Outcomes of children with life-threatening status asthmaticus requiring isoflurane therapy and extracorporeal life support.

BACKGROUND: Severe, refractory asthma is a life-threatening emergency that may be treated with isoflurane and extracorporeal life support. The objective of this study was to describe the clinical response to isoflurane and outcomes after discharge of children who received isoflurane and/or extracorporeal life-support for near-fatal asthma. METHODS: This was a retrospective descriptive study using electronic medical record data from two pediatric intensive care units within a single healthcare system in Atlanta, GA. RESULTS: Forty-five children received isoflurane, and 14 children received extracorporeal life support, 9 without a trial of isoflurane. Hypercarbia and acidosis improved within four hours of starting isoflurane. Four children died during the index admission for asthma. Twenty-seven percent had a change in Functional Status Score of three or more points from baseline to PICU discharge. Patients had median percent predicted FEV1 and FEV1/FVC ratios pre- and post-bronchodilator values below normal pediatric values. CONCLUSION: Children who received isoflurane and/or ECLS had a high frequency of previous PICU admission and intubation. Improvement in ventilation and acidosis occurred within the first four hours of starting isoflurane. Children who required isoflurane or ECLS may develop long-lasting deficits in their functional status. Children with near-fatal asthma are a high-risk group and require improved follow-up in the year following PICU discharge.

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

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.

Adverse Childhood Experiences and Patient-Reported Outcome Measures in Critically Ill Children.

Adverse childhood experiences (ACEs) are linked to adverse health outcomes for adults and children in the United States. The prevalence of critically ill children who are exposed to ACEs is not known. Our objective was to compare the frequency of ACEs of critically ill children with that of the general pediatric population of Georgia and the United States using publicly available National Survey of Children's Health (NSCH) data. The impact of ACEs on patient-reported outcome measures of emotional, social, and physical health in critically ill children is not known. We sought to determine whether a higher total number of ACEs was associated with poorer patient-reported measures of emotional, social, and physical health. We conducted a prospective cross-sectional study of children < 18 years of age who were admitted to a 36-bed free-standing, quaternary academic pediatric intensive care unit in Atlanta, Georgia from June 2020-December 2021. Parents of patients who were admitted to the pediatric intensive care unit completed a survey regarding their child's ACEs, health care use patterns, and patient-reported outcome measures (PROMIS) of emotional, social, and physical health. Prevalence estimates of ACEs were compared with national and state data from the NSCH using Rao-Scott Chi-square tests. PROMIS measures reported within the PICU cohort were compared with population normed T-scores. The association of cumulative ACEs within the PICU cohort with patient-reported outcomes of emotional, social, and physical health were evaluated with a t-test. Among the 84 participants, 54% had ≥ 1 ACE, 29% had ≥ 2 ACEs, and 10% had ≥ 3 ACEs. Children with ≥ 2 ACEs had poorer anxiety and family relationship T-scores compared to those with ≤ 1 ACE. Given the high burden of ACEs in critically ill children, screening for ACEs may identify vulnerable children that would benefit from interventions and support to mitigate the negative effects of ACEs and toxic stress on emotional, social, and physical health.

Geospatial Analysis of Social Determinants of Health Identifies Neighborhood Hot Spots Associated With Pediatric Intensive Care Use for Acute Respiratory Failure Requiring Mechanical Ventilation.

OBJECTIVES: Poverty, racial bias, and disparities are linked to adverse health outcomes for children in the United States. The social vulnerability and child opportunity indices are composite measures of the social, economic, education, health, and environmental qualities that affect human health for every U.S. census tract. Composite measures of social vulnerability and child opportunity were compared for neighborhood hot spots, where PICU admissions for acute respiratory failure requiring invasive mechanical ventilation were at the 90th percentile or greater per 1,000 children, versus non-hot spots. DESIGN: Population-based ecological study. SETTING: Two urban free-standing children's hospital PICUs consisting of a 36-bed quaternary academic and a 56-bed tertiary community center, in Atlanta, GA. PATIENTS: Mechanically ventilated children who were 17 years of age or younger with a geocodable Georgia residential address admitted to a PICU for at least 1 day. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Residential addresses were geocoded and spatially joined to census tracts. Composite measures of social vulnerability and childhood opportunity, PICU readmission rates, and hospital length of stay were compared between neighborhood hot spots versus non-hot spots. There were 340 of 3,514 children (9.7%) who lived within a hot spot. Hot spots were associated with a higher (worse) composite social vulnerability index ranking, reflecting differences in socioeconomic status, household composition and disability, and housing type and transportation. Hot spots also had a lower (worse) composite childhood opportunity index percentile ranking, reflecting differences in the education, health and environment, and social and economic domains. Higher social vulnerability and lower childhood opportunity were not associated with readmission rates but were associated with longer total median duration of hospital days per 1,000 children in a census tract. CONCLUSIONS: Social determinants of health identified by geospatial analyses are associated with acute respiratory failure requiring invasive mechanical ventilation in critically ill children. Interventions addressing the neighborhood social vulnerability and child opportunity are needed to decrease disparities in intensive care admissions for acute respiratory failure requiring mechanical ventilation.

Social Vulnerability Is Associated with Poorer Outcomes in Preschool Children With Recurrent Wheezing Despite Standardized and Supervised Medical Care.

BACKGROUND: Social determinants of health are associated with disparate asthma outcomes in school-age children. Social determinants have not been studied in preschool children with recurrent wheezing. OBJECTIVE: We hypothesized that preschool children with recurrent wheezing at highest risk of social vulnerability would have more frequent symptoms and exacerbations when followed over 1 year, despite receiving standardized and supervised asthma care. METHODS: A multicenter population of adherent preschool children receiving standardized and supervised care for wheezing was stratified by a composite measure of social vulnerability based on individual-level variables. Primary outcomes included days with upper respiratory infections and days with asthma symptom flares. Other outcomes included symptom scores during upper respiratory infections and respiratory symptom flare days, exacerbation occurrence, quality of life during the exacerbation, and hospitalization. RESULTS: Preschool children at highest risk of social vulnerability did not have more frequent upper respiratory infections, respiratory symptoms, or exacerbations, but instead had more severe symptoms during upper respiratory infections and respiratory flare days, as well as more severe exacerbations with significantly poorer caregiver quality of life. Children at highest risk of social vulnerability also lived in poorer housing conditions with differing exposures and self-reported triggers. CONCLUSIONS: Individual-level social determinants of health reflecting social vulnerability are associated with poorer outcomes in preschool children with recurrent wheezing despite access to supervised and standardized care. Comprehensive assessment of social determinants of health is warranted in even the youngest children with wheezing, because mitigation of these social inequities is an essential first step toward improving outcomes in pediatric patients.

Geospatial Analysis of Social Determinants of Health Identifies Neighborhood Hot Spots Associated With Pediatric Intensive Care Use for Life-Threatening Asthma.

BACKGROUND: Social determinants of health are associated with asthma prevalence and healthcare use in children with asthma, but are multifactorial and complex. Whether social determinants similarly influence exacerbation severity is not clear. OBJECTIVE: Composite measures of social determinants of health and readmission outcomes were evaluated in a large regional cohort of 1,403 school-age children admitted to a pediatric intensive care unit (PICU) for asthma. METHODS: Residential addresses were geocoded and spatially joined to census tracts. Composite measures of social vulnerability and childhood opportunity, PICU readmission rates, and hospital length of stay were compared between neighborhood hot spots, where PICU admission rates per 1,000 children are at or above the 90th percentile, versus non-hot spots. RESULTS: A total of 228 children resided within a neighborhood hot spot (16%). Hot spots were associated with a higher (ie, poorer) composite Social Vulnerability Index ranking, reflecting differences in socioeconomic status, household composition and disability, and housing type and transportation. Hot spots also had a lower (ie, poorer) composite Childhood Opportunity Index percentile ranking, reflecting differences in the education, health and environment, and social and economic domains. Higher social vulnerability and lower childhood opportunity were associated with PICU readmission. Residing within a hot spot was further associated with a longer duration of hospital stay, individual inpatient bed days, and total census tract inpatient bed days. CONCLUSIONS: Social determinants of health identified by geospatial analyses are associated with more severe asthma exacerbation outcomes in children. Outpatient strategies that address both biological and social determinants of health are needed to care for and prevent PICU admissions optimally in children with asthma.

Cluster analysis and profiling of airway fluid metabolites in pediatric acute hypoxemic respiratory failure.

Hierarchal clustering of amino acid metabolites may identify a metabolic signature in children with pediatric acute hypoxemic respiratory failure. Seventy-four immunocompetent children, 41 (55.4%) with pediatric acute respiratory distress syndrome (PARDS), who were between 2 days to 18 years of age and within 72 h of intubation for acute hypoxemic respiratory failure, were enrolled. We used hierarchal clustering and partial least squares-discriminant analysis to profile the tracheal aspirate airway fluid using quantitative LC-MS/MS to explore clusters of metabolites that correlated with acute hypoxemia severity and ventilator-free days. Three clusters of children that differed by severity of hypoxemia and ventilator-free days were identified. Quantitative pathway enrichment analysis showed that cysteine and methionine metabolism, selenocompound metabolism, glycine, serine and threonine metabolism, arginine biosynthesis, and valine, leucine, and isoleucine biosynthesis were the top five enriched, impactful pathways. We identified three clusters of amino acid metabolites found in the airway fluid of intubated children important to acute hypoxemia severity that correlated with ventilator-free days < 21 days. Further studies are needed to validate our findings and to test our models.

Machine Learning-Based Discovery of a Gene Expression Signature in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: To identify differentially expressed genes and networks from the airway cells within 72 hours of intubation of children with and without pediatric acute respiratory distress syndrome. To test the use of a neutrophil transcription reporter assay to identify immunogenic responses to airway fluid from children with and without pediatric acute respiratory distress syndrome. DESIGN: Prospective cohort study. SETTING: Thirty-six bed academic PICU. PATIENTS: Fifty-four immunocompetent children, 28 with pediatric acute respiratory distress syndrome, who were between 2 days to 18 years old within 72 hours of intubation for acute hypoxemic respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied machine learning methods to a Nanostring transcriptomics on primary airway cells and a neutrophil reporter assay to discover gene networks differentiating pediatric acute respiratory distress syndrome from no pediatric acute respiratory distress syndrome. An analysis of moderate or severe pediatric acute respiratory distress syndrome versus no or mild pediatric acute respiratory distress syndrome was performed. Pathway network visualization was used to map pathways from 62 genes selected by ElasticNet associated with pediatric acute respiratory distress syndrome. The Janus kinase/signal transducer and activator of transcription pathway emerged. Support vector machine performed best for the primary airway cells and the neutrophil reporter assay using a leave-one-out cross-validation with an area under the operating curve and 95% CI of 0.75 (0.63-0.87) and 0.80 (0.70-1.0), respectively. CONCLUSIONS: We identified gene networks important to the pediatric acute respiratory distress syndrome airway immune response using semitargeted transcriptomics from primary airway cells and a neutrophil reporter assay. These pathways will drive mechanistic investigations into pediatric acute respiratory distress syndrome. Further studies are needed to validate our findings and to test our models.

Differential type I interferon response and primary airway neutrophil extracellular trap release in children with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a heterogeneous condition characterized by the recruitment of large numbers of neutrophils into the lungs. Neutrophils isolated from the blood of adults with ARDS have elevated expression of interferon (IFN) stimulated genes (ISGs) associated with decreased capacity of neutrophils to kill Staphylococcus aureus and worse clinical outcomes. Neutrophil extracellular traps (NETs) are elevated in adults with ARDS. Whether pediatric ARDS (PARDS) is similarly associated with altered neutrophil expression of ISGs and neutrophil extracellular trap release is not known. Tracheal aspirate fluid and cells were collected within 72 h from seventy-seven intubated children. Primary airway neutrophils were analyzed for differential ISG expression by PCR, STAT1 phosphorylation and markers of degranulation and activation by flow cytometry. Airway fluid was analyzed for the release of NETs by myeloperoxidase-DNA complexes using an ELISA. Higher STAT1 phosphorylation, markers of neutrophil degranulation, activation and NET release were found in children with versus without PARDS. Higher NETs were detected in the airways of children with ventilator-free days less than 20 days. Increased airway cell IFN signaling, neutrophil activation, and NET production is associated with PARDS. Higher levels of airway NETs are associated with fewer ventilator-free days.