Background Pediatric patients with cancer are at high risk for severe infections. Delayed diagnosis and treatment increases mortality. Infections can trigger changes of vital signs long before clinical symptoms arise. Continuous recording may detect such changes earlier than discrete measurements. We aimed to assess the feasibility of continuous recording of vital sings by a wearable device (WD) in pediatric patients undergoing chemotherapy for cancer. Methods In this prospective, observational single-center pilot study (NCT04134429) pediatric patients undergoing chemotherapy for cancer wore the Everion® WD for 14 days. Results Twenty patients were included (median age, 6 years; range, 2-16). Six patients (predefined feasibility criterion, ≥15 patients) aged 3-16 years fulfilled the patient specific goal, defined as heart rate recorded with good quality during ≥18 hours/day on ≥7 consecutive days. The quality of heart rate recording was good during 3992 of 6576 (61%) hours studied, poor during 300 (5%) hours, and no data was recorded during 2284 (35%) hours. Eighteen of 20 participants indicated that this WD is acceptable to measure vital sings in children undergoing chemotherapy for cancer. Conclusion We found that continuous recording of vital signs by the Everion® WD is feasible across a very wide age range in pediatric patients undergoing chemotherapy for cancer. In the configuration studied, however, the predefined feasibility criterion was not fulfilled. This was mainly due to important compliance problems and independent of the WD itself. These results will influence the design of future WD-studies including those aiming to identify patterns predicting fever or infection.

Background. Fever in neutropenia (FN) remains an unavoidable, potentially lethal complication of chemotherapy. Timely administration of empirical broad-spectrum intravenous antibiotics has become standard of care. But the impact of time to antibiotics (TTA), the lag period between recognition of fever or arrival at the hospital to start of antibiotics, remains unclear. Here we aimed to analyze the association between TTA and safety relevant events (SRE) in data from a prospective multicenter study. Procedure. We analyzed the association between time from recognition of fever to start of antibiotics (F-TTA) and SRE (death, admission to intensive care unit (ICU), severe sepsis and bacteremia) with three-level mixed logistic regression. We adjusted for possible triage bias using a propensity score and stratified the analysis by severity of disease at presentation. Results. We analyzed 266 FN episodes, including 53 (20%) with SRE, reported in 140 of 269 patients recruited from April 2016 to August 2018. F-TTA (median, 120min; interquartile range, 49 to 180min) was not associated with SRE, with a trend for less SREs in episodes with longer F-TTA. Analyses applying the propensity score suggested a relevant triage bias. Only in patients with severe disease at presentation there was a trend for an association of longer TTA with more SRE. Conclusion. We found little evidence that longer TTA leads to a higher risk of poor clinical outcome in pediatric patients with FN, except for those with severe disease at presentation. We saw strong evidence for triage bias which could only be partially adjusted.

Background Fever in neutropenia (FN) remains a frequent complication in pediatric patients undergoing chemotherapy for cancer. There are only conflicting and weak recommendations for and against antibiotic prophylaxis during chemotherapy. Procedure Pediatric patients were observed in a prospective multicenter study (NCT02324231). A score predicting the risk to develop FN with safety relevant events (SRE; bacteremia, severe sepsis, intensive care unit admission, death) was developed using multivariate mixed Poisson regression. Its predictive performance was assessed by internal cross-validation and compared with the performance of published rules. Results In 238 patients, 318 FN episodes were recorded, including 53 (17%) with bacteremia and 68 (21%) with SRE. The risk prediction score used three variables: chemotherapy intensity, time since diagnosis and type of malignancy. Its cross-validated performance, assessed by the time needed to cover (TNC) one event, exceeded the performance of published rules. Two clinically useful score thresholds were found: a threshold of ≥11 resulted in 2.3% time at risk and 4.1 months TNC; a threshold of ≥8 in 24.9% time at risk and 12.1 months TNC. Using external information on efficacy and timing of intermittent antibiotic prophylaxis, 4.3 months of prophylaxis were needed to prevent one FN with bacteremia, and 5.2 months to prevent one FN with SRE, using a threshold of ≥11. Conclusions This score, based on three routinely accessible characteristics, accurately identifies pediatric patients at risk to develop FN with SRE during chemothearpy. The score can help to design clinical decision rules on targeted primary antibiotic prophylaxis and corresponding efficacy studies.

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.

Purpose: Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumor in children, which can be accompanied by life-threatening thrombocytopenia, referred to as Kasabach-Merritt Phenomenon (KMP). The mTOR inhibitor sirolimus is emerging as targeted therapy in KHE. As the sirolimus effect on KHE occurs only after several weeks we aimed to evaluate if additional transarterial embolization is of benefit for children with KHE and KMP. Methods: 17 patients with KHE and KMP acquired from 11 hospitals in Germany were retrospectively divided into two cohorts. Children being treated with adjunct transarterial embolization and systemic sirolimus, and those being treated with sirolimus without additional embolization. Bleeding rate as defined by WHO was determined for all patients. Response of the primary tumor at 6 and 12 months assessed by Magnetic Resonance Imaging (MRI), time to response of KMP defined as thrombocyte increase >150 x 103/µl, as well as rebound rates of both after cessation of sirolimus were compared. Results: N= 8 patients had undergone additive embolization to systemic sirolimus therapy, sirolimus in this group was started after a mean of 6.5 ± 3 days following embolization. N=9 patients were identified who had received sirolimus without additional embolization. Adjunct embolization induced a more rapid resolution of KMP within a median of 7 days vs 3 months, however tumor response as well as rebound rates were similar between both groups. Conclusion: Additive embolization may be of value for a more rapid rescue of consumptive coagulopathy in children with KHE and KMP compared to systemic sirolimus only.