Changes in Lung Function and Chylous Effusions in Patients With Lymphangioleiomyomatosis Treated With Sirolimus

Abstract

Background Lymphangioleiomyomatosis (LAM) is a disorder that affects women and is characterized by cystic lung destruction, chylous effusions, lymphangioleiomyomas, and angiomyolipomas. It is caused by proliferation of abnormal smooth muscle–like cells. Sirolimus is a mammalian target of rapamycin inhibitor that has been reported to decrease the size of neoplastic growths in animal models of tuberous sclerosis complex and to reduce the size of angiomyolipomas and stabilize lung function in humans. Objective To assess whether sirolimus therapy is associated with improvement in lung function and a decrease in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. Design Observational study. Setting The National Institutes of Health Clinical Center. Patients 19 patients with rapidly progressing LAM or chylous effusions. Intervention Treatment with sirolimus. Measurements Lung function and the size of chylous effusions and lymphangioleiomyomas before and during sirolimus therapy. Results Over a mean of 2.5 years before beginning sirolimus therapy, the mean (±SE) FEV1 decreased by 2.8% ± 0.8% predicted and diffusing capacity of the lung for carbon monoxide (DLCO) decreased by 4.8% ± 0.9% predicted per year. In contrast, over a mean of 2.6 years of sirolimus therapy, the mean (± SE) FEV1 increased by 1.8% ± 0.5% predicted and DLCO increased by 0.8% ± 0.5% predicted per year (P < 0.001). After beginning sirolimus therapy, 12 patients with chylous effusions and 11 patients with lymphangioleiomyomas experienced almost complete resolution of these conditions. In 2 of the 12 patients, sirolimus therapy enabled discontinuation of pleural fluid drainage. Limitations This was an observational study. The resolution of effusions may have affected improvements in lung function. Conclusion Sirolimus therapy is associated with improvement or stabilization of lung function and reduction in the size of chylous effusions and lymphangioleiomyomas in patients with LAM. Primary Funding Source Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health.

mTOR Inhibitors in Tuberous Sclerosis Complex

“…Several other clinical stidues have demonstrated the efficacy of sirolimus in reducing the size of a range of different tumor types in patients with LAM [12, 58-62]. …”

Effect of Fasting on the Size of Lymphangioleiomyomas in Patients With Lymphangioleiomyomatosis

“…25,35 Th e current study shows that fasting also reduces the size of lymphangioleiomyomas. Th is was evident aft er 15 and 22 h of fasting regardless of whether the measurements within the fasting period were done in the morning or the evening.…”

“…34 Th ese pathologic fi ndings are associated with symptoms of hemoptysis at rest and during exercise or sexual intercourse and greater severity and rate of progression Figure 1 -A of lung disease. 11,34 Second, there is evidence for an increase in lung water, presumably chyle, [35][36][37] showing lung infi ltrates on imaging studies and suggesting pulmonary edema that shift s with body position and resolves aft er treatment with mammalian target of rapamycin inhibitors. [35][36][37] Th e lymphangioleiomyomas appear to be the result of lymphatic infi ltration by LAM cells, resulting in blockade and the accumulation of chyle and cystic structures.…”

A Case of Successful Therapy by Intrapleural Injection of Fibrin Glue for Chylothorax after Lung Transplantation for Lymphangioleiomyomatosis

“…10) Treatment by sirolimus, a mTOR inhibitor, has been shown to be associated with a reduction in the size of chylous effusions in patients with LAM. 11) In addition, oral administration of sirolimus was also reported as a treatment option for chylothorax after transplant. 12) Ohara et al reported a successful case using sirolimus treatment for chylous pleural effusion after bilateral living donor lung transplantation for LAM.…”