Comment
Non-cystic fibrosis bronchiectasis is a disorder associated with permanent dilatation of proximal cartilage-containing bronchi; the prevalence of this disorder is increasing worldwide.1–3 The pathogenesis of bronchiectasis has been described as a vicious circle of events with three main components: airway damage, infection, and ongoing inflammation.1,2 The airway inflammatory response is associated with accumulation of various cells (eg, neutrophils, lymphocytes, and macrophages) and proinflammatory mediators.1–3 Neutrophilic inflammation can be present even without overt infection, suggesting some dysregulation of the innate immune response.4 Treatment of bronchiectasis is directed at addressing the three components of the disease process, and recent research has focused on the potential benefit of various anti-inflammatory therapeutic approaches.1,2,4,5 Long-term, low-dose macrolide treatment has been the most promising anti-inflammatory strategy, and use of these agents in selected patients with bronchiectasis is recommended.1,2,4,5 Alternative anti-inflammatory treatments include oral and inhaled corticosteroids, oral and inhaled non-steroidal anti-inflammatory drugs, agents targeting specific mediators (such as the interleukins), and various other novel compounds, but with scant evidence of efficacy and a paucity of data.1,4,5 Recent findings suggest that statins could be useful in patients with bronchiectasis because of their noted anti-inflammatory and immunomodulatory effects,4,6,7 and at least two clinical studies of atorvastatin are ongoing.4 Statins have several modulatory effects on neutrophils, including decreasing production of reactive oxygen species and reduction of neutrophil migration.8 Furthermore, in people with bronchiectasis, clearance of apoptotic cells in the airway is defective, which contributes to ongoing airway inflammation.4,9 Statins augment the clearance of apoptotic cells (efferocytosis) both in vivo and in vitro.4,8,10 In The Lancet Respiratory Medicine, Pallavi Mandal and colleagues present the results of a randomised controlled trial of atorvastatin in patients with stable bronchiectasis.11 Patients had clinically significant bronchiectasis, confirmed on chest CT, with cough and sputum production in the stable state and two or more chest infections in the preceding year.
Adults (aged 18–79 years) received either atorvastatin 80 mg daily (n=30) or placebo (n=30) over a 6-month period. The primary outcome was a reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, which the authors had validated previously for use in bronchiectasis. Several secondary outcomes were also assessed, including statin safety. At 6 months, the change in LCQ score from baseline differed significantly between treatment groups, with a mean increase of 1·5 in the statin-treated group compared with a mean decrease of 0·7 in the placebo group (difference 2·2, 95% CI 0·5–3·9; p=0·01); this difference was also evident at 3 months. When the change was analysed as a proportion of improvement in LCQ score, the difference remained significant (difference 23%, 95% CI 1–45; p=0·04). Other important findings in the statin-treated group were an increase in the number of apoptotic neutrophils, a decrease in the total number of neutrophils in sputum, a reduction in levels of interleukin 8 in serum, and a mild improvement in the St George’s Respiratory Questionnaire (that measures health-related quality of life). Ten patients in the statin group had an adverse event compared with three in the placebo group (difference 23%, 95% CI 3–43; p=0·02), without any serious adverse events. This proof-of-concept study is the first to investigate the potential benefit of statins in patients with non-cystic fibrosis bronchiectasis. The primary outcome measure—a reduction in cough—was achieved, and it is an important endpoint because the first recommendation for treatment of patients with bronchiectasis is airway clearance.1,2 Concomitant with the reduction in cough were improvements in various indices of neutrophilic inflammation, consistent with the known pleotropic effects of statins. The study has several potential limitations; in particular, the smoking habits of the two treatment groups differed significantly, with more patients in the statin group than in the placebo group being neversmokers (87% vs 60%). The effects that this difference might have had on the study outcomes are difficult to ascertain. Furthermore, would a difference be noted with use of other statin agents? Would a lower dose of statin be as effective, in view of the greater rate of
www.thelancet.com/respiratory Published online March 24, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70070-0
Chassenet/Science Photo Library
Statins for non-cystic fibrosis bronchiectasis
Lancet Respir Med 2014 Published Online March 24, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70070-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(14)70050-5
1
Comment
adverse events in the statin-treated group? If statins are judged effective for patients with bronchiectasis, when should treatment be initiated? Although a better understanding of the likely role of statins in patients with bronchiectasis awaits larger multicentre studies, these findings provide a glimmer of hope that we might soon have an effective anti-inflammatory treatment for patients with bronchiectasis. Charles Feldman Division of Pulmonology, Department of Internal Medicine, Faculty of Health Sciences, University of Witwatersrand, Parktown, Johannesburg 2193, South Africa [email protected] I declare that I have no competing interests. I would like to thank Ronald Anderson for reviewing this Comment. 1
2
Goeminne P, Dupont L. Non-cystic fibrosis bronchiectasis: diagnosis and management in 21st century. Postgrad Med J 2010; 86: 493–501.
2 3
4 5 6 7 8
9
10
11
McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013; 188: 647–56. Bergin DA, Hurley K, Mehta A, et al. Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis. J Inflamm Res 2013; 6: 1–11. Amorim A, Gamboa F, Azevedo P. New advances in the therapy of non-cystic fibrosis bronchiectasis. Rev Port Pneumol 2013; 19: 256–75. Feldman C. The use of anti-inflammatory therapy and macrolides in bronchiectasis. Clin Chest Med 2012; 33: 371–80. Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol 2011; 22: 165–70. Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med 2011; 4: 261–71. Chalmers JD, Short PM, Mandal P, Akram AR, Hill AT. Statins in community acquired pneumonia: evidence from experimental and clinical studies. Respir Med 2010; 104: 1081–91. Vandivier RW, Fadok VA, Hoffmann PR, et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 2002; 109: 661–70. Morimoto K, Janssen WJ, Fessler MB, et al. Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol 2006; 176: 7657–65. Mandal P, Chalmers JD, Graham C, et al. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med 2014; published online March 24. http://dx.doi.org/10.1016/S2213-2600(14) 70050-5.
www.thelancet.com/respiratory Published online March 24, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70070-0
Non-cystic fibrosis bronchiectasis is a disorder associated with permanent dilatation of proximal cartilage-containing bronchi; the prevalence of this disorder is increasing worldwide.1–3 The pathogenesis of bronchiectasis has been described as a vicious circle of events with three main components: airway damage, infection, and ongoing inflammation.1,2 The airway inflammatory response is associated with accumulation of various cells (eg, neutrophils, lymphocytes, and macrophages) and proinflammatory mediators.1–3 Neutrophilic inflammation can be present even without overt infection, suggesting some dysregulation of the innate immune response.4 Treatment of bronchiectasis is directed at addressing the three components of the disease process, and recent research has focused on the potential benefit of various anti-inflammatory therapeutic approaches.1,2,4,5 Long-term, low-dose macrolide treatment has been the most promising anti-inflammatory strategy, and use of these agents in selected patients with bronchiectasis is recommended.1,2,4,5 Alternative anti-inflammatory treatments include oral and inhaled corticosteroids, oral and inhaled non-steroidal anti-inflammatory drugs, agents targeting specific mediators (such as the interleukins), and various other novel compounds, but with scant evidence of efficacy and a paucity of data.1,4,5 Recent findings suggest that statins could be useful in patients with bronchiectasis because of their noted anti-inflammatory and immunomodulatory effects,4,6,7 and at least two clinical studies of atorvastatin are ongoing.4 Statins have several modulatory effects on neutrophils, including decreasing production of reactive oxygen species and reduction of neutrophil migration.8 Furthermore, in people with bronchiectasis, clearance of apoptotic cells in the airway is defective, which contributes to ongoing airway inflammation.4,9 Statins augment the clearance of apoptotic cells (efferocytosis) both in vivo and in vitro.4,8,10 In The Lancet Respiratory Medicine, Pallavi Mandal and colleagues present the results of a randomised controlled trial of atorvastatin in patients with stable bronchiectasis.11 Patients had clinically significant bronchiectasis, confirmed on chest CT, with cough and sputum production in the stable state and two or more chest infections in the preceding year.
Adults (aged 18–79 years) received either atorvastatin 80 mg daily (n=30) or placebo (n=30) over a 6-month period. The primary outcome was a reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, which the authors had validated previously for use in bronchiectasis. Several secondary outcomes were also assessed, including statin safety. At 6 months, the change in LCQ score from baseline differed significantly between treatment groups, with a mean increase of 1·5 in the statin-treated group compared with a mean decrease of 0·7 in the placebo group (difference 2·2, 95% CI 0·5–3·9; p=0·01); this difference was also evident at 3 months. When the change was analysed as a proportion of improvement in LCQ score, the difference remained significant (difference 23%, 95% CI 1–45; p=0·04). Other important findings in the statin-treated group were an increase in the number of apoptotic neutrophils, a decrease in the total number of neutrophils in sputum, a reduction in levels of interleukin 8 in serum, and a mild improvement in the St George’s Respiratory Questionnaire (that measures health-related quality of life). Ten patients in the statin group had an adverse event compared with three in the placebo group (difference 23%, 95% CI 3–43; p=0·02), without any serious adverse events. This proof-of-concept study is the first to investigate the potential benefit of statins in patients with non-cystic fibrosis bronchiectasis. The primary outcome measure—a reduction in cough—was achieved, and it is an important endpoint because the first recommendation for treatment of patients with bronchiectasis is airway clearance.1,2 Concomitant with the reduction in cough were improvements in various indices of neutrophilic inflammation, consistent with the known pleotropic effects of statins. The study has several potential limitations; in particular, the smoking habits of the two treatment groups differed significantly, with more patients in the statin group than in the placebo group being neversmokers (87% vs 60%). The effects that this difference might have had on the study outcomes are difficult to ascertain. Furthermore, would a difference be noted with use of other statin agents? Would a lower dose of statin be as effective, in view of the greater rate of
www.thelancet.com/respiratory Published online March 24, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70070-0
Chassenet/Science Photo Library
Statins for non-cystic fibrosis bronchiectasis
Lancet Respir Med 2014 Published Online March 24, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70070-0 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(14)70050-5
1
Comment
adverse events in the statin-treated group? If statins are judged effective for patients with bronchiectasis, when should treatment be initiated? Although a better understanding of the likely role of statins in patients with bronchiectasis awaits larger multicentre studies, these findings provide a glimmer of hope that we might soon have an effective anti-inflammatory treatment for patients with bronchiectasis. Charles Feldman Division of Pulmonology, Department of Internal Medicine, Faculty of Health Sciences, University of Witwatersrand, Parktown, Johannesburg 2193, South Africa [email protected] I declare that I have no competing interests. I would like to thank Ronald Anderson for reviewing this Comment. 1
2
Goeminne P, Dupont L. Non-cystic fibrosis bronchiectasis: diagnosis and management in 21st century. Postgrad Med J 2010; 86: 493–501.
2 3
4 5 6 7 8
9
10
11
McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013; 188: 647–56. Bergin DA, Hurley K, Mehta A, et al. Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis. J Inflamm Res 2013; 6: 1–11. Amorim A, Gamboa F, Azevedo P. New advances in the therapy of non-cystic fibrosis bronchiectasis. Rev Port Pneumol 2013; 19: 256–75. Feldman C. The use of anti-inflammatory therapy and macrolides in bronchiectasis. Clin Chest Med 2012; 33: 371–80. Bu DX, Griffin G, Lichtman AH. Mechanisms for the anti-inflammatory effects of statins. Curr Opin Lipidol 2011; 22: 165–70. Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med 2011; 4: 261–71. Chalmers JD, Short PM, Mandal P, Akram AR, Hill AT. Statins in community acquired pneumonia: evidence from experimental and clinical studies. Respir Med 2010; 104: 1081–91. Vandivier RW, Fadok VA, Hoffmann PR, et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J Clin Invest 2002; 109: 661–70. Morimoto K, Janssen WJ, Fessler MB, et al. Lovastatin enhances clearance of apoptotic cells (efferocytosis) with implications for chronic obstructive pulmonary disease. J Immunol 2006; 176: 7657–65. Mandal P, Chalmers JD, Graham C, et al. Atorvastatin as a stable treatment in bronchiectasis: a randomised controlled trial. Lancet Respir Med 2014; published online March 24. http://dx.doi.org/10.1016/S2213-2600(14) 70050-5.
www.thelancet.com/respiratory Published online March 24, 2014 http://dx.doi.org/10.1016/S2213-2600(14)70070-0
