In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRβ repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.

Background Intravenous salbutamol is used to treat children with refractory status asthmaticus, however insufficient pharmacokinetic data are available to guide initial and subsequent dosing recommendations for its intravenous use. The pharmacologic activity of salbutamol resides predominantly in the (R)-enantiomer, with little or no activity and even concerns of adverse reactions attributed to the (S)-enantiomer. Objective Our aim was to develop a population pharmacokinetic model to characterize the pharmacokinetic profile for intravenous salbutamol in children with status asthmaticus admitted to the pediatric intensive care unit (PICU), and to use this model to study the effect of different dosing schemes with and without a loading dose. Methods From 19 children (median age 4.9 years [range 9 months-15.3 years], median weight 18 kg [range 7.8-70 kg]) treated with continuous intravenous salbutamol at the PICU, plasma samples for R-and S-salbutamol concentrations (111 samples), as well as asthma scores, were collected prospectively at the same time points. Possible adverse reactions and patients' clinical data (age, sex, weight, drug doses, liver and kidney function) were recorded. With these data, a population pharmacokinetic model was developed using NONMEM 7.2. After validation, the model was used for simulations to evaluate the effect of different dosing regimens with or without a loading dose. Results A two-compartment model with separate clearance for R-and S-salbutamol (16.3 L/h and 8.8 L/h, respectively) best described the data. Weight was found to be a significant covariate for clearance and volume of distribution. No other covariates were identified. Simulations showed that a loading dose can result in higher R-salbutamol concentrations in the early phase after the start of infusion therapy, preventing accumulation of S-salbutamol. Conclusions The pharmacokinetic model of intravenous R-and S-salbutamol described the data well and showed that a loading dose should be considered in children. This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol in children, and, as a next step, the effectiveness and tolerability of intravenous salbutamol in children with severe asthma. Nienke J. Vet and Brenda C. M. de Winter contributed equally to this work.In this prospective study, we developed a population pharmacokinetic model of intravenous R-and S-salbutamol in children with status asthmaticus admitted to the intensive care unit.The model described the data well and showed that a loading dose seems valid to reach higher initial R-salbutamol concentrations with a possible therapeutic advantage.This model can be used to evaluate the pharmacokinetic-pharmacodynamic relationship of intravenous salbutamol.

No abstract

No abstract

ObjectivesTo develop a population pharmacokinetic model of R-albuterol and S-albuterol for children suffering from status asthmaticus following continuous intravenous administration.MethodsAt the pediatric ICU 19 children suffering from severe status asthmaticus were treated using continuous intravenous albuterol in doses based on clinical symptoms (range 0.1–10 µg/kg/min). During therapy 111 blood samples were collected and analysed for R- and S-albuterol using a validated LC/MS-MS method. A population pharmacokinetic analysis was conducted using non-linear mixed effects modelling (NONMEM 7.2). Data was logarithmically transformed. Model selection criteria were decrease in objective function, diagnostic plots and NPDE. The covariates (range) analysed were bodyweight (7.8–70 kg), age (0.8–15.3 years), creatinine concentration (17–70 µmol/L), alanine transaminase (5–29 IU/L), and urea (1.6–4.8 mmol/L).ResultsA two-compartment model with separated clearance for R- (16.3 L/h) and S-albuterol (8.8 L/h) best described the data. Separated values for central volume of distribution (12.9 L), peripheral volume of distribution (45.2 L) and intercompartmental clearance (20.0 L/h) did not improve the model. Between-subject variability was described for clearance of R-albuterol (42%), clearance of S-albuterol (37%) and central volume of distribution (280%). Weight is a significant covariate using a power function. The exponent of the powerfunction was fixed at 0.75 for clearance and intercompartmental and at 1 for central and peripheral volume of distribution. Estimation of the exponent resulted in similar values and did not improve the model. No other covariates were identified.ConclusionThe population pharmacokinetics of R- and S-albuterol are described. This model can be used to evaluate the correlation between albuterol pharmacokinetics and effect in a population pharmacokinetic-pharmacodynamic analysis.