Rahul G Argula1, Maria Kokosi2, Pechin Lo3, Hyun J Kim3, James G Ravenel4, Cristopher Meyer5, Jonathan Goldin3, Hye-Seung Lee6, Charlie Strange1, Francis X McCormack7. 1. 1 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine and. 2. 2 Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom. 3. 3 Department of Radiology, University of California, Los Angeles, Los Angeles, California. 4. 4 Department of Radiology, Medical University of South Carolina, Charleston, South Carolina. 5. 5 Department of Radiology, University of Wisconsin, Madison, Wisconsin. 6. 6 Pediatric Epidemiology Center, University of South Florida, Tampa, Florida; and. 7. 7 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
Abstract
RATIONALE: The Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial demonstrated that sirolimus stabilized lung function and improved measures of functional performance and quality of life in patients with lymphangioleiomyomatosis. The physiologic mechanisms of these beneficial actions of sirolimus are incompletely understood. OBJECTIVES: To prospectively determine the longitudinal computed tomographic lung imaging correlates of lung function change in MILES patients treated withplacebo or sirolimus. METHODS: We determined the baseline to 12-month change in computed tomographic image-derived lung volumes and the volume of the lung occupied by cysts in the 31 MILES participants (17 in sirolimus group, 14 in placebo group) with baseline and 12-month scans. MEASUREMENTS AND MAIN RESULTS: There was a trend toward an increase in median expiratory cyst volume percentage in the placebo group and a reduction in the sirolimus group (+2.68% vs. +0.97%, respectively; P = 0.10). The computed tomographic image-derived residual volume and the ratio of residual volume to total lung capacity increased more in the placebo group than in the sirolimus group (+214.4 ml vs. +2.9 ml [P = 0.054] and +0.05 ml vs. -0.01 ml [P = 0.0498], respectively). A Markov transition chain analysis of respiratory cycle cyst volume changes revealed greater dynamic variation in the sirolimus group than in the placebo group at the 12-month time point. CONCLUSIONS: Collectively, these data suggest that sirolimus attenuates progressive gas trapping in lymphangioleiomyomatosis, consistent with a beneficial effect of the drug on airflow obstruction. We speculate that a reduction in lymphangioleiomyomatosis cell burden around small airways and cyst walls alleviates progressive airflow limitation and facilitates cyst emptying.
RCT Entities:
RATIONALE: The Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial demonstrated that sirolimus stabilized lung function and improved measures of functional performance and quality of life in patients with lymphangioleiomyomatosis. The physiologic mechanisms of these beneficial actions of sirolimus are incompletely understood. OBJECTIVES: To prospectively determine the longitudinal computed tomographic lung imaging correlates of lung function change in MILES patients treated with placebo or sirolimus. METHODS: We determined the baseline to 12-month change in computed tomographic image-derived lung volumes and the volume of the lung occupied by cysts in the 31 MILES participants (17 in sirolimus group, 14 in placebo group) with baseline and 12-month scans. MEASUREMENTS AND MAIN RESULTS: There was a trend toward an increase in median expiratory cyst volume percentage in the placebo group and a reduction in the sirolimus group (+2.68% vs. +0.97%, respectively; P = 0.10). The computed tomographic image-derived residual volume and the ratio of residual volume to total lung capacity increased more in the placebo group than in the sirolimus group (+214.4 ml vs. +2.9 ml [P = 0.054] and +0.05 ml vs. -0.01 ml [P = 0.0498], respectively). A Markov transition chain analysis of respiratory cycle cyst volume changes revealed greater dynamic variation in the sirolimus group than in the placebo group at the 12-month time point. CONCLUSIONS: Collectively, these data suggest that sirolimus attenuates progressive gas trapping in lymphangioleiomyomatosis, consistent with a beneficial effect of the drug on airflow obstruction. We speculate that a reduction in lymphangioleiomyomatosis cell burden around small airways and cyst walls alleviates progressive airflow limitation and facilitates cyst emptying.
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