Objectives: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies. Methods:We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow. Results:We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4).SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis.Conclusions: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Objectives: Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use". Methods: We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a pre-designed workflow. Results: We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n=4), Gorham-Stout disease (n=2), central conducting lymphatic anomaly (n=1), lymphatic malformation (n=4), tufted angioma (n=1), kaposiform hemangioendothelioma (n=1), and venous malformation in a CLOVES syndrome (n=1). Three patients presented two SAEs.The age at initiation of sirolimus therapy was under the age of 2 years (5x), 2 to 6 years (5x) and older than 12 years (4x). SAEs occurred during the first 3 months of sirolimus therapy (7x), between 3 and 12 months (7x) and after one year of therapy (3x). The most frequent SAE was viral pneumonia (8x) resulting in death due to a metapneumovirus infection in a 3 months old and generalized adenovirus infection in a 28 months old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis during sirolimus therapy. Conclusions: Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence risk factors, i.e. underlying vascular anomaly or immune status, may contribute to the risk of SAEs.

We report the case of a 61 year-old male who underwent heart transplantation eight months before developing a systemic condition with central nervous system, lung, kidney, colonic, cutaneous, and hematologic involvement, found to be secondary to a systemic toxoplasmosis despite co-trimoxazole prophylaxis in a previous-to-transplant seronegative patient receiving a heart from a seropositive donor. A review of prophylactic options in our environment is discussed.Key words: Toxoplasmosis; heart transplantation; immune tolerance; seroconversion. doi: https://doi.org/10.7705/biomedica.v34i2.3189Toxoplasmosis diseminada en un paciente con trasplante de corazón a pesar de la profilaxis con trimetoprim-sulfametoxazol Se reporta el caso de un paciente de sexo masculino, de 61 años de edad, quien ocho meses después de someterse a un trasplante de corazón presentó una enfermedad sistémica con compromiso del sistema nervioso central y del sistema inmunológico, así como de pulmón, riñón, colon y piel, y a quien finalmente se le diagnosticó toxoplasmosis diseminada, a pesar de haber recibido profilaxis con trimetoprim-sulfametoxazol, debido a que el órgano provenía de un donante positivo para toxoplasmosis siendo él un receptor negativo. Se discuten las opciones de profilaxis en nuestro medio.Palabras clave: toxoplasmosis; trasplante de corazón; tolerancia inmunológica; seroconversión.