Nasal Epithelium Transcriptomics Predict Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) has made a substantial positive impact for people living with CF (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF prior to ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in FEV1 (∆FEV1), year's best FEV1 (∆ybFEV1), and body mass index (∆BMI). Using the top differentially expressed genes (DEGs), we generated transcriptomic risk scores (TRS) and evaluated their predictive performance. The study included 40 pwCF aged ≥6 years (mean 27.7 [SD=15.1] years; 40% female). After ETI initiation, FEV1 improved ≥5% in 22 (61.1%) participants and ybFEV1 improved ≥5% in 19 (50%). TRS were constructed using top over-expressed and under-expressed genes for each. Adding the ∆FEV1 TRS for to a model with age, sex, and baseline FEV1 increased the AUC from 0.41 to 0.88; the ∆ybFEV1 TRS increased the AUC from 0.51 to 0.88; and the ∆BMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ~85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRS could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.

Persistent cat ownership and asthma in a longitudinal study of Puerto Rican youth.

BACKGROUND: Epidemiologic studies have reported conflicting findings for cat or dog exposure and childhood asthma. No study has evaluated whether persistent pet exposure from early life to school age is associated with asthma or allergic sensitization in youth. OBJECTIVE: To evaluate whether persistent ownership of a cat or a dog throughout childhood is associated with asthma in Puerto Rican youth, a group disproportionately affected with asthma. METHODS: Prospective study of 384 youth who completed a baseline visit at ages 6 to 14 years and a second visit at ages 9 to 20 years. Persistent cat or dog ownership was defined as ownership of a cat or a dog in early life (during pregnancy or the first year of life) at either study visit (at school age). An allergen-specific IgE result was considered positive if more than or equal to 0.35 IU/mL. Logistic regression was used for the multivariable analysis of asthma and allergic sensitization. RESULTS: In an analysis adjusting for household income, family history of atopy, persistent overweight or obesity, a persistent unhealthy diet, the time interval between study visits, and other covariates, persistent cat ownership was significantly associated with 68% reduced odds of asthma (95% CI for odds ratio = 0.11-0.92) but not with any allergic sensitization or sensitization to cat allergen. In contrast, persistent dog ownership was not significantly associated with asthma or allergic sensitization. CONCLUSION: Among school-aged Puerto Rican youth followed for an average of 5 years, persistent cat ownership from early life to school age was inversely associated with asthma.

Effect of vitamin D supplementation on total and allergen-specific IgE in children with asthma and low vitamin D levels.

BACKGROUND: Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization. OBJECTIVE: To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of 2 common indoor allergens in children with asthma and low vitamin D levels. METHODS: Total IgE, IgE to Dermatophagoides pteronyssinus, and IgE to Blattella germanica were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma Study, a multicenter, double-blind, randomized placebo-controlled trial of vitamin D3 supplementation (4000 IU/d) to prevent severe exacerbations in children with persistent asthma and vitamin D levels less than 30 ng/mL. Multivariable linear regression was used for the analysis of the effect of vitamin D supplementation on change in each IgE measure. RESULTS: Participants were followed for an average of 316 days. At the exit visit, more subjects in the vitamin D arm achieved a vitamin D level equal to or more than 30 ng/mL compared with those in the placebo arm (87% vs 30%; P < .001). In a multivariable analysis, vitamin D3 supplementation had no significant effect on change in total IgE, IgE to Dermatophagoides pteronyssinus, or IgE to Blattella germanica between the exit and randomization visits (eg, for log10 total IgE, ß = 0.007; 95% CI, -0.061 to 0.074; P = .85). CONCLUSIONS: Vitamin D supplementation, compared with placebo, has no significant effect on serum levels of total IgE, IgE to dust mite, or IgE to cockroach in children with asthma and low vitamin D levels.

Violence-related distress and lung function in two longitudinal studies of youth.

BACKGROUND: Exposure to violence has been associated with lower lung function in cross-sectional studies. METHODS: We examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomised clinical trial in 98 youth with asthma (aged 9-16 years) treated with low-dose inhaled corticosteroids (Vitamin D Kids Asthma Study (VDKA)). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5.4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ)). RESULTS: In a multivariable analysis in VDKA, each 1-point increment in CCDS score was associated with decrements of 3.27% in forced expiratory volume in 1 s (FEV1) % pred (95% CI -6.44- -0.22%; p=0.04), 2.65% in forced vital capacity (FVC) % pred (95% CI -4.86- -0.45%; p=0.02) and 0.30 points in the overall PAQLQ score (95% CI -0.50- -0.10 points; p<0.01). Similar findings for FEV1 and FVC were obtained in the prospective study of Puerto Rican youth. CONCLUSIONS: Our findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids), and further support policies to reduce exposure to violence among children in the USA and Puerto Rico.

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial.

Importance: Severe asthma exacerbations cause significant morbidity and costs. Whether vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear. Objective: To determine whether vitamin D3 supplementation improves the time to a severe exacerbation in children with asthma and low vitamin D levels. Design, Setting, and Participants: The Vitamin D to Prevent Severe Asthma Exacerbations (VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3 supplementation to improve the time to severe exacerbations in high-risk children with asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum 25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was terminated early (March 2019) due to futility, and follow-up ended in September 2019. Interventions: Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo (n = 96) for 48 weeks and maintained with fluticasone propionate, 176 µg/d (6-11 years old), or 220 µg/d (12-16 years old). Main Outcomes and Measures: The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of inhaled corticosteroid was reduced halfway through the trial, and the cumulative fluticasone dose during the trial. Results: Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180 (93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation: the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the placebo group (mean group difference, -13.1 days [95% CI, -42.6 to 16.4]; adjusted hazard ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with placebo, likewise did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of inhaled corticosteroid was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9). Conclusions and Relevance: Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02687815.

Asthma in Hispanics. An 8-year update.

This review provides an update on asthma in Hispanics, a diverse group tracing their ancestry to countries previously under Spanish rule. A marked variability in the prevalence and morbidity from asthma remains among Hispanic subgroups in the United States and Hispanic America. In the United States, Puerto Ricans and Mexican Americans have high and low burdens of asthma, respectively (the "Hispanic Paradox"). This wide divergence in asthma morbidity among Hispanic subgroups is multifactorial, likely reflecting the effects of known (secondhand tobacco smoke, air pollution, psychosocial stress, obesity, inadequate treatment) and potential (genetic variants, urbanization, vitamin D insufficiency, and eradication of parasitic infections) risk factors. Barriers to adequate asthma management in Hispanics include economic and educational disadvantages, lack of health insurance, and no access to or poor adherence with controller medications such as inhaled corticosteroids. Although considerable progress has been made in our understanding of asthma in Hispanic subgroups, many questions remain. Studies of asthma in Hispanic America should focus on environmental or lifestyle factors that are more relevant to asthma in this region (e.g., urbanization, air pollution, parasitism, and stress). In the United States, research studies should focus on risk factors that are known to or may diverge among Hispanic subgroups, including but not limited to epigenetic variation, prematurity, vitamin D level, diet, and stress. Clinical trials of culturally appropriate interventions that address multiple aspects of asthma management in Hispanic subgroups should be prioritized for funding. Ensuring high-quality healthcare for all remains a pillar of eliminating asthma disparities.

Long-Term PM2.5 Exposure and Upregulation of CLCA1 Expression in Nasal Epithelium from Youth with Asthma.

BACKGROUND: Little is known about long-term PM2.5 exposure and airway epithelial gene expression. OBJECTIVE: To test for association between long-term PM2.5 exposure and nasal epithelial gene expression in youth with asthma. METHODS: Transcriptome-wide association study (TWAS) of long-term PM2.5 in nasal epithelium from youth aged 6-20 years in the: 1) Epigenetic Variation and Childhood Asthma in Puerto Ricans study (EVA-PR, n=182); 2) Vitamin D Kids Asthma Study (VDKA, n=58); and 3) Stress and Treatment Response in Puerto Rican and African American Children with Asthma study (STAR, n=81). Satellite hybrid models were used to estimate PM2.5 exposure in the prior year at each participant's residence. Multivariable negative binomial regression was used for each TWAS, adjusting for age, sex, and other covariates. A meta-analysis of all TWAS results was then conducted using an inverse variance-weighted average approach. RESULTS: Most participants (~95%) in the meta-analysis of TWAS for PM2.5 exposure identified as Puerto Rican or Black. Long-term PM2.5 was associated with: 1) upregulated expression of CLCA1 (calcium-activated chloride channel regulator 1, false discovery rate-adjusted P [FDR-P]=0.008), SYCP2 (synaptonemal complex protein 2, FDR-P=0.01), and CYP2A6 (cytochrome p450 family 2 subfamily A member 6, FDR-P=0.02), and 2) downregulated expression of EDAR (ectodysplasin A receptor, FDR-P=0.01). In a meta-analysis, CLCA1 upregulation was associated with ≥1 positive allergen-specific IgE (FDR-P <0.001) and increased blood eosinophils (FDR-P <0.001) and total IgE (FDR-P <0.001). CONCLUSIONS: In a meta-analysis of TWASs in predominantly Puerto Rican and Black youth with asthma, long-term PM2.5 exposure was associated with upregulated airway epithelial CLCA1 expression, in turn linked to biomarkers of T2-high immunity.

Socioeconomic status, diet, and recurrent severe asthma exacerbations in Puerto Rican youth.

Background: Why Puerto Rican youths have higher rates of severe asthma exacerbations (SAEs) than their non-Hispanic White peers is unclear. Objective: We aimed to identify risk factors associated with recurrent SAEs in Puerto Rican youths with asthma. Methods: We performed cross-sectional and longitudinal analyses of recurrent SAEs in 209 Puerto Rican youths with asthma who participated in 2 cross-sectional studies approximately 5.2 years apart: the Puerto Rico Genetics of Asthma and Lifestyle study (visit 1, participants aged 6-14 years) and the Epigenetic Variation and Childhood Asthma in Puerto Ricans study (visit 2, participants aged 9-20 years). Recurrent SAEs were defined as at least 2 SAEs in the previous year. Results: Of the youths in our study, there were 80 (38.3%) and 47 (22.4%) with recurrent SAEs at visit 1 and visit 2, respectively, and 31 participants (14.8%) had persistent recurrent SAEs (ie, recurrent SAEs at both visits). In multivariable analyses, low household income was significantly associated with 2.4 to 12.3 times increased odds of recurrent SAEs in all analyses, with stronger longitudinal associations. Low parental education level, nonprivate or employer-based health insurance, overweight or obesity, residential proximity to a major road, and low or moderate level of outdoor activity were each significantly associated with recurrent SAEs in at least 1 analysis. Further, persistence of low parental numeracy level, low household income, and an unhealthy diet were each associated with persistent recurrent SAEs. Conclusion: In this study of Puerto Rican youths with asthma, persistence of low parental numeracy level, a low household income, and an unhealthy diet were associated with persistent recurrent SAEs. Our findings support policies promoting equity and healthy lifestyles for Puerto Rican children and their families.

Air Quality Index and Childhood Asthma: A Pilot Randomized Clinical Trial Intervention.

INTRODUCTION: To reduce air pollution exposure, the U.S. asthma guidelines recommend that children check the Air Quality Index before outdoor activity. Whether adding the Air Quality Index and recommendations to asthma action plans reduces exacerbations and improves control and quality of life in children with asthma is unknown. METHODS: A pilot, unblinded, randomized clinical trial of 40 children with persistent asthma, stratified by age and randomized 1:1, recruited from the University of Pittsburgh Medical Center Children's Hospital of Pittsburgh (Pittsburgh, PA) was conducted. All participants received asthma action plans and Air Quality Index education. The intervention group received printed Air Quality Index information and showed the ability to use AirNow. Asthma exacerbations were assessed through a questionnaire, asthma control was assessed with the Asthma Control Test and Childhood Asthma Control Test, and quality of life was assessed with the Pediatric Asthma Quality of Life Questionnaire. After randomization (July-October 2020), participants were followed monthly for 6 months (exit January-March 2021). Outcome differences between groups were evaluated at the exit visit and over time (analysis was in 2021). RESULTS: At randomization, there were no significant differences in age, sex, race, or asthma severity. At exit, more intervention participants checked the Air Quality Index (63% vs 15%) with no differences in the proportion of asthma exacerbations or mean Childhood Asthma Control Test or Pediatric Asthma Quality of Life Questionnaire scores. The mean change in Asthma Control Test score was higher in the intervention group (change in Asthma Control Test=2.00 vs 0.15 for the control), which was modified by time (ß=1.85, CI=0.09, 3.61). Physical activity was decreased overall and showed modification by treatment and time. CONCLUSIONS: Addition of the Air Quality Index to asthma action plans led to improved asthma control by Asthma Control Test scores but may decrease outdoor activity.

Exposure to violence and asthma in Puerto Rican youth with high Th2 immunity.

BACKGROUND: Little is known about the determinants of asthma among youth with high T helper 2 (Th2) immunity. We hypothesized that exposure to violence (ETV) and violence-related distress are associated with asthma in children and adolescents with high Th2 immunity. METHODS: We analyzed data from Puerto Ricans with high Th2 immunity aged 9-20 years in the Puerto Rico Genetics of Asthma and Lifestyle (PR-GOAL) and the Epigenetic Variation of Childhood Asthma in Puerto Ricans (EVA-PR) studies, and in a prospective study (PROPRA). High Th2-immunity was defined as ≥1 positive allergen-specific IgE and/or a total IgE ≥ 100 IU/mL and/or an eosinophil count ≥ 150 cells/µL. Asthma was defined as physician-diagnosed asthma and current wheeze. ETV and violence-related distress were assessed with the validated ETV Scale and Checklist of Children's Distress Symptoms (CCDS) questionnaires, respectively. RESULTS: In multivariable analyses, each 1-point increment in ETV score was significantly associated with 1.13-1.17 times increased odds of asthma in PR-GOAL and in EVA-PR (both at p ≤ 0.01), and each 1-point increment in CCDS score was significantly associated with 1.53-1.54 increased odds of asthma in PR-GOAL and in EVA-PR (both at p ≤ 0.03). Further, a persistently high ETV score was significantly associated with asthma in PROPRA (odds ratio [OR] = 2.83, 95% confidence interval [CI] = 1.10-7.29). Similar results were obtained in a sensitivity analysis using an eosinophil count ≥ 300 cells/µL instead of ≥150 cells/µL to define high Th2 immunity. CONCLUSIONS: ETV during childhood is associated with increased risk of persistent or new-onset asthma in youth with high Th2 immunity.

Parental knowledge and usage of air quality in childhood asthma management.

Background: The current United States asthma management guidelines recommend usage of the Air Quality Index (AQI) for outdoor activity modification when air pollution is high. Little is known about parental knowledge and usage of air quality including the AQI in managing childhood asthma. Methods: Forty parents (or legal guardians) of children with persistent asthma completed a questionnaire designed to assess 4 areas related to outdoor air pollution: awareness, perception, behavioral modification, and prior healthcare provider discussion. Descriptive statistics were obtained and Fisher's exact test was used for analysis of behavioral change by selected variables. Results: Almost all parents reported awareness of air quality alerts or AQI, however, only 20% checked the AQI on the AirNow app or website. Most parents reported air pollution as a trigger (65%), yet few parents reported behavioral modification of their child's outdoor activity based on the perception of poor air quality (43%) or based on AQI or alerts (40%). Over half of parents reported a healthcare provider had ever discussed air pollution as a trigger, with few parents (23%) reporting recommendations for behavior change. Perception of air pollution as a trigger, healthcare provider discussion and recommendations, and usage of AirNow were associated with increased reported activity change. Conclusion: Healthcare providers should discuss outdoor air pollution during asthma management in children and should discuss AirNow as a source for AQI information and behavioral recommendations.

Risk factors for atopic and nonatopic asthma in Puerto Rican children.

BACKGROUND: Little is known about the risk factors for atopic and nonatopic asthma among children in Puerto Rico. We aimed to identify modifiable risk factors for atopic and nonatopic asthma in this vulnerable population. METHODS: Case-control study of children with (n = 305) and without (n = 327) asthma in San Juan (Puerto Rico). Asthma was defined as physician-diagnosed asthma and wheeze in the previous year. Atopic asthma (n = 210) was defined as asthma and greater than or equal to one positive IgE to aero-allergens. Nonatopic asthma (n = 95) was defined as asthma and no positive IgE to the allergens tested. Logistic regression was used for the multivariable analysis of atopic and nonatopic asthma. RESULTS: In a multivariable analysis, body mass index (BMI) z score, prematurity, parental asthma, lifetime exposure to gun violence, and having a bird in the child's home were associated with increased odds of atopic asthma, while each one-point increment in a dietary score (range: -2 [least healthy diet] to +2 [healthiest diet]) was associated with 37% reduced odds of atopic asthma (95% confidence interval [CI] = 0.48-0.81; P < .01). In a separate multivariable analysis, parental asthma, early-life second-hand smoke (SHS) exposure, and daycare attendance in the first year of life were significantly associated with increased odds of nonatopic asthma, while each one-point increment in the dietary score was associated with 42% reduced odds of nonatopic asthma (95% CI = 0.45-0.76; P < .01). CONCLUSIONS: We have identified potentially modifiable risk factors for atopic asthma (eg, BMI and gun violence), nonatopic asthma (eg, early-life SHS and daycare attendance), or both (eg, an unhealthy diet) in Puerto Rican children.