Common Cancer Drug Sirolimus Linked to Frequent Infections in Children with Vascular Anomalies

A drug that has quietly transformed the care of children with disfiguring and sometimes dangerous vascular malformations may carry a heavier infectious price than many clinicians have assumed. A retrospective study from King Faisal Specialist Hospital and Research Centre in Riyadh, published in BMC Pediatrics, found that nearly two-thirds of pediatric patients treated with sirolimus developed at least one infection during their first year of therapy, and that these infections were serious enough to trigger emergency visits, hospitalizations and, in a small number of cases, intensive care. The findings, drawn from six years of clinical records, offer one of the clearest single-center pictures yet of the infection burden accompanying mTOR inhibitor therapy in this vulnerable population.

Sirolimus, also known by its original brand name rapamycin, works by inhibiting mammalian target of rapamycin, or mTOR, a central cellular signaling hub that governs growth, proliferation and the response of lymphatic endothelial cells to injury. In vascular anomalies, particularly lymphatic and veno-lymphatic malformations, aberrant signaling through the PI3K-AKT-mTOR pathway drives the abnormal proliferation of lymphatic vessels, producing masses that can swell, leak, deform tissue and compress airways. By damping this pathway, sirolimus can shrink lesions and dramatically improve symptoms, which is why it has become a mainstay of medical therapy for complex vascular anomalies worldwide. But mTOR signaling is also indispensable to the immune system, where it coordinates T cell activation, lymphocyte proliferation and the coordination of innate and adaptive defenses. Immunosuppression is the pharmacological flip side of the drug’s therapeutic action, and it is the reason sirolimus has long been used to prevent organ transplant rejection.

The research team, led by Fadiah Alkhattabi and colleagues, assembled a cohort of 95 pediatric patients who received sirolimus between January 2019 and June 2025. The median age of the children was 12 years. Lymphatic malformations accounted for 46.3 percent of cases and veno-lymphatic malformations for 34.7 percent, reflecting the fact that these lymphatic-predominant lesions respond most reliably to mTOR inhibition. The investigators systematically collected every infection occurring within twelve months of therapy initiation, capturing outpatient episodes, emergency department encounters, hospital admissions and intensive care stays. This twelve-month window was chosen deliberately, since it spans the period of dose titration and steady-state immunosuppression during which clinicians most worry about opportunistic and community-acquired pathogens alike.

The headline number is striking: 63.2 percent of the children developed at least one infection during the observation period, and among those affected, the median count was three infections per patient. That is not a background rate of ordinary childhood illness; it is a sustained pattern of recurrent infection concentrated in a defined therapeutic window. The microbiological geography of these infections was also telling. Respiratory infections dominated, accounting for 80 percent of all infectious episodes, followed by skin and soft tissue infections at 11.7 percent and bloodstream infections at 5 percent. The respiratory predominance makes biological sense. The lung mucosa is a vast immunological interface, constantly patrolled by resident lymphocytes whose function depends on intact mTOR signaling, and lymphatic malformations themselves can compromise airway architecture and mucociliary clearance, compounding the vulnerability.

The clinical consequences were far from trivial. Infections drove emergency department visits in 70 percent of affected episodes and required hospitalization in 23.3 percent. Among children who were hospitalized, 28.6 percent deteriorated enough to require intensive care admission. One infection-related death occurred in the cohort, a sobering reminder that in children whose immune systems are pharmacologically dampened, common pathogens can occasionally follow malignant trajectories. Beyond the acute morbidity, the study documented a second, subtler cost: disruption of the treatment itself. Sirolimus doses had to be adjusted in 58.3 percent of infection episodes, and the drug was temporarily discontinued in 40 percent of cases. For a therapy whose benefit depends on continuous suppression of aberrant lymphatic growth, these interruptions risk lesion regrowth and symptom recurrence, creating a clinical dilemma in which the treatment of the infection and the treatment of the malformation pull in opposite directions.

One of the study’s most provocative findings concerns dosing. Children who developed infections had received a lower initial sirolimus dose than those who did not, with a median of 1.20 milligrams per square meter of body surface area compared with 1.60 in the infection-free group, a difference that reached statistical significance. At first glance this seems paradoxical: more drug, fewer infections. The authors’ data do not establish causation, and the retrospective design precludes firm mechanistic conclusions, but several explanations are plausible. Children prescribed higher initial doses may have been systematically different in ways the analysis could not fully capture, including the extent of their disease, their nutritional status or the intensity of monitoring they received. Alternatively, the association may reflect confounding by indication in reverse, with clinicians reserving more aggressive dosing for children they judged to be more robust. Whatever the mechanism, the finding underscores how little is known about the dose-response relationship between sirolimus exposure and infectious risk in this population, and it cautions against the assumption that lower doses are automatically safer.

Equally consequential is what the study found about antibiotic prophylaxis. Roughly a quarter to a third of children in both groups received prophylactic antibiotics, 28.3 percent of those who developed infections and 25.7 percent of those who did not, and the difference in infection rates between the two groups was not statistically significant. In other words, prophylactic antibiotics did not appear to protect the children who received them. This null result matters because prophylaxis is not a benign intervention. Chronic antibiotic exposure selects for resistant organisms, disrupts the microbiome and carries its own burden of side effects, all without demonstrated benefit in this cohort. The findings suggest that routine prophylaxis for all children on sirolimus cannot be justified by the current evidence, and that a more nuanced, risk-adapted approach is warranted, reserving preventive strategies for children with identifiable additional vulnerabilities such as profound lymphatic involvement of the airway, a history of recurrent pneumonia or coexisting immunodeficiency.

The study’s design imposes important limits on interpretation. As a single-center retrospective analysis, it depends on the completeness and consistency of clinical documentation over six years, and infection ascertainment may vary with how diligently clinicians recorded outpatient episodes. Without a control group of children with vascular anomalies who were not treated with sirolimus, the study cannot isolate the drug’s contribution to infection risk from the baseline susceptibility conferred by the malformations themselves. Children with lymphatic malformations are known to experience recurrent infections even without immunosuppressive therapy, because malformed lymphatic tissue impairs local immune surveillance and fluid drainage. The true attributable risk of sirolimus, therefore, likely lies somewhere below the raw 63.2 percent figure, though the recurrent and severe nature of the observed infections suggests the drug is a meaningful contributor.

Nevertheless, the practical implications for pediatric practice are immediate. Clinicians managing children with vascular anomalies on sirolimus should maintain a low threshold for evaluating respiratory symptoms, counsel families about early signs of infection, and coordinate care between dermatology, hematology-oncology, pulmonology and infectious disease specialists. Therapeutic drug monitoring, already standard practice for sirolimus, may need to be paired with a more explicit accounting of infection history when titrating doses, and treatment interruptions during acute illness should be weighed carefully against the risk of lesion progression. The authors argue that close monitoring and risk-adapted infection prevention strategies may help optimize sirolimus therapy, a formulation that acknowledges both the drug’s undeniable value and the infectious toll documented in their data.

As sirolimus and the newer generation of PI3K and mTOR pathway inhibitors expand into ever broader pediatric populations, studies of this kind become essential scaffolding for safe practice. The Riyadh cohort demonstrates that infections during sirolimus therapy are common, clinically significant and frequently disruptive to treatment continuity, while simultaneously showing that the reflexive answer of antibiotic prophylaxis does not work. What is needed next is prospective, multicenter surveillance with standardized infection definitions, pharmacokinetic correlates and, ideally, biomarkers of immune function that can identify which children truly need intensified protection. Until such data exist, the study stands as a clear signal that the benefits of mTOR inhibition in vascular anomalies must be actively balanced against a substantial and measurable infectious burden, one that deserves the same clinical attention devoted to the malformations themselves.

Subject of Research: Infection risk in pediatric patients with vascular anomalies treated with sirolimus

Article Title: The proportion of infections in patients with vascular anomalies treated with sirolimus: a retrospective study

Article References: Alkhattabi, F., Alsaleem, A., Aledaili, S., Alhuthil, R., & Alobieda, S. (2026). The proportion of infections in patients with vascular anomalies treated with sirolimus: a retrospective study. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07707-4

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07707-4

Keywords: sirolimus, vascular anomalies, lymphatic malformations, pediatrics, mTOR inhibitor, infections, antibiotic prophylaxis, immunosuppression, respiratory infections, drug safety, retrospective study, BMC Pediatrics