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BackgroundThe imposition of lockdowns during the severe acute respiratory syndrome coronavirus-2 pandemic led to a significant decrease in pediatric care utilization in 2020. After restrictions were loosened, a surge in pediatric respiratory disease was observed in pediatric wards. The aim of this study was to quantify the effect of the lockdown(s) on the incidence of pediatric respiratory disease. MethodsFor this multicenter retrospective study, emergency department (ED) visit and admission data between January 2017 and September 2021 was collected from eight general hospitals in the Netherlands. Clinical diagnoses were extracted and categorized in groups ("communicable infectious disease," "all respiratory infections," "upper respiratory tract infection," "lower respiratory tract infection," and "asthma/preschool wheezing"). The incidence of admissions and ED visits during 2020 and 2021 was compared to the incidence in 2017-2019. ResultsSuccessive lockdowns resulted in a maximum decrease of 61% and 57% in ED visits and admissions, respectively. After loosening restrictions during the summer of 2021, a 48% overall increase in ED visits and 31% overall increase in admission numbers was observed in July compared to the average July in 2017-2019. This was explained by a 381% increase in ED visits and a 528% increase in ward admissions due to overall respiratory infections, mainly due to lower respiratory tract infections. ConclusionsSuccessive lockdowns in the spring and winter of 2020 and 2021 led to a decreased incidence of communicable infections, especially respiratory tract infections. The resulting lack of pediatric immunity resulted in an off-season surge in care utilization at an unexpected moment.

Primary endpoints in pediatric clinical trials are currently very similar to those in adult trials1, and focus on quantifying or counting hard endpoints like mortality, hospital admissions and length of stay. Additionally, biochemical biomarkers in serum are often measured to assess drug effects on a biochemical level. The occurrence of mortality and hospital admissions is rare thanks to the improvements in clinical care that have occurred in the last century, and adopting these as primary endpoints in clinical trials gives disproportional weight to rare events which most patients will not experience. Conversely, length of stay for many clinical conditions is short, and this duration only captures a small part of the clinical recovery trajectory that patients must undergo. This dissertation described the development, technical validation and clinical validation of a new type of clinical endpoints ('value based endpoints') and a new clinical trial paradigm (The remote clinical trial), consisting of digital endpoints and non-invasive pharmacokinetic sampling. Both have the potential to transform pediatric clinical trials and pediatric clinical care. The process towards implementation is challenging and can only proceed after a rigorous validation process. The current work provides a roadmap towards selection, validation, and implementation of digital endpoints, and describes preliminary steps taken for several candidates. The digital endpoints investigated in this work fulfill several validation criteria in a range of clinical conditions and, combined with non-invasive pharmacokinetics, may move the pediatric clinical trial completely towards the home.

Concentrations of drugs acting in the lungs are difficult to measure, resulting in relatively unknown local pharmacokinetics. The aim of this study is to assess the potential of exhaled breath condensate (EBC) as a matrix for pharmacokinetic analysis of inhaled and intravenous medication. A 4-way crossover study was conducted in 12 volunteers with tobramycin and salbutamol intravenously and via inhalation. EBC and plasma samples were collected postdose and analysed for drug concentrations. Sample dilution, calculated using urea concentrations, was used to estimate the epithelial lining fluid concentration. Salbutamol and tobramycin were largely undetectable in EBC after intravenous administration and were detectable after inhaled administration in all subjects in 50.8 and 51.5% of EBC samples, respectively. Correction of EBC concentrations for sample dilution did not explain the high variability. This high variability of EBC drug concentrations seems to preclude EBC as a matrix for pharmacokinetic analysis of tobramycin and salbutamol.