INTRODUCTION
Vascular anomalies (VAs) are a collection of rare disorders resulting from abnormal development, structure, and function of the vasculature.1-3 VAs can cause pain, coagulopathy, disability, and disfigurement,4-8 and some VAs are associated with overgrowth of bone, muscle, or fatty tissue.1,4 In 2011, Hammill, et al. published the first report of successful treatment of complicated VAs with sirolimus, an inhibitor of mammalian target of rapamycin (mTOR).9Following this study, several clinical trials and case series have demonstrated the efficacy of sirolimus in treating certain types of VAs, especially VAs with lymphatic components.10-13 As a result, sirolimus has become a central component of treatment strategies for VAs.14,15
Many VAs are driven by post-zygotic, somatic variants of genes in the mTOR pathway, especially PIK3CA and TEK.3 The mTOR pathway controls cell proliferation, adhesion, migration, metabolism, and survival.16 Gain of function variants in this pathway can lead to overgrowth of veins, capillaries, and lymphatic vessels that constitute VAs. The mTOR pathway is also integral to the immune response, and mTOR inhibitors were initially developed and continue to be used primarily as immunosuppressant agents.17 Likely as a result of this immunosuppressive effect, some patients with VAs treated with sirolimus have developed serious infections.18 However, the reported rates of infections across studies have varied widely, from 16%19 to 42%.20 Because of the known inhibitor effect on T cell function, many centers also advocate for Pneumocystis jirovecii prophylaxis while taking the agent. Clinicians must determine which patients might be at higher risk of serious infections, how to respond to symptoms of infection in these patients, whether patients require antibiotic prophylaxis, and how to counsel patients about the potential risks of taking sirolimus. To date, no systematic review has assessed the types and severity of reported infectious complications in patients with VAs treated with sirolimus. In this systematic review, we describe all reported infectious complications of sirolimus in patients with VAs to provide evidence to guide clinical decisions.