Results
In this retrospective chart review, 7 centers reported on 17 SAEs in 14 patients, 3 patients had two SAEs. 4 patients were treated for GLA, 2 for GSD, 1 for CCLA, 4 for LM, 1 for a tufted angioma, 1 for a KHE with KMP and 1 for a VM in CLOVES (Table 1). The age at initiation of sirolimus therapy was younger than 2 years (6x), 2 to 6 years (4x) and older than 12 years (4x).
From 14 patients sirolimus blood level results at the timepoint of SAEs were available and ranged between 2.7 and 21 ng/L. “Low-dose” sirolimus resulting in a target plasma concentration of 2–6.9 ng/ml [14] was administered in 8 (57%) patients, “high-dose” with 7.0-15.0 ng/ml in 6 (43%) patients. One patient (P12) exceeded the recommended dosing resulting in elevated sirolimus levels. Five patients received anti-infectious prophylaxis: 4 patients TMP‐SMX and 1 child penicillin. Eight of the 17 (47%) SAEs occurred during the first 3 months of sirolimus therapy, additional 6 SAEs (35%) were observed between 3 and 12 months. Three SAE (18%) occurred after more than 1 year on sirolimus.
The most frequent SAE, 8 of 17 instances (47%), was respiratory infection demanding hospitalization and oxygen therapy. In 5 of such respiratory SAEs, the infectious agent could be identified: rhinovirus/enterovirus (P01, P12), HHV7 virus (P12), metapneumovirus (P02, P06), parainfluenca virus (P06), adenovirus (P03) and pneumococcus (P12) could be isolated. Pneumococcus was also responsible for a sepsis with meningitis in one of these patients (P03). In three patients, SAE were due to an infection of a foreign body, such as a port-à-cath system (P04) or osteosynthesis material stabilizing a pathological fracture in two GSD patients (P08,P13). A HSV-infection and paralytic ileus occurred after cessation of sirolimus during intensive care treatment (P14). Finally, an accompanying local candida albicans infection proven by buccal swap was found (P12).
The type of underlying vascular anomaly appeared to put the patient at a certain risk for specific SAEs. A GLA patient with a paraspinal soft tissue lesion (P11) experienced claudication and loss of balance, and a VM patient (P07) thrombophlebitis. Two episodes with severe diarrhea as consecutive SAEs (P09) and one episode with an ileus (P03) were reported, all in patients with a GLA and an underlying bowel involvement.
All except three SAEs (P02, P03, P14) were completely resolved after 3 to 15 days of hospitalization, P14 had a partial recovery after 2 months and could be weaned from the tracheostomy but needed non-invasive ventilation at night. Nine patients continued while 5 patients discontinued the drug after the first SAE, 1 patient (P09) stopped after the second SAE. Notably, the patient with KHE and KMP (P04) experiencing 2 SAEs continued sirolimus even after the second SAE.
Two SAEs resulted in death of the patients. The first was a 3 months old child with a microcystic LM in the face (P02) who had a metapneumovirus infection 2 months after start of sirolimus and died immediately 4 days later. The second fatal SAE was observed in a 28 months old child with protein losing enteropathy in the context of GLA (P03) and an acute ileus accompanied by an adenovirus respiratory infection. Three days after hospitalization, the child succumbed to the infection. Importantly, the child was under a penicillin prophylaxis, which had been initiated after a first SAE at the age of 14 months for a pneumococcus infection 2 weeks into sirolimus therapy. It cannot be excluded that these patients in addition suffered from an underlying immunodeficiency that rendered them more susceptible to severe infections.