title: A Novel Quantitative Computed Tomographic Analysis Suggests How Sirolimus Stabilizes Progressive Air Trapping in Lymphangioleiomyomatosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 1 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine and.
authors.forename: Rahul G
authors.identifier: http://orcid.org/0000-0002-6184-4093
authors.initials: RG
authors.lastname: Argula
authors.affiliation: 2 Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Kokosi
authors.affiliation: 3 Department of Radiology, University of California, Los Angeles, Los Angeles, California.
authors.forename: Pechin
authors.initials: P
authors.lastname: Lo
authors.affiliation: 3 Department of Radiology, University of California, Los Angeles, Los Angeles, California.
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: 4 Department of Radiology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: James G
authors.initials: JG
authors.lastname: Ravenel
authors.affiliation: 5 Department of Radiology, University of Wisconsin, Madison, Wisconsin.
authors.forename: Cristopher
authors.initials: C
authors.lastname: Meyer
authors.affiliation: 3 Department of Radiology, University of California, Los Angeles, Los Angeles, California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goldin
authors.affiliation: 6 Pediatric Epidemiology Center, University of South Florida, Tampa, Florida; and.
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: 1 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine and.
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.affiliation: 7 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D003560:Cysts / Q000000981:diagnostic imaging*; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D008137:Longitudinal Studies; D008168:Lung / Q000000981:diagnostic imaging / Q000503:physiopathology; D008175:Lung Neoplasms / Q000188:drug therapy*; D008176:Lung Volume Measurements; D018192:Lymphangioleiomyomatosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012123:Pulmonary Ventilation; D011788:Quality of Life; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014481:United States
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus
keywords: airflow obstruction; computed tomography biomarkers; cyst characteristics; lymphangioleiomyomatosis; sirolimus