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.