- Email: [email protected]
Solvitur Ambulando…or Maybe Not?
CHEST Solvitur Ambulando…or Maybe Not? of Sinope (412 [est]-323 bc), also known Diogenes as Diogenes the Cynic, was a Greek philosopher
probably best known for his fruitless search for an honest man (Fig 1). However, equally remarkable was his ability to act out the message he was trying to convey. Lore states that in a debate about the nature of motion, Diogenes, in response to an adversary’s argument that motion does not exist, stands up and walks away, prompting the Latin phrase solvitur ambulando. Interestingly, although the literal translation of solvitur ambulando is “it is solved by walking,” the common interpretation of the phrase is that a problem is only solved by practical experiment. In this issue of CHEST (see page 315), Fritz and colleagues1 attempt to address a problem that has long plagued the field of pulmonary hypertension, namely, the clinical relevance of the 6-min walk test (6MWT) in pulmonary arterial hypertension (PAH). Two other recent publications, one by our group2 and one by Gabler and colleagues,3 have also examined this issue, albeit in different ways (Table 1). Taken together, these three studies offer important insight into not only the usefulness of 6MWT in PAH but also the limitations of the use of biomarkers as surrogate end points in clinical trials.
Figure 1. Diogenes looking for an honest man. Attributed to JHW Tischbein (c. 1780).
Editorials CHEST | Volume 143 | Number 2 | February 2013
For the past decade, the 6MWT has been widely used as the primary outcome measure in clinical trials of therapies for PAH. Its use in this capacity was based on several studies, including the pivotal trial of epoprostenol in PAH, that demonstrated the predictive value of baseline 6MWT in this disease4,5 and subsequent observational studies that defined “thresholds” of distance achieved in 6MWT (the 6-min walk distance [6MWD]) after several months of PAH-specific therapy associated with survival.6,7 Given the simplicity and reproducibility of the test, along with the physiologic rationale for using a measure of exercise capacity as a surrogate in PAH, the 6MWT subsequently has been the most accepted metric for the evaluation of therapeutic efficacy in PAH by the US Food and Drug Administration (FDA) and the European Agency for Evaluation of Medicinal Products. This practice has persisted despite a surprising lack of validation of the 6MWT as a surrogate in PAH,8 particularly since the change in 6MWD (⌬6MWD) in response to an intervention is perceived as a surrogate for survival. For a surrogate to be valid, it must meet several criteria: reliability, placement in the causal pathway to the outcome, epidemiologic evidence relating the surrogate to the outcome, and demonstration that quantitative modification in the surrogate results in quantitative modification (in the appropriate direction) of the outcome.9 It is in this last realm that the validation of the 6MWT has lacked. Recent meta-analyses of the relationship between ⌬6MWD and short-term survival have yielded disparate results.10,11 However, neither of these studies had access to individual-level data nor did they examine long-term mortality. Recently, using individual-level data from a randomized, clinical trial, our group described an estimate of the minimal important difference (MID) for the 6MWT of around 33 m.2 In this study, the MID, defined as the smallest change or difference in an outcome measure, perceived as beneficial, that would justify a change in medical management,12 was based on relating a ⌬6MWD to a clinically relevant change in quality of life rather than a clinical event or survival. Since PAH remains a chronic disease without a cure (in the absence of lung transplantation), improvements in functional capacity that are associated with improvements in quality of life may be of particular importance
journal.publications.chestnet.org
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Table 1—Summary of Recent Studies of the Clinical Relevance of the 6MWT in PAH Study
Study Question
Result
Implications
Fritz et al
Does 6MWT predict long-term outcome in PAH?
Baseline and end-of-study 6MWT predict survival in PAH, but ⌬6MWD does not.
Gabler et al3
Is ⌬6MWD a valid surrogate for short-term outcomes in PAH?
⌬6MWD only explains 22% of the treatment effect in PAH clinical trials.
Mathai et al2
What is the minimal important difference for the 6MWT in PAH?
Approximately a 33-m change in 6MWD is associated with a clinically significant improvement in quality of life.
1
Goal-directed therapy may not be a valid strategy. Short-term ⌬6MWD may not be a valid surrogate of long-term survival in PAH. ⌬6MWD is not a valid surrogate for development of short-term clinical events, including survival, in PAH. Provides a framework for assessing clinical response to PAH therapy.
6MWT 5 6-min walk test; ⌬6MWD 5 change in 6-min walk distance; PAH 5 pulmonary arterial hypertension.
to the individual patient, even in the absence of a mortality benefit. However, as noted, this MID does not relate ⌬6MWD to survival. Gabler and colleagues3 recently examined the validity of 6MWT as a surrogate end point for short-term outcomes in PAH trials using individual-level data for all subjects in phase 3 placebo-controlled randomized clinical trials of PAH therapy submitted to the FDA through 2008. The authors sought to determine the relationship between ⌬6MWD and occurrence of clinical events (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, withdrawal for worsening right-sided heart failure, or addition of other PAH medications) at 12 weeks. Using rigorous statistical methods, the authors found that although ⌬6MWD fulfilled the criteria as a mediator of the relationship between treatment and development of a clinical event at 12 weeks, this ⌬6MWD only explained 22% of the effect of treatment on preventing clinical events, falling below suggested thresholds for a valid surrogate.13 Additionally, the authors found that a statistically significant reduction in clinical events at 12 weeks was found in subjects who achieved a . 41.8-m improvement in 6MWD, well above the reported change in 6MWD found in the vast majority of clinical trials of FDAapproved PAH therapies.14 In the current study, Fritz and colleagues1 examine the relationship between 6MWD (and brain natriuretic peptide) and 2-year survival using the data from two randomized, clinical trials of ambrisentan in PAH. Using classification and regression tree analysis, the authors compare the predictive value of baseline 6MWD, end-of-study 6MWD, and ⌬6MWD. As previously demonstrated in other cohorts, 6MWD at baseline and at end of study are associated with survival. However, the authors find (1) no difference in the predictive ability of the end-of-study 6MWD compared with the baseline 6MWD, and (2) no relationship
between ⌬6MWD and long-term survival. These data suggest that failure to achieve certain 6MWD thresholds after initial PAH therapy may not be a sufficient metric to warrant changes in therapy, at least if improved survival is the intended goal. This, of course, is in contradistinction to calls for goal-directed therapy based on change in exercise capacity with PAH therapy15 and highlights a need for further study of the usefulness of such a treatment strategy in a randomized, clinical trial. Further, and perhaps more importantly, the lack of association between ⌬6MWD and survival calls into question the validity of 6MWT as a surrogate for survival in PAH. These studies highlight the inherent limitations of biomarkers; although all surrogates are biomarkers, only a select few biomarkers (BP in cardiovascular disease, hemoglobin A1c in diabetes) fulfill criteria as valid surrogate end points. Despite strong epidemiologic data showing a consistent relationship between 6MWD and survival, the current studies suggest that ⌬6MWD lacks the necessary strength of association with either short-term clinical events or long-term survival to be considered a valid surrogate end point for survival in PAH. However, the relationship between ⌬6MWD and patient-important outcomes, such as quality of life, may represent an important area for further validation of 6MWT. In conclusion, similar to Diogenes’ walking away from his debate on motion, maybe the time has come for us to “walk away” from the 6MWT as a surrogate for survival in PAH. Then, to continue our homage to the eminent philosopher, we can pursue a muchneeded quest for a valid surrogate for survival in PAH, we hope with more success than Diogenes’ search for an honest man (Fig 1). Perhaps someone has a lamp we can borrow…
286
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 02/07/2013
Stephen C. Mathai, MD, MHS, FCCP Baltimore, MD Editorials
Affiliations: From the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine. Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Mathai has served as a consultant to Actelion Pharmaceuticals US Inc; Bayer AG; Gilead; Novartis AG; and United Therapeutics Corporation. Correspondence to: Stephen C. Mathai, MD, MHS, FCCP, Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 E Monument St, Rm 516, Baltimore, MD 21205; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-1819
References 1. Fritz JS, Blair C, Oudiz RJ, et al. Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest. 2013; 143(2):315-323. 2. Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the six minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(5):428-433. 3. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126(3):349-356. 4. Barst RJ, Rubin LJ, Long WA, et al; The Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996; 334(5):296-302. 5. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000; 161(2 pt 1):487-492. 6. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4): 780-788. 7. Provencher S, Sitbon O, Humbert M, Cabrol S, Jaïs X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J. 2006;27(5):589-595. 8. Snow JL, Kawut SM. Surrogate end points in pulmonary arterial hypertension: assessing the response to therapy. Clin Chest Med. 2007;28(1):75-89. 9. Hlatky MA, Greenland P, Arnett DK, et al; American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119(17):2408-2416. 10. Macchia A, Marchioli R, Marfisi R, et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J. 2007;153(6): 1037-1047. 11. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394-403. 12. Beaton DE, Boers M, Wells GA. Many faces of the minimal clinically important difference (MCID): a literature review and directions for future research. Curr Opin Rheumatol. 2002;14(2):109-114. 13. Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics. 1998; 54(3):1014-1029.
14. Farber HW. Validation of the 6-minute walk in patients with pulmonary arterial hypertension: trying to fit a square PEG into a round hole? Circulation. 2012;126(3):258-260. 15. Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263.
Preparing for the Unexpected Lessons Learned About Respiratory Infection From the Japanese Tsunami of 2011 Luck is what happens when preparation meets opportunity. Seneca, Roman philosopher (5 bc-65 ad)
March 2011, a tsunami flooded numerous comInmunities in the Tohoku region of northeastern
Japan following an earthquake of 9.0 magnitude just off the Pacific coast. Six months later, . 20,000 people were reported killed or missing. Immediately after the tsunami, physicians were called on to provide care to the survivors; certainly, nobody was prepared for the medical problems that followed. However, the 2004 tsunami in Indonesia and Southeast Asia led to a careful description of a variety of medical problems related to trauma, near drowning, and subsequent pneumonia in the aftermath of this natural disaster, providing Japanese clinicians with information about what to expect in the weeks to come.1,2 Although blunt trauma and drowning accounted for deaths that immediately followed the Japanese tsunami, among survivors, traumatic injury, which was the most important early problem, was followed by infectious diseases in the next few weeks. These infections included communicable diseases as well as the respiratory complications of near drowning.3 Following natural disasters, communicable diseases develop in relation to the lack of access to fresh water, which can lead to diarrheal diseases, hepatitis, and leptospirosis.4 Overcrowding can predispose to other illnesses, including acute respiratory infections, particularly in young children, and the risk is enhanced by exposure to indoor cooking with open flames and malnutrition. Vector-borne diseases, such as malaria and dengue, can follow earthquakes and flooding conditions. Respiratory infections were a particular problem among survivors of the tsunami in 2004, especially in the first 2 months. In Banda Aceh, Indonesia, acute respiratory infections accounted for nearly 25% of consultations to the World Health Organization, peaking in incidence at 5 weeks after
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 02/07/2013
CHEST / 143 / 2 / FEBRUARY 2013
287
probably best known for his fruitless search for an honest man (Fig 1). However, equally remarkable was his ability to act out the message he was trying to convey. Lore states that in a debate about the nature of motion, Diogenes, in response to an adversary’s argument that motion does not exist, stands up and walks away, prompting the Latin phrase solvitur ambulando. Interestingly, although the literal translation of solvitur ambulando is “it is solved by walking,” the common interpretation of the phrase is that a problem is only solved by practical experiment. In this issue of CHEST (see page 315), Fritz and colleagues1 attempt to address a problem that has long plagued the field of pulmonary hypertension, namely, the clinical relevance of the 6-min walk test (6MWT) in pulmonary arterial hypertension (PAH). Two other recent publications, one by our group2 and one by Gabler and colleagues,3 have also examined this issue, albeit in different ways (Table 1). Taken together, these three studies offer important insight into not only the usefulness of 6MWT in PAH but also the limitations of the use of biomarkers as surrogate end points in clinical trials.
Figure 1. Diogenes looking for an honest man. Attributed to JHW Tischbein (c. 1780).
Editorials CHEST | Volume 143 | Number 2 | February 2013
For the past decade, the 6MWT has been widely used as the primary outcome measure in clinical trials of therapies for PAH. Its use in this capacity was based on several studies, including the pivotal trial of epoprostenol in PAH, that demonstrated the predictive value of baseline 6MWT in this disease4,5 and subsequent observational studies that defined “thresholds” of distance achieved in 6MWT (the 6-min walk distance [6MWD]) after several months of PAH-specific therapy associated with survival.6,7 Given the simplicity and reproducibility of the test, along with the physiologic rationale for using a measure of exercise capacity as a surrogate in PAH, the 6MWT subsequently has been the most accepted metric for the evaluation of therapeutic efficacy in PAH by the US Food and Drug Administration (FDA) and the European Agency for Evaluation of Medicinal Products. This practice has persisted despite a surprising lack of validation of the 6MWT as a surrogate in PAH,8 particularly since the change in 6MWD (⌬6MWD) in response to an intervention is perceived as a surrogate for survival. For a surrogate to be valid, it must meet several criteria: reliability, placement in the causal pathway to the outcome, epidemiologic evidence relating the surrogate to the outcome, and demonstration that quantitative modification in the surrogate results in quantitative modification (in the appropriate direction) of the outcome.9 It is in this last realm that the validation of the 6MWT has lacked. Recent meta-analyses of the relationship between ⌬6MWD and short-term survival have yielded disparate results.10,11 However, neither of these studies had access to individual-level data nor did they examine long-term mortality. Recently, using individual-level data from a randomized, clinical trial, our group described an estimate of the minimal important difference (MID) for the 6MWT of around 33 m.2 In this study, the MID, defined as the smallest change or difference in an outcome measure, perceived as beneficial, that would justify a change in medical management,12 was based on relating a ⌬6MWD to a clinically relevant change in quality of life rather than a clinical event or survival. Since PAH remains a chronic disease without a cure (in the absence of lung transplantation), improvements in functional capacity that are associated with improvements in quality of life may be of particular importance
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 02/07/2013
CHEST / 143 / 2 / FEBRUARY 2013
285
Table 1—Summary of Recent Studies of the Clinical Relevance of the 6MWT in PAH Study
Study Question
Result
Implications
Fritz et al
Does 6MWT predict long-term outcome in PAH?
Baseline and end-of-study 6MWT predict survival in PAH, but ⌬6MWD does not.
Gabler et al3
Is ⌬6MWD a valid surrogate for short-term outcomes in PAH?
⌬6MWD only explains 22% of the treatment effect in PAH clinical trials.
Mathai et al2
What is the minimal important difference for the 6MWT in PAH?
Approximately a 33-m change in 6MWD is associated with a clinically significant improvement in quality of life.
1
Goal-directed therapy may not be a valid strategy. Short-term ⌬6MWD may not be a valid surrogate of long-term survival in PAH. ⌬6MWD is not a valid surrogate for development of short-term clinical events, including survival, in PAH. Provides a framework for assessing clinical response to PAH therapy.
6MWT 5 6-min walk test; ⌬6MWD 5 change in 6-min walk distance; PAH 5 pulmonary arterial hypertension.
to the individual patient, even in the absence of a mortality benefit. However, as noted, this MID does not relate ⌬6MWD to survival. Gabler and colleagues3 recently examined the validity of 6MWT as a surrogate end point for short-term outcomes in PAH trials using individual-level data for all subjects in phase 3 placebo-controlled randomized clinical trials of PAH therapy submitted to the FDA through 2008. The authors sought to determine the relationship between ⌬6MWD and occurrence of clinical events (defined as death, lung transplantation, atrial septostomy, hospitalization because of worsening PAH, withdrawal for worsening right-sided heart failure, or addition of other PAH medications) at 12 weeks. Using rigorous statistical methods, the authors found that although ⌬6MWD fulfilled the criteria as a mediator of the relationship between treatment and development of a clinical event at 12 weeks, this ⌬6MWD only explained 22% of the effect of treatment on preventing clinical events, falling below suggested thresholds for a valid surrogate.13 Additionally, the authors found that a statistically significant reduction in clinical events at 12 weeks was found in subjects who achieved a . 41.8-m improvement in 6MWD, well above the reported change in 6MWD found in the vast majority of clinical trials of FDAapproved PAH therapies.14 In the current study, Fritz and colleagues1 examine the relationship between 6MWD (and brain natriuretic peptide) and 2-year survival using the data from two randomized, clinical trials of ambrisentan in PAH. Using classification and regression tree analysis, the authors compare the predictive value of baseline 6MWD, end-of-study 6MWD, and ⌬6MWD. As previously demonstrated in other cohorts, 6MWD at baseline and at end of study are associated with survival. However, the authors find (1) no difference in the predictive ability of the end-of-study 6MWD compared with the baseline 6MWD, and (2) no relationship
between ⌬6MWD and long-term survival. These data suggest that failure to achieve certain 6MWD thresholds after initial PAH therapy may not be a sufficient metric to warrant changes in therapy, at least if improved survival is the intended goal. This, of course, is in contradistinction to calls for goal-directed therapy based on change in exercise capacity with PAH therapy15 and highlights a need for further study of the usefulness of such a treatment strategy in a randomized, clinical trial. Further, and perhaps more importantly, the lack of association between ⌬6MWD and survival calls into question the validity of 6MWT as a surrogate for survival in PAH. These studies highlight the inherent limitations of biomarkers; although all surrogates are biomarkers, only a select few biomarkers (BP in cardiovascular disease, hemoglobin A1c in diabetes) fulfill criteria as valid surrogate end points. Despite strong epidemiologic data showing a consistent relationship between 6MWD and survival, the current studies suggest that ⌬6MWD lacks the necessary strength of association with either short-term clinical events or long-term survival to be considered a valid surrogate end point for survival in PAH. However, the relationship between ⌬6MWD and patient-important outcomes, such as quality of life, may represent an important area for further validation of 6MWT. In conclusion, similar to Diogenes’ walking away from his debate on motion, maybe the time has come for us to “walk away” from the 6MWT as a surrogate for survival in PAH. Then, to continue our homage to the eminent philosopher, we can pursue a muchneeded quest for a valid surrogate for survival in PAH, we hope with more success than Diogenes’ search for an honest man (Fig 1). Perhaps someone has a lamp we can borrow…
286
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 02/07/2013
Stephen C. Mathai, MD, MHS, FCCP Baltimore, MD Editorials
Affiliations: From the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine. Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Mathai has served as a consultant to Actelion Pharmaceuticals US Inc; Bayer AG; Gilead; Novartis AG; and United Therapeutics Corporation. Correspondence to: Stephen C. Mathai, MD, MHS, FCCP, Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, 1830 E Monument St, Rm 516, Baltimore, MD 21205; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-1819
References 1. Fritz JS, Blair C, Oudiz RJ, et al. Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension. Chest. 2013; 143(2):315-323. 2. Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the six minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(5):428-433. 3. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126(3):349-356. 4. Barst RJ, Rubin LJ, Long WA, et al; The Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med. 1996; 334(5):296-302. 5. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000; 161(2 pt 1):487-492. 6. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40(4): 780-788. 7. Provencher S, Sitbon O, Humbert M, Cabrol S, Jaïs X, Simonneau G. Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension. Eur Heart J. 2006;27(5):589-595. 8. Snow JL, Kawut SM. Surrogate end points in pulmonary arterial hypertension: assessing the response to therapy. Clin Chest Med. 2007;28(1):75-89. 9. Hlatky MA, Greenland P, Arnett DK, et al; American Heart Association Expert Panel on Subclinical Atherosclerotic Diseases and Emerging Risk Factors and the Stroke Council. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2009;119(17):2408-2416. 10. Macchia A, Marchioli R, Marfisi R, et al. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J. 2007;153(6): 1037-1047. 11. Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani ML, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension. Eur Heart J. 2009;30(4):394-403. 12. Beaton DE, Boers M, Wells GA. Many faces of the minimal clinically important difference (MCID): a literature review and directions for future research. Curr Opin Rheumatol. 2002;14(2):109-114. 13. Buyse M, Molenberghs G. Criteria for the validation of surrogate endpoints in randomized experiments. Biometrics. 1998; 54(3):1014-1029.
14. Farber HW. Validation of the 6-minute walk in patients with pulmonary arterial hypertension: trying to fit a square PEG into a round hole? Circulation. 2012;126(3):258-260. 15. Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263.
Preparing for the Unexpected Lessons Learned About Respiratory Infection From the Japanese Tsunami of 2011 Luck is what happens when preparation meets opportunity. Seneca, Roman philosopher (5 bc-65 ad)
March 2011, a tsunami flooded numerous comInmunities in the Tohoku region of northeastern
Japan following an earthquake of 9.0 magnitude just off the Pacific coast. Six months later, . 20,000 people were reported killed or missing. Immediately after the tsunami, physicians were called on to provide care to the survivors; certainly, nobody was prepared for the medical problems that followed. However, the 2004 tsunami in Indonesia and Southeast Asia led to a careful description of a variety of medical problems related to trauma, near drowning, and subsequent pneumonia in the aftermath of this natural disaster, providing Japanese clinicians with information about what to expect in the weeks to come.1,2 Although blunt trauma and drowning accounted for deaths that immediately followed the Japanese tsunami, among survivors, traumatic injury, which was the most important early problem, was followed by infectious diseases in the next few weeks. These infections included communicable diseases as well as the respiratory complications of near drowning.3 Following natural disasters, communicable diseases develop in relation to the lack of access to fresh water, which can lead to diarrheal diseases, hepatitis, and leptospirosis.4 Overcrowding can predispose to other illnesses, including acute respiratory infections, particularly in young children, and the risk is enhanced by exposure to indoor cooking with open flames and malnutrition. Vector-borne diseases, such as malaria and dengue, can follow earthquakes and flooding conditions. Respiratory infections were a particular problem among survivors of the tsunami in 2004, especially in the first 2 months. In Banda Aceh, Indonesia, acute respiratory infections accounted for nearly 25% of consultations to the World Health Organization, peaking in incidence at 5 weeks after
journal.publications.chestnet.org
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 02/07/2013
CHEST / 143 / 2 / FEBRUARY 2013
287