EDITORIALS have been studied in animal and cell models of human diseases (7). A phase II clinical trial for ONO-4819CD, an EP4 agonist, was completed for the treatment of mild to moderate ulcerative colitis (http://clinicaltrials.gov/ct2/show/NCT00296556) (18). Therefore, it is possible to conduct clinical trials using either PGE2 derivatives or EP4 agonists in lung transplant patients for the prevention of PGD. However, there are still a significant number of questions that need to be answered experimentally before embarking on a human study. Should the treatment target PGE2, EP4, EP2/EP4, or all of them? A personalized medicine approach would suggest that specific genotypes of lung transplant recipients in PGE2 genes dictate the candidacy for this therapy. Should the treatment start at the time of organ procurement? How long should the treatment be and should this treatment replace some of the immunosuppression drugs? What are the systemic effects of this kind of treatment? In conclusion, the study by Diamond and colleagues represents an important advance in lung transplant research. It will serve as the basis for future animal and translational studies to further elucidate the therapeutic potential of PGE2 in PGD. Understanding the mechanistic roles of PGE2 pathway in PGD may lay the foundation for the development of personalized therapies to prevent or treat the devastating effects of PGD and thus lead to significantly improved survival for patients undergoing lung transplantation. n Author disclosures are available with the text of this article at www.atsjournals.org. Acknowledgment: The author thanks Danny Kass for his careful review of this work. Yingze Zhang, Ph.D.
Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania
References 1. Lee JC, Christie JD. Primary graft dysfunction. Clin Chest Med 2011;32: 279–293. 2. Daud SA, Yusen RD, Meyers BF, Chakinala MM, Walter MJ, Aloush AA, Patterson GA, Trulock EP, Hachem RR. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2007;175:507–513. 3. Diamond JM, Akimova T, Kazi A, Shah RJ, Cantu E, Feng R, Levine MH, Kawut SM, Meyer NJ, Lee JC, et al. Genetic variation in prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med 2014;189:567–575. 4. Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol 2012;188:21–28.
5. Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin Immunol 2006;119: 229–240. 6. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 2004;103:147–166. 7. Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 2013;138: 485–502. 8. Vancheri C, Mastruzzo C, Sortino MA, Crimi N. The lung as a privileged site for the beneficial actions of PGE2. Trends Immunol 2004;25: 40–46. 9. Huang SK, Peters-Golden M. Eicosanoid lipid mediators in fibrotic lung diseases: ready for prime time? Chest 2008;133:1442–1450. 10. Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, Lama VN. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008;181:4389–4396. 11. Walker NM, Badri LN, Wadhwa A, Wettlaufer S, Peters-Golden M, Lama VN. Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts. Am J Respir Crit Care Med 2012;185:77–84. 12. Stone CD, Rosengard BR, Boorstein SM, Robbins RC, Hennein HA, Clark RE. Prostaglandin E2 inhibits in vitro and in vivo lymphocyte responses in allogeneic transplantation. Ann Thorac Surg 1990; 49:927–930, discussion 931. 13. Kerkela¨ R, Boucher M, Zaka R, Gao E, Harris D, Piuhola J, Song J, Serpi R, Woulfe KC, Cheung JY, et al. Cytosolic phospholipase A(2)a protects against ischemia/reperfusion injury in the heart. Clin Transl Sci 2011;4:236–242. 14. Hwang HS, Yang KJ, Park KC, Choi HS, Kim SH, Hong SY, Jeon BH, Chang YK, Park CW, Kim SY, et al. Pretreatment with paricalcitol attenuates inflammation in ischemia-reperfusion injury via the upregulation of cyclooxygenase-2 and prostaglandin E2. Nephrol Dial Transplant 2013;28:1156–1166. 15. Liang X, Lin L, Woodling NS, Wang Q, Anacker C, Pan T, Merchant M, Andreasson K. Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest 2011;121:4362–4371. 16. Panettieri RA Jr, Lazaar AL, Pure´ E, Albelda SM. Activation of cAMPdependent pathways in human airway smooth muscle cells inhibits TNF-alpha-induced ICAM-1 and VCAM-1 expression and T lymphocyte adhesion. J Immunol 1995;154:2358–2365. 17. N emeth ´ K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009;15: 42–49. 18. Nakase H, Fujiyama Y, Oshitani N, Oga T, Nonomura K, Matsuoka T, Esaki Y, Murayama T, Teramukai S, Chiba T, et al. Effect of EP4 agonist (ONO-4819CD) for patients with mild to moderate ulcerative colitis refractory to 5-aminosalicylates: a randomized phase II, placebo-controlled trial. Inflamm Bowel Dis 2010; 16:731–733.
Copyright © 2014 by the American Thoracic Society
Bronchiectasis Severity: Time to Score Bronchiectasis is a common condition caused by a diverse range of etiologies that is being increasingly identified (1). The airway dilation results in chronic airway infection, which progressively impairs lung function and quality of life and causes frequent exacerbations requiring antibiotic therapy (1, 2). Bronchiectasis as
508
a diagnostic label usually excludes cystic fibrosis (CF), and is caused by a range of genetic and acquired conditions. The diagnosis is based on computed tomography (CT) scan changes, and although there is long-term progressive impact on lung function measured by spirometry, FEV1 is of limited value in clinical decision making,
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 5 | March 1 2014
EDITORIALS as CT scan changes correlate poorly with lung function, and the magnitude of change in FEV1 in response to treatment is small (3). People with bronchiectasis have persistent cough and sputum with intermittent exacerbations of increased respiratory symptoms but little change in spirometry (3). In contrast to other chronic lung conditions such as asthma, chronic obstructive pulmonary disease (COPD), CF, and interstitial lung disease, there are no validated tools to assess severity of people with bronchiectasis, which limits management plans for clinical care and clear definition in clinical trials. In this issue of the Journal, Chalmers and colleagues (pp. 576– 585) describe a novel Bronchiectasis Severity Index (BSI) from an international derivation and validation cohort study (4). A prospective derivation cohort followed over a 4-year period from the United Kingdom was independently validated at four other sites, two from the United Kingdom, one from Belgium, and one from Italy. The authors identified predictive independently associated factors and constructed a BSI score that was able to predict future hospitalizations, exacerbations, quality of life, and mortality. These factors include prior hospital admission and exacerbations, symptoms (Medical Research Council dyspnea score), lung function (FEV1), prior Pseudomonas and other bacterial colonization, and lung involvement documented by high-resolution CT (HRCT). The authors stratified the BSI score as low, intermediate, and high, and validated the results in other derivation cohorts showing similar results. Several important points are remarkable out of this multinational collaborative effort. The development of a severity tool that may be used for clinical and research purposes is very welcome, as it provides a tool that predicts important outcomes that may help in deciding on therapies for patients with bronchiectasis. This study is of an acceptable size and is generalizable to other centers, due to the multinational characteristics of the validation cohorts. The results observed in the different evaluated outcomes, including quality of life, add important new data to the literature by considering the patient’s symptoms in addition to objective assessments. Finally, the authors added information regarding HRCT to document structural changes in patients with non-CF bronchiectasis as part of the stratification tool. These differences and similarities with other obstructive conditions, such as asthma, COPD, and CF, overlap with the need to have a stratification tool to be used in clinical practice. How do we use this information in clinical practice? This tool has important parameters closely related to the new COPD Global Initiative for Chronic Obstructive Lung Disease classification (5, 6). Therefore, therapies could be recommended according to the severity of the disease of the patients and the likelihood of expected poor clinical outcomes. This score will help determine the need for interventions with limited evidence base in bronchiectasis such as inhaled antibiotics and inform decisions regarding use of therapies such as macrolides (7, 8). For clinical and translational researchers, the BSI score may be used in future randomized control trials to assess the clinical efficacy of pharmacological and nonpharmacological interventions. It may also determine, as in COPD trials, that certain phenotypic populations are more or less likely to respond to certain therapies. Treatment for people with bronchiectasis is difficult, as there are no treatments approved by regulatory authorities in North America or Europe, but a number of inhaled antibiotics and mucoactive
Editorials
drugs are under investigation (9). Optimal generic treatment of bronchiectasis may vary according to severity or etiology. For example, treatment of specific conditions such as primary immunodeficiency with immunoglobulin replacement is important. However, the drugs to treat bronchiectasis symptoms are largely extrapolated from experience in treating bronchiectasis associated with CF and from managing severe COPD. Neither of these approaches is satisfactory, as some therapies, such as dornase-alfa and inhaled corticosteroids, have even been shown to have little or no efficacy in bronchiectasis. Stratifying patients according to disease severity is likely to be important, but other approaches to stratification on airway microbiology, underlying diagnosis, and possibly changes on imaging may also be important in developing and prescribing effective therapies for people with this condition. The data published in this paper help to determine key issues around severity of disease in bronchiectasis. Stratification aimed at reducing pulmonary exacerbations is likely to be of significant further benefit. n Author disclosures are available with the text of this article at www.atsjournals.org. Marcos Restrepo, M.D., M.Sc. Audie L. Murphy Division South Texas Veterans Healthcare System San Antonio, Texas and University of Texas Health Science Center at San Antonio San Antonio, Texas J. Stuart Elborn, M.D. Centre for Infection and Immunity Queens University Belfast Belfast, United Kingdom
References 1. McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013;188: 647–656. 2. Bronchiectasis in The European Lung White Book. 2014. Available from: www.erswhitebook.org 3. Drain M, Elborn JS. Assessment and investigation of adults with bronchiectasis. ERS Monogr 2011;52:32–43. 4. Chalmers JD, Goeminne P, Aliberti S, McDonnel MJ, Lonni S, Davidson J, Poppelwell L, Salih W, Pesci A, Dupont LF, et al. The Bronchiectasis Severity Index: an international derivation and validation study. Am J Respir Crit Care Med 2014;189:576–585. 5. Vestbo J, Hurd SS, Agust´ı AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–365. 6. West JB. GOLD executive summary [letter]. Am J Respir Crit Care Med 2013;188:1366–1367. 7. O’Donnell AE. Antimicrobial therapy for bronchiectasis. Clin Chest Med 2012;33:381–386. 8. Elborn JS, Tunney MM. Macrolides and bronchiectasis: clinical benefit with a resistance price. JAMA 2013;309:1295–1296. 9. Sidhu MK, Mandal P, Hill AT. Bronchiectasis: an update on current pharmacotherapy and future perspectives. Expert Opin Pharmacother 2014;15:505–525.
Copyright © 2014 by the American Thoracic Society
509
Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania
References 1. Lee JC, Christie JD. Primary graft dysfunction. Clin Chest Med 2011;32: 279–293. 2. Daud SA, Yusen RD, Meyers BF, Chakinala MM, Walter MJ, Aloush AA, Patterson GA, Trulock EP, Hachem RR. Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2007;175:507–513. 3. Diamond JM, Akimova T, Kazi A, Shah RJ, Cantu E, Feng R, Levine MH, Kawut SM, Meyer NJ, Lee JC, et al. Genetic variation in prostaglandin E2 pathway is associated with primary graft dysfunction. Am J Respir Crit Care Med 2014;189:567–575. 4. Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol 2012;188:21–28.
5. Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin Immunol 2006;119: 229–240. 6. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther 2004;103:147–166. 7. Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 2013;138: 485–502. 8. Vancheri C, Mastruzzo C, Sortino MA, Crimi N. The lung as a privileged site for the beneficial actions of PGE2. Trends Immunol 2004;25: 40–46. 9. Huang SK, Peters-Golden M. Eicosanoid lipid mediators in fibrotic lung diseases: ready for prime time? Chest 2008;133:1442–1450. 10. Jarvinen L, Badri L, Wettlaufer S, Ohtsuka T, Standiford TJ, Toews GB, Pinsky DJ, Peters-Golden M, Lama VN. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008;181:4389–4396. 11. Walker NM, Badri LN, Wadhwa A, Wettlaufer S, Peters-Golden M, Lama VN. Prostaglandin E2 as an inhibitory modulator of fibrogenesis in human lung allografts. Am J Respir Crit Care Med 2012;185:77–84. 12. Stone CD, Rosengard BR, Boorstein SM, Robbins RC, Hennein HA, Clark RE. Prostaglandin E2 inhibits in vitro and in vivo lymphocyte responses in allogeneic transplantation. Ann Thorac Surg 1990; 49:927–930, discussion 931. 13. Kerkela¨ R, Boucher M, Zaka R, Gao E, Harris D, Piuhola J, Song J, Serpi R, Woulfe KC, Cheung JY, et al. Cytosolic phospholipase A(2)a protects against ischemia/reperfusion injury in the heart. Clin Transl Sci 2011;4:236–242. 14. Hwang HS, Yang KJ, Park KC, Choi HS, Kim SH, Hong SY, Jeon BH, Chang YK, Park CW, Kim SY, et al. Pretreatment with paricalcitol attenuates inflammation in ischemia-reperfusion injury via the upregulation of cyclooxygenase-2 and prostaglandin E2. Nephrol Dial Transplant 2013;28:1156–1166. 15. Liang X, Lin L, Woodling NS, Wang Q, Anacker C, Pan T, Merchant M, Andreasson K. Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest 2011;121:4362–4371. 16. Panettieri RA Jr, Lazaar AL, Pure´ E, Albelda SM. Activation of cAMPdependent pathways in human airway smooth muscle cells inhibits TNF-alpha-induced ICAM-1 and VCAM-1 expression and T lymphocyte adhesion. J Immunol 1995;154:2358–2365. 17. N emeth ´ K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009;15: 42–49. 18. Nakase H, Fujiyama Y, Oshitani N, Oga T, Nonomura K, Matsuoka T, Esaki Y, Murayama T, Teramukai S, Chiba T, et al. Effect of EP4 agonist (ONO-4819CD) for patients with mild to moderate ulcerative colitis refractory to 5-aminosalicylates: a randomized phase II, placebo-controlled trial. Inflamm Bowel Dis 2010; 16:731–733.
Copyright © 2014 by the American Thoracic Society
Bronchiectasis Severity: Time to Score Bronchiectasis is a common condition caused by a diverse range of etiologies that is being increasingly identified (1). The airway dilation results in chronic airway infection, which progressively impairs lung function and quality of life and causes frequent exacerbations requiring antibiotic therapy (1, 2). Bronchiectasis as
508
a diagnostic label usually excludes cystic fibrosis (CF), and is caused by a range of genetic and acquired conditions. The diagnosis is based on computed tomography (CT) scan changes, and although there is long-term progressive impact on lung function measured by spirometry, FEV1 is of limited value in clinical decision making,
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 5 | March 1 2014
EDITORIALS as CT scan changes correlate poorly with lung function, and the magnitude of change in FEV1 in response to treatment is small (3). People with bronchiectasis have persistent cough and sputum with intermittent exacerbations of increased respiratory symptoms but little change in spirometry (3). In contrast to other chronic lung conditions such as asthma, chronic obstructive pulmonary disease (COPD), CF, and interstitial lung disease, there are no validated tools to assess severity of people with bronchiectasis, which limits management plans for clinical care and clear definition in clinical trials. In this issue of the Journal, Chalmers and colleagues (pp. 576– 585) describe a novel Bronchiectasis Severity Index (BSI) from an international derivation and validation cohort study (4). A prospective derivation cohort followed over a 4-year period from the United Kingdom was independently validated at four other sites, two from the United Kingdom, one from Belgium, and one from Italy. The authors identified predictive independently associated factors and constructed a BSI score that was able to predict future hospitalizations, exacerbations, quality of life, and mortality. These factors include prior hospital admission and exacerbations, symptoms (Medical Research Council dyspnea score), lung function (FEV1), prior Pseudomonas and other bacterial colonization, and lung involvement documented by high-resolution CT (HRCT). The authors stratified the BSI score as low, intermediate, and high, and validated the results in other derivation cohorts showing similar results. Several important points are remarkable out of this multinational collaborative effort. The development of a severity tool that may be used for clinical and research purposes is very welcome, as it provides a tool that predicts important outcomes that may help in deciding on therapies for patients with bronchiectasis. This study is of an acceptable size and is generalizable to other centers, due to the multinational characteristics of the validation cohorts. The results observed in the different evaluated outcomes, including quality of life, add important new data to the literature by considering the patient’s symptoms in addition to objective assessments. Finally, the authors added information regarding HRCT to document structural changes in patients with non-CF bronchiectasis as part of the stratification tool. These differences and similarities with other obstructive conditions, such as asthma, COPD, and CF, overlap with the need to have a stratification tool to be used in clinical practice. How do we use this information in clinical practice? This tool has important parameters closely related to the new COPD Global Initiative for Chronic Obstructive Lung Disease classification (5, 6). Therefore, therapies could be recommended according to the severity of the disease of the patients and the likelihood of expected poor clinical outcomes. This score will help determine the need for interventions with limited evidence base in bronchiectasis such as inhaled antibiotics and inform decisions regarding use of therapies such as macrolides (7, 8). For clinical and translational researchers, the BSI score may be used in future randomized control trials to assess the clinical efficacy of pharmacological and nonpharmacological interventions. It may also determine, as in COPD trials, that certain phenotypic populations are more or less likely to respond to certain therapies. Treatment for people with bronchiectasis is difficult, as there are no treatments approved by regulatory authorities in North America or Europe, but a number of inhaled antibiotics and mucoactive
Editorials
drugs are under investigation (9). Optimal generic treatment of bronchiectasis may vary according to severity or etiology. For example, treatment of specific conditions such as primary immunodeficiency with immunoglobulin replacement is important. However, the drugs to treat bronchiectasis symptoms are largely extrapolated from experience in treating bronchiectasis associated with CF and from managing severe COPD. Neither of these approaches is satisfactory, as some therapies, such as dornase-alfa and inhaled corticosteroids, have even been shown to have little or no efficacy in bronchiectasis. Stratifying patients according to disease severity is likely to be important, but other approaches to stratification on airway microbiology, underlying diagnosis, and possibly changes on imaging may also be important in developing and prescribing effective therapies for people with this condition. The data published in this paper help to determine key issues around severity of disease in bronchiectasis. Stratification aimed at reducing pulmonary exacerbations is likely to be of significant further benefit. n Author disclosures are available with the text of this article at www.atsjournals.org. Marcos Restrepo, M.D., M.Sc. Audie L. Murphy Division South Texas Veterans Healthcare System San Antonio, Texas and University of Texas Health Science Center at San Antonio San Antonio, Texas J. Stuart Elborn, M.D. Centre for Infection and Immunity Queens University Belfast Belfast, United Kingdom
References 1. McShane PJ, Naureckas ET, Tino G, Strek ME. Non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2013;188: 647–656. 2. Bronchiectasis in The European Lung White Book. 2014. Available from: www.erswhitebook.org 3. Drain M, Elborn JS. Assessment and investigation of adults with bronchiectasis. ERS Monogr 2011;52:32–43. 4. Chalmers JD, Goeminne P, Aliberti S, McDonnel MJ, Lonni S, Davidson J, Poppelwell L, Salih W, Pesci A, Dupont LF, et al. The Bronchiectasis Severity Index: an international derivation and validation study. Am J Respir Crit Care Med 2014;189:576–585. 5. Vestbo J, Hurd SS, Agust´ı AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–365. 6. West JB. GOLD executive summary [letter]. Am J Respir Crit Care Med 2013;188:1366–1367. 7. O’Donnell AE. Antimicrobial therapy for bronchiectasis. Clin Chest Med 2012;33:381–386. 8. Elborn JS, Tunney MM. Macrolides and bronchiectasis: clinical benefit with a resistance price. JAMA 2013;309:1295–1296. 9. Sidhu MK, Mandal P, Hill AT. Bronchiectasis: an update on current pharmacotherapy and future perspectives. Expert Opin Pharmacother 2014;15:505–525.
Copyright © 2014 by the American Thoracic Society
509
