COPD Exacerbations: Pharmacogenetic Approaches to Therapy

The applicants propose to recruit patients with COPD from patients admitted to hospitals for treatment of COPD, established pulmonary practices in major teaching hospitals, and an associated large health care provider network. Strategies for recruitment include the use of several large clinical databases that have identified patients with COPD. The scientific focus of the proposal is on the prevention and treatment of exacerbations. Exacerbations of COPD, defined as an increase in shortness of breath and an increase in the amount and/or purulence of sputum, are a major determinant of patient quality of life and account for substantial health care expenditures. The applicants propose 2 protocols for consideration by the network; one is directed at treatment of acute exacerbations with inhaled corticosteroids and the second at prevention of exacerbations by use of a leukotriene inhibitor.

Raul San Jose Estepar

Raúl San José Estépar, PhD

Co-Director, Applied Chest Imaging Laboratory
Lead Investigator, Brigham and Women's Hospital
Associate Professor of Radiology, Harvard Medical School
Raúl is co-director of the Applied Chest Imaging Laboratory, lead scientist at Brigham and Women's Hospital and Associate Professor of Radiology at Harvard Medical School. 
1249 Boylston St, Room 216
Boston, MA, 02215
p: 617 525-6227
Diaz AA, Bartholmai B, San José Estépar R, Ross J, Matsuoka S, Yamashiro T, Hatabu H, Reilly JJ, Silverman EK, Washko GR. Relationship of emphysema and airway disease assessed by CT to exercise capacity in COPD. Respir Med 2010;104(8):1145-51.Abstract
OBJECTIVE: To assess the association of emphysema and airway disease assessed by volumetric computed tomography (CT) with exercise capacity in subjects with chronic obstructive pulmonary disease (COPD). METHODS: We studied 93 subjects with COPD (Forced Expiratory Volume in 1 s [FEV(1)] %predicted mean +/- SD 57.1 +/- 24.3%, female gender = 40) enrolled in the Lung Tissue Research Consortium. Emphysema was defined as percentage of low attenuation areas less than a threshold of -950 Hounsfield units (%LAA-950) on CT scan. The wall area percentage (WA%) of the 3rd to 6th generations of the apical bronchus of right upper lobe (RB1) were analyzed. The 6-min walk distance (6MWD) test was used as a measure of exercise capacity. RESULTS: The 6MWD was inversely associated with %LAA-950 (r = -0.53, p < 0.0001) and with the WA% of 6th generation of RB1 only (r = -0.28, p = 0.009). In a multivariate regression model including CT indices of emphysema and airway disease that were adjusted for demographic and physiologic variables as well as brand of CT scanner, only the %LAA-950 remained significantly associated with exercise performance. Holding other covariates fixed, this model showed that a 10% increase of CT emphysema reduced the distance walked in 6 min 28.6 m (95% Confidence Interval = -51.2, -6.0, p = 0.01). CONCLUSION: These results suggest that the extent of emphysema but not airway disease measured by volumetric CT contributes independently to exercise limitation in subjects with COPD.
Washko GR, Martinez FJ, Hoffman EA, Loring SH, San José Estépar R, Diaz AA, Sciurba FC, Silverman EK, Han MLK, Decamp M, Reilly JJ. Physiological and computed tomographic predictors of outcome from lung volume reduction surgery. Am J Respir Crit Care Med 2010;181(5):494-500.Abstract
RATIONALE: Previous investigations have identified several potential predictors of outcomes from lung volume reduction surgery (LVRS). A concern regarding these studies has been their small sample size, which may limit generalizability. We therefore sought to examine radiographic and physiologic predictors of surgical outcomes in a large, multicenter clinical investigation, the National Emphysema Treatment Trial. OBJECTIVES: To identify objective radiographic and physiological indices of lung disease that have prognostic value in subjects with chronic obstructive pulmonary disease being evaluated for LVRS. METHODS: A subset of the subjects undergoing LVRS in the National Emphysema Treatment Trial underwent preoperative high-resolution computed tomographic (CT) scanning of the chest and measures of static lung recoil at total lung capacity (SRtlc) and inspiratory resistance (Ri). The relationship between CT measures of emphysema, the ratio of upper to lower zone emphysema, CT measures of airway disease, SRtlc, Ri, the ratio of residual volume to total lung capacity (RV/TLC), and both 6-month postoperative changes in FEV(1) and maximal exercise capacity were assessed. MEASUREMENTS AND MAIN RESULTS: Physiological measures of lung elastic recoil and inspiratory resistance were not correlated with improvement in either the FEV(1) (R = -0.03, P = 0.78 and R = -0.17, P = 0.16, respectively) or maximal exercise capacity (R = -0.02, P = 0.83 and R = 0.08, P = 0.53, respectively). The RV/TLC ratio and CT measures of emphysema and its upper to lower zone ratio were only weakly predictive of postoperative changes in both the FEV(1) (R = 0.11, P = 0.01; R = 0.2, P < 0.0001; and R = 0.23, P < 0.0001, respectively) and maximal exercise capacity (R = 0.17, P = 0.0001; R = 0.15, P = 0.002; and R = 0.15, P = 0.002, respectively). CT assessments of airway disease were not predictive of change in FEV(1) or exercise capacity in this cohort. CONCLUSIONS: The RV/TLC ratio and CT measures of emphysema and its distribution are weak but statistically significant predictors of outcome after LVRS.