EDITORIALS 4. Girodet PO, Ozier A, Bara I, Tunon de Lara JM, Marthan R, Berger P. Airway remodeling in asthma: new mechanisms and potential for pharmacological intervention. Pharmacol Ther 2011;130: 325–337. 5. Roth M, Johnson PR, Borger P, Bihl MP, Rudiger ¨ JJ, King GG, Ge Q, Hostettler K, Burgess JK, Black JL, et al. Dysfunctional interaction of C/EBPalpha and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med 2004;351: 560–574. 6. Chang P-J, Michaeloudes C, Zhu J, Shaikh N, Baker J, Chung KF, Bhavsar PK. Impaired nuclear translocation of the glucocorticoid receptor in corticosteroid-insensitive airway smooth muscle in severe asthma. Am J Respir Crit Care Med 2015;191:54–62. 7. Chang PJ, Bhavsar PK, Michaeloudes C, Khorasani N, Chung KF. Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma. J Allergy Clin Immunol 2012; 130:877–885. 8. Berger P, Girodet PO, Begueret H, Ousova O, Perng DW, Marthan R, Walls AF, Tunon de Lara JM. Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis. FASEB J 2003;17:2139–2141. 9. El-Shazly A, Berger P, Girodet PO, Ousova O, Fayon M, Vernejoux JM, Marthan R, Tunon-de-Lara JM. Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma. J Immunol 2006;176:1860–1868. 10. Castro M, Rubin AS, Laviolette M, Fiterman J, De Andrade Lima M, Shah PL, Fiss E, Olivenstein R, Thomson NC, Niven RM, et al.; AIR2 Trial Study Group. Effectiveness and
safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, shamcontrolled clinical trial. Am J Respir Crit Care Med 2010;181: 116–124. 11. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 2007;204: 3173–3181. 12. Begueret H, Berger P, Vernejoux JM, Dubuisson L, Marthan R, Tunonde-Lara JM. Inflammation of bronchial smooth muscle in allergic asthma. Thorax 2007;62:8–15. 13. Ramos-Barbon ´ D, Fraga-Iriso R, Brienza NS, Montero-Mart´ınez C, Verea-Hernando H, Olivenstein R, Lemiere C, Ernst P, Hamid QA, Martin JG. T Cells localize with proliferating smooth muscle alpha-actin1 cell compartments in asthma. Am J Respir Crit Care Med 2010;182:317–324. 14. Bara I, Ozier A, Girodet PO, Carvalho G, Cattiaux J, Begueret H, Thumerel M, Ousova O, Kolbeck R, Coyle AJ, et al. Role of YKL-40 in bronchial smooth muscle remodeling in asthma. Am J Respir Crit Care Med 2012;185:715–722. 15. Trian T, Girodet PO, Ousova O, Marthan R, Tunon-de-Lara JM, Berger P. RNA interference decreases PAR-2 expression and function in human airway smooth muscle cells. Am J Respir Cell Mol Biol 2006; 34:49–55.
Copyright © 2015 by the American Thoracic Society
Uncovering the Bronchovascular Links in Patients with Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension Despite decades of scientific research, there are still no effective therapies for chronic obstructive pulmonary disease (COPD) that can cure the disease, nor substantially slow its progression. COPD is currently the third leading cause of death in the United States (1), and it is thought that if we continue on this course without effective treatments, in the next 10 years, the total deaths attributed to COPD will increase by more than 30% (2). This is a sobering statistic, and one of the reasons research into the pathogenesis of COPD is so important. However, it is also important to recognize that COPD is not simply a “disease” but is a syndrome encompassing a vast collection of pathologies and mechanisms that reach far beyond the lung, with particularly significant cardiovascular consequences including pulmonary hypertension. This has important clinical implications because it has been shown that in patients with COPD, the presence of pulmonary hypertension is associated with a greater risk for hospitalization (3) and death (4). The pathogenesis of pulmonary hypertension in COPD is complex, and the process by which chronic tobacco smoke exposure leads to pulmonary hypertension is not completely understood. Although several mechanisms have been proposed, including pulmonary arterial vasoconstriction in response to hypoxia, vascular deformation resulting from lung hyperinflation 8
and vessel loss accompanied by emphysematous tissue destruction, pulmonary hypertension has been shown to develop in patients with COPD without these underlying causes (5–7). However, even though the mechanisms are not well understood, what is known is that systemic inflammation is a component of COPD, and studies have revealed that elevated levels of inflammatory markers (IL-6, C-reactive protein) are associated with increased mean pulmonary arterial pressure (8, 9). Interestingly, although airway remodeling in COPD is a direct result of the lung’s inflammatory response to chronic exposure to cigarette smoke, the association between airway remodeling and pulmonary hypertension has never before been investigated. In this issue of the Journal, Dournes and colleagues (pp. 63–70) aimed to elucidate these complex cardiopulmonary interactions by investigating the relationship between computed tomography (CT) measures of emphysema and airway remodeling with pulmonary hypertension in advanced COPD (10). A total of 60 patients with COPD were obtained by referral to a tertiary unit for examination of chronic respiratory failure, and pulmonary hypertension was defined by right heart catheterization. Of the 60 patients with COPD investigated, 34 patients were diagnosed with pulmonary hypertension. In addition to obtaining CT and hemodynamic measures,
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
EDITORIALS Dournes and colleagues (10) obtained other measures known to be associated with pulmonary hypertension in COPD, including airflow limitation, hypoxemia, and pulmonary arterial enlargement. The authors found that although measures of CT airway remodeling, hypoxemia, and pulmonary arterial enlargement were all significant independent predictors in a multivariate regression model for mean pulmonary arterial pressure, CT measures of airway remodeling explained the greatest proportion of the variance. This interesting finding suggests that the process driving airway remodeling is also likely involved in the complex pathophysiological pathways that lead to pulmonary hypertension in COPD. There were some limitations in the study by Dournes and colleagues (10) that deserve mention, including a small sample size and the fact that patients were referred to the tertiary care unit at their institution, and therefore these findings cannot be generalized to the entire COPD population. Another limitation of this study is that it was observational, and therefore the causal relationship between airway wall remodeling and the development of pulmonary hypertension cannot be illuminated. Although the temporal linkage between airway and vascular remodeling remains unclear, the authors have clearly established that a link exits between remodeling of the airways and vasculature, leading to pulmonary hypertension in smokers with advanced COPD. If the process behind airway remodeling is also involved in the pathogenesis of vascular disease in patients with advanced COPD, it leaves the question, is there a relationship between airway and vascular remodeling in patients with milder disease? Furthermore, can airway remodeling measurements be used to predict the subsequent development of pulmonary hypertension in patients with COPD? Pathological studies have shown that pulmonary vascular remodeling is present in mild COPD, as well as in smokers with normal pulmonary function (5). Moreover, a recent imaging study (11) in former smokers without COPD showed a relationship between three-dimensionalultrasound measurements of carotid vessel wall thickness and hyperpolarized 3 He magnetic resonance imaging ventilation defect measures, thought to reflect airway remodeling, providing strong support for the bronchovascular link in early or subclinical COPD. Although not all patients with early evidence of vascular remodeling are likely to develop clinically relevant pulmonary hypertension over time, perhaps CT measures of airway remodeling can help identify these individuals at increased risk of developing pulmonary hypertension. This current study also raises a number of other interesting questions for future investigation. As the authors point out, the size of the airway evaluated is important, as the association between CT wall area thickness and mean pulmonary arterial pressure increased for airways from the third to the fifth generation. It is therefore of interest to investigate other emerging imaging modalities or analysis tools capable of assessing the small airways in patients with early evidence of vascular remodeling, such as novel CT registration-based analysis tools (12), optical coherence tomography (13) and hyperpolarized noble gas magnetic resonance imaging (11). Although these emerging imaging techniques require further investigation and validation, Editorials
longitudinal studies that incorporate these emerging imaging tools may enable us to uncover the links between remodeling of the small airways and the vasculature to better understand the development of pulmonary hypertension in COPD and to determine whether airway remodeling measurements can predict, and potentially be an early indicator of, pulmonary hypertension. In summary, this interesting study has uncovered a new piece of information in the pulmonary hypertension in COPD puzzle. Indeed, the authors have demonstrated that bronchial remodeling is an important feature of this disease phenotype. Whether uncovering this link will lead to a better understanding of the underlying mechanisms or pathways or lead to more targeted patient management or treatment is yet to be seen but is an exciting possibility. n Author disclosures are available with the text of this article at www.atsjournals.org. Miranda Kirby, Ph.D. Harvey O. Coxson, Ph.D. Department of Radiology University of British Columbia Vancouver, British Columbia, Canada and Centre for Heart Lung Innovation St. Paul’s Hospital Vancouver, British Columbia, Canada
References 1. US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA 2013;310: 591–608. 2. World Health Organization. The global burden of disease: 2004 update. Geneva, Switzerland: World Health Organization; 2008 [accessed 2014 Nov 16]. Available from: www.who.int/ healthinfo/global_burden_disease/GBD_report_2004update_ full.pdf 3. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:158–164. 4. Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, Kessler R. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest 1995;107:1193–1198. 5. Santos S, Peinado VI, Ram´ırez J, Melgosa T, Roca J, RodriguezRoisin R, Barbera` JA. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 2002;19:632–638. 6. Haniuda M, Kubo K, Fujimoto K, Aoki T, Yamanda T, Amano J. Different effects of lung volume reduction surgery and lobectomy on pulmonary circulation. Ann Surg 2000;231:119–125. 7. Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE; National Emphysema Treatment Trial (NETT) Group. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002;166:314–322. 8. Chaouat A, Savale L, Chouaid C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset B, Brandt C, Le Corvoisier P, et al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 2009;136:678–687. 9. Kwon YS, Chi SY, Shin HJ, Kim EY, Yoon BK, Ban HJ, Oh IJ, Kim KS, Kim YC, Lim SC. Plasma C-reactive protein and endothelin-1 level in patients with chronic obstructive pulmonary disease and pulmonary hypertension. J Korean Med Sci 2010;25: 1487–1491.
9
EDITORIALS 10. Dournes G, Laurent F, Coste F, Dromer C, Blanchard E, Picard F, Baldacci F, Montaudon M, Girodet P-O, Marthan R, et al. Computed tomographic measurement of airway remodeling and emphysema in advanced chronic obstructive pulmonary disease: correlation with pulmonary hypertension. Am J Respir Crit Care Med 2015;191:63–70. 11. Pike D, Kirby M, Lindenmaier TJ, Sheikh K, Neron CE, Hackam DG, Spence JD, Fenster A, Paterson NA, Sin DD, et al. Pulmonary abnormalities and carotid atherosclerosis in ex-smokers without airflow limitation. COPD [online ahead of print] 12 Jun 2014; DOI: 10.3109/15412555.2014.908833.
12. Galban ´ CJ, Han MK, Boes JL, Chughtai KA, Meyer CR, Johnson TD, Galban ´ S, Rehemtulla A, Kazerooni EA, Martinez FJ, et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med 2012;18:1711–1715. 13. Coxson HO, Mayo J, Lam S, Santyr G, Parraga G, Sin DD. New and current clinical imaging techniques to study chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:588–597.
Copyright © 2015 by the American Thoracic Society
Willie Sutton and the Future of Acute Respiratory Distress Syndrome Research Albeit apocryphally, infamous bank robber Willie Sutton, in response to a reporter’s question about why he robbed banks, once quipped, “Because that’s where the money is.” For much of the nearly half century since the acute respiratory distress syndrome (ARDS) was first described, it has been viewed through the lens of a pulmonary syndrome. A number of major clinical trials in ARDS can be broadly defined as those focusing on strategies for mechanical ventilation (1–3) and optimizing oxygenation (4, 5). For many of us (perhaps as a result of our training in pulmonary medicine and anesthesia), these strategies made sense as these patients were clearly suffering from severe respiratory failure. In other words, we’ve always looked between the clavicles and the diaphragm and channeled Sutton in saying, “that’s where the money is.” Although more than two decades of clinical ARDS research has resulted in significant declines in short-term mortality (6), recent studies have failed to demonstrate mortality improvements, and even in the highly selective environment of randomized clinical trials, roughly 1 of 5 patients with ARDS will die; and those who survive are afflicted with significant physical, cognitive, and/or psychological dysfunction for years afterwards (7–9). Yet we have also recognized for some time that the major driver of mortality and morbidity in patients with ARDS is not failing lungs; rather, it is the failure of nonpulmonary organs either alone or in concert (8, 10, 11). Thus, ARDS is now viewed through a lens that sees it as a systemic syndrome not limited to the thorax. Yet little research has focused on the contributions of specific nonpulmonary organ failures to outcomes in patients with ARDS, which begs the question, in the pursuit of reducing mortality in ARDS, is it time we “robbed” a different bank? In this issue of the Journal, Hsieh and colleagues (pp. 71–78) begin to address this important gap in knowledge by evaluating the association between ARDS and the most common form of organ failure in the intensive care unit (ICU), acute brain dysfunction (i.e., delirium and coma) (12). In a prospective, multicenter cohort of 564 critically ill patients admitted to the ICU with a spectrum of acute respiratory failure severity, the prevalence of delirium increased in a “dose-dependent” manner such that those patients with ARDS were the most likely to be delirious or comatose during their ICU stay. After adjusting for a number of potential risk factors for developing delirium, patients with ARDS were seven times more likely than those who were not intubated to be delirious 10
during their ICU stay. Additionally, patients with ARDS spent significantly fewer days alive with normal brain function (i.e., without delirium or coma) than patients with less severe respiratory failure. In fact, the average patient with ARDS in this study spent almost the entire duration of their ICU stay either delirious or comatose (likely both disease-induced and druginduced organ dysfunction). Surprisingly, the severity of ARDS, as graded by the Berlin criteria (13), did not alter the prevalence or the duration of acute brain dysfunction. Next, the authors evaluated the effect of delirium on short-term mortality. To accomplish this, the authors created two statistical models describing the association between acute respiratory failure and in-hospital mortality, first evaluating this association without considering the effect of delirium and coma and second by adjusting for the presence of these covariates. Before considering the effect of delirium and coma, patients with ARDS were 10.4 times more likely to die in the hospital than those who were critically ill but who were not intubated. After adjusting for the effect of delirium and coma, however, the odds of in-hospital mortality decreased by almost half, to 5.6, suggesting that some of the short-term mortality from ARDS may be attributable to acute brain dysfunction. This is a well-designed and edifying investigation, yet some methodological issues that may have biased the results are worthy of mention. The authors used logistic regression to model the association between ARDS and mortality. Although this method can be used to determine the association between an exposure and mortality, it fails to account for a key source of bias: follow-up time (14). Follow-up time is the time between entry into the study and occurrence of the event or end of observation due to censoring. Censoring occurs when follow-up ends before a patient develops the event of interest, and thus the information about the patient and the outcome is incomplete. In this study, because in-hospital mortality was chosen—an outcome that varies from patient to patient—follow-up time differed between patients. Thus, those who remained in the hospital longer were also observed for the event for a lengthier period of time, potentially biasing the results. Additionally, although we know that those who survived to hospital discharge were alive at that time point, we do not know for how much longer they survived. These biases can be addressed in future studies through the use of fixed follow-up time points (e.g., 90 d, 1 yr, etc.) or through the use of time-to-event analysis (survival analysis) techniques that deal with the issues relating to
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, shamcontrolled clinical trial. Am J Respir Crit Care Med 2010;181: 116–124. 11. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, Ousova O, Vernejoux JM, Marthan R, Tunon-de-Lara JM, et al. Bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med 2007;204: 3173–3181. 12. Begueret H, Berger P, Vernejoux JM, Dubuisson L, Marthan R, Tunonde-Lara JM. Inflammation of bronchial smooth muscle in allergic asthma. Thorax 2007;62:8–15. 13. Ramos-Barbon ´ D, Fraga-Iriso R, Brienza NS, Montero-Mart´ınez C, Verea-Hernando H, Olivenstein R, Lemiere C, Ernst P, Hamid QA, Martin JG. T Cells localize with proliferating smooth muscle alpha-actin1 cell compartments in asthma. Am J Respir Crit Care Med 2010;182:317–324. 14. Bara I, Ozier A, Girodet PO, Carvalho G, Cattiaux J, Begueret H, Thumerel M, Ousova O, Kolbeck R, Coyle AJ, et al. Role of YKL-40 in bronchial smooth muscle remodeling in asthma. Am J Respir Crit Care Med 2012;185:715–722. 15. Trian T, Girodet PO, Ousova O, Marthan R, Tunon-de-Lara JM, Berger P. RNA interference decreases PAR-2 expression and function in human airway smooth muscle cells. Am J Respir Cell Mol Biol 2006; 34:49–55.
Copyright © 2015 by the American Thoracic Society
Uncovering the Bronchovascular Links in Patients with Chronic Obstructive Pulmonary Disease with Pulmonary Hypertension Despite decades of scientific research, there are still no effective therapies for chronic obstructive pulmonary disease (COPD) that can cure the disease, nor substantially slow its progression. COPD is currently the third leading cause of death in the United States (1), and it is thought that if we continue on this course without effective treatments, in the next 10 years, the total deaths attributed to COPD will increase by more than 30% (2). This is a sobering statistic, and one of the reasons research into the pathogenesis of COPD is so important. However, it is also important to recognize that COPD is not simply a “disease” but is a syndrome encompassing a vast collection of pathologies and mechanisms that reach far beyond the lung, with particularly significant cardiovascular consequences including pulmonary hypertension. This has important clinical implications because it has been shown that in patients with COPD, the presence of pulmonary hypertension is associated with a greater risk for hospitalization (3) and death (4). The pathogenesis of pulmonary hypertension in COPD is complex, and the process by which chronic tobacco smoke exposure leads to pulmonary hypertension is not completely understood. Although several mechanisms have been proposed, including pulmonary arterial vasoconstriction in response to hypoxia, vascular deformation resulting from lung hyperinflation 8
and vessel loss accompanied by emphysematous tissue destruction, pulmonary hypertension has been shown to develop in patients with COPD without these underlying causes (5–7). However, even though the mechanisms are not well understood, what is known is that systemic inflammation is a component of COPD, and studies have revealed that elevated levels of inflammatory markers (IL-6, C-reactive protein) are associated with increased mean pulmonary arterial pressure (8, 9). Interestingly, although airway remodeling in COPD is a direct result of the lung’s inflammatory response to chronic exposure to cigarette smoke, the association between airway remodeling and pulmonary hypertension has never before been investigated. In this issue of the Journal, Dournes and colleagues (pp. 63–70) aimed to elucidate these complex cardiopulmonary interactions by investigating the relationship between computed tomography (CT) measures of emphysema and airway remodeling with pulmonary hypertension in advanced COPD (10). A total of 60 patients with COPD were obtained by referral to a tertiary unit for examination of chronic respiratory failure, and pulmonary hypertension was defined by right heart catheterization. Of the 60 patients with COPD investigated, 34 patients were diagnosed with pulmonary hypertension. In addition to obtaining CT and hemodynamic measures,
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
EDITORIALS Dournes and colleagues (10) obtained other measures known to be associated with pulmonary hypertension in COPD, including airflow limitation, hypoxemia, and pulmonary arterial enlargement. The authors found that although measures of CT airway remodeling, hypoxemia, and pulmonary arterial enlargement were all significant independent predictors in a multivariate regression model for mean pulmonary arterial pressure, CT measures of airway remodeling explained the greatest proportion of the variance. This interesting finding suggests that the process driving airway remodeling is also likely involved in the complex pathophysiological pathways that lead to pulmonary hypertension in COPD. There were some limitations in the study by Dournes and colleagues (10) that deserve mention, including a small sample size and the fact that patients were referred to the tertiary care unit at their institution, and therefore these findings cannot be generalized to the entire COPD population. Another limitation of this study is that it was observational, and therefore the causal relationship between airway wall remodeling and the development of pulmonary hypertension cannot be illuminated. Although the temporal linkage between airway and vascular remodeling remains unclear, the authors have clearly established that a link exits between remodeling of the airways and vasculature, leading to pulmonary hypertension in smokers with advanced COPD. If the process behind airway remodeling is also involved in the pathogenesis of vascular disease in patients with advanced COPD, it leaves the question, is there a relationship between airway and vascular remodeling in patients with milder disease? Furthermore, can airway remodeling measurements be used to predict the subsequent development of pulmonary hypertension in patients with COPD? Pathological studies have shown that pulmonary vascular remodeling is present in mild COPD, as well as in smokers with normal pulmonary function (5). Moreover, a recent imaging study (11) in former smokers without COPD showed a relationship between three-dimensionalultrasound measurements of carotid vessel wall thickness and hyperpolarized 3 He magnetic resonance imaging ventilation defect measures, thought to reflect airway remodeling, providing strong support for the bronchovascular link in early or subclinical COPD. Although not all patients with early evidence of vascular remodeling are likely to develop clinically relevant pulmonary hypertension over time, perhaps CT measures of airway remodeling can help identify these individuals at increased risk of developing pulmonary hypertension. This current study also raises a number of other interesting questions for future investigation. As the authors point out, the size of the airway evaluated is important, as the association between CT wall area thickness and mean pulmonary arterial pressure increased for airways from the third to the fifth generation. It is therefore of interest to investigate other emerging imaging modalities or analysis tools capable of assessing the small airways in patients with early evidence of vascular remodeling, such as novel CT registration-based analysis tools (12), optical coherence tomography (13) and hyperpolarized noble gas magnetic resonance imaging (11). Although these emerging imaging techniques require further investigation and validation, Editorials
longitudinal studies that incorporate these emerging imaging tools may enable us to uncover the links between remodeling of the small airways and the vasculature to better understand the development of pulmonary hypertension in COPD and to determine whether airway remodeling measurements can predict, and potentially be an early indicator of, pulmonary hypertension. In summary, this interesting study has uncovered a new piece of information in the pulmonary hypertension in COPD puzzle. Indeed, the authors have demonstrated that bronchial remodeling is an important feature of this disease phenotype. Whether uncovering this link will lead to a better understanding of the underlying mechanisms or pathways or lead to more targeted patient management or treatment is yet to be seen but is an exciting possibility. n Author disclosures are available with the text of this article at www.atsjournals.org. Miranda Kirby, Ph.D. Harvey O. Coxson, Ph.D. Department of Radiology University of British Columbia Vancouver, British Columbia, Canada and Centre for Heart Lung Innovation St. Paul’s Hospital Vancouver, British Columbia, Canada
References 1. US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA 2013;310: 591–608. 2. World Health Organization. The global burden of disease: 2004 update. Geneva, Switzerland: World Health Organization; 2008 [accessed 2014 Nov 16]. Available from: www.who.int/ healthinfo/global_burden_disease/GBD_report_2004update_ full.pdf 3. Kessler R, Faller M, Fourgaut G, Mennecier B, Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:158–164. 4. Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, Kessler R. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest 1995;107:1193–1198. 5. Santos S, Peinado VI, Ram´ırez J, Melgosa T, Roca J, RodriguezRoisin R, Barbera` JA. Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 2002;19:632–638. 6. Haniuda M, Kubo K, Fujimoto K, Aoki T, Yamanda T, Amano J. Different effects of lung volume reduction surgery and lobectomy on pulmonary circulation. Ann Surg 2000;231:119–125. 7. Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE; National Emphysema Treatment Trial (NETT) Group. Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 2002;166:314–322. 8. Chaouat A, Savale L, Chouaid C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset B, Brandt C, Le Corvoisier P, et al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 2009;136:678–687. 9. Kwon YS, Chi SY, Shin HJ, Kim EY, Yoon BK, Ban HJ, Oh IJ, Kim KS, Kim YC, Lim SC. Plasma C-reactive protein and endothelin-1 level in patients with chronic obstructive pulmonary disease and pulmonary hypertension. J Korean Med Sci 2010;25: 1487–1491.
9
EDITORIALS 10. Dournes G, Laurent F, Coste F, Dromer C, Blanchard E, Picard F, Baldacci F, Montaudon M, Girodet P-O, Marthan R, et al. Computed tomographic measurement of airway remodeling and emphysema in advanced chronic obstructive pulmonary disease: correlation with pulmonary hypertension. Am J Respir Crit Care Med 2015;191:63–70. 11. Pike D, Kirby M, Lindenmaier TJ, Sheikh K, Neron CE, Hackam DG, Spence JD, Fenster A, Paterson NA, Sin DD, et al. Pulmonary abnormalities and carotid atherosclerosis in ex-smokers without airflow limitation. COPD [online ahead of print] 12 Jun 2014; DOI: 10.3109/15412555.2014.908833.
12. Galban ´ CJ, Han MK, Boes JL, Chughtai KA, Meyer CR, Johnson TD, Galban ´ S, Rehemtulla A, Kazerooni EA, Martinez FJ, et al. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med 2012;18:1711–1715. 13. Coxson HO, Mayo J, Lam S, Santyr G, Parraga G, Sin DD. New and current clinical imaging techniques to study chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009;180:588–597.
Copyright © 2015 by the American Thoracic Society
Willie Sutton and the Future of Acute Respiratory Distress Syndrome Research Albeit apocryphally, infamous bank robber Willie Sutton, in response to a reporter’s question about why he robbed banks, once quipped, “Because that’s where the money is.” For much of the nearly half century since the acute respiratory distress syndrome (ARDS) was first described, it has been viewed through the lens of a pulmonary syndrome. A number of major clinical trials in ARDS can be broadly defined as those focusing on strategies for mechanical ventilation (1–3) and optimizing oxygenation (4, 5). For many of us (perhaps as a result of our training in pulmonary medicine and anesthesia), these strategies made sense as these patients were clearly suffering from severe respiratory failure. In other words, we’ve always looked between the clavicles and the diaphragm and channeled Sutton in saying, “that’s where the money is.” Although more than two decades of clinical ARDS research has resulted in significant declines in short-term mortality (6), recent studies have failed to demonstrate mortality improvements, and even in the highly selective environment of randomized clinical trials, roughly 1 of 5 patients with ARDS will die; and those who survive are afflicted with significant physical, cognitive, and/or psychological dysfunction for years afterwards (7–9). Yet we have also recognized for some time that the major driver of mortality and morbidity in patients with ARDS is not failing lungs; rather, it is the failure of nonpulmonary organs either alone or in concert (8, 10, 11). Thus, ARDS is now viewed through a lens that sees it as a systemic syndrome not limited to the thorax. Yet little research has focused on the contributions of specific nonpulmonary organ failures to outcomes in patients with ARDS, which begs the question, in the pursuit of reducing mortality in ARDS, is it time we “robbed” a different bank? In this issue of the Journal, Hsieh and colleagues (pp. 71–78) begin to address this important gap in knowledge by evaluating the association between ARDS and the most common form of organ failure in the intensive care unit (ICU), acute brain dysfunction (i.e., delirium and coma) (12). In a prospective, multicenter cohort of 564 critically ill patients admitted to the ICU with a spectrum of acute respiratory failure severity, the prevalence of delirium increased in a “dose-dependent” manner such that those patients with ARDS were the most likely to be delirious or comatose during their ICU stay. After adjusting for a number of potential risk factors for developing delirium, patients with ARDS were seven times more likely than those who were not intubated to be delirious 10
during their ICU stay. Additionally, patients with ARDS spent significantly fewer days alive with normal brain function (i.e., without delirium or coma) than patients with less severe respiratory failure. In fact, the average patient with ARDS in this study spent almost the entire duration of their ICU stay either delirious or comatose (likely both disease-induced and druginduced organ dysfunction). Surprisingly, the severity of ARDS, as graded by the Berlin criteria (13), did not alter the prevalence or the duration of acute brain dysfunction. Next, the authors evaluated the effect of delirium on short-term mortality. To accomplish this, the authors created two statistical models describing the association between acute respiratory failure and in-hospital mortality, first evaluating this association without considering the effect of delirium and coma and second by adjusting for the presence of these covariates. Before considering the effect of delirium and coma, patients with ARDS were 10.4 times more likely to die in the hospital than those who were critically ill but who were not intubated. After adjusting for the effect of delirium and coma, however, the odds of in-hospital mortality decreased by almost half, to 5.6, suggesting that some of the short-term mortality from ARDS may be attributable to acute brain dysfunction. This is a well-designed and edifying investigation, yet some methodological issues that may have biased the results are worthy of mention. The authors used logistic regression to model the association between ARDS and mortality. Although this method can be used to determine the association between an exposure and mortality, it fails to account for a key source of bias: follow-up time (14). Follow-up time is the time between entry into the study and occurrence of the event or end of observation due to censoring. Censoring occurs when follow-up ends before a patient develops the event of interest, and thus the information about the patient and the outcome is incomplete. In this study, because in-hospital mortality was chosen—an outcome that varies from patient to patient—follow-up time differed between patients. Thus, those who remained in the hospital longer were also observed for the event for a lengthier period of time, potentially biasing the results. Additionally, although we know that those who survived to hospital discharge were alive at that time point, we do not know for how much longer they survived. These biases can be addressed in future studies through the use of fixed follow-up time points (e.g., 90 d, 1 yr, etc.) or through the use of time-to-event analysis (survival analysis) techniques that deal with the issues relating to
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
