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.

Figure 1. FEV₁ (top) and D_LCO (bottom) measurements obtained at each visit before and after sirolimus therapy

Data at 0 y were obtained just before starting sirolimus therapy. One of the 19 patients with chylothorax and continuous pleural drainage could not undergo pulmonary function tests. D_LCO = diffusing capacity of the lung for carbon monoxide.

Figure 2. Mean annual changes in FVC, FEV₁, and D_LCO before and after sirolimus therapy in patients with lymphangioleiomyomatosis

Data were obtained by using mixed-effects models. During sirolimus therapy, the FVC, FEV₁, and _DLCO increased instead of decreasing. D_LCO = diffusing capacity of the lung for carbon monoxide. * Eighteen patients were included in these analyses because 1 patient could not undergo pulmonary function tests.

Figure 3. CT scans in 3 patients with lymphangioleiomyomatosis before and after sirolimus therapy

CT = computed tomography. A. CT scan of a 29-year-old woman with bilateral chylothorax (black arrows). B. Repeated CT scan of the same patient 30 months after starting sirolimus therapy that shows complete resolution of the pleural effusions. C. CT scan of a 45-year-old woman with bilateral lung infiltrates. D. Repeated CT scan of the same patient performed after 2.5 years of sirolimus therapy that shows complete clearing of the infiltrates; her lung function also had improved. E. CT scan of a 39-year-old woman with a large lymphangioleiomyoma (white arrow). F. Repeated CT scan of the same patient after 11 months of sirolimus therapy that shows the lymphangioleiomyoma completely resolved.

Appendix Figure. Follow-up Visit CT scan in a patient with lymphangioleiomyomatosis with pleural effusion requiring persistent drainage

CT = computed tomography. A. CT scan of a 62-year-old woman who had undergone unsuccessful chemical pleurodesis and required daily drainage of substantial amounts of pleural fluid. B. Repeated CT scan after 6 months of sirolimus therapy showing nearly complete resolution of pleural effusion.