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\begin{document}

\title{Infectious Complications of Vascular Anomalies Treated with Sirolimus: A
Systematic Review}



\author[1]{Rachel Kalbfell}%
\author[2]{Sally J. Cohen-Cutler}%
\author[3]{Eric Grisham}%
\author[1]{Christine Bereitschaft}%
\author[2]{Alexandra Borst}%
\author[4]{Abby M. Green}%
\author[1]{Daniel Willis}%
\author[1]{Lauren Yaeger}%
\author[5]{Julie Blatt}%
\author[1]{Bryan Sisk}%
\affil[1]{Washington University in St Louis School of Medicine}%
\affil[2]{The Children's Hospital of Philadelphia}%
\affil[3]{St Louis Children's Hospital}%
\affil[4]{Washington University in St Louis Division of Infectious Diseases}%
\affil[5]{The University of North Carolina at Chapel Hill Division of Hematology}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background and Objectives: Initially developed as immunosuppressive
agents, mTOR inhibitors are currently used widely in the management of
vascular malformations and tumors. The incidence of infectious
complications in the vascular anomalies (VA) population is not well
defined. The goal of this systematic review was to better define the
types and severity of reported infectious complications in patients with
VAs treated with mTOR inhibition. Methods: This was a systematic review
conducted following PRISMA guidelines evaluating all research articles
focused on infectious complications in patients with VAs treated with
sirolimus or everolimus. Thirty articles including 1181 total patients
and 315 infections (in 290 unique patients) were ultimately included.
Results: The majority of infections were viral upper respiratory (n=137,
54\%), followed by pneumonia (n=52, 20\%), and cutaneous infections
(n=20, 8\%). There were 6 total infection-related fatalities, which all
occurred in patients younger than 2 years. Only 1 case of
\emph{Pneumocystis jirovecii} pneumonia (PJP) was reported. This was in
an infant with KHE who was also treated with steroids and did not
receive PJP prophylaxis. Almost 1/3 (n=95, 32\%) of infectious
complications were graded 3 to 4 according to CTCAE criteria. Details of
patient age, subtype of VA, and timing of infection were lacking from
many reports. Conclusions: Most infectious complications reported in
patients with VA on mTOR inhibitors were viral respiratory infections
and non-severe. Bacteremia, infectious fatalities, and PJP are
exceedingly rare. Future studies are needed to clarify the spectrum of
infectious risks in VA patients and to provide guidance for infection
prevention.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Vascular anomalies (VAs) are a collection of rare disorders resulting
from abnormal development, structure, and function of the
vasculature.\textsuperscript{1-3} VAs can cause pain, coagulopathy,
disability, and disfigurement,\textsuperscript{4-8} and some VAs are
associated with overgrowth of bone, muscle, or fatty
tissue.\textsuperscript{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).\textsuperscript{9}Following 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.\textsuperscript{10-13} As a result, sirolimus has become a
central component of treatment strategies for
VAs.\textsuperscript{14,15}

Many VAs are driven by post-zygotic, somatic variants of genes in the
mTOR pathway, especially PIK3CA and TEK.\textsuperscript{3} The mTOR
pathway controls cell proliferation, adhesion, migration, metabolism,
and survival.\textsuperscript{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.\textsuperscript{17} Likely as a result of this immunosuppressive
effect, some patients with VAs treated with sirolimus have developed
serious infections.\textsuperscript{18} However, the reported rates of
infections across studies have varied widely, from
16\%\textsuperscript{19} to 42\%.\textsuperscript{20} Because of the
known inhibitor effect on T cell function, many centers also advocate
for \emph{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.



\textbf{METHODS}

We conducted a systematic review following the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for
reporting results,\textsuperscript{21} posing the question: ``What are
the reported infectious complications of mTOR inhibitors when used to
treat VAs?'' We did not register this review protocol.

\emph{Inclusion and Exclusion Criteria}

This review is inclusive of all research articles presenting original
data that reported infectious complications of mTOR inhibitors
(sirolimus/rapamycin or everolimus) in the treatment of VAs. We did not
restrict inclusion based on the year of publication. For inclusion,
patients reported in the study had to have (1) been diagnosed with a VA,
(2) received sirolimus or everolimus, and (3) had a reported infectious
complication. Exclusion criteria included articles that (1) did not
report original data (e.g. review articles and commentaries), (2) did
not report infections, (3) were not available in English, or (4) were
abstracts, trial protocols, or dissertations. We included studies of
both children and adults with VAs.

\emph{Search Strategy}

A medical librarian (LHY) searched the literature for records including
the concepts of VAs, sirolimus, rapamycin, everolimus, and infection.
This search strategy included broad categories (e.g. vascular anomaly,
vascular malformation, vascular tumor), types of VAs (e.g. hemangioma,
lymphatic malformation, hemangioendothelioma), and syndromes (e.g.
CLOVES, Sturge-Weber Syndrome, Klippel-Trenaunay Syndrome). We included
disorders listed in the International Society for the Study of Vascular
Anomalies classification of vascular anomalies. The librarian created
search strategies using a combination of keywords and controlled
vocabulary in Embase.com 1947- , Ovid Medline 1946- , Scopus 1823- , and
Cochrane Central Register of Controlled Trials (CENTRAL). All search
strategies were completed November 11, 2022 with no added limits. Book
chapters, conference papers, editorials, and systematic reviews were
removed when possible. A total of 3,874 results were found. 302
duplicate records were deleted after using the de-duplication processes
described in ``De-duplication of database search results for systematic
reviews in EndNote,''\textsuperscript{22} resulting in a total of 3,572
unique citations included in the project library. Fully reproducible
search strategies for each database can be found in Appendix 1.

\emph{Screening and Data Abstraction}

We utilized Covidence\selectlanguage{ngerman}® web-based systematic review software for
screening the studies. All screenings were performed in duplicate, and
any disagreements were reconciled through group discussion. Four authors
(BAS, EG, RMK, and CB) and one additional staff member collaboratively
screened the studies in a two-stage format. First, RMK and EG screened
titles and abstracts. In this stage, only studies that included patients
with VAs treated with an mTOR inhibitor were accepted. Second, RMK, EG,
CB, and another staff member completed a full text review to confirm
that included studies reported on infections in this population. In this
stage, we indicated reasons for exclusion based on the following:
duplicates, wrong intervention, wrong study design or publication type,
infection not reported, wrong patient population, or text unavailable in
English. We only included studies that explicitly reported infections,
because the absence of reporting infections does not necessarily mean
that patients did not experience infections. It is possible that case
reports or case series failed to report infections if this was not the
focus of their report, or if the infection was minor. At the end of
screening, all eligible studies were reviewed by BAS, a pediatric
hematologist oncologist with expertise in treating VAs. Two authors (BAS
and CB) abstracted data in duplicate from all included studies, reviewed
the other's abstraction, and resolved differences through discussion.

\emph{Critical Appraisal}

One author (SCC) performed critical appraisal of all included studies
using JBI Research Institute critical appraisal checklists for
randomized controlled trials, quasi-experimental studies, cohort
studies, case series, and case reports.\textsuperscript{23} We chose
this collection of critical appraisal tools because it included
checklists for the variety of study designs included in this review.



\textbf{RESULTS}

\emph{Study Characteristics}

Our initial search yielded 3572 unique articles. Exclusions related to
irrelevant content (n=3196), wrong patient population (n=125), infection
not mentioned (n=113), wrong study design (n=64), wrong intervention
(n=33), or text unavailable in English (n=11) (Figure 1). Thirty
remaining studies were evaluated, of which most were case series or
retrospective chart reviews (n=17, 57\%). Studies were reported from
geographically diverse populations, including 11 studies from Europe
(37\%), 9 studies from China (30\%), and 7 studies from North America
(24\%) (Table 1). See Supplemental Table S1 for full details of each
included study.

\emph{Patient Characteristics}

These 30 studies reported on 1181 total patients, of which 290 patients
had a total of 315 infections. Of note, one study only listed the number
of infections without specifying whether any patient had more than one
infection, so we counted each infection in this study as a unique
patient to avoid underestimating the number of patients experiencing
infections.\textsuperscript{24} Patients in all included studies
received sirolimus. Many studies lacked sufficient detail to determine
key demographics of patients with infections. For example, age was not
specified in 237/290 patients (82\%). The remainder were younger than 1
year (n=16, 5\%), 2 to 17 years (n=28, 10\%), or older than 18 years
(n=9, 3\%). Similarly, sex was not specified for 268/290 patients
(n=92\%). The remainder were male (n=14, 5\%) and female (n=8, 3\%).
Similarly, these studies lacked granular detail about the sites of VA
disease (not specified in 83\%) and whether sirolimus was held during
infections (not specified in 81\%). Patients with infections for whom
they type of VA was reported (n=121/290) had a wide variety of VAs, with
slow flow vascular malformations (n=60, 50\%) and kaposiform
hemangioendothelioma (KHE)/tufted angioma (n=24, 20\%) most commonly
reported. Given the limited granular reporting, 58\% of participants did
not have a specific VA diagnoses listed and instead were aggregated into
the category ``multiple VAs'' (Table 2).

\emph{Infection Characteristics}

The type of infection was reported for 81\% of infections (n=255/315).
Of these, most infections were reported as upper respiratory infections
or ``viral infections'' (n=137, 54\%), followed by pneumonia (n=52,
20\%), and cutaneous infections (n=20, 8\%). Within the pneumonia
category, one patient was reported to have\emph{Pneumocystis}
\emph{jirovecii}pneumonia (PJP).\textsuperscript{25} This patient was 4
months old with a diagnosis of KHE with Kasabach-Merritt Phenomenon
(KMP), receiving treatment with sirolimus at 0.05 mg/kg per dose twice a
day with a trough goal of 8 to 15 ng/mL. At 2 months of age, this
patient was treated with vincristine, prednisolone, and propranolol. At
3 months of age, the patient discontinued vincristine and propranolol,
started sirolimus, and began a steroid wean. Four weeks after initiation
of sirolimus therapy, the patient developed PJP. Sirolimus was
temporarily held, and the pneumonia was treated successfully with
sulfamethoxazole-trimethoprim and methylprednisolone. Notably, this
patient had not received PJP prophylaxis. Four cases of bacteremia (1\%)
were reported. Common Terminology Criteria for Adverse Events (CTCAE)
grading was reported for 91\% of infections. Most infections were grade
1 to 2 (n=194, 66\%), and 32\% (n=95) were grade 3 to 4. Six patients
(n=2\%) had grade 5 infections (i.e., they died as a result of
infection). Most patients received antibiotic prophylaxis against PJP
(n=175, 80\%), while 42 (19\%) did not receive prophylaxis. Of note,
prophylaxis was not specified for 73 patients.

\emph{Characteristics of Fatal Infections}

Six infectious deaths were reported in patients with VAs receiving
sirolimus (Table 3). One patient received PJP prophylaxis, one did not,
and 4 studies did not report prophylaxis status. All of these patients
were 2 years or younger, and 5/6 patients were infants (\textless{} 12
months of age). Four patients had KHE with KMP, one patient had
microcystic lymphatic malformation, and one patient had generalized
lymphatic anomaly (GLA). These fatal infections occurred within 2 months
of starting sirolimus in 4/6 cases. Five of these deaths resulted from
pneumonia and one case did not specify the type of infection. One
patient with viral pneumonia also had ileitis. The responsible pathogens
included viral (adenovirus, metapneumovirus), bacterial
(\emph{Mycoplasma} ), and unknown pathogens. Sirolimus was held at the
time of infection in all cases. Co-administered steroids were not
specified in 3/6 cases. Two patients were weaning off steroids at the
time of the infection, and one patient did not receive any steroids.
Deaths occurred 4 to 11 days after onset of infection. Further
information on possible comorbidities was not reported.

\emph{Characteristics of Bacteremia Infections}

Bacteremia was reported in 4 patients: 2 patients had KHE, 1 patient had
a slow flow vascular malformation, and 1 patient did not have their
disease specified in the manuscript (Table 4). Two of these patients had
central lines, and 2 did not have central lines. One central line
infection was caused by \emph{Staphylococcus epidermidis} . The other
central line infection did not specify the pathogen. For the two
patients without central lines who developed bacteremia, one patient had
methicillin-resistant \emph{Staphylococcus aureus} and the other patient
had \emph{Pseudomonas aeruginosa} . These studies did not report whether
the patients had other comorbidities or whether they were receiving
concomitant immunosuppression, such as steroids.

\emph{Critical Appraisal}

The most common deficiencies in reporting related to granularity of
demographics and disease characteristics (Supplemental Table S2). Only 1
study specifically focused on reporting infectious complications, and
this study provided granular details for characteristics of each
infection (n= 12 patients and 15 infections). The remaining 29 studies
aimed to report clinical outcomes of sirolimus treatment, and they
provided less detail about infections. For example, fewer than 20\% of
studies reported the following characteristics specific to the
participants with infections: age, sex, sites of VA disease, and whether
sirolimus was held.

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.



\textbf{CONCLUSION}

Sirolimus has become a mainstay of treatment for patients with VAs, and
many patients receiving sirolimus for VAs have also been reported to
develop infectious complications. Although most infections were minor,
one-third of reported infections were serious. However, reports of
bacteremia and infectious fatalities are exceedingly rare, and only 1
episode of PJP has been reported in this patient population. In the
future, multicenter studies should aim to further characterize the
infectious complications of sirolimus for treatment of VAs. This future
work will be essential to provide guidance to clinicians and families on
how to best monitor and manage these patients.

\textbf{CONFLICT OF INTEREST STATEMENT --}

Dr. Sisk serves as a consultant for Novartis pharmaceuticals. Otherwise,
the authors do not have any conflicts of interest pertinent to the
current study.

\textbf{ACKNOWLEDGEMENTS --}

N/A



\textbf{REFERENCES}

1. Wolfe AD. Pediatric Vascular Anomalies: Opportunities in Primary
Care. In: Kamat DM, Frei-Jones M, eds. \emph{Benign Hematologic
Disorders in Children: A Clinical Guide.} Cham: Springer International
Publishing; 2021:453-486.

2. Anomalies ISftSoV. ISSVA Classification of Vascular Anomalies. 2018;
https://www.issva.org/classification. Accessed March 2, 2021.

3. Canaud G, Hammill AM, Adams D, Vikkula M, Keppler-Noreuil KM. A
review of mechanisms of disease across PIK3CA-related disorders with
vascular manifestations. \emph{Orphanet Journal of Rare
Diseases.}2021;16(1):306.

4. Trenor CC, Adams DM, eds. \emph{Vascular Anomalies: A Guide for the
Hematologist/Oncologist.} 1 ed. Switzerland: Springer International
Publishing; 2020.

5. Kerr AM, Haas SM. Parental uncertainty in illness: managing
uncertainty surrounding an ''orphan'' illness. \emph{Journal of
pediatric nursing.} 2014;29(5):393-400.

6. Kerr AM, Harrington NG, Scott AM. Communication and the Appraisal of
Uncertainty: Exploring Parents' Communication with Credible Authorities
in the Context of Chronic Childhood Illness. \emph{Health
communication.} 2017;34(2):201-211.

7. Kerr AM, Harrington NG, Scott AM. Uncertainty Management and Decision
Making: Parents' Experiences During their First Visit to a
Multidisciplinary Clinic for their Child's Vascular
Anomaly.\emph{Journal of pediatric nursing.} 2020;52:18-24.

8. Kerr AM, Thompson CM, Rubinsky V. Memorable Messages Parents of
Children with Vascular Birthmarks Receive from Others: Implications for
Stigma and Identity. \emph{Health communication.} 2020;35(6):685-695.

9. Hammill AM, M. W, A. G, et al. Sirolimus for the treatment of
complicated vascular anomalies in children. \emph{Pediatric Blood and
Cancer.} 2011;57(6):1018-1024.

10. Adams DM, Trenor CC, 3rd, Hammill AM, et al. Efficacy and Safety of
Sirolimus in the Treatment of Complicated Vascular
Anomalies.\emph{Pediatrics.} 2016;137(2):e20153257.

11. Ji Y, Chen S, Yang K, et al. A prospective multicenter study of
sirolimus for complicated vascular anomalies. \emph{J Vasc Surg.} 2021.

12. Harbers VEM, Rongen G, van der Vleuten CJM, et al. Patients with
Congenital Low-Flow Vascular Malformation Treated with Low Dose
Sirolimus. \emph{Adv Ther.} 2021.

13. Maruani A, Tavernier E, Boccara O, et al. Sirolimus (Rapamycin) for
Slow-Flow Malformations in Children: The Observational-Phase Randomized
Clinical PERFORMUS Trial. \emph{JAMA Dermatol.} 2021.

14. Shimano KA, Eng W, Adams DM. How we approach the use of sirolimus
and new agents: Medical therapy to treat vascular
anomalies.\emph{Pediatr Blood Cancer.} 2022:e29603.

15. Ricci KW, Iacobas I. How we approach the diagnosis and management of
complex lymphatic anomalies. \emph{Pediatr Blood Cancer.} 2021:e28985.

16. Queisser A, Seront E, Boon LM, Vikkula M. Genetic Basis and
Therapies for Vascular Anomalies. \emph{Circ Res.} 2021;129(1):155-173.

17. O'Shea AE, Valdera FA, Ensley D, et al. Immunologic and dose
dependent effects of rapamycin and its evolving role in
chemoprevention.\emph{Clin Immunol.} 2022;245:109095.

18. Rossler J, Eulalia B, Victoria D, et al. Severe adverse events
during sirolimus ''off-label'' therapy for vascular
anomalies.\emph{Pediatric blood \& cancer.} 2021;68(8):e28936.

19. Adams DM, C. TC, M. HA, et al. Efficacy and safety of sirolimus in
the treatment of complicated vascular anomalies.
\emph{Pediatrics.}2016;137(2).

20. Maruani A, E. T, O. B, et al. Sirolimus (Rapamycin) for Slow-Flow
Malformations in Children: The Observational-Phase Randomized Clinical
PERFORMUS Trial. \emph{JAMA Dermatology.} 2021;157(11):1289-1298.

21. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA Statement for
Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate
Health Care Interventions: Explanation and Elaboration. \emph{PLOS
Medicine.} 2009;6(7):e1000100.

22. Bramer WM, Giustini D, de Jonge GB, Holland L, Bekhuis T.
De-duplication of database search results for systematic reviews in
EndNote. \emph{J Med Libr Assoc.} 2016;104(3):240-243.

23. Munn Z, Barker TH, Moola S, et al. Methodological quality of case
series studies: an introduction to the JBI critical appraisal tool. JBI
Evidence Synthesis. 2020;18(10):2127-2133.

24. Ji Y, S. C, J. Z, et al. Sirolimus plus prednisolone vs sirolimus
monotherapy for kaposiform hemangioendothelioma: a randomized clinical
trial. \emph{Blood.} 2022;139(11):1619-1630.

25. Russell TB, K. RE, S. DC, B. GL, W. MT. Pneumocystis jirovecii
pneumonia during sirolimus therapy for kaposiform
hemangioendothelioma.\emph{Pediatrics.} 2018;141:S421-S424.

26. Mäkinen T, Boon LM, Vikkula M, Alitalo K. Lymphatic Malformations:
Genetics, Mechanisms and Therapeutic Strategies. \emph{Circ
Res.}2021;129(1):136-154.

27. Malpica L, Moll S. Practical approach to monitoring and prevention
of infectious complications associated with systemic corticosteroids,
antimetabolites, cyclosporine, and cyclophosphamide in nonmalignant
hematologic diseases. \emph{Hematology Am Soc Hematol Educ
Program.}2020;2020(1):319-327.

28. Malpica L, van Duin D, Moll S. Preventing infectious complications
when treating non-malignant immune-mediated hematologic
disorders.\emph{Am J Hematol.} 2019;94(12):1396-1412.

29. Wang Z, W. Y, H. S, et al. Sirolimus therapy for kaposiform
hemangioendothelioma with long-term follow-up. \emph{Journal of
Dermatology.} 2019;46(11):956-961.

30. Wang Y, L. K, B. S, J. C, W. S. Sirolimus for Kaposiform
Hemangioendothelioma With Kasabach-Merritt Phenomenon in Two
Infants.\emph{The Journal of craniofacial surgery.}
2020;31(4):1074-1077.

31. Ying H, C. Q, X. Y, X. L. A case report of 2 sirolimus-related
deaths among infants with kaposiform
hemangioendotheliomas.\emph{Pediatrics.} 2018;141:S425-S429.

32. Sandbank S, V. M-P, A. F, A. B, S. G. Oral and topical sirolimus for
vascular anomalies: A multicentre study and review. \emph{Acta
Dermato-Venereologica.} 2019;99(11):990-996.

\textbf{Tables and Figures}

\textbf{Table 1. Study Characteristics}

\textbf{Table 2. Patient and Infection Characteristics}

\textbf{Table 3. Characteristics of Fatal Infections (n=5)}

\textbf{Table 4. Characteristics of Patients with Bacteremia}

\textbf{Figure 1. PRISMA Flow Diagram}

Table 1. Study Characteristics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Study Characteristic (n=30)} & \textbf{n (\%)}\tabularnewline
\midrule
\endhead
\textbf{Study Design} &\tabularnewline
Randomized Controlled Trial & 1 (4)\tabularnewline
Randomized Observational Phase Trial & 1 (4)\tabularnewline
Non-Randomized Experimental Study & 4 (13)\tabularnewline
Cohort Study & 3 (9)\tabularnewline
Case Series / Retrospective Chart Review & 17 (57)\tabularnewline
Case Report & 4 (13)\tabularnewline
\textbf{Country} &\tabularnewline
China & 9 (30)\tabularnewline
Europe & 11 (37)\tabularnewline
North America & 7 (24)\tabularnewline
Europe and North America & 1 (3)\tabularnewline
Japan & 1 (3)\tabularnewline
Middle East & 1 (3)\tabularnewline
\bottomrule
\end{longtable}

Table 2. Patient and Infection Characteristics\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{Patient Characteristics (n=290)} & \textbf{n (\%)}
&\tabularnewline
\midrule
\endhead
\textbf{Types of Vascular Anomalies} & \textbf{Types of Vascular
Anomalies} & \textbf{Types of Vascular Anomalies}\tabularnewline
\emph{Vascular Tumors} & &\tabularnewline
KHE/Tufted Angioma \textsuperscript{a} & 24 (8) &\tabularnewline
Epithelioid Hemangioendothelioma & 8 (3) &\tabularnewline
\emph{Vascular Malformations} & &\tabularnewline
Complex Lymphatic Anomaly \textsuperscript{b} & 7 (2) &\tabularnewline
PIK3CA-Related Overgrowth Spectrum & 18 (6) &\tabularnewline
Slow Flow Vascular Malformation & 60 (21) &\tabularnewline
Arteriovenous Malformation & 3 (1) &\tabularnewline
Blue Rubber Bleb Nevus Syndrome & 1 (\textless{}1) &\tabularnewline
Multiple Vascular Anomalies & 169 (58) &\tabularnewline
\textbf{Type of Infection \textsuperscript{c} (n=315 total infections)}
& \textbf{Type of Infection \textsuperscript{c} (n=315 total
infections)} & \textbf{Type of Infection \textsuperscript{c} (n=315
total infections)}\tabularnewline
Upper Respiratory Infection / ''Viral Infection'' \textsuperscript{d} &
137 (54) &\tabularnewline
Pneumonia \textsuperscript{e} & 52 (20) &\tabularnewline
Cutaneous Infection & 20 (8) &\tabularnewline
Gastroenteritis & 14 (5) &\tabularnewline
Urinary Tract Infection/Pyelonephritis & 7 (3) &\tabularnewline
Lymph Gland Infection & 11 (4) &\tabularnewline
Bacteremia & 4 (1) &\tabularnewline
Osteomyelitis/Septic Arthritis & 3 (1) &\tabularnewline
Meningitis & 2 (\textless{}1) &\tabularnewline
Herpes Reactivation & 2 (\textless{}1) &\tabularnewline
Infectious thrombophlebitis & 1 (\textless{}1) &\tabularnewline
Culture Negative Sepsis & 1 (\textless{}1) &\tabularnewline
CMV & 1 (\textless{}1) &\tabularnewline
\textbf{CTCAE Grade of Infections \textsuperscript{f}} & \textbf{CTCAE
Grade of Infections \textsuperscript{f}} &\tabularnewline
1 to 2 & 194 (66) &\tabularnewline
3 to 4 & 95 (32) &\tabularnewline
5 & 6 (2) &\tabularnewline
\textbf{Sirolimus Trough (Target or Actual) \textsuperscript{g}} &
\textbf{Sirolimus Trough (Target or Actual) \textsuperscript{g}}
&\tabularnewline
2 to 5 & 21 (9) &\tabularnewline
5 to 10 & 49 (20) &\tabularnewline
5 to 15 & 5 (2) &\tabularnewline
10 to 15 & 159 (65) &\tabularnewline
\textgreater{}15 & 11 (4) &\tabularnewline
\textbf{Antibiotic Prophylaxis \textsuperscript{h}} & \textbf{Antibiotic
Prophylaxis \textsuperscript{h}} &\tabularnewline
Penicillin & 1 (\textless{}1) &\tabularnewline
PJP Prophylaxis & 175 (80) &\tabularnewline
None & 42 (19) &\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: KHE, kaposiform hemangioendothelioma; CMV,
cytomegalovirus; PJP,\emph{pneumocystis jirovecii} pneumonia.
\textsuperscript{a} In KHE category, 11 patients with Kasabach Merrit
Phenomenon (KMP), 12 patients in which KMP was not specified, and 1
patient with Tufted Angioma.\textsuperscript{b} In Complex Lymphatic
Anomaly category, 4 patients with Generalized Lymphangiomatosis, 2
patients with Gorham Stout Disease, and 1 patient with Central
Conducting Lymphatic Anomaly.\textsuperscript{c}More than one infection
was noted for some patients, so number of infections exceeds number of
reported patients. Additionally, the type of infection was not specified
for 60 patients.\textsuperscript{d} URI/''Viral Infections'' includes
reported cases of Flu and COVID-19. \textsuperscript{e} Pneumonia
category includes 5 bacterial pathogens (including 1 \emph{pneumocystis
jirovecii} pneumonia), 8 viral pathogens, and 39 unspecified
pathogens.\textsuperscript{f} Grade of infection was not reported for 20
infections. \textsuperscript{g} While some reported actual trough prior
to infection, the vast majority of studies reported the goal range of
troughs maintained during treatment. Of note, 16 participants counted in
the ``2 to 5'' range were actually reported at ``2 to 6''. Similarly, in
the ``5 to 10'' range, 25 were actually reported as ``4 to 12'' and 8
were reported as ``4 to 13''. Sirolimus dosing was not specified for 45
patients. \textsuperscript{h} Antibiotic prophylaxis was not specified
for 72 patients.

Table 3. Characteristics of Fatal Infections (n=5)\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Study}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Sex}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Type of Vascular Anomaly}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Location of Vascular Anomaly}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Type of Infection}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Co-Administered Steroids}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Sirolimus dose, trough, or target trough}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Duration of Infection before Death}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Time after starting sirolimus}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Antibiotic Prophylaxis}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Wang, Z. et al. (2019).\textsuperscript{29}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Multifocal KHE with KMP\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Right shoulder, chest, lung, right axilla, chylothorax\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
Wang, Y. et al. (2020).\textsuperscript{30}\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
1 month\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
KHE with KMP\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
Right neck\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
Bacterial vs fungal pneumonia\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
Steroid wean\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
0.7 mg/m2/d, q12 hours\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
8 days\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
2 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.09\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Rossler, J. et al. (2021). \textsuperscript{18}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Microcystic LM\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Face\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Viral pneumonia - metapneumovirus\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6.9 ng/ml\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
4 days\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2 years\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
GLA\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Lung, bowel, spleen\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Viral pneumonia and ileitis -- adenovirus\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
8 ng/ml\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6 days\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
24 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
TMP-SMX and PCN\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Ying, H. et al. (2018).\textsuperscript{31}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
3 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
KHE with KMP\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Face\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Pneumonia -- unknown pathogen\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.1 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
10 days\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
2 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
No\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
KHE with KMP\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Forearm\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Pneumonia -- mycoplasma\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Steroid wean\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.1 mg/kg\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
11 days\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
1.5 months\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
N.S.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: KHE, kaposiform hemangioendothelioma; KMP, Kasabach
Merrit Phenomenon; PJP,\emph{pneumocystis jirovecii} pneumonia; GLA,
generalized lymphatic anomaly; LM, lymphatic malformation; TMP-SMX,
trimethoprim-sulfamethoxazole; PCN, penicillin; N.S., not
specified.\textsuperscript{a} In KHE category, 11 patients with), Note
-- Sirolimus was held in all cases.

Table 4. Characteristics of Patients with Bacteremia\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
Study & Age \textsuperscript{a} & Type of Vascular Anomaly & Location of
Vascular Anomaly & Type of Infection & Co-Administered Steroids &
Sirolimus (Trough or Target) & Time after starting sirolimus &
Antibiotic Prophylaxis\tabularnewline
\midrule
\endhead
Hammill 2011\textsuperscript{9} & 10 months old & KHE with KMP &
Abdomen, back, chest, left leg, pelvis, retroperitoneum & Central Line
Infection after RSV and Flu respiratory distress & Steroid burst &
Target 10-15 ng/ml & N.S. & PJP prophylaxis\tabularnewline
Rossler 2021\textsuperscript{18} & 2 years old & KHE & Retroperitoneal
with mediastinal extension & Central Line Infection, staph epidermidis &
N.S. & Trough 6.5 ng/ml & 5 months & PJP prophylaxis\tabularnewline
Sandbank 2019\textsuperscript{32} & N.S. & N.S. & N.S. & Bacteremia,
MRSA & N.S. & N.S. & N.S. & N.S.\tabularnewline
Maruani 2021\textsuperscript{20} & N.S. & Slow flow vascular
malformation & N.S. & Bacteremia, Pseudomonas aeruginosa & N.S. & Target
4 -- 12 ng/ml & N.S. & None\tabularnewline
\bottomrule
\end{longtable}

KHE, kaposiform hemangioendothelioma; KMP, Kasabach Merrit Phenomenon;
PJP, \emph{pneumocystis jirovecii} pneumonia; N.S., not specified; MRSA,
methicillin-resistant \emph{staphylococcus aureus} .
\textsuperscript{a}Hamill et al. reported age at start of treatment,
rather than age at time of infection. Rossler et al. reported age at
time of diagnosis. The patient described in Hammill et al. was female.
Other studies did not report sex of affected patient.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

