© 2006 American Thoracic Society doi: 10.1164/rccm.2602003
Predicting Mortality in Chronic Obstructive Pulmonary DiseaseChasing the "Holy Grail"Caritas–St. Elizabeth's Medical Center, Boston, Massachusetts and Tufts University, Boston, Massachusetts Chronic obstructive pulmonary disease (COPD) has the dubious distinction of being one of the few major causes of death that continues to rise in the United States and the world (1). Since the studies of Fletcher and colleagues (2), the natural history of COPD has been associated with the accelerated progressive decline of the FEV1. The FEV1 became the defining feature of the disease and, because it predicts mortality, it constitutes the logical target for disease-modifying interventions and the most important, if not the only, factor used to assess response to therapeutic interventions. Over time, it has become evident that COPD is associated with clinical manifestations not closely related to the FEV1, such as worsened dyspnea, reduction in exercise capacity, peripheral muscle weakness, and malnutrition. Moreover, all of these factors have proven more important predictors of mortality than the FEV1 (3, 4). These observations are extremely important because they have prompted a change in our thinking about COPD, from one centered around airflow limitation as the "Holy Grail" to one that considers COPD as a disease primarily of the lungs with important systemic consequences (5). In this issue of the Journal (pp. 1326–1334), Martinez and coworkers explore the factors predicting mortality in the patients participating in the National Emphysema Therapy Trial (NETT) who were randomized to optimal medical treatment (6). As expected, these patients suffered from severe airflow obstruction and hyperinflation, and primarily expressed the emphysematous phenotype of COPD. The authors confirmed the value of several baseline variables that have been associated with higher mortality, including older age, lower body mass index, utilization of oxygen, greater hyperinflation, decreased exercise capacity, and a higher modified multidimensional index score that includes body mass index (B), obstruction (O), dyspnea (D), and exercise endurance (E)—the BODE index (7). The importance of the work by Martinez and colleagues is that even in patients with a narrow specific phenotypic type of severe emphysema deemed to be candidates for lung reduction surgery, variables other than the degree of airflow limitation showed stronger association with mortality than the FEV1. If we gain insight into the mechanisms responsible for the association between these predictive variables and mortality, we could possibly impact COPD outcome independent of changes in the FEV1. After all, for over two decades we have known that supplemental oxygen in hypoxemic patients is capable of improving survival by mechanisms that are likely unrelated to changes in airflow limitation. Given our current understanding about COPD, the question is then, which of those variables could we change? The first of these factors concerning the progression of COPD relates to the emerging evidence that poor exercise capacity and peripheral muscle dysfunction may be linked by the presence of systemic inflammation. Patients with COPD have higher levels of C-reactive protein independent of coexisting cardiac or noncardiac risks (8, 9). Those patients also manifest increased levels of peripheral muscle apoptosis (10) and local oxidative stress (11). Exercise training as part of pulmonary rehabilitation appears to buffer the increased oxidative stress brought about by exercise (12). Taken together, these independent findings provide strong scientific support to the clinical observation that rehabilitation improves several of the variables associated with poor outcomes, such as exercise capacity and dyspnea, as well as the multidimensional BODE index (13). In this study, the changes in the BODE index were predictive of final outcome. Thus, we should be able to plan interventions aimed at improving or reversing the systemic inflammatory state as suggested by the recent demonstration that inhaled corticosteroids may modulate serum levels of interleukin-6 and C-reactive protein (14), or to modulate the consequences of that state on peripheral organs. We should borrow from the experience in other prevalent chronic diseases where treatment of abnormalities distant from the primary organ has resulted in improved outcome. One such case is diabetes mellitus, where treatment with angiotensin enzyme inhibitors for patients with microalbuminuria improves survival. It is entirely possible that we could achieve similar results in patients with COPD if we targeted associated consequences of the disease that are not intimately linked with the degree of airflow limitation. Systemic inflammation and peripheral muscle dysfunction are not the only potentially modifiable factors in COPD. In the original NETT report, a subgroup of patients with upper lobe disease and poor exercise capacity manifested a survival advantage after lung volume reduction surgery compared with patients randomized to medical therapy (15). One can speculate that, through mechanisms not yet clarified, reduction in hyperinflation, one of the variables known to be associated with poor outcome in the current report and in another study (16), results in improved survival. Although we have concentrated primarily on the deleterious effects of dynamic hyperinflation on exercise limitation and dyspnea, this new evidence indicates that we should study how and why hyperinflation impacts survival. Furthermore, we should explore if simple interventions addressing hyperinflation could affect outcome. After all, the most effective intervention that affects survival in patients with the acute respiratory distress syndrome has been the simple implementation of low tidal volume ventilation. We are witnessing a change in the COPD paradigm from a simple problem of airflow limitation to a multicomponent disease where other manifestations may become targets of interventions. Unfortunately, the regulatory agencies, the medical public at large, and many in our midst still cling to the old concept that it is only by changing the FEV1 that we modify the course of the disease. I am optimistic that, in COPD, we are closing in on the "Holy Grail." FOOTNOTES Conflict of Interest Statement: B.R.C. has been reimbursed for attending advisory boards and participation in sponsored conference as well as national and international meetings (GlaxoSmithKline, Boehringer Ingelheim, Altana, AstraZeneca). The laboratory directed by B.R.C. received grants for studies from GlaxoSmithKline and Boehringer Ingelheim for more than $250,000 over the last 5 yr. REFERENCES
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