Background:SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of... Show moreBackground:SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data.Methods:This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity.Results:We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curacao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies.Conclusions:Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections. Show less
Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and... Show moreMultisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3(+) CD4(+) T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-gamma associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines. Show less
Microtracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral... Show moreMicrotracer studies present a new opportunity to gain knowledge on drug disposition in the intensive care. Using this modality in children in the pediatric intensive care, we showed that enteral administration of acetaminophen results in less predictable exposure and higher likelihood of subtherapeutic blood concentration than does IV administration. IV dosing may be preferable to ensure adequate pain relief.\nDecreasing morbidity and mortality by rationalizing drug treatment in the critically ill is of paramount importance but challenging as the underlying clinical condition may lead to large variation in drug disposition and response. New microtracer methodology is now available to gain knowledge on drug disposition in the intensive care. On the basis of studies in healthy adults, physicians tend to assume that oral doses of acetaminophen will be completely absorbed and therefore prescribe the same dose per kilogram for oral and IV administration. As the oral bioavailability of acetaminophen in critically ill children is unknown, we designed a microtracer study to shed a light on this issue.\nAn innovative microtracer study design with population pharmacokinetics.\nA tertiary referral PICU.\nStable critically ill children, 0-6 years old, and already receiving IV acetaminophen.\nConcomitant administration of an oral C radiolabeled acetaminophen microtracer (3 ng/kg) with IV acetaminophen treatment (15 mg/kg every 6 hr).\nBlood was drawn from an indwelling arterial or central venous catheter up to 24 hours after C acetaminophen microtracer administration. Acetaminophen concentrations were measured by liquid chromatography-mass spectrometry and C concentrations by accelerated mass spectrometry.\nIn 47 patients (median age of 6.1 mo; Q1-Q3, 1.8-20 mo) the mean enteral bioavailability was 72% (range, 11-91%). With a standard dose (15 mg/kg 4 times daily), therapeutic steady-state concentrations were 2.5 times more likely to be reached with IV than with oral administration. Show less
RATIONALE Various in vitro, animal and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on Cytochrome P450 3A (CYP3A)-mediated drug metabolism. Studies... Show moreRATIONALE Various in vitro, animal and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on Cytochrome P450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, while clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES To prospectively study the relationship between inflammation, organ failure and midazolam clearance, as validated marker of CYP3A mediated drug metabolism, in critically ill children. METHODS From 83 critically ill children (median age 5.1 months (range 0.02-202 months)), midazolam plasma levels (n=532), cytokines (e.g. IL-6, TNF-a), C-reactive protein (CRP) and organ dysfunction scores (PRISM II, PIM2, PELOD), as well as number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MAIN RESULTS In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. Both CRP and organ failure were significantly associated with clearance (p<0.01), explaining both inter-individual and inter-occasional variability. In simulations a CRP of 300 mg/L was associated with a 65% lower clearance compared to 10 mg/L and three failing organs were associated with a 35% lower clearance compared to 1 failing organ. CONCLUSIONS Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity. Show less
