Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.

The Child Opportunity Index and asthma morbidity among children younger than 5 years old in Washington, DC.

BACKGROUND: Place-based social determinants of health are associated with pediatric asthma morbidity. However, there is little evidence on how social determinants of health correlate to the disproportionately high rates of asthma morbidity experienced by children <5 years old. OBJECTIVES: This study sought to evaluate census tract associations between the Child Opportunity Index ±COI) and at-risk rates (ARRs) for pediatric asthma-related emergency department (ED) encounters and hospitalizations in Washington, DC. METHODS: This was a cross-sectional study of children <5 years old with physician-diagnosed asthma included in the DC Asthma Registry between January 2018 and December 2019. Census tract COI score (1-100) and its 3 domains (social/economic, health/environmental, and educational) were the exposures (source: www.diversitydatakids.org). ED and hospitalization ARRs (outcomes) were created by dividing counts of ED encounters and hospitalizations by populations with asthma for each census tract and adjusted for population-level demographic (age, sex, insurance), clinical (asthma severity), and community (violent crime and limited English proficiency) covariates. RESULTS: Within a study population of 3806 children with a mean age of 2.4 ± 1.4 years, 2132 (56%) had 5852 ED encounters, and 821 (22%) had 1418 hospitalizations. Greater census tract overall COI, social/economic COI, and educational COI were associated with fewer ED ARRs. There were no associations between the health/environmental COI and ED ARRs or between the COI and hospitalization ARRs. CONCLUSION: Improving community-level social, economic, and educational opportunity within specific census tracts may reduce ED ARRs in this population.

Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial.

BACKGROUND: Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. METHODS: This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per µL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. FINDINGS: Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. INTERPRETATION: Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. FUNDING: US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: a multicentre prospective study.

BACKGROUND: Severe bronchiolitis (i.e. bronchiolitis requiring hospitalisation) during infancy is a major risk factor for childhood asthma. However, the exact mechanism linking these common conditions remains unclear. We examined the longitudinal relationship between nasal airway miRNAs during severe bronchiolitis and the risk of developing asthma. METHODS: In a 17-centre prospective cohort study of infants with severe bronchiolitis, we sequenced their nasal microRNA at hospitalisation. First, we identified differentially expressed microRNAs (DEmiRNAs) associated with the risk of developing asthma by age 6 years. Second, we characterised the DEmiRNAs based on their association with asthma-related clinical features, and expression level by tissue and cell types. Third, we conducted pathway and network analyses by integrating DEmiRNAs and their mRNA targets. Finally, we investigated the association of DEmiRNAs and nasal cytokines. RESULTS: In 575 infants (median age 3 months), we identified 23 DEmiRNAs associated with asthma development (e.g. hsa-miR-29a-3p; false discovery rate (FDR) <0.10), particularly in infants with respiratory syncytial virus infection (FDR for the interaction <0.05). These DEmiRNAs were associated with 16 asthma-related clinical features (FDR <0.05), e.g. infant eczema and corticosteroid use during hospitalisation. In addition, these DEmiRNAs were highly expressed in lung tissue and immune cells (e.g. T-helper cells, neutrophils). Third, DEmiRNAs were negatively correlated with their mRNA targets (e.g. hsa-miR-324-3p/IL13), which were enriched in asthma-related pathways (FDR <0.05), e.g. toll-like receptor, PI3K-Akt and FcɛR signalling pathways, and validated by cytokine data. CONCLUSION: In a multicentre cohort of infants with severe bronchiolitis, we identified nasal miRNAs during illness that were associated with major asthma-related clinical features, immune response, and risk of asthma development.

Stressful life events, caregiver depressive symptoms, and child asthma symptom-free days: a longitudinal analysis.

OBJECTIVE: To examine relationships among stressful life events (SLE), caregiver depression, and asthma symptom free days (SFDs) in publicly insured Black children aged 4-12 years with persistent asthma. METHODS: Secondary analysis of longitudinal data from a clinical trial assessing the efficacy of a six-month parental stress management intervention. Using repeated measures Poisson regression, we constructed four models of SLE (Rochester Youth Development Stressful Life Events scale-Parent Items), caregiver depression (Center for Epidemiologic Studies Depression scale ≥ 11), and child asthma symptom-free days (SFDs) in the prior 14 days. RESULTS: There was no association between SLE and child SFDs, but there was for caregiver depression (Incidence Rate Ratio [IRR]: 0.904; 95% CI 0.86-0.95). The interaction between SLE and caregiver depression was not significant. A specific SLE (recent serious family accident or illness) predicted fewer child SFDs (IRR: 0.91, 95% CI: 0.85-0.98). In the interaction model between caregiver depression and recent accident/illness, caregiver depression was associated with fewer child SFDs (IRR: 0.95, 95% CI: 0.91-0.99) as was the interaction between caregiver depression and recent accident/illness (IRR: 0.77, 95% CI 0.66-0.91); but the relationship between recent accident/illness and child SFDs was not (IRR: 1.00, 95% CI, 0.92-1.09), meaning accident/illness was only associated with fewer child SFDs among depressed caregivers. CONCLUSIONS: In a sample of publicly insured Black children with persistent asthma, caregiver depression was negatively associated with child SFDs while overall SLE were not. A recent family accident or illness was negatively associated with child SFDs only when the caregiver was depressed.

Implementation of caregiver depression screening in an urban, community-based asthma clinic: a quality improvement project.

OBJECTIVE: Caregiver depressive symptoms are prevalent among children with asthma and associated with greater asthma morbidity. Identifying caregivers with depression and connecting them to appropriate treatment may reduce child asthma morbidity. The goal of this project was to implement a workflow for caregiver depression screening and treatment referral in an urban, community-based, asthma clinic serving under-resourced children. METHODS: The Model for Improvement with weekly Plan-Do-Study-Act cycles was utilized. A two-item depression screening tool (Patient Health Questionnaire-2; PHQ-2) and an acceptability question using a 5-point Likert scale were added to an existing social needs screening checklist administered to all caregivers during the child's clinic visit. Caregivers with a positive PHQ-2 score (≥3) received the PHQ-9. Positive screens on the PHQ-9 (≥5) received information and referrals by level of risk. PHQ-9 positive caregivers received a follow-up phone call two weeks post-visit to assess connection to support, improvement in depressive symptoms, and satisfaction with resources provided. RESULTS: The PHQ-2 was completed by 84.4% of caregivers (233/276). Caregivers had a mean age of 33.8 years (SD = 8.3; Range: 18-68) and were predominately female (86.4%), Black (80.4%), and non-Hispanic (78.4%). The majority (72.3%) found the screening acceptable (agree/strongly agree). Nearly one in six caregivers (37/233, 15.9%) reported depressive symptoms (PHQ-2 ≥ 3); 11.6% (27/233) had clinically significant symptoms (PHQ-9 score ≥ 10); and 2.1% (5/233) reported suicidal thoughts. Of those with depressive symptoms, 70.3% (26/37) participated in the follow-up phone call. While 50% (13/26) reported the resources given in clinic were "extremely helpful," no caregivers contacted or used them. CONCLUSIONS: Caregiver depression screening was successfully integrated into a pediatric asthma clinic serving under-resourced children. While caregivers found screening to be acceptable, it did not facilitate short-term connection to treatment among those with depressive symptoms.

StethAid: A Digital Auscultation Platform for Pediatrics.

(1) Background: Mastery of auscultation can be challenging for many healthcare providers. Artificial intelligence (AI)-powered digital support is emerging as an aid to assist with the interpretation of auscultated sounds. A few AI-augmented digital stethoscopes exist but none are dedicated to pediatrics. Our goal was to develop a digital auscultation platform for pediatric medicine. (2) Methods: We developed StethAid-a digital platform for artificial intelligence-assisted auscultation and telehealth in pediatrics-that consists of a wireless digital stethoscope, mobile applications, customized patient-provider portals, and deep learning algorithms. To validate the StethAid platform, we characterized our stethoscope and used the platform in two clinical applications: (1) Still's murmur identification and (2) wheeze detection. The platform has been deployed in four children's medical centers to build the first and largest pediatric cardiopulmonary datasets, to our knowledge. We have trained and tested deep-learning models using these datasets. (3) Results: The frequency response of the StethAid stethoscope was comparable to those of the commercially available Eko Core, Thinklabs One, and Littman 3200 stethoscopes. The labels provided by our expert physician offline were in concordance with the labels of providers at the bedside using their acoustic stethoscopes for 79.3% of lungs cases and 98.3% of heart cases. Our deep learning algorithms achieved high sensitivity and specificity for both Still's murmur identification (sensitivity of 91.9% and specificity of 92.6%) and wheeze detection (sensitivity of 83.7% and specificity of 84.4%). (4) Conclusions: Our team has created a technically and clinically validated pediatric digital AI-enabled auscultation platform. Use of our platform could improve efficacy and efficiency of clinical care for pediatric patients, reduce parental anxiety, and result in cost savings.

Association of mold levels in urban children's homes with difficult-to-control asthma.

BACKGROUND: Mold sensitization and exposure are associated with asthma severity, but the specific species that contribute to difficult-to-control (DTC) asthma are unknown. OBJECTIVE: We sought to determine the association between overall and specific mold levels in the homes of urban children and DTC asthma. METHODS: The Asthma Phenotypes in the Inner-City study recruited participants, aged 6 to 17 years, from 8 US cities and classified each participant as having either DTC asthma or easy-to-control (ETC) asthma on the basis of treatment step level. Dust samples had been collected in each participant's home (n = 485), and any dust remaining (n = 265 samples), after other analyses, was frozen at -20oC. The dust samples (n = 265) were analyzed using quantitative PCR to determine the concentrations of the 36 molds in the Environmental Relative Moldiness Index. Logistic regression was performed to discriminate specific mold content of dust from homes of children with DTC versus ETC asthma. RESULTS: Frozen-dust samples were available from 54% of homes of children with DTC (139 of 253) and ETC asthma (126 of 232). Only the average concentration of the mold Mucor was significantly (P < .001) greater in homes of children with DTC asthma. In homes with window air-conditioning units, the Mucor concentration contributed about a 22% increase (1.6 odds ratio; 95% CI, 1.2-2.2) in the ability to discriminate between cases of DTC and ETC asthma. CONCLUSIONS: Mucor levels in the homes of urban youth were a predictor of DTC asthma, and these higher Mucor levels were more likely in homes with a window air-conditioner.

Seasonal airway microbiome and transcriptome interactions promote childhood asthma exacerbations.

BACKGROUND: Seasonal variation in respiratory illnesses and exacerbations in pediatric populations with asthma is well described, though whether upper airway microbes play season-specific roles in these events is unknown. OBJECTIVE: We hypothesized that nasal microbiota composition is seasonally dynamic and that discrete microbe-host interactions modify risk of asthma exacerbation in a season-specific manner. METHODS: Repeated nasal samples from children with exacerbation-prone asthma collected during periods of respiratory health (baseline; n = 181 samples) or first captured respiratory illness (n = 97) across all seasons, underwent bacterial (16S ribosomal RNA gene) and fungal (internal transcribed spacer region 2) biomarker sequencing. Virus detection was performed by multiplex PCR. Paired nasal transcriptome data were examined for seasonal dynamics and integrative analyses. RESULTS: Upper airway bacterial and fungal microbiota and rhinovirus detection exhibited significant seasonal dynamics. In seasonally adjusted analysis, variation in both baseline and respiratory illness microbiota related to subsequent exacerbation. Specifically, in the fall, when respiratory illness and exacerbation events were most frequent, several Moraxella and Haemophilus members were enriched both in virus-positive respiratory illnesses and those that progressed to exacerbations. The abundance of 2 discrete bacterial networks, characteristically comprising either Streptococcus or Staphylococcus, exhibited opposing interactions with an exacerbation-associated SMAD3 nasal epithelial transcriptional module to significantly increase the odds of subsequent exacerbation (odds ratio = 14.7, 95% confidence interval = 1.50-144, P = .02; odds ratio = 39.17, 95% confidence interval = 2.44-626, P = .008, respectively). CONCLUSIONS: Upper airway microbiomes covary with season and with seasonal trends in respiratory illnesses and asthma exacerbations. Seasonally adjusted analyses reveal specific bacteria-host interactions that significantly increase risk of asthma exacerbation in these children.

Risk factors for SARS-CoV-2 infection and transmission in households with children with asthma and allergy: A prospective surveillance study.

BACKGROUND: Whether children and people with asthma and allergic diseases are at increased risk for severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection is unknown. OBJECTIVE: Our aims were to determine the incidence of SARS-CoV-2 infection in households with children and to also determine whether self-reported asthma and/or other allergic diseases are associated with infection and household transmission. METHODS: For 6 months, biweekly nasal swabs and weekly surveys were conducted within 1394 households (N = 4142 participants) to identify incident SARS-CoV-2 infections from May 2020 to February 2021, which was the pandemic period largely before a vaccine and before the emergence of SARS-CoV-2 variants. Participant and household infection and household transmission probabilities were calculated by using time-to-event analyses, and factors associated with infection and transmission risk were determined by using regression analyses. RESULTS: In all, 147 households (261 participants) tested positive for SARS-CoV-2. The household SARS-CoV-2 infection probability was 25.8%; the participant infection probability was similar for children (14.0% [95% CI = 8.0%-19.6%]), teenagers (12.1% [95% CI = 8.2%-15.9%]), and adults (14.0% [95% CI = 9.5%-18.4%]). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Self-reported doctor-diagnosed asthma was not a risk factor for infection (adjusted hazard ratio [aHR] = 1.04 [95% CI = 0.73-1.46]), nor was upper respiratory allergy or eczema. Self-reported doctor-diagnosed food allergy was associated with lower infection risk (aHR = 0.50 [95% CI = 0.32-0.81]); higher body mass index was associated with increased infection risk (aHR per 10-point increase = 1.09 [95% CI = 1.03-1.15]). The household secondary attack rate was 57.7%. Asthma was not associated with household transmission, but transmission was lower in households with food allergy (adjusted odds ratio = 0.43 [95% CI = 0.19-0.96]; P = .04). CONCLUSION: Asthma does not increase the risk of SARS-CoV-2 infection. Food allergy is associated with lower infection risk, whereas body mass index is associated with increased infection risk. Understanding how these factors modify infection risk may offer new avenues for preventing infection.

Effect of the coronavirus disease 2019 pandemic on morbidity among children hospitalized for an asthma exacerbation.

BACKGROUND: Pediatric asthma exacerbations account for substantial morbidity, including emergency department (ED) visits and hospitalizations. Although the coronavirus disease 2019 (COVID-19) pandemic was associated with a decrease in pediatric asthma ED visits and hospitalizations, there is limited information on the clinical characteristics of children hospitalized with an asthma exacerbation during the pandemic. OBJECTIVE: To investigate the clinical characteristics of children hospitalized with an asthma exacerbation during the pandemic as compared with those hospitalized during the same months in the year prior. METHODS: A retrospective case-control study was conducted at the Children's National Hospital, Washington, DC, comparing demographic and clinical characteristics of all children, 2 to 18 years old, hospitalized for an asthma exacerbation between April to September 2020 (cases) and April to September 2019 (controls). RESULTS: We identified 50 cases and 243 controls. Cases were significantly older than controls (9.8 ± 4.3 years vs 6.7 ± 3.8 years; P < .001), had significantly less eczema (16% vs 32.1%; P = .02) and food allergies (6% vs 18.5%; P = .03), and were more noncompliant with controller medications (46% vs 24.7%; P = .002) than controls. Magnesium sulfate was more frequently administered in the ED to the cases than to the controls (84% vs 63%; P = .004). Its use was associated with older age, African American race, and Hispanic ethnicity, but was independent of comorbid conditions. CONCLUSION: Patients hospitalized for asthma during the COVID-19 pandemic were older and have less atopy than those hospitalized prepandemic. A larger proportion received magnesium sulfate in the ED, suggesting patients had with more severe asthma presentation during the pandemic.

Creation and validation of a citywide pediatric asthma registry for the District of Columbia.

OBJECTIVE: To create and validate a citywide pediatric Asthma Registry to improve the care and outcomes of children and adolescents in Washington, DC through data-driven quality improvement (QI). METHODS: All available electronic health record data from inpatient and outpatient domains of Children's National Hospital were aggregated from an existing enterprise data warehouse. Inclusion criteria included asthma relevant ICD-10 codes over the prior 24 months. Available Asthma Registry measures include patient demographics, ambulatory visits, hospital admissions, persistent asthma diagnoses, and prescription of controller medications. Data capture was validated using US Census data and current asthma prevalence estimate of the Behavioral Risk Factor Surveillance System (BRFSS). RESULTS: The registry identified 15,991 DC children and adolescents with asthma aged 0-17 years, inclusive, at the end of 2020. This was 14.2% higher than the estimate of 14,001 children derived from BRFSS. Characteristics of those in the registry included: mean age of 9.5 (1.4) years, 57.9% male, 72.3% Black, and 66.7% publicly insured. Over the prior 24 months, 30.3% had ≥1 emergency department visit, and 10.5% had ≥1 hospital admission. Controller medications were prescribed for 59.6% of children with persistent asthma. Rates varied by sampled primary care practice sites. CONCLUSIONS: A population-level pediatric asthma registry captures more children and adolescents with asthma in DC then a BRFSS-derived estimate, and provides city-wide measures of asthma-related utilization. The registry allows for stratification by primary care practice locations and asthma characteristics, supporting the design, implementation, and evaluation of QI projects at the practice, health system, and population levels.Supplemental data for this article can be accessed at publisher's website.

Inducible expression quantitative trait locus analysis of the MUC5AC gene in asthma in urban populations of children.

BACKGROUND: Mucus plugging can worsen asthma control, lead to reduced lung function and fatal exacerbations. MUC5AC is the secretory mucin implicated in mucus plugging, and MUC5AC gene expression has been associated with development of airway obstruction and asthma exacerbations in urban children with asthma. However, the genetic determinants of MUC5AC expression are not established. OBJECTIVES: This study sought to assess single-nucleotide polymorphisms (SNPs) that influence MUC5AC expression and relate to pulmonary functions in childhood asthma. METHODS: This study used RNA-sequencing data from upper airway samples and performed cis-expression quantitative trait loci (eQTL) and allele-specific expression analyses in 2 cohorts of predominantly Black and Hispanic urban children, a high asthma-risk birth cohort, and an exacerbation-prone asthma cohort. Inducible MUC5AC eQTLs were further investigated during incipient asthma exacerbations. Significant eQTLs SNPs were tested for associations with lung function measurements and their functional consequences were investigated in DNA regulatory databases. RESULTS: Two independent groups of SNPs in the MUC5AC gene that were significantly associated with MUC5AC expression were identified. Moreover, these SNPs showed stronger eQTL associations with MUC5AC expression during asthma exacerbations, which is consistent with inducible expression. SNPs in 1 group also showed significant association with decreased pulmonary functions. These SNPs included multiple EGR1 transcription factor binding sites, suggesting a mechanism of effect. CONCLUSIONS: These findings demonstrate the applicability of organ-specific RNA-sequencing data to determine genetic factors contributing to a key disease pathway. Specifically, they suggest important genetic variations that may underlie propensity to mucus plugging in asthma and could be important in targeted asthma phenotyping and disease management strategies.

Serum Soluble Receptor for Advanced Glycation End Products in Infants With Bronchiolitis: Associations With Acute Severity and Recurrent Wheeze.

BACKGROUND: Although bronchiolitis contributes to substantial acute (eg, intensive care use) and chronic (eg, recurrent wheeze) morbidities in young children, the pathobiology remains uncertain. We examined the associations of serum soluble receptor for advanced glycation end products (sRAGE) with acute and chronic morbidities of bronchiolitis including recurrent wheeze. METHODS: A multicenter, multiyear, cohort study of infants hospitalized for bronchiolitis was analyzed. We measured the serum sRAGE level at hospitalization and its association with intensive care use (use of mechanical ventilation and/or admission to the intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze. RESULTS: In 886 infants with bronchiolitis, the median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze. In multivariable modeling adjusting for 11 confounders, a higher presenting sRAGE level was associated with lower risk of intensive care (odds ratio for each 1-log increment, 0.39; 95% confidence interval [CI], .16 -.91; P = .03) and significantly lower rate of recurrent wheeze (hazard ratio [HR], 0.58; 95% CI, .36 -.94; P = .03). In mediation analysis, the direct effect was significant (HR, 0.60; 95% CI, .37 -.97; P = .04), while the indirect effect was not (P = .30). CONCLUSIONS: Serum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. The effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.

Development of nasal allergen challenge with cockroach in children with asthma.

BACKGROUND: Nasal allergen challenge (NAC) could be a means to assess indication and/or an outcome of allergen-specific therapies, particularly for perennial allergens. NACs are not commonly conducted in children with asthma, and cockroach NACs are not well established. This study's objective was to identify a range of German cockroach extract doses that induce nasal symptoms and to assess the safety of cockroach NAC in children with asthma. METHODS: Ten adults (18-37 years) followed by 25 children (8-14 years) with well-controlled, persistent asthma and cockroach sensitization underwent NAC with diluent followed by up to 8 escalating doses of cockroach extract (0.00381-11.9 µg/mL Bla g 1). NAC outcome was determined by Total Nasal Symptom Score (TNSS) and/or sneeze score. Cockroach allergen-induced T-cell activation and IL-5 production were measured in peripheral blood mononuclear cells. RESULTS: 67% (6/9) of adults and 68% (17/25) of children had a positive NAC at a median response dose of 0.120 µg/mL [IQR 0.0380-0.379 µg/mL] of Bla g 1. Additionally, three children responded to diluent alone and did not receive any cockroach extract. Overall, 32% (11/34) were positive with sneezes alone, 15% (5/34) with TNSS alone, and 21% (7/34) with both criteria. At baseline, NAC responders had higher cockroach-specific IgE (P = .03), lower cockroach-specific IgG/IgE ratios (children, P = .002), and increased cockroach-specific IL-5-producing T lymphocytes (P = .045). The NAC was well tolerated. CONCLUSION: We report the methodology of NAC development for children with persistent asthma and cockroach sensitization. This NAC could be considered a tool to confirm clinically relevant sensitization and to assess responses in therapeutic studies.

Outcomes from a pilot patient-centered hospital-to-home transition program for children hospitalized with asthma.

OBJECTIVE: To evaluate a multi-component hospital-to-home (H2H) transition program for children hospitalized with an asthma exacerbation. METHODS: A pilot prospective randomized clinical trial of guideline-based asthma care with and without a patient-centered multi-component H2H program among children enrolled in K-8th grade on Medicaid hospitalized for an asthma exacerbation. H2H program includes 5 components: medications in-hand at discharge, school-based asthma therapy (SBAT) for controller medications, referral for home trigger assessments, communication with the primary care provider (PCP), and patient navigator support. Primary outcomes included feasibility and acceptability. Secondary outcomes included healthcare utilization, asthma morbidity, and caregiver quality of life. RESULTS: A total of 32 children were enrolled and randomized. Feasibility outcomes in the intervention group included: medications in-hand at discharge (100%); SBAT for controller medication initiated (100%); home visit referrals made (100%) and home visits completed within 4 weeks of discharge (44%); PCP communication (100%); patient navigator communication at 3 days (81.3%) and 14 days (46.7%). Acceptability outcomes in the intervention group included: 87.5% of families continued SBAT, and 87.5% of families reported it was extremely helpful to have the home visit referral. Adjusting for baseline differences in age, asthma severity and control, there was no significant difference in healthcare utilization outcomes. CONCLUSION: These pilot data suggest that comprehensive care coordination initiated during the inpatient stay is feasible and acceptable. A larger trial is justified to determine if the intervention may reduce healthcare utilization for urban, minority children with asthma.

Randomized clinical trial of parental psychosocial stress management to improve asthma outcomes.

OBJECTIVE: Because higher parental psychosocial stress is associated with worsened asthma outcomes in children, we sought to determine if a parent-focused stress management intervention would improve outcomes among their at-risk African American children. METHODS: We enrolled self-identified African American parent-child dyads (children aged 4-12 years old with persistent asthma, no co-morbidities, on Medicaid) in a prospective, single-blind, randomized clinical trial with follow-up at 3, 6, and 12 months. All children received care based on the guidelines of the National Institutes of Health. Developed with extensive local stakeholder engagement, the intervention consisted of four individual sessions with a community wellness coach (delivered over 3 months) supplemented with weekly text messaging and twice monthly group sessions (both delivered for 6 months). The main outcome was asthma symptom-free days in the prior 14 days by repeated measures at 3 and 6 months follow-up. RESULTS: We randomized 217 parent-child dyads and followed 196 (90.3%) for 12 months. Coaches completed 338/428 (79%) of all individual sessions. Symptom-free days increased significantly from baseline in both groups at 3, 6, and 12 months, but there were no significant differences between groups over the first 6 months. At 12 months, the intervention group sustained a significantly greater increase in symptom-free days from baseline [adjusted difference = 0.92 days, 95% confidence interval (0.04, 1.8)]. CONCLUSION: The intervention did not achieve its primary outcome. The efficacy of providing psychosocial stress management training to parents of at-risk African American children with persistent asthma in order to improve the children's outcomes may be limited. CLINICALTRIALS.GOV: NCT02374138.

2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.

The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.

Pathways to Improve Pediatric Asthma Care: A Multisite, National Study of Emergency Department Asthma Pathway Implementation.

OBJECTIVE: To determine the effects of pediatric asthma pathway implementation in a diverse, national sample of emergency departments (EDs). STUDY DESIGN: In this quality improvement study, a national sample of EDs were provided pathways to tailor to local needs. Implementation strategies included local champions, external facilitators/mentors, educational seminars, and audit and feedback. Outcomes included systemic corticosteroid administration within 60 minutes (primary), assessment of severity at ED triage, chest radiograph use, hospital admission or transfer for higher level of care, and ED length of stay (balancing). Each month, EDs reviewed all charts (to a maximum of 20) of children ages 2-17 years with a primary diagnosis of asthma. Analyses were done using multilevel regression models with an interrupted time-series approach, adjusting for patient characteristics. RESULTS: We enrolled 83 EDs (37 in children's hospitals, 46 in community hospitals) and 61 (73%) completed the study (n = 22 963 visits). Pathway implementation was associated with significantly increased odds of systemic corticosteroid administration within 60 minutes of arrival (aOR, 1.26; 95% CI, 1.02-1.55), increased odds of severity assessment at triage (aOR, 1.88; 95% CI, 1.22-2.90), and decreased rate of change in odds of hospital admission/transfer (aOR, 0.97; 95% CI, 0.95-0.99). Pathway implementation was not associated with chest radiograph use or ED length of stay. CONCLUSIONS: Pathway implementation was associated with improved quality of care for children with asthma in a diverse, national group of EDs.