Home and School Pollutant Exposure, Respiratory Outcomes, and Influence of Historical Redlining.

BACKGROUND: The discriminatory and racist policy of historical redlining in the United States (U.S.) during the 1930s played a role in perpetuating contemporary environmental health disparities. OBJECTIVE: Our objectives were to determine associations between home and school pollutant exposure (fine particulate matter (PM2.5), nitrogen dioxide (NO2)) and respiratory outcomes (Composite Asthma Severity Index (CASI), lung function) among school-aged children with asthma and examine whether associations differed between children who resided and/or attended school in historically redlined compared to non-redlined neighborhoods. METHODS: Children ages 6 to 17 with moderate-to-severe asthma (N=240) from 9 U.S. cities were included. Combined home and school exposure to PM2.5 and NO2 was calculated based on geospatially assessed monthly averaged outdoor pollutant concentrations. Repeated measures of CASI and lung function were collected. RESULTS: Overall, 37.5% of children resided and/or attended schools in historically redlined neighborhoods. Children in historically redlined neighborhoods had greater exposure to NO2 (median: 15.4 vs 12.1 ppb) and closer distance to a highway (median: 0.86 vs 1.23 km), compared to those in non-redlined neighborhoods (p<0.01). Overall, PM2.5 was not associated with asthma severity or lung function. However, among children in redlined neighborhoods, higher PM2.5 was associated with worse asthma severity (p<0.005). No association was observed between pollutants and lung function or asthma severity among children in non-redlined neighborhoods (p>0.005). CONCLUSIONS: Our findings highlight the significance of historical redlining and current environmental health disparities among school-aged children with asthma, specifically, the environmental injustice of PM2.5 exposure and its associations with respiratory health.

Multi-omics in nasal epithelium reveals three axes of dysregulation for asthma risk in the African Diaspora populations.

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10-9) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10-16 and CPA3; p = 2.39 × 10-14) and wound healing (FN1; p = 7.63 × 10-9). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora.

A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy.

BACKGROUND: Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children. OBJECTIVES: We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT. METHODS: Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal transcriptomic responses during NAC, skin prick test wheal size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed. RESULTS: Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (P = .63). Nasal transcriptomic responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (P = .04). A 200-fold increase in cockroach serum-specific IgG4 was observed among subjects receiving SCIT (P < .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (P = .002), while no effect was observed for IL-10 or IFN-γ. CONCLUSIONS: A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG4 serum production and down-modulation of allergen-stimulated T-cell responses.

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.

The Child Opportunity Index 2.0 and exacerbation-prone asthma in a cohort of urban children.

RATIONALE: Social determinants of health underlie disparities in asthma. However, the effects of individual determinants likely interact, so a summary metric may better capture their impact. The Child Opportunity Index 2.0 (COI) is one such tool, yet its association with exacerbation-prone (EP) asthma is unknown. OBJECTIVE: To investigate the association between the COI and EP asthma and clinical measures of asthma severity in children. METHODS: We analyzed data from two prospective observational pediatric asthma cohorts (n = 193). Children were classified as EP (≥1 exacerbation in the past 12 months) or exacerbation-null (no exacerbations in the past 5 years). Spirometry, exhaled nitric oxide, IgE, and Composite Asthma Severity Index (CASI) were obtained. The association between COI and EP status was assessed with logistic regression. We fit linear and logistic regression models to test the association between COI and each clinical measure. RESULTS: A 20-point COI decrease conferred 40% higher odds of EP asthma (OR 1.4; 95%CI 1.1-1.76). The effect was similar when adjusted for age and sex (OR 1.38, 95%CI 1.1-1.75) but was attenuated with additional adjustment for race and ethnicity (OR 1.19, 95%CI 0.92-1.54). A similar effect was seen for the Social/Economic and Education COI domains but not the Health/Environment Domain. A 20-point COI decrease was associated with an increase in CASI of 0.34. COI was not associated with other clinical measures. CONCLUSIONS: Lower COI was associated with greater odds of EP asthma. This highlights the potential use of the COI to understand neighborhood-level risk and identify community targets to reduce asthma disparities.

Activated sputum eosinophils associated with exacerbations in children on mepolizumab.

BACKGROUND: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. OBJECTIVE: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. METHODS: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. RESULTS: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). CONCLUSIONS: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.

Public perceptions of synthetic cooling agents in electronic cigarettes on Twitter.

Amid a potential menthol ban, electronic cigarette (e-cigarette) companies are incorporating synthetic cooling agents like WS-3 and WS-23 to replicate menthol/mint sensations. This study examines public views on synthetic cooling agents in e-cigarettes via Twitter data. From May 2021 to March 2023, we used Twitter Streaming Application Programming Interface (API), to collect tweets related to synthetic cooling agents with keywords such as 'WS-23,' 'ice,' and 'frozen.' The deep learning RoBERTa (Robustly Optimized BERT-Pretraining Approach) model that can be optimized for contextual language understanding was used to classify attitudes expressed in tweets about synthetic cooling agents and identify e-cigarette users. The BERTopic (a topic modeling technique that leverages Bidirectional Encoder Representations from Transformers) deep-learning model, specializing in extracting and clustering topics from large texts, identified major topics of positive and negative tweets. Two proportion Z-tests were used to compare the proportions of positive and negative attitudes between e-cigarette users (vapers) and non-e-cigarette-users (non-vapers). Of 6,940,065 e-cigarettes-related tweets, 5,788 were non-commercial tweets related to synthetic cooling agents. The longitudinal trend analysis showed a clear upward trend in discussions. Vapers posted most of the tweets (73.05%, 4,228/5,788). Nearly half (47.87%, 2,771/5,788) held a positive attitude toward synthetic cooling agents, which is significantly higher than those with a negative attitude (19.92%,1,153/5,788) with a P-value < 0.0001. The likelihood of vapers expressing positive attitudes (60.17%, 2,544/4,228) was significantly higher (P < 0.0001) than that of non-vapers (14.55%, 227/1,560). Conversely, negative attitudes from non-vapers (30%, 468/1,560) were significantly (P < 0.0001) higher than vapers (16.2%, 685/4,228). Prevalent topics from positive tweets included "enjoyment of specific vape flavors," "preference for lush ice vapes," and "liking of minty/icy feelings." Major topics from negative tweets included "disliking certain vape flavors" and "dislike of others vaping around them." On Twitter, vapers are more likely to have a positive attitude toward synthetic cooling agents than non-vapers. Our study provides important insights into how the public perceives synthetic cooling agents in e-cigarettes. These insights are crucial for shaping future U.S. Food and Drug Administration (FDA) regulations aimed at safeguarding public health.

Emergency management and asthma risk in young Medicaid-enrolled children with recurrent wheeze.

OBJECTIVES: To describe clinical characteristics of young children presenting to the emergency department (ED) for early recurrent wheeze, and determine factors associated with subsequent persistent wheeze and risk for early childhood asthma. METHODS: Retrospective cohort study of Medicaid-enrolled children 0-3 years old with an index ED visit for wheeze (e.g. bronchiolitis, reactive airway disease) from 2009 to 2013, and at least one prior documented episode of wheeze at an ED or primary care visit. The primary outcome was persistent wheeze between 4 and 6 years of age. Demographics and clinical characteristics were collected from the index ED visit. Logistic regression was used to estimate the association between potential risk factors and subsequent persistent wheeze. RESULTS: During the study period, 41,710 children presented to the ED for recurrent wheeze. Mean age was 1.3 years; 59% were male, 42% Black, and 6% Hispanic. At index ED visits, the most common diagnosis was acute bronchiolitis (40%); 77% of children received an oral corticosteroid prescription. Between 4 and 6 years of age, 11,708 (28%) children had persistent wheeze. A greater number of wheezing episodes was associated with an increased odds of ED treatment with asthma medications. Subsequent persistent wheeze was associated with male sex, Black race, atopy, prescription for bronchodilators or corticosteroids, and greater number of visits for wheeze. CONCLUSIONS: Young children with persistent wheeze are at risk for childhood asthma. Thus, identification of risk factors associated with persistent wheeze in young children with recurrent wheeze might aid in early detection of asthma and initiation of preventative therapies.

Assessing the contributions of phylogenetic and environmental determinants of allergic cosensitization to fungi in humans.

BACKGROUND: Understanding how allergies to 1 environmental fungus can lead to cosensitization to related fungi is important for the clinical management of allergies. Cosensitization can be caused by monosensitization combined with antibody cross-reactivity, or by coexposures driving independent sensitizations. A pioneering study showed that patterns of IgE cosensitization among 17 fungal species mirror fungal phylogeny. This could reflect either epitope or habitat similarity. Thanks to an improved understanding of fungal phylogeny, larger serologic testing datasets, and environmental data on household fungi, we can now characterize the relationship between cosensitization, species similarity, and likely coexposure with greater precision. OBJECTIVE: To assess the degree to which IgE cosensitization in a group of 17 fungi can be attributed to species similarity or environmental coexposure. METHODS: Cosensitization patterns among 17 fungal species were estimated from a dataset of approximately 8 million serologic tests on 1.6 million patients. Linear regression of cosensitization on phylogenetic distance and imputed coexposure was performed. In addition, branch lengths for the phylogenetic tree were re-estimated on the basis of cosensitization and compared with corresponding phylogenetic branch lengths. RESULTS: Phylogenetic distance explains much of the observed cosensitization (adjusted r2 = .68, p < .001). Imputed environmental coexposures and test co-ordering patterns do not significantly predict cosensitization. Branch length comparisons between the cosensitization and phylogenetic trees identified several species as less cosensitizing than phylogenetic distance predicts. CONCLUSION: Combined evidence from clinical IgE testing data on fungi, along with phylogenetic and environmental exposure data, supports the hypothesis that cosensitization is caused primarily by monosensitization plus cross-reactivity, rather than multisensitization. A serologic test result should be interpreted as pointing to a group of related species that include the sensitizing agent rather than as uniquely identifying the agent. The identified patterns of cross-reactivity may help optimize test panel design.

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.

A Wireless Wearable Patch for Remote Monitoring of Respiratory and Cardiac Rhythm in Children.

Remote patient monitoring (RPM) is an innovative strategy to promote health and improve patient management and care. Recent advances in healthcare technologies have seen the emergence of wearable sensors allowing longitudinal physiological measurements in any environment. This paper introduces a wireless wearable patch 'Leo' for continuous remote monitoring of physiological data at home and healthcare settings. This includes single lead ECG, chest impedance, heart rate (HR), respiration rate (RR) and body posture. To test Leo's ability to capture longitudinal physiological data at home, 15 children experiencing acute severe asthma exacerbations were recruited during their emergency department (ED) visits. Participants wore the Leo device for 7 (+/-2) days post-hospital discharge. Nocturnal RR and HR and variability were higher during the first half of the night on Day1 compared to Day7 (p<0.005). Participants also completed a usability questionnaire and reported the patch wear to be comfortable (average score of 3.3 out of 5) and easy to wear during the night (average score of 3.5 out of 5) with 5/15 (33%) reported very slight barely perceptible skin irritation/redness and 2 (13%) reported well defined skin irritation and redness.Clinical Relevance- These results highlight the potential use of the Leo device in clinical practice for continuous un-obstructive monitoring of diseased populations, such as asthma.

Public perceptions of synthetic cooling agents in electronic cigarettes on Twitter.

Amid a potential menthol ban, electronic cigarette (e-cigarette) companies are incorporating synthetic cooling agents like WS-3 and WS-23 to replicate menthol/mint sensations. This study examines public views on synthetic cooling agents in e-cigarettes via Twitter data. From May 2021 to March 2023, we used Twitter Streaming API, to collect tweets related to synthetic cooling agents with keywords such as 'WS-23,' 'ice,' and 'frozen.' Two deep learning roBERTa models, classified attitudes expressed in tweets about synthetic cooling agents and identified e-cigarette users. The BERTopic deep-learning model identified major topics of positive and negative tweets. Two proportion Z-tests were used to compare the proportions of positive and negative attitudes between e-cigarette users (vapers) and non-e-cigarette-users (non-vapers). Of 6,940,065 e-cigarettes related tweets, 5,788 non-commercial tweets related to synthetic cooling agents. The longitudinal trend analysis showed a clear upwards trend in discussions. Vapers posted most of the tweets (73.05%, 4,228/5,788). Nearly half (47.87%, 2,771/5,788) held a positive attitude toward synthetic cooling agents, which is significantly higher than those with a negative attitude (19.92%,1,153/5,788) with a P-value < 0.0001. The likelihood of Vapers expressing positive attitudes (60.17%, 2,544/4,228) was significantly higher (P < 0.0001) than that from non-vapers (14.55%, 227/1,560). Conversely, negative attitudes from non-vapers (30%, 468/1,560) was significantly (P < 0.0001) higher than vapers (16.2%, 685/4,228). Prevalent topics from positive tweets included "enjoyment of specific vape flavors," "preference for lush ice vapes," and "liking of minty/icy feelings." Major topics from negative tweets included "disliking certain vape flavors" and "dislike of others vaping around them." On Twitter, vapers are more likely to have a positive attitude toward synthetic cooling agents than non-vapers. Our study provides important insights into how the public perceives synthetic cooling agents in e-cigarettes, insights that are crucial for shaping future FDA regulations aimed at safeguarding public health.

Breathing zone pollutant levels are associated with asthma exacerbations in high-risk children.

Background: Indoor and outdoor air pollution levels are associated with poor asthma outcomes in children. However, few studies have evaluated whether breathing zone pollutant levels associate with asthma outcomes. Objective: Determine breathing zone exposure levels of NO 2 , O 3 , total PM 10 and PM 10 constituents among children with exacerbation-prone asthma, and examine correspondence with in-home and community measurements and associations with outcomes. Methods: We assessed children's personal breathing zone exposures using wearable monitors. Personal exposures were compared to in-home and community measurements and tested for association with lung function, asthma control, and asthma exacerbations. Results: 81 children completed 219 monitoring sessions. Correlations between personal and community levels of PM 10 , NO 2 , and O 3 were poor, whereas personal PM 10 and NO 2 levels correlated with in-home measurements. However, in-home monitoring underdetected brown carbon (Personal:79%, Home:36.8%) and ETS (Personal:83.7%, Home:4.1%) personal exposures, and detected black carbon in participants without these personal exposures (Personal: 26.5%, Home: 96%). Personal exposures were not associated with lung function or asthma control. Children experiencing an asthma exacerbation within 60 days of personal exposure monitoring had 1.98, 2.21 and 2.04 times higher brown carbon (p<0.001), ETS (p=0.007), and endotoxin (p=0.012), respectively. These outcomes were not associated with community or in-home exposure levels. Conclusions: Monitoring pollutant levels in the breathing zone is essential to understand how exposures influence asthma outcomes, as agreement between personal and in-home monitors is limited. Inhaled exposure to PM 10 constituents modifies asthma exacerbation risk, suggesting efforts to limit these exposures among high-risk children may decrease their asthma burden. CLINICAL IMPLICATIONS: In-home and community monitoring of environmental pollutants may underestimate personal exposures. Levels of inhaled exposure to PM 10 constituents appear to strongly influence asthma exacerbation risk. Therefore, efforts should be made to mitigate these exposures. CAPSULE SUMMARY: Leveraging wearable, breathing-zone monitors, we show exposures to inhaled pollutants are poorly proxied by in-home and community monitors, among children with exacerbation-prone asthma. Inhaled exposure to multiple PM 10 constituents is associated with asthma exacerbation risk.

Fungal allergen sensitization: Prevalence, risk factors, and geographic variation in the United States.

BACKGROUND: Many fungal species are associated with the pathogenesis of allergic disease, yet most epidemiologic studies on IgE-mediated fungal sensitization have only included a few species. OBJECTIVE: We investigated fungal allergen sensitization prevalence, risk factors, and geographic variation in the United States. METHODS: From 2014 to 2019, a total of 7,912,504 serum-specific IgE (sIgE) test results for 17 fungal species were measured in 1,651,203 patients aged 0-85 years by a US-wide clinical laboratory. Fungal sensitization prevalence, patterns, and relationship with demographic characteristics, clinical diagnoses, and geographic regions were analyzed. RESULTS: Twenty-two percent of patients were positive (sIgE > 0.10 kUA/L) to at least 1 fungal allergen; 13.7% were positive to >2 fungal allergens. Fungal species-specific positivity rates ranged 7.4-18.6% and were highest for Candida albicans (18.6%), Alternaria alternata (16.6%), Stemphylium herbarum (14.9%), and Aspergillus fumigatus (14.2%). Other fungi that were frequently tested had relatively low positivity rates (eg, Cladosporium herbarum 11.1%, Penicillium chrysogenum 10.7%). Independent risk factors for test positivity for all fungal species included male sex, teen age (highest in those aged 10-19 years), atopic dermatitis, and asthma. Fungal sensitization was generally higher in urban areas and ecoregions composed predominantly of grasslands and prairies compared to woodlands and forest, although there was greater variation in sensitization risk to different fungi in different ecoregions. CONCLUSION: Independent risk factors for fungal sensitization include male sex, teen ages, atopic dermatitis, asthma, and ecoregion.

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.

Anionic Pulmonary Surfactant Lipid Treatment Inhibits Rhinovirus A Infection of the Human Airway Epithelium.

Rhinoviruses (RVs) are major instigators of acute exacerbations of asthma, COPD, and other respiratory diseases. RVs are categorized into three species (RV-A, RV-B, and RV-C), which comprise more than 160 serotypes, making it difficult to develop an effective vaccine. Currently, no effective treatment for RV infection is available. Pulmonary surfactant is an extracellular complex of lipids and proteins that plays a central role in regulating innate immunity in the lung. The minor pulmonary surfactant lipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), are potent regulators of inflammatory processes and exert antiviral activity against respiratory syncytial virus (RSV) and influenza A viruses (IAV). In the current study, we examined the potencies of POPG and PI against rhinovirus A16 (RV-A16) in primary human airway epithelial cells (AECs) differentiated at an air-liquid interface (ALI). After AECs were infected with RV-A16, PI reduced the viral RNA copy number by 70% and downregulated (55-75%) the expression of antiviral (MDA5, IRF7, and IFN-lambda) and CXCL11 chemokine genes. In contrast, POPG only slightly decreased MDA5 (24%) and IRF7 (11%) gene expression but did not inhibit IFN-lambda gene expression or RV-A16 replication in AECs. However, both POPG and PI inhibited (50-80%) IL6 gene expression and protein secretion and CXCL11 protein secretion. PI treatment dramatically attenuated global gene expression changes induced by RV-A16 infection alone in AECs. The observed inhibitory effects were indirect and resulted mainly from the inhibition of virus replication. Cell-type enrichment analysis of viral-regulated genes opposed by PI treatment revealed the PI-inhibited viral induction of goblet cell metaplasia and the virus-induced downregulation of ciliated, club, and ionocyte cell types. Notably, the PI treatment also altered the ability of RV-A16 to regulate the expression of some phosphatidylinositol 4-kinase (PI4K); acyl-CoA-binding, domain-containing (ACBD); and low-density lipoprotein receptor (LDLR) genes that play critical roles in the formation and functioning of replication organelles (ROs) required for RV replication in host cells. These data suggest PI can be used as a potent, non-toxic, antiviral agent for RV infection prophylaxis and treatment.

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.

Associations between outdoor air pollutants and non-viral asthma exacerbations and airway inflammatory responses in children and adolescents living in urban areas in the USA: a retrospective secondary analysis.

BACKGROUND: Asthma prevalence and severity have markedly increased with urbanisation, and children in low-income urban centres have among the greatest asthma morbidity. Outdoor air pollution has been associated with adverse respiratory effects in children with asthma. However, the mechanisms by which air pollution exposure exacerbates asthma, and how these mechanisms compare with exacerbations induced by respiratory viruses, are poorly understood. We aimed to investigate the associations between regional air pollutant concentrations, respiratory illnesses, lung function, and upper airway transcriptional signatures in children with asthma, with particular focus on asthma exacerbations occurring in the absence of respiratory virus. METHODS: We performed a retrospective analysis of data from the MUPPITS1 cohort and validated our findings in the ICATA cohort. The MUPPITS1 cohort recruited 208 children aged 6-17 years living in urban areas across nine US cities with exacerbation-prone asthma between Oct 7, 2015, and Oct 18, 2016, and monitored them during reported respiratory illnesses. The last MUPPITS1 study visit occurred on Jan 6, 2017. The ICATA cohort recruited 419 participants aged 6-20 years with persistent allergic asthma living in urban sites across eight US cities between Oct 23, 2006, and March 25, 2008, and the last study visit occurred on Dec 30, 2009. We included participants from the MUPPITS1 cohort who reported a respiratory illness at some point during the follow-up and participants from the ICATA cohort who had nasal samples collected during respiratory illness or at a scheduled visit. We used air quality index values and air pollutant concentrations for PM2·5, PM10, O3, NO2, SO2, CO, and Pb from the US Environmental Protection Agency spanning the years of both cohorts, and matched values and concentrations to each illness for each participant. We investigated the associations between regional air pollutant concentrations and respiratory illnesses and asthma exacerbations, pulmonary function, and upper airway transcriptional signatures by use of a combination of generalised additive models, case crossover analyses, and generalised linear mixed-effects models. FINDINGS: Of the 208 participants from the MUPPITS1 cohort and 419 participants from the ICATA cohort, 168 participants in the MUPPITS1 cohort (98 male participants and 70 female participants) and 189 participants in the ICATA cohort (115 male participants and 74 female participants) were included in our analysis. We identified that increased air quality index values, driven predominantly by increased PM2·5 and O3 concentrations, were significantly associated with asthma exacerbations and decreases in pulmonary function that occurred in the absence of a provoking viral infection. Moreover, individual pollutants were significantly associated with altered gene expression in coordinated inflammatory pathways, including PM2·5 with increased epithelial induction of tissue kallikreins, mucus hypersecretion, and barrier functions and O3 with increased type-2 inflammation. INTERPRETATION: Our findings suggest that air pollution is an important independent risk factor for asthma exacerbations in children living in urban areas and is potentially linked to exacerbations through specific inflammatory pathways in the airway. Further investigation of these potential mechanistic pathways could inform asthma prevention and management approaches. FUNDING: National Institutes of Health, National Institute of Allergy and Infectious Diseases.