Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

Cannabis use and the prevalence of current asthma among adolescents and adults in the United States.

OBJECTIVES: Cannabis use has increased among adolescents and adults in the United States (US) in recent years. Few data are available on the prevalence of asthma by frequency of cannabis use. This study aimed to estimate the prevalence of asthma by frequency of past 30-day cannabis use among US individuals. METHODS: Data were drawn from the 2020 National Survey on Drug Use and Health (NSDUH), a nationally representative, annual cross-sectional survey of US individuals aged 12 and older in the United States (N = 32,893). Logistic regression models were used to examine the relationship between frequency of any cannabis and/or blunt (i.e., cannabis smoked in a hollowed-out cigar) use in the past 30 days and current asthma, adjusting for demographics and current cigarette smoking. RESULTS: Current asthma was more common among US individuals who reported cannabis use in the past 30-days, relative to those who did not (9.8% vs. 7.4%, p < 0.0001). The odds of asthma was significantly greater among individuals reporting cannabis use 20-30 days/month (Adjusted Odds Ratio [AOR] = 1.67, 95% CI:1.21, 2.31), blunt use 6-15 and 20-30 days/month (AOR = 1.9, 95% CI:1.1, 3.2; AOR = 2.2, 95% CI:1.4, 3.6), respectively, than among those without. A positive linear relationship was observed between frequency of a) cannabis use (p < 0.0001) and b) blunt use (p < 0.0001) and current asthma prevalence. CONCLUSIONS: Findings suggest a dose-response relationship between frequency of current cannabis use and the prevalence of current asthma in the US individuals.

Crosstalk between CD4+ T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma.

Rationale: Pediatric obesity-related asthma is a nonatopic asthma phenotype with high disease burden and few effective therapies. RhoGTPase upregulation in peripheral blood T helper (Th) cells is associated with the phenotype, but the mechanisms that underlie this association are not known. Objectives: To investigate the mechanisms by which upregulation of CDC42 (Cell Division Cycle 42), a RhoGTPase, in Th cells is associated with airway smooth muscle (ASM) biology. Methods: Chemotaxis of obese asthma and healthy-weight asthma Th cells, and their adhesion to obese and healthy-weight nonasthmatic ASM, was investigated. Transcriptomics and proteomics were used to determine the differential effect of obese and healthy-weight asthma Th cell adhesion to obese or healthy-weight ASM biology. Measurements and Main Results: Chemotaxis of obese asthma Th cells with CDC42 upregulation was resistant to CDC42 inhibition. Obese asthma Th cells were more adherent to obese ASM compared with healthy-weight asthma Th cells to healthy-weight ASM. Compared with coculture with healthy-weight ASM, obese asthma Th cell coculture with obese ASM was positively enriched for genes and proteins involved in actin cytoskeleton organization, transmembrane receptor protein kinase signaling, and cell mitosis, and negatively enriched for extracellular matrix organization. Targeted gene evaluation revealed upregulation of IFNG, TNF (tumor necrosis factor), and Cluster of Differentiation 247 (CD247) among Th cell genes, and of Ak strain transforming (AKT), Ras homolog family member A (RHOA), and CD38, with downregulation of PRKCA (Protein kinase C-alpha), among smooth muscle genes. Conclusions: Obese asthma Th cells have uninhibited chemotaxis and are more adherent to obese ASM, which is associated with upregulation of genes and proteins associated with smooth muscle proliferation and reciprocal nonatopic Th cell activation.

Impact of family socioeconomic position on childhood asthma outcomes, severity, and specialist referral - a Danish nationwide study.

BACKGROUND: Asthma is the most common chronic illness in children, carrying a major burden. Socioeconomic position (SEP) affects adult asthma outcomes, but its impact on childhood asthma, particularly in primary versus specialist care, has not been studied thoroughly. METHODS: In a Danish cohort consisting of all children aged 2-17 years redeeming inhaled corticosteroids in 2015, parental SEP impact on asthma outcomes was investigated. Workforce attachment, income, education, and metropolitan residence were chosen as covariates in logistic regression. Outcomes were uncontrolled (excessive use of short-acting beta2-agonists), exacerbating (oral corticosteroid use or hospitalization), and severe asthma (according to GINA 2020). RESULTS: The cohort comprised 29,851 children (median age 8.0, 59% boys). 16% had uncontrolled asthma, 8% had ≥1 exacerbation. Lower income and metropolitan residence correlated with higher odds of poor control, exacerbations, and severe asthma. Lower education correlated with worse asthma outcomes. Education and income were protective factors in primary care, but not in specialist care. Metropolitan residence was the sole factor linked to specialist care referral for severe asthma. CONCLUSION: Low parental SEP and metropolitan residence associated with poor asthma outcomes. However, specialist care often mitigated these effects, though such care was less likely for at-risk children in non-metropolitan areas.

Burden and unmet need for specialist care in poorly controlled and severe childhood asthma in a Danish nationwide cohort.

BACKGROUND: Asthma is a common disease in childhood and adolescence with lifelong consequences particularly among those at risk of severe disease, poor control and/or frequent exacerbations. Specialist care is recommended for at-risk children and adolescents, yet access to specialist management in free-to-access healthcare settings remains poorly understood. METHODS: A Danish nationwide cohort of children and adolescents aged 2-17 years with persistent asthma, defined as repeated redemption of inhaled corticosteroids (ICS) during 2015, were followed for two years, to identify at-risk children and adolescents comprising those with severe asthma (classified according to GINA 2020 guidelines), poor control (defined as use of 400/600 (ages 2-11/12 +) annual doses of short-acting bronchodilators), or frequent exacerbations (defined as use of oral steroids or hospitalization), and access to specialist care. The population is chosen due to detailed medical records in the setting of universal health care. RESULTS: The cohort comprised of 29,851 children and adolescents (59% boys), with a median age of 9 years. While 17% of children were on high dose ICS, 22% were on daily ICS below GINA low dose cut-off. Prevalence of severe asthma (3.0-6.5%) was lower than poor asthma control (6.4-25%); both declined from childhood to adolescence. Exacerbations occurred in 7.1-9.0% of children, with median number of exacerbations being 1 (IQR 1-1). Despite being classified as having mild-to-moderate asthma, 15% had poor asthma control and 3.8% experienced exacerbation(s), respectively. While 61% of children with severe asthma and 58% with exacerbation-prone disease were in specialist care, only 24% with uncontrolled disease were receiving specialist care. Of children and adolescents using high-dose ICS, 71% were managed in primary care, while the use of additional controllers was more common in specialist care. CONCLUSIONS: Throughout childhood and adolescence, there was a high prevalence of severe asthma and poor control, although their prevalence declined with age. We demonstrate a large unmet need for specialist care among children with at-risk asthma, particularly among those with poorly controlled asthma, even in a system with free-to-access, tax-funded healthcare.

Association of fractional exhaled nitric oxide with asthma morbidity in urban minority children.

OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is a well-established measure of allergic airway inflammation and possible useful adjunct disease management tool. We investigated the association of baseline and follow-up FeNO measurements with disease burden in minority children with persistent asthma. METHODS: A retrospective chart review was conducted on 352 African American and Hispanic children seen at an urban Asthma Center in Bronx, NY. Demographic, clinical characteristics, and pulmonary function tests (PFTs) were compared between children with low, intermediate, and high baseline FeNO levels. Among 95 children with subsequent follow up visits, associations of change in FeNO with demographics, clinical characteristics, and PFTs were examined using mixed effects linear regression models. RESULTS: A higher proportion of children with intermediate (54%) and high FeNO (58%) levels had lower airways obstruction compared to those with low FeNO levels (33%). Children with intermediate FeNO levels had more annual hospitalizations (2.8 ± 6.2) compared to those with low and high FeNO levels (1.3 ± 2.8 and 1.3 ± 2.5). These associations did not differ between ethnicities. An increase in FeNO over time was associated with higher BMI z-scores (ß = 6.2, 95% CI: 1.0 to 11.4) and two or more hospitalizations in the past year (ß = 16.1, 95% CI: 1.5 to 30.8). CONCLUSIONS: Intermediate and high FeNO levels are associated with lower airways obstruction and hospitalizations. Initial and serial FeNO measurements can be a useful adjunctive tool in identifying asthma-related morbidity in urban African American and Hispanic children.

Obesity-related pediatric asthma: relationships between pulmonary function and clinical outcomes.

OBJECTIVE: We hypothesized that children with obesity-related asthma would have worse self-reported asthma control, report an increased number of asthma symptoms and have lower FEV1/FVC associated with worse clinical asthma outcomes compared to children with asthma only. METHODS: Cross sectional analyses examined two hundred and eighteen (obesity-related asthma = 109, asthma only = 109) children, ages 7-15 that were recruited from clinics and hospitals within the Bronx, NY. Pulmonary function was assessed by forced expiratory volume in the first second (percent predicted FEV1) and the ratio of FEV1 to the forced vital capacity of the lungs (FEV1/FVC). Structural equation modeling examined if pulmonary function was associated with asthma control and clinical outcomes between groups. RESULTS: Lower percent predicted FEV1 was associated with increased hospitalizations (p = 0.03) and oral steroid bursts in the past 12 months (p = 0.03) in the obesity-related asthma group but not in the asthma only group. FEV1/FVC was also associated with increased hospitalizations (p = 0.02) and oral steroid bursts (p = 0.008) in the obesity-related asthma group but not the asthma only group. Lower FEV1/FVC was associated with the number of asthma symptoms endorsed in the asthma only group but not in the obesity-related asthma group. Percent predicted FEV1 and FEV1/FVC was not associated with asthma control in either group. CONCLUSIONS: Pulmonary function was associated with oral steroid bursts and hospitalizations but not self-reported asthma control, suggesting the importance of incorporating measures of pulmonary function into the treatment of pediatric obesity-related asthma.

Attention-Deficit Hyperactivity Disorder Symptoms, Underperception of Respiratory Compromise, and Illness Representations in Black and Latino Children With Asthma.

OBJECTIVE: This study examined the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, underperception of respiratory compromise, and illness representations in Black and Latino children with asthma. We hypothesized that increased child-reported ADHD symptoms, as well as parent reports for their child, would be associated with underperception of respiratory compromise, and maladaptive asthma beliefs. METHODS: Two hundred ninety-six parent-child dyads were recruited from pediatric asthma and primary care clinics in the Bronx. Participants completed demographic questionnaires, the Conners-3 ADHD Index to measure ADHD symptoms, and the Asthma Illness Representation Scale to assess asthma beliefs. Perception of respiratory compromise was assessed by programmable electronic peak flow monitors that measured the child's subjective estimates of peak expiratory flow (PEF) and actual PEF, with underperception as the primary measure. RESULTS: Child-reported ADHD symptoms were associated with greater underperception (ß = .117, p = .049) of respiratory compromise. Parent-reported ADHD symptoms were associated with greater underperception (ß = .129, p = .028) of respiratory compromise. Child-reported ADHD symptoms (ß = -.188, p < .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 13.135. Parent-reported ADHD symptoms (ß = -.203, p ≤ .001) were associated with more maladaptive asthma beliefs, F(1, 341) = 15.644. CONCLUSIONS: ADHD symptoms were associated with a greater underperception of respiratory compromise and more maladaptive asthma beliefs. Deficits of attentional processes and/or hyperactivity levels might be contributing factors. We emphasize the need for psychoeducation and interventions that improve perception and health beliefs in children with comorbid ADHD and asthma.

Risk Factors for Pneumothorax and Its Association with Ventilation in Neonates.

OBJECTIVE: The mode of ventilation that is implicated in pneumothorax is the one at the time of its diagnosis. Although there is evidence that air leak starts many hours before it is clinically evident, there are no prior studies that have investigated the association of pneumothorax with the mode of ventilation few hours before rather than at the time of its diagnosis. STUDY DESIGN: A retrospective case-control study was conducted in the neonatal intensive care unit (NICU) between 2006 and 2016 where cases of neonates with pneumothorax were compared with gestational age-matched control neonates without pneumothorax. Respiratory support associated with pneumothorax was classified as the mode of ventilation 6 hours before the clinical diagnosis of pneumothorax. We investigated the factors that were different between cases and controls, and between cases of pneumothorax on bubble continuous positive airway pressure (bCPAP) and invasive mechanical ventilation (IMV). RESULT: Of the 8,029 neonates admitted in the NICU during the study period, 223 (2.8%) developed pneumothorax. Among these, 127 occurred among 2,980 (4.3%) neonates on bCPAP, 38 among 809 (4.7%) neonates on IMV, and the remaining 58 among 4,240 (1.3%) neonates on room air. Those with pneumothorax were more likely to be male, have higher body weight, require respiratory support and surfactant administration, and have bronchopulmonary dysplasia (BPD). Among those who developed pneumothorax, there were differences in the gestational age, gender, and use of antenatal steroids between those who were on bCPAP as compared to those on IMV. IMV was associated with increased odds of pneumothorax as compared to those on bCPAP in a multivariable regression analysis. Cases on IMV had higher incidence of intraventricular hemorrhage, retinopathy of prematurity, BPD, and necrotizing enterocolitis, as well as longer length of stay as compared to those on bCPAP. CONCLUSION: Neonates who require any respiratory support have higher incidence of pneumothorax. Among those on respiratory support, those on IMV had higher odds of pneumothorax and worse clinical outcomes as compared to those on bCPAP. KEY POINTS: · The process of air leak leading to pneumothorax in majority of neonates starts much before it is clinically diagnosed.. · It is possible to detect the air leak early in the process by subtle changes in the signs, symptoms and changes in lung function.. · True association of the ventilation associated with pneumothorax is not at the time of diagnosis of pneumothorax but few hours before it is diagnosed.. · There is higher incidence of pneumothorax in neonates on any respiratory support.. · There is significantly higher incidence of pneumothorax among neonates on invasive ventilations as compared to noninvasive ventilation after correction for all other clinical factors..

Endotyping pediatric obesity-related asthma: Contribution of anthropometrics, metabolism, nutrients, and CD4+ lymphocytes to pulmonary function.

BACKGROUND: Obesity-related complications including visceral fat, metabolic abnormalities, nutrient deficiencies, and immune perturbations are interdependent but have been individually associated with childhood asthma. OBJECTIVE: We sought to endotype childhood obesity-related asthma by quantifying contributions of obesity-related complications to symptoms and pulmonary function. METHODS: Multiomics analysis using Similarity Network Fusion followed by mediation analysis were performed to quantify prediction of obese asthma phenotype by different combinations of anthropometric, metabolic, nutrient, and TH-cell transcriptome and DNA methylome data sets. RESULTS: Two clusters (n = 28 and 26) distinct in their anthropometric (neck and midarm circumference, waist to hip ratio [WHR], and body mass index [BMI] z score), metabolic, nutrient, and TH-cell transcriptome and DNA methylome footprint predicted 5 or more pulmonary function indices across 7 different data set combinations. Metabolic measures attenuated the association of neck, WHR, and BMI z score with FEV1/forced vital capacity (FVC) ratio and expiratory reserve volume (ERV), of neck, midarm, and BMI z score with functional residual capacity, but only of WHR with inspiratory capacity. Nutrient levels attenuated the association of neck, midarm circumference, and BMI z score with functional residual capacity, and of WHR with FEV1/FVC ratio, ERV, and inspiratory capacity. TH-cell transcriptome attenuated the association of all 4 anthropometric measures with FEV1/FVC ratio, but only of WHR with ERV and inspiratory capacity. The DNA methylome attenuated the association of all 4 anthropometric measures with FEV1/FVC ratio and ERV, but only of WHR with inspiratory capacity. CONCLUSIONS: Anthropometric, metabolic, nutrient, and immune perturbations have individual but interdependent contributions to obese asthma phenotype, with the most consistent effect of WHR, highlighting the role of truncal adiposity in endotyping childhood obesity-related asthma.

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.

Impact of caregiver depression on child asthma outcomes in Mexicans and Puerto Ricans.

OBJECTIVE: Examine whether caregiver depressive symptoms at baseline predict longitudinal child asthma outcomes in the two populations with the largest asthma disparities: Mexicans and Puerto Ricans. METHODS: Two hundred and sixty-seven Hispanic caregiver-child dyads (Mexican = 188, Puerto Rican = 79; children 5-12 years) were recruited from clinics and hospitals in Phoenix, AZ and the Bronx, NY. The Center for Epidemiological Studies Depression Scale assessed caregiver depressive symptoms; higher scores indicate greater depressive symptomology. Medical records verified child asthma diagnosis. Assessments for outcome variables occurred at baseline, 3, 6, 9, and 12-month follow-ups. Pulmonary function was measured by spirometry, asthma control was measured by the Asthma Control Test, steroid bursts and acute healthcare utilization were assessed by caregiver report and medical records, and adherence was measured by doser devices on controller medications. Structural equation modeling analyzed baseline caregiver depressive symptoms as a predictor of longitudinal child asthma outcomes, and differences between subgroups. RESULTS: Higher caregiver depressive symptoms predicted better pulmonary function (ß = .02, p = .001) in Mexican children, and fewer steroid bursts (ß = -.41, p = .01) and better medication adherence (ß = .02, p = .07) in Puerto Rican children. Caregiver depressive symptoms did not predict pediatric asthma control or acute healthcare utilization in either subgroup. CONCLUSIONS: Caregiver depressive symptomology had unexpected effects on child asthma outcomes. Results may be explained by the Hispanic paradox, caregiver resilience, acculturation, and the study's longitudinal nature. Further research is needed on social determinants of health that may influence differences in child asthma outcomes in heterogeneous Hispanic communities.

Defining pediatric asthma: phenotypes to endotypes and beyond.

Asthma is the most common chronic pediatric lung disease that has traditionally been defined as a syndrome of airway inflammation characterized by clinical symptoms of cough and wheeze. Highlighting the complex and heterogeneous nature of asthma, this review summarizes recent advances in asthma classification that are based on pathobiology, and thereby directly addresses limitations of existent definitions of asthma. By reviewing and contrasting clinical and mechanistic features of adult and childhood asthma, the review summarizes key biomarkers that distinguish childhood asthma subtypes. While atopy and its severity are important features of childhood asthma, there is evidence to support the existence of a childhood asthma endotype distinct from the atopic endotype. Although biomarkers of non-atopic asthma are an area of future research, we summarize a clinical approach that includes existing measures of airway-specific and systemic measures of atopy, co-existing morbidities, and disease severity and control, in the definition of childhood asthma, to empower health care providers to better characterize asthma disease burden in children. Identification of biomarkers of non-atopic asthma and the contribution of genetics and epigenetics to pediatric asthma burden remains a research need, which can potentially allow delivery of precision medicine to pediatric asthma. IMPACT: This review highlights asthma as a complex and heterogeneous disease and discusses recent advances in the understanding of the pathobiology of asthma to demonstrate the need for a more nuanced definitions of asthma. We review current knowledge of asthma phenotypes and endotypes and put forth an approach to endotyping asthma that may be useful for defining asthma for clinical care as well as for future research studies in the realm of personalized medicine for asthma.

Contribution of systemic and airway immune responses to pediatric obesity-related asthma.

Childhood obesity contributes to many diseases, including asthma. Although the precise mechanism by which obesity causes asthma is not known, there is literature to suggest that innate and adaptive systemic and airway immune responses in obese children with asthma differ from those in normal-weight children with asthma. Both non-allergic or non-T2 phenotype with systemic T helper (Th)1 polarization and allergic Th cell responses have been reported in childhood obesity-related asthma. There is preliminary evidence to suggest that genetic and epigenetic mechanisms contribute to these immune responses. Initial investigations into the biology of non-T2 immune responses have identified upregulation of genes in the CDC42 pathway. CDC42 is a RhoGTPase that plays a key role in Th cell physiology, including preferential naïve Th cell differentiation to Th1 cells, as well as cytokine production and exocytosis. These novel pathways are promising findings to direct targeted therapy development for obesity-related asthma to address the disease burden.

The airway epithelium during infancy and childhood: A complex multicellular immune barrier. Basic review for clinicians.

The airway epithelium is a complex multicellular layer that extends from the nasopharynx to the small airways. It functions as an immune respiratory barrier during early life that develops, matures, and regenerates to adapt to the changes in the environment. While airway epithelial abnormalities have been identified in several clinical disorders, there is increasing interest in understanding its basic regulation and structure in humans. Indeed, recent advances in technology (e.g. single-cell analysis and new human airway epithelial cell models) have allowed us to identify additional cellular subtypes and functions that overall have greatly improved our understanding of the airway epithelium during health and disease. In this review we summarize key features of the airway epithelium including: 1) multilayer structure and cell heterogeneity; 2) adaptability to different environmental and developmental stimuli; 3) innate recognition; and 4) orchestration of immune responses. We discuss these features with a translational and clinical prospective focusing on the development of human respiratory immunity, particularly during early life.

The interplay between airway epithelium and the immune system - A primer for the respiratory clinician.

The respiratory epithelium is one of the primary interfaces between the body's immune system and the external environment. This review discusses the innate and adaptive immunomodulatory effects of the respiratory epithelium, highlighting the physiologic immune responses associated with health and the disease-causing sequelae when these physiologic responses go awry. Airway macrophages, dendritic cells, and innate lymphoid cells are discussed as orchestrators of physiological and pathological innate immune responses and T cells, B cells, mast cells, and granulocytes (eosinophils and neutrophils) as orchestrators of physiologic and pathologic adaptive immune responses. The interplay between the airway epithelium and the varied immune cells as well as the interplay between these immune cells is discussed, highlighting the importance of the dose of noxious stimuli and pathogens in immune programming and the timing of their interaction with the immune cells that determine the pattern of immune responses. Although each cell type has been researched individually, this review highlights the need for simultaneous temporal investigation of immune responses from these varied cells to noxious stimuli and pathogens.

Association between asthma and dental caries in US (United States) adult population.

OBJECTIVE: To investigate the associations of asthma with dental-caries-experience (DFT: decayed and filled teeth) and untreated-dental-caries (DT: decayed teeth) in the US adult population. METHODS: Data from the National Health and Nutritional Examination Survey, 2009-2014 were analyzed. Study-participants were classified into current, former and never asthmatics based on their asthma-status. Former-asthmatics were excluded. Both the outcomes, dental-caries-experience and untreated-dental-caries were dichotomized as being either present or absent, and were also categorized into tertiles based on their distributions in our study-sample. Logistic regression analyses were performed to determine the associations of asthma with dichotomized outcomes. The generalized logit model was applied for multilevel categorical outcomes. Multivariable models were developed to control for common demographic, clinical, and lifestyle factors. RESULTS: Total study-participants were 13,135, representing 175.26 million US adults. In the adjusted models, current-asthmatics, when compared to the reference group of never-asthmatics, were more likely to have dental-caries-experience (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.13-1.66) and untreated-dental-caries (OR, 1.38; 95% CI, 1.10-1.73) in ≥1 tooth. Asthma was associated with all three categories of dental-caries-experience in our study-sample. We observed a positive gradient in the OR with an increasing extent of untreated-dental-caries. Relative to never-asthmatics, asthma doubled the odds of having untreated dental caries in the subgroup of current-smokers. CONCLUSION: Current-asthmatic adults had higher odds of dental-caries-experience and untreated-dental-caries as compared to never-asthmatic adults in the US. Based on the observations from this study, interprofessional collaboration should be recommended to institute caries control and health promotion in current-asthmatic adult population.

Functional Genomics of the Pediatric Obese Asthma Phenotype Reveal Enrichment of Rho-GTPase Pathways.

Rationale: Obesity-related asthma disproportionately affects minority children and is associated with nonatopic T-helper type 1 (Th1) cell polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood.Objectives: To use functional genomics to identify cellular mechanisms associated with nonatopic inflammation in obese minority children with asthma.Methods: CD4+ (cluster of differentiation 4-positive) Th cells from 59 obese Hispanic and African American children with asthma and 61 normal-weight Hispanic and African American children with asthma underwent quantification of the transcriptome and DNA methylome and genotyping. Expression and methylation quantitative trait loci revealed the contribution of genetic variation to transcription and DNA methylation. Adjusting for Th-cell subtype proportions discriminated loci where transcription or methylation differences were driven by differences in subtype proportions from loci that were independently associated with obesity-related asthma.Measurements and Main Results: Obese children with asthma had more memory and fewer naive Th cells than normal-weight children with asthma. Differentially expressed and methylated genes and methylation quantitative trait loci in obese children with asthma, independent of Th-cell subtype proportions, were enriched in Rho-GTPase pathways. Inhibition of CDC42 (cell division cycle 42), one of the Rho-GTPases associated with Th-cell differentiation, was associated with downregulation of the IFNγ, but not the IL-4, gene. Differential expression of the RPS27L (40S ribosomal protein S27-like) gene, part of the p53/mammalian target of rapamycin pathway, was due to nonrandom distribution of expression quantitative trait loci variants between groups. Differentially expressed and/or methylated genes, including RPS27L, were associated with pulmonary function deficits in obese children with asthma.Conclusions: We found enrichment of Rho-GTPase pathways in obese asthmatic Th cells, identifying them as a novel therapeutic target for obesity-related asthma, a disease that is suboptimally responsive to current therapies.

Comparison of severity of asthma hospitalization between African American and Hispanic children in the Bronx.

Objective: There are racial and ethnic disparities in childhood asthma burden and outcomes. Although there have been comparisons between whites and minorities, there are few between minority groups. This study aimed to compare characteristics of asthma hospitalizations in African American and Hispanic children.Methods: A retrospective chart review was conducted to compare asthma characteristics between African American and Hispanic children aged 2-18 years hospitalized at an urban, tertiary care hospital for an acute asthma exacerbation. Length of stay (LOS), need for intensive care unit (ICU), and need for additional medications or respiratory support were compared between the groups.Results: Of the 925 children that met the inclusion criteria, 64% were Hispanic and 36% were African American. The groups were similar in age, gender, insurance status, and weight classification. African American children were more likely to have severe persistent asthma (12% vs. 7%, p = .02). They were also more likely to require magnesium sulfate (45% vs. 32%, p < .001) and admission to the ICU from the emergency department (ED) (14% vs. 8%, p = .01), which were independent of asthma severity. There was no significant difference in LOS or other characteristics of hospitalization.Conclusions: African American children hospitalized for asthma have more severe exacerbations compared to Hispanic children, which is independent of their asthma severity. However, this was not associated with longer LOS, which may indicate greater responsiveness to inpatient asthma management. Further investigation is needed to understand the mechanisms underlying asthma and exacerbation severity among minority groups.