• Wenshuai Xu, Chenlu Yang, Chongsheng Cheng, Yani Wang, Danjing Hu, Jiannan Huang, Yudi He, Jun Wang, Keqi Chen, Luning Yang, Wangji Zhou, Tengyue Zhang, Song Liu, Jinrong Dai, Shuzhen Meng, Xue Li, Yanli Yang, Shao-Ting Wang, Ruie Feng, Weihong Zhang, Hongbing Zhang, Li Wang, Xinlun Tian, and Kai-Feng Xu.
• Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
• Chest. 2023 Jul 1; 164 (1): 137148137-148.

BackgroundLymphangioleiomyomatosis is a progressive diffuse cystic lung disease with approximately 85% survival at 10 years. The determinants of disease progression and mortality after the introduction of sirolimus therapy and vascular endothelial growth factor D (VEGF-D) as a biomarker have not been well defined.Research QuestionWhich factors, including VEGF-D and sirolimus therapy, influence disease progression and survival prognosis in patients with lymphangioleiomyomatosis?Study Design And MethodsThe progression dataset and the survival dataset included 282 and 574 patients, respectively, from Peking Union Medical College Hospital, Beijing, China. A mixed-effects model was used to compute the rate of decline in FEV1, and generalized linear models were used to identify variables affecting FEV1 decline. A Cox proportional hazards model was used to explore the association between clinical variables and the outcomes of death or lung transplantation in patients with lymphangioleiomyomatosis.ResultsVEGF-D levels and sirolimus treatment were associated with FEV1 changes and survival prognosis. Compared with patients with VEGF-D of < 800 pg/mL at baseline, patients with VEGF-D of ≥ 800 pg/mL lost FEV1 faster (SE, -38.86 mL/y; 95% CI, -73.90 to -3.82 mL/y; P = .031). The 8-year cumulative survival rates of patients with VEGF-D of ≥ 2,000 pg/mL and < 2,000 pg/mL were 82.9% and 95.1%, respectively (P = .014). The generalized linear regression model also demonstrated the benefit of delaying the decline of FEV1 by 65.56 mL/y (95% CI, 29.06-102.06 mL/y) in patients treated with sirolimus compared with those without sirolimus (P < .001). The 8-year risk of death was reduced by 85.1% (hazard ratio, 0.149; 95% CI, 0.075-0.299) after sirolimus treatment. After inverse treatment probability weighting, the risks of death in the sirolimus group were reduced by 85.6%. CT scan results of grade III severity were associated with worse progression than results of grades I or II severity. Patients with baseline FEV1 of 70% predicted or St. George's Respiratory Questionnaire Symptoms domain 50 or higher predicted a higher risk of worse survival.InterpretationSerum VEGF-D levels, a biomarker of lymphangioleiomyomatosis, are associated with disease progression and survival. Sirolimus therapy is associated with slower disease progression and better survival in patients with lymphangioleiomyomatosis.Trial RegistryClinicalTrials.gov; No.: NCT03193892; URL: www.Clinicaltrialsgov.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

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