of neutrophils, T lymphocytes (CD3), and TNF-α positive cells has also been reported.2 With more severe AECOPD, airway neutrophils are increased. Oxidative stress is a key factor in the development of airway inflammation in COPD.1 Patients with severe exacerbations have augmented large airway interleukin-8 (IL-8) levels and increased oxidative stress as demonstrated by markers such as hydrogen peroxide and 8-isoprostane.6
How do acute exacerbations affect the course of the disease?
In general, as the severity of the underlying COPD increases, exacerbations become both more severe and more frequent. Patients with frequent exacerbations have a worse quality of life than patients with a history of less frequent exacerbations.8 Frequent exacerbations have also been linked to a decline in lung function, with studies suggesting that there might be a decline of 7 mL in forced expiratory volume in 1 second (FEV1) per lower respiratory tract infection per year,9,10 and approximately 8 mL per year in patients with frequent exacerbations as compared to those with sporadic exacerbations.11
What are the triggers for COPD exacerbation?
Respiratory infections are estimated to trigger approximately two-thirds of exacerbations.2 Viral and bacterial infections cause most exacerbations. The effect of the infective triggers is to increase inflammation, cause bronchoconstriction, edema, and mucus production, with a resultant increase in dynamic hyperinflation.12 Thus, any intervention that reduces inflammation in COPD reduces the number and severity of exacerbations, whereas bronchodilators have an impact on exacerbation by their effects on reducing dynamic hyperinflation. The triggers for the one-third of exacerbations not triggered by infection are postulated to be related to other medical conditions, including pulmonary embolism, aspiration, heart failure, and myocardial ischemia.6
What are the pharmacologic options available for prevention of AECOPD?
In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society5 have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.
Roflumilast
Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.13 In 2 large clinical trials,14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV1 < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.
Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.
Of note, earlier trials with roflumilast included patients with ICS and LAMA use.14,16 These trials were focused on FEV1 improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.17 While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.4 This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.
Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.18 Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.6 Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.5
N-acetylcysteine
N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.19 Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,20-22 although the largest clinical trial to date was reported in 2014.23 Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV1/forced vital capacity ratio < 0.7, and FEV1 < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.
Macrolides
Continuous prophylactic use of antibiotics in older studies had no effect on the frequency of AECOPD.24,25 But it is known that macrolide antibiotics have several antimicrobial, anti-inflammatory and immunomodulating effects and have been used for many years in the management of other chronic airway disease, including diffuse pan-bronchiolitis and cystic fibrosis.5 One recent study showed that the use of once-daily generic azithromycin 5 days per week appeared to have an impact on AECOPD incidence.26 In this study, the rate of AECOPD was reduced from 1.83 to 1.48 exacerbations per patient-year (relative risk, 0.83; 95% CI, 0.72–0.95; P = 0.01). Azithromycin also prevented severe AECOPD. Greater benefit was obtained with milder forms of the disease and in the elderly. Azithromycin did not appear to provide any benefit in those who continued to smoke (hazard ratio, 0.99).27 Other studies have shown that azithromycin was associated with an increased incidence of bacterial resistance and impaired hearing.28 Overall data from the available clinical trials are robust and demonstrate that regular macrolide therapy definitely reduces the risk of AECOPD. Due to potential adverse effects, however, macrolide therapy is an option rather than a strong recommendation.5 The prescribing clinician also needs to consider potential of prolongation of the QT interval.26
Immunostimulants
Immunostimulants have also been reported to reduce frequency of AECOPD.29,30 Bacterial lysates, reconstituted mixtures of bacterial antigens present in the lower airways of COPD patients, act as immunostimulants through the induction of cellular maturation, stimulating lymphocyte chemotaxis and increasing opsonization when administered to individuals with COPD.6 Studies have demonstrated a reduction in the severe complications of exacerbations and hospital admissions in COPD patients with OM-85, a detoxified oral immunoactive bacterial extract.29,30 However, most of these trials were conducted prior to the routine use of long-acting bronchodilators and ICS in COPD. A study that evaluated the efficacy of ismigen, a bacterial lysate, in reducing AECOPD31 found no difference in the exacerbation rate between ismigen and placebo or the time to first exacerbation. Additional studies are needed to examine the long-term effects of this therapy in patients receiving currently recommended COPD maintenance therapy.6
β-Blockers
Observational studies of β-blocker use in preventing AECOPD have yielded encouraging results, with one study showing a reduction in AECOPD risk (incidence risk ratio, 0.73; 95% CI, 0.60–0.90) in patients receiving β-blockers versus those not on β-blockers.32 Based on these findings, a clinical trial investigating the impact of metoprolol on risk of AECOPD is ongoing.33
Proton Pump Inhibitors
Gastroesophageal reflux disease is an independent risk factor for exacerbations.34 Two small, single-center studies,35,36 have shown that use of lansoprazole decreases the risk and frequency of AECOPD. However, data from the Predicting Outcome using Systemic Markers in Severe Exacerbations of COPD (PROMISE-COPD) study,6 which was a multicenter prospective observational study, suggested that patients with stable COPD receiving a proton pump inhibitor were at high risk of frequent and severe exacerbations.37 Thus, at this stage, their definitive role needs to be defined, possibly with a randomized, placebo-controlled study.
1. Wedzicha JA, Singh R, Mackay AJ. Acute COPD exacerbations. Clin Chest Med. 2014;35:157-163.
2. Wedzicha JA, Seemungal TAR. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796.
3. Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23:698-702.
4. Blanchette CM, Gross NJ, Altman P. Rising costs of COPD and the potential for maintenance therapy to slow the trend. Am Health Drug Benef. 2014;7:98.
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894-942.
6. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 report. Respirology. 2017;22:575-601.
7. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181.
8. Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418-1422.
9. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1995;122:823-832.
10. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164:358-364.
11. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-852.
12. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173:1114-1121.
13. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163:53-67.
14. Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694.
15. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695-703.
16. Lee S, Hui DSC, Mahayiddin AA, et al. Roflumilast in Asian patients with COPD: a randomized placebo-controlled trial. Respirology. 2011;16:1249-1257.
17. Calverley PM, Martinez FJ, Fabbri LM, et al. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Obstruct Pulmon Dis. 2012;7:375-382.
18. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013(11):CD002309.
19. Sheffner AL, Medler EM, Jacobs LW, Sarett HP. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. Am Rev Respir Dis. 1964;90:721-729.
20. Boman G, Bäcker U, Larsson S, et al. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis. 1983;64:405-415.
21. Grassi C, Morandini GC. A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis. Eur J Clin Pharmacol. 1976;9:393-396.
22. Hansen NCG, Skriver A, Brorsen-Riis L, et al. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med. 1994;88:531-535.
23. 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;2:187-194.
24. Francis RS, Spicer CC. Chemotherapy in chronic bronchitis: Influence of daily penicillin and tetracycline on exacerbations and their cost: A report to the research committee of the British Tuberculosis Association by Their Chronic Bronchitis Subcommittee. BMJ. 1960;1:297-303.
25. Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis. BMJ. 1961;2:979.
26. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.
27. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.
28. Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:361-368.
29. Collet JP, Shapiro S, Ernst P, et al. Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997;156:1719-1724.
30. Jing LI. Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary. Age. 2004;67:828-834.
31. Braido F, Tarantini F, Ghiglione V, et al. Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory recurrent infections. Int J Chron Obstruct Pulmon Dis. 2007;2:335.
32. Bhatt SP, Wells JM, Kinney GL, et al. β-Blockers are associated with a reduction in COPD exacerbations. Thorax. 2016;71:8-14.
33. Bhatt SP, Connett JE, Voelker H, et al. β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol. BMJ Open. 2016;6:e012292.
34. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128-1138.
35. Sasaki T, Nakayama K, Yasuda H, et al. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57:1453-1457.
36. Xiong W, Zhang Qs, Zhao W, et al. A 12-month follow-up study on the preventive effect of oral lansoprazole on acute exacerbation of chronic obstructive pulmonary disease. Int J Exper Pathol. 2016;97:107-113.
37. Baumeler L, Papakonstantinou E, Milenkovic B, et al. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD. Respirology. 2016;21:883-890.
1. Wedzicha JA, Singh R, Mackay AJ. Acute COPD exacerbations. Clin Chest Med. 2014;35:157-163.
2. Wedzicha JA, Seemungal TAR. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786-796.
3. Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23:698-702.
4. Blanchette CM, Gross NJ, Altman P. Rising costs of COPD and the potential for maintenance therapy to slow the trend. Am Health Drug Benef. 2014;7:98.
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acute exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147:894-942.
6. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive lung disease 2017 report. Respirology. 2017;22:575-601.
7. Wedzicha JA, Brill SE, Allinson JP, Donaldson GC. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181.
8. Seemungal TAR, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418-1422.
9. Ries AL, Kaplan RM, Limberg TM, Prewitt LM. Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease. Ann Intern Med. 1995;122:823-832.
10. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med. 2001;164:358-364.
11. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847-852.
12. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173:1114-1121.
13. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163:53-67.
14. Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694.
15. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695-703.
16. Lee S, Hui DSC, Mahayiddin AA, et al. Roflumilast in Asian patients with COPD: a randomized placebo-controlled trial. Respirology. 2011;16:1249-1257.
17. Calverley PM, Martinez FJ, Fabbri LM, et al. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Obstruct Pulmon Dis. 2012;7:375-382.
18. Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013(11):CD002309.
19. Sheffner AL, Medler EM, Jacobs LW, Sarett HP. The in vitro reduction in viscosity of human tracheobronchial secretions by acetylcysteine. Am Rev Respir Dis. 1964;90:721-729.
20. Boman G, Bäcker U, Larsson S, et al. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. Eur J Respir Dis. 1983;64:405-415.
21. Grassi C, Morandini GC. A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis. Eur J Clin Pharmacol. 1976;9:393-396.
22. Hansen NCG, Skriver A, Brorsen-Riis L, et al. Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Respir Med. 1994;88:531-535.
23. 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;2:187-194.
24. Francis RS, Spicer CC. Chemotherapy in chronic bronchitis: Influence of daily penicillin and tetracycline on exacerbations and their cost: A report to the research committee of the British Tuberculosis Association by Their Chronic Bronchitis Subcommittee. BMJ. 1960;1:297-303.
25. Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis. BMJ. 1961;2:979.
26. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.
27. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503-1508.
28. Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:361-368.
29. Collet JP, Shapiro S, Ernst P, et al. Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997;156:1719-1724.
30. Jing LI. Protective effect of a bacterial extract against acute exacerbation in patients with chronic bronchitis accompanied by chronic obstructive pulmonary. Age. 2004;67:828-834.
31. Braido F, Tarantini F, Ghiglione V, et al. Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory recurrent infections. Int J Chron Obstruct Pulmon Dis. 2007;2:335.
32. Bhatt SP, Wells JM, Kinney GL, et al. β-Blockers are associated with a reduction in COPD exacerbations. Thorax. 2016;71:8-14.
33. Bhatt SP, Connett JE, Voelker H, et al. β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol. BMJ Open. 2016;6:e012292.
34. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128-1138.
35. Sasaki T, Nakayama K, Yasuda H, et al. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57:1453-1457.
36. Xiong W, Zhang Qs, Zhao W, et al. A 12-month follow-up study on the preventive effect of oral lansoprazole on acute exacerbation of chronic obstructive pulmonary disease. Int J Exper Pathol. 2016;97:107-113.
37. Baumeler L, Papakonstantinou E, Milenkovic B, et al. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD. Respirology. 2016;21:883-890.