Dataset Information

Functional immunophenotyping of children with critical status asthmaticus identifies differential gene expression responses in neutrophils exposed to a poly(I:C) stimulus.

ABSTRACT: The host immune response to a viral immune stimulus has not been examined in children during a life-threatening asthma attack. We determined whether we could identify clusters of children with critical asthma by functional immunophenotyping using an intracellular viral analog stimulus. We performed a single-center, prospective, observational cohort study of 43 children ages 6-17 years admitted to a pediatric intensive care unit for an asthma attack between July 2019 to February 2021. Neutrophils were isolated from children, stimulated overnight with LyoVec poly(I:C), and mRNA was analyzed using a targeted Nanostring immunology array. Network analysis of the differentially expressed transcripts for the paired LyoVec poly(I:C) samples was performed. We identified two clusters by functional immunophenotyping that differed by the Asthma Control Test score. Cluster 1 (n = 23) had a higher proportion of children with uncontrolled asthma in the four weeks prior to PICU admission compared with cluster 2 (n = 20). Pathways up-regulated in cluster 1 versus cluster 2 included chemokine receptor/chemokines, interleukin-10 (IL-10), IL-4, and IL-13 signaling. Larger validation studies and clinical phenotyping of children with critical asthma are needed to determine the predictive utility of these clusters in a larger clinical setting.

SUBMITTER: Grunwell JR

PROVIDER: S-EPMC9666940 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Functional immunophenotyping of children with critical status asthmaticus identifies differential gene expression responses in neutrophils exposed to a poly(I:C) stimulus.

Grunwell Jocelyn R JR Rad Milad G MG Stephenson Susan T ST Mohammad Ahmad F AF Opolka Cydney C Fitzpatrick Anne M AM Kamaleswaran Rishikesan R

Scientific reports 20221116 1

The host immune response to a viral immune stimulus has not been examined in children during a life-threatening asthma attack. We determined whether we could identify clusters of children with critical asthma by functional immunophenotyping using an intracellular viral analog stimulus. We performed a single-center, prospective, observational cohort study of 43 children ages 6-17 years admitted to a pediatric intensive care unit for an asthma attack between July 2019 to February 2021. Neutrophils ...[more]

PMID: 36385161

Similar Datasets

Project description:BackgroundPreschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population.ObjectiveWe performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n = 16; no sensitization, n = 36).MethodsBlood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid [poly(I:C)] as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase, and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation.ResultsA total of 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (ie, more myeloperoxidase and extracellular DNA) and less neutrophil proinflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (ie, M2) phenotype in sensitized children and a more proinflammatory (ie, M1) phenotype in nonsensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled health care were also higher in children without aeroallergen sensitization after enrollment.ConclusionsSystemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at type 2-high inflammation.

Project description:BackgroundIntravenous 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.ObjectiveOur 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.MethodsFrom 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.ResultsA 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.ConclusionsThe 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.

Project description:ObjectivesTo determine risk factors associated with admission to a PICU with or without endotracheal intubation for an asthma exacerbation. We hypothesized that children with critical and near-fatal asthma would have distinguishing clinical features but varying degrees of asthma severity and measures of type 2 inflammation.DesignRetrospective analysis of prospectively collected data of children with asthma recruited into outpatient asthma clinical research studies at Emory University between 2004 and 2015.SettingLarge, free-standing academic quaternary care children's hospital in Atlanta, GA.PatientsChildren 6-18 years old with physician-diagnosed and confirmed asthma.InterventionsNone.Measurements and main resultsA total of 579 children were analyzed with 170 children (29.4%) being admitted to the PICU for an asthma exacerbation in their lifetime. Of these 170 children with a history of critical asthma, 24.1% were classified as having mild-to-moderate asthma, and 83 of 170 children (48.8%) had been intubated and experienced near-fatal asthma. Multiple logistic regression was used to identify risk factors associated with increased odds of PICU admission with or without endotracheal intubation. Hospitalization within the prior 12 months of survey (odds ratio, 8.19; 95% CI, 4.83-13.89), a history of pneumonia (odds ratio, 2.56; 95% CI, 1.52-4.29), having a designation of increased chronic asthma severity on high-dose inhaled corticosteroids (odds ratio, 2.76; 95% CI, 1.62-4.70), having a father with asthma (odds ratio, 2.15; 95% CI, 1.23-3.76), living in a region with a higher burden of poverty (odds ratio, 1.28; 95% CI, 1.02-1.61), and being of black race (odds ratio, 2.01; 95% CI, 1.05-3.84) were all associated with increased odds of PICU admission with or without intubation.ConclusionsOur findings suggest that there are factors associated with critical and near-fatal asthma, distinct from the chronic asthma severity designations, that should be the focus of future investigation.

Dataset Information

Functional immunophenotyping of children with critical status asthmaticus identifies differential gene expression responses in neutrophils exposed to a poly(I:C) stimulus.

Publications

Functional immunophenotyping of children with critical status asthmaticus identifies differential gene expression responses in neutrophils exposed to a poly(I:C) stimulus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets