Dysfunctional neutrophil type 1 interferon responses in preschool children with recurrent wheezing and IL-4-mediated aeroallergen sensitization.

Background: The innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood. Objective: We sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression. Methods: Blood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months. Results: A total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4-treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment. Conclusions: Type 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population.

Pediatric emergency department-based asthma education tools and parent/child asthma knowledge.

Asthma exacerbations are a leading cause of pediatric hospitalizations despite multiple efforts to educate patients and families on disease course and medication management. Asthma education in the pediatric emergency department (ED) is challenging, and although the use of written action plans has been associated with reduction in hospitalizations and ED visits, written tools may not be useful for individuals with low health literacy. Moreover, asthmatic children should participate in their asthma education. In this prospective randomized study of 53 families presenting to a pediatric ED with a child experiencing an asthma exacerbation, education on asthma was presented via an interactive mobile-based video-game versus a standard-of-care asthma education video (SAV). Median age was 10 years; 64% were males. Many patients had moderate-to-severe asthma, with 57% experiencing ≥ 2 asthma-related ED visits in the last year, 58% requiring hospitalization and 32% reporting a critical care admission. In this cohort, the mobile-based video-game was found to be a feasible, acceptable educational tool; 86% of parents and 96% of children liked the game, while 96% of parents and 76% of children preferred playing the game over watching a SAV. Despite a history of persistent asthma, only 34% of children used an inhaled corticosteroid while 70% required rescue inhaler use in the prior week. Basic asthma knowledge was sub-optimal with only 60% of parents and 43% of children correctly recognizing symptoms that should prompt immediate medical care. This reflects a major gap in asthma knowledge that coexists with parental misconceptions regarding optimal asthma management.

Environmental Injustice Is Associated With Poorer Asthma Outcomes in School-Age Children With Asthma in Metropolitan Atlanta, Georgia.

BACKGROUND: Environmental justice mandates that no person suffers disproportionately from environmental exposures. The Environmental Justice Index (EJI) provides an estimate of the environmental burden for each census tract but has not yet been used in asthma populations. OBJECTIVE: We hypothesized that children from census tracts with high environmental injustice determined by the EJI would have a greater burden of asthma exacerbations, poorer asthma control, and poorer lung function over 12 months. METHODS: Children aged 6 to 18 years with asthma (N = 575) from metropolitan Atlanta, Georgia, completed a baseline research visit. Participant addresses were geocoded to obtain the EJI Social-Environmental Ranking for each participant's census tract, which was divided into tertiles. Medical records were reviewed for 12 months for asthma exacerbations. A subset of participants completed a second research visit involving spirometry and questionnaires. RESULTS: Census tracts with the greatest environmental injustice had more racial and ethnic minorities, lower socioeconomic status, more hazardous exposures (particularly to airborne pollutants), and greater proximity to railroads and heavily trafficked roadways. Children with asthma residing in high injustice census tracts had a longer duration of asthma, greater historical asthma-related health care utilization, poorer asthma symptom control and quality of life, and more impaired lung function. By 12 months, children from high injustice census tracts also had more asthma exacerbations with a shorter time to exacerbation and persistently more symptoms, poorer asthma control, and reduced lung function. CONCLUSIONS: Disparities in environmental justice are present in metropolitan Atlanta that may contribute to asthma outcomes in children. These findings require an additional study and action to improve health equity.

Altered Symptom Perception in Children With Asthma Is Associated With Poor Childhood Opportunity and Adverse Outcomes.

BACKGROUND: Effective asthma self-management requires that children recognize their asthma symptoms when they occur. However, some children have altered symptom perception, which impairs their ability to respond to their asthma symptoms in a timely manner. OBJECTIVE: To characterize the prevalence and features of altered symptom perception in children aged 5 to 18 years. We hypothesized that children with altered symptom perception would have more features of uncontrolled asthma, more health inequity, and poorer longitudinal asthma outcomes over 12 months. METHODS: Children (N = 371) completed an outpatient research visit for clinical characterization. Altered symptom perception was defined by discordance between child responses on the 6-item Asthma Control Questionnaire and medical provider-elicited symptoms. Electronic medical records were reviewed for 12 months for the occurrence of an asthma exacerbation treated with systemic corticosteroids and an asthma exacerbation prompting an emergency department visit. RESULTS: Approximately 15% of children had altered symptom perception and their asthma features were similar to those of children with uncontrolled asthma. Children with altered symptom perception were uniquely distinguished by non-White race and more severe prior exacerbations. These children also resided in ZIP codes with the poorest childhood opportunity (ie, poorest education, health and environmental features, and socioeconomic features). Outcomes of children with altered symptom perception were equally disparate with approximately 2-fold higher odds of a future exacerbation and approximately 3-fold higher odds of an emergency department visit for asthma. CONCLUSIONS: Altered symptom perception is present in a small but significant number of children with asthma and is related to poorer childhood opportunity and other health inequities that require additional intervention.

Metabolomics identifies disturbances in arginine, phenylalanine, and glycine metabolism as differentiating features of exacerbating atopic asthma in children.

Background: Asthma exacerbations are highly prevalent in children, but only a few studies have examined the biologic mechanisms underlying exacerbations in this population. Objective: High-resolution metabolomics analyses were performed to understand the differences in metabolites in children with exacerbating asthma who were hospitalized in a pediatric intensive care unit for status asthmaticus. We hypothesized that compared with a similar population of stable outpatients with asthma, children with exacerbating asthma would have differing metabolite abundance patterns with distinct clustering profiles. Methods: A total of 98 children aged 6 through 17 years with exacerbating asthma (n = 69) and stable asthma (n = 29) underwent clinical characterization procedures and submitted plasma samples for metabolomic analyses. High-confidence metabolites were retained and utilized for pathway enrichment analyses to identify the most relevant metabolic pathways that discriminated between groups. Results: In all, 118 and 131 high-confidence metabolites were identified in positive and negative ionization mode, respectively. A total of 103 unique metabolites differed significantly between children with exacerbating asthma and children with stable asthma. In all, 8 significantly enriched pathways that were largely associated with alterations in arginine, phenylalanine, and glycine metabolism were identified. However, other metabolites and pathways of interest were also identified. Conclusion: Metabolomic analyses identified multiple perturbed metabolites and pathways that discriminated children with exacerbating asthma who were hospitalized for status asthmaticus. These results highlight the complex biology of inflammation in children with exacerbating asthma and argue for additional studies of the metabolic determinants of asthma exacerbations in children because many of the identified metabolites of interest may be amenable to targeted interventions.

Functional immunophenotyping of blood neutrophils identifies novel endotypes of viral response in preschool children with recurrent wheezing.

BACKGROUND: Preschool 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. OBJECTIVE: We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n = 16; no sensitization, n = 36). METHODS: Blood 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. RESULTS: A 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. CONCLUSIONS: Systemic 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.

Rhinoviruses A and C elicit long-lasting antibody responses with limited cross-neutralization.

Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.

Examining decisional needs and contextual factors influencing fertility status assessment among young female survivors of childhood cancer: A sequential mixed methods study protocol.

INTRODUCTION: Female cancer survivors who received gonadotoxic cancer treatment are at risk for profound diminished ovarian reserve and/or primary ovarian insufficiency with resulting infertility, which can be associated with distress and decreased quality of life.. Despite prioritizing future parenthood, many survivors are unsure of the impact of their treatment on their future fertility, and little is known about the perceived reproductive health needs and factors associated with receipt of a fertility status assessment (FSA). There is a lack of developmentally appropriate reproductive health decisional support interventions available for emerging adult cancer survivors. This study will explore the perceived reproductive health needs of emerging adult female survivors of childhood cancer and to identify decisional and contextual factors that influence pursuit of FSA using an explanatory sequential quantitative to qualitative mixed methods design. METHODS AND ANALYSIS: This study will enroll 325 female survivors (aged 18 to 29 years and >1-year post treatment; diagnosed with cancer < age 21 years) from four cancer centers in the United States. Sociodemographic and developmental factors, reproductive knowledge and values, decisional needs, and receipt of an FSA will be assessed through a web-based survey. Informed by survey findings, a subset of participants will be recruited for qualitative interviews to explore decisional factors associated with uptake of an FSA. Clinical data will be abstracted from the medical records. Multivariable logistic regression models will be developed to identify factors associated with FSA and qualitative descriptive analysis will be used to develop themes from the interviews. Quantitative and qualitative findings will be merged using a joint display to develop integrated study conclusions and direct future interventional research.

RNA Sequencing Analysis of CD4+ T Cells Exposed to Airway Fluid From Children With Pediatric Acute Respiratory Distress Syndrome.

CD4+ T cells contribute to lung inflammation in acute respiratory distress syndrome. The CD4+ T-cell response in pediatric acute respiratory distress syndrome (PARDS) is unknown. OBJECTIVES: To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor CD4+ T cells exposed to the airway fluid of intubated children with mild versus severe PARDS. DESIGN: In vitro pilot study. SETTING: Laboratory-based study using human airway fluid samples admitted to a 36-bed university-affiliated pediatric intensive care unit. PATIENTS/SUBJECTS: Seven children with severe PARDS, nine children with mild PARDS, and four intubated children without lung injury as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed bulk RNA sequencing using a transcriptomic reporter assay of CD4+ T cells exposed to airway fluid from intubated children to discover gene networks differentiating severe from mild PARDS. We found that innate immunity pathways, type I (α and ß), and type II (γ) interferon response and cytokine/chemokine signaling are downregulated in CD4+ T cells exposed to airway fluid from intubated children with severe PARDS compared with those with mild PARDS. CONCLUSIONS: We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a novel CD4+ T-cell reporter assay that exposed CD4+ T cells to airway fluid from intubated children with severe and mild PARDS. These pathways will help drive mechanistic investigations into PARDS. Validation of our findings using this transcriptomic reporter assay strategy is needed.

Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease.

Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.

The 'omics of obesity in B-cell acute lymphoblastic leukemia.

The obesity pandemic currently affects more than 70 million Americans and more than 650 million individuals worldwide. In addition to increasing susceptibility to pathogenic infections (eg, SARS-CoV-2), obesity promotes the development of many cancer subtypes and increases mortality rates in most cases. We and others have demonstrated that, in the context of B-cell acute lymphoblastic leukemia (B-ALL), adipocytes promote multidrug chemoresistance. Furthermore, others have demonstrated that B-ALL cells exposed to the adipocyte secretome alter their metabolic states to circumvent chemotherapy-mediated cytotoxicity. To better understand how adipocytes impact the function of human B-ALL cells, we used a multi-omic RNA-sequencing (single-cell and bulk transcriptomic) and mass spectroscopy (metabolomic and proteomic) approaches to define adipocyte-induced changes in normal and malignant B cells. These analyses revealed that the adipocyte secretome directly modulates programs in human B-ALL cells associated with metabolism, protection from oxidative stress, increased survival, B-cell development, and drivers of chemoresistance. Single-cell RNA sequencing analysis of mice on low- and high-fat diets revealed that obesity suppresses an immunologically active B-cell subpopulation and that the loss of this transcriptomic signature in patients with B-ALL is associated with poor survival outcomes. Analyses of sera and plasma samples from healthy donors and those with B-ALL revealed that obesity is associated with higher circulating levels of immunoglobulin-associated proteins, which support observations in obese mice of altered immunological homeostasis. In all, our multi-omics approach increases our understanding of pathways that may promote chemoresistance in human B-ALL and highlight a novel B-cell-specific signature in patients associated with survival outcomes.

The Fungal Microbiome of the Upper Airway Is Associated With Future Loss of Asthma Control and Exacerbation Among Children With Asthma.

BACKGROUND: Accumulating evidence suggests that the upper airway bacterial microbiota is implicated in asthma inception, severity, and exacerbation. Unlike bacterial microbiota, the role of the upper airway fungal microbiome (mycobiome) in asthma control is poorly understood. RESEARCH QUESTION: What are the upper airway fungal colonization patterns among children with asthma and their relationship with subsequent loss of asthma control and exacerbation of asthma? STUDY DESIGN AND METHODS: The study was coupled with the Step Up Yellow Zone Inhaled Corticosteroids to Prevent Exacerbations (ClinicalTrials.gov Identifier: NCT02066129) clinical trial. The upper airway mycobiome was investigated using Internal transcribed spacer 1 (ITS1) sequencing of nasal blow samples collected from children with asthma when asthma was well controlled (baseline, n = 194) and during early signs of loss of asthma control (yellow zone [YZ], n = 107). RESULTS: At baseline, 499 fungal genera were detected in the upper airway samples, with two commensal fungal species, Malassezia globosa and Malassezia restricta, being most dominant. The relative abundance of Malassezia species varies by age, BMI, and race. Higher relative abundance of M globosa at baseline was associated with lower risk of future YZ episodes (P = .038) and longer time to development of first YZ episode (P = .022). Higher relative abundance of M globosa at YZ episode was associated with lower risk of progression from YZ episode to severe asthma exacerbation (P = .04). The upper airway mycobiome underwent significant changes from baseline to YZ episode, and increased fungal diversity was correlated highly with increased bacterial diversity (ρ = 0.41). INTERPRETATION: The upper airway commensal mycobiome is associated with future asthma control. This work highlights the importance of the mycobiota in asthma control and may contribute to the development of fungi-based markers to predict asthma exacerbation.

Social determinants of health influence preschool and caregiver experiences during symptoms and exacerbations of wheezing.

BACKGROUND: Social determinants of health have been inadequately studied in preschool children with wheezing and their caregivers but may influence the care received. OBJECTIVE: To evaluate the symptom and exacerbation experiences of wheezing preschool children and their caregivers, stratified by risk of social vulnerability, over 1 year of longitudinal follow-up. METHODS: A total of 79 caregivers and their preschool children with recurrent wheezing and at least 1 exacerbation in the previous year were stratified by a composite measure of social vulnerability into "low" (N = 19), "intermediate" (N = 27), and "high" (N = 33) risk groups. Outcome measures at the follow-up visits included child respiratory symptom scores, asthma control, caregiver-reported outcome measures of mental and social health, exacerbations, and health care utilization. The severity of exacerbations reflected by symptom scores and albuterol use and exacerbation-related caregiver quality of life were also assessed. RESULTS: Preschool children at high risk of social vulnerability had greater day-to-day symptom severity and more severe symptoms during acute exacerbations. High-risk caregivers were also distinguished by lower general life satisfaction at all visits and lower global and emotional quality of life during acute exacerbations which did not improve with exacerbation resolution. Rates of exacerbation or emergency department visits did not differ, but intermediate- and high-risk families were significantly less likely to seek unscheduled outpatient care. CONCLUSION: Social determinants of health influence wheezing outcomes in preschool children and their caregivers. These findings argue for routine assessment of social determinants of health during medical encounters and tailored interventions in high-risk families to promote health equity and improve respiratory outcomes.

Cluster analysis of plasma cytokines identifies two unique endotypes of children with asthma in the pediatric intensive care unit.

Children with life-threatening asthma exacerbations who are admitted to a pediatric intensive care unit (PICU) are a heterogeneous group with poorly studied inflammatory features. We hypothesized that distinct clusters of children with asthma in a PICU would be identified based on differences in plasma cytokine levels and that these clusters would have differing underlying inflammation and asthma outcomes within 1 year. Plasma cytokines and differential gene expression were measured in neutrophils isolated from children admitted to a PICU for asthma. Participants were clustered by differential plasma cytokine abundance. Gene expression differences were compared by cluster and pathway over-representation analysis was performed. We identified two clusters in 69 children with no clinical differences. Cluster 1 (n = 41) had higher cytokines compared to Cluster 2 (n = 28). Cluster 2 had a hazard ratio of 2.71 (95% CI 1.11-6.64) compared to Cluster 1 for time to subsequent exacerbation. Gene expression pathways that differed by cluster included interleukin-10 signaling; nucleotide-binding domain, leucine rich repeat containing receptor (NLR signaling); and toll-like receptor (TLR) signaling. These observations suggest that a subset of children may have a unique pattern of inflammation during PICU hospitalization that might require alternative treatment approaches.

Poorer Caregiver Mental and Social Health Is Associated With Worse Respiratory Outcomes in Preschool Children With Recurrent Wheezing.

BACKGROUND: Mental and social health in caregivers of preschool children has been inadequately studied, but it may influence respiratory symptom recognition and management. OBJECTIVE: To identify preschool caregivers at highest risk for poor mental and social health outcomes on the basis of patient-reported outcome measures. METHODS: Female caregivers 18 to 50 years old (N = 129) with a preschool child aged 12 to 59 months with recurrent wheezing and at least 1 exacerbation in the previous year completed 8 validated patient-reported outcome measures of mental and social health. k-means cluster analysis was performed using the T score for each instrument. Caregiver/child dyads were followed for 6 months. Primary outcomes included caregiver quality of life and wheezing episodes in their preschool children. RESULTS: Three clusters of caregivers were identified: low risk (n = 38), moderate risk (n = 56), and high risk (n = 35). The high-risk cluster had the lowest life satisfaction, meaning and purpose, and emotional support and the highest social isolation, depression, anger, perceived stress, and anxiety that persisted for more than 6 months. This cluster had the poorest quality of life and marked disparities in social determinants of health. Preschool children from caregivers in the high-risk cluster had more frequent respiratory symptoms and a higher occurrence of any wheezing episode, but a lower outpatient physician utilization for wheezing management. CONCLUSIONS: Caregiver mental and social health is associated with respiratory outcomes in preschool children. Routine assessment of mental and social health in caregivers is warranted to promote health equity and improve wheezing outcomes in preschool children.

Blood Eosinophils for Prediction of Exacerbation in Preschool Children With Recurrent Wheezing.

BACKGROUND: Although clinical features of type 2 inflammation have been associated with poorer longitudinal outcomes in preschool children with recurrent wheezing, it remains difficult to predict which children are at highest risk for poor outcomes during a routine clinical encounter. OBJECTIVE: We tested the hypothesis that prespecified cut points of blood eosinophil counts would predict exacerbation and treatment response outcomes in preschool children with recurrent wheezing and that prediction could be improved with the addition of a second biomarker. METHODS: Data from 3 clinical trials of 1,074 preschool children aged 12 to 71 months with recurrent wheezing were merged. The primary outcome was the occurrence of any exacerbation during follow-up. Secondary outcomes included the annualized rate of wheezing exacerbations and the occurrence of any exacerbation requiring hospitalization. Exploratory analyses focused on exacerbation outcomes, offline exhaled nitric oxide concentrations, and caregiver-reported asthma control scores after inhaled corticosteroid treatment initiation. RESULTS: Each blood eosinophil cut point was associated with increased odds of exacerbation, higher exacerbation rates, and greater hospitalization occurrence in preschool children with recurrent wheezing. However, outcome detection was improved in children with more elevated blood eosinophil counts. Addition of a second biomarker of type 2 inflammation improved outcome detection and was further associated with an improved response to initiation of daily inhaled corticosteroids in exploratory analyses. However, the specificity of blood eosinophils was poor. CONCLUSIONS: Although validation studies are warranted, blood eosinophil cut points may be useful for clinical assessment and future studies of exacerbation and treatment response in preschool children with recurrent wheezing.

Association of Asthma With Treatments and Outcomes in Children With Critical Influenza.

BACKGROUND: Hospitalization for severe influenza infection in childhood may result in postdischarge sequelae. OBJECTIVE: To evaluate inpatient management and postdischarge sequelae in children with critical respiratory illness owing to influenza with or without preexisting asthma. METHODS: This was a prospective, observational multicenter study of children (aged 8 months to 17 years) admitted to a pediatric intensive care or high-acuity unit (in November 2019 to April 2020) for influenza. Results were stratified by preexisting asthma. Prehospital status, hospital treatments, and outcomes were collected. Surveys at approximately 90 days after discharge evaluated postdischarge health resource use, functional status, and respiratory symptoms. RESULTS: A total of 165 children had influenza: 56 with preexisting asthma (33.9%) and 109 without it (66.1%; 41.1% and 39.4%, respectively, were fully vaccinated against influenza). Fifteen patients with preexisting asthma (26.7%) and 34 without it (31.1%) were intubated. More patients with versus without preexisting asthma received pharmacologic asthma treatments during hospitalization (76.7% vs 28.4%). Of 136 patients with 90-day survey data (82.4%; 46 with preexisting asthma [33.8%] and 90 without it [66.1%]), a similar proportion had an emergency department/urgent care visit (4.3% vs 6.6%) or hospital readmission (8.6% vs 3.3%) for a respiratory condition. Patients with preexisting asthma more frequently experienced asthma symptoms (78.2% vs 3.3%) and had respiratory specialist visits (52% vs 20%) after discharge. Of 109 patients without preexisting asthma, 10 reported receiving a new diagnosis of asthma (11.1%). CONCLUSIONS: Respiratory health resource use and symptoms are important postdischarge outcomes after influenza critical illness in children with and without preexisting asthma. Less than half of children were vaccinated for influenza, a tool that could mitigate critical illness and its sequelae.