Discussion
In this systematic review, we identified 315 infections in 290 patients
with VAs undergoing treatment with sirolimus. Notably, serious
infections, infection-related deaths, bacteremia, and PJP were
infrequent. The vast majority of infections were respiratory infections,
with 54% upper respiratory infections and 20% pneumonias. Overall,
25% of all patients reported in evaluable studies had an infection
reported, and fewer than 10% of all reported patients had serious
adverse events related to infections (CTCAE grade 3 or greater).
Furthermore, it is unclear how many of these infections were
attributable to sirolimus. For example, 54% of infections were upper
respiratory viral illnesses. While sirolimus could theoretically
increase the risk of developing these viral infections, such infections
are also common in the general pediatric and adult population.
Furthermore, cutaneous infections (or inflammation mimicking cutaneous
infections) often occur on the skin overlying vascular malformations,
and sirolimus is used to decrease the frequency of these
flares.26 As such, the 20 reported cutaneous
infections could be related to the underlying VA, rather than as a
result of sirolimus’ immunosuppressive effects, and they might not
actually represent infections.
All reported fatalities occurred in children 2 years of age or younger,
and were most common in infants and related to pulmonary infection.
These deaths generally occurred within 2 months of starting sirolimus.
Furthermore, the majority of these deaths occurred in infants with KHE
who also had KMP, a consumptive coagulopathy.4 While
these findings could underrepresent the true frequency of
infection-related fatalities due to insufficient reporting, they suggest
that death is very infrequent, and infants with KMP or other
complications are most at risk. Furthermore, they suggest that
clinicians should maintain vigilance for respiratory infections and
pneumonia in patients treated with sirolimus. These data also leave
several questions unanswered. Future studies should address whether
patients with KHE have a higher risk of infectious complications with
sirolimus usage, whether concomitant steroid usage is a significant risk
factor, and whether patients are at a higher risk of serious infectious
complications soon after initiating sirolimus therapy. Furthermore,
studies should evaluate whether KMP or other complications represent a
selected patient population that is at increased risk of infection due
to comorbidities.
Bacteremia was a very uncommon infectious complication. Of all 1181
patients reported in these studies, 0.2% of patients developed
bacteremia. Furthermore, bacteremia accounted for 0.6% (4/315) of
infections ever reported in this literature. Of these 4 cases, 2
patients had central lines that served as a likely nidus for infection.
For the remaining 2 patients, there was no clear source of the infection
reported in the studies. For patients without a central line, these data
suggest that bacteremia is a rare occurrence and these patients do not
routinely require blood cultures and antibiotics with febrile episodes.
Patients with a central line, however, should continue to be evaluated
for central line associated bacteremia with fevers, as is standard of
care for all patients with an indwelling central catheter.
We only identified one patient who developed PJP while receiving
sirolimus (0.08% of 1181 total patients reported in these studies), and
this patient was an infant with KHE and KMP who was weaning off
steroids. Steroids alone in infants can increase the risk of PJP, thus
warranting PJP prophylaxis in this patient.27,28 As
such, PJP is an extremely rare event for patients with VAs receiving
sirolimus. Although many patients in these studies likely received PJP
prophylaxis, our findings should encourage a re-evaluation of the risks
and benefits of PJP prophylaxis. Given the documented PJP in an infant,
it would be reasonable to encourage prophylaxis for infants with VAs
receiving sirolimus, especially if they have complicating factors like
steroid treatment, KMP, or other comorbidities. However, these data
suggest that PJP prophylaxis might not be warranted for many patients
with VAs receiving sirolimus without significant comorbidities or
concomitant immunosuppression. Future multicenter studies should aim to
assess the incidence and risk factors of PJP using retrospective cohort
studies, informatics queries, or claims data to better guide prophylaxis
decisions.
This study should be interpreted in light of limitations. First, we
excluded abstracts to avoid incomplete data or duplication with
subsequent publications. However, abstracts could have contributed
additional evidence of infectious complications. Furthermore, the
frequency of published reports of infections does not necessarily
represent the clinical experience with infections in this patient
population. Reporting bias could result from either increased reporting
of infections (overestimation) or decreased reporting of infections
(underestimation). Furthermore, several key characteristics of
infections were omitted from included studies. As such, we are limited
in our ability to generate hypotheses about which patient
characteristics might place patients at higher risk of infectious
complications.