Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease.

BACKGROUND: Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. METHODS: Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. RESULTS: Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. CONCLUSIONS: BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Low parental numeracy and severe asthma exacerbations in a prospective study of Puerto Rican youth.

BACKGROUND: Numeracy is the mathematical knowledge required to understand and act on instructions from health care providers. Whether persistently low parental numeracy is linked to childhood asthma exacerbations is unknown. OBJECTIVE: To evaluate whether low parental numeracy at 2 time points is associated with asthma exacerbations and worse lung function in Puerto Rican youth. METHODS: Prospective study of 225 youth with asthma in San Juan (PR) who participated in 2 visits approximately 5.3 years apart, with the first at ages 6 to 14 years and the second at ages 9 to 20 years. Parental numeracy was assessed with a modified version of the Asthma Numeracy Questionnaire (score range = 0-3 points), and persistently low parental numeracy was defined as a score less than or equal to 1 point at both visits. Asthma exacerbation outcomes included more than or equal to 1 emergency department (ED) visit, more than or equal to 1 hospitalization, and more than or equal to 1 severe exacerbation (≥1 ED visit or ≥1 hospitalization) for asthma in the year before the second visit. Spirometry was conducted using an EasyOne spirometer (NDD Medical Technologies, Andover, Massachusetts). RESULTS: In an analysis adjusting for age, sex, parental education, use of inhaled corticosteroids, and the time between study visits, persistently low parental numeracy was associated with more than or equal to 1 ED visit for asthma (odds ratio [ORs], 2.17; 95% confidence interval [CI], 1.10-4.26), more than or equal to 1 hospitalization for asthma (OR, 3.92; 95% CI, 1.42-10.84), and more than or equal to 1 severe asthma exacerbation (OR, 1.99; 95% CI, 1.01-3.87) in the year before the follow-up visit. Persistently low parental numeracy was not significantly associated with change in lung function measures. CONCLUSION: Persistently low parental numeracy is associated with asthma exacerbation outcomes in Puerto Rican youth.

Genome-wide interaction study of dust mite allergen on lung function in children with asthma.

BACKGROUND: Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes. OBJECTIVE: We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure. METHODS: A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study. RESULTS: Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV1 with dust mite allergen level in PRGOAL (interaction P = 3.1 × 10-8), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interaction P = .0065 for replication cohorts and 7.4 × 10-9 for all cohorts). Rs117902240 was positively associated with FEV1 in children exposed to low dust mite allergen levels, but negatively associated with FEV1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV1/forced vital capacity replicated in the independent cohorts. CONCLUSIONS: Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions.

A Multiomics Approach to Identify Genes Associated with Childhood Asthma Risk and Morbidity.

Childhood asthma is a complex disease. In this study, we aim to identify genes associated with childhood asthma through a multiomics "vertical" approach that integrates multiple analytical steps using linear and logistic regression models. In a case-control study of childhood asthma in Puerto Ricans (n = 1,127), we used adjusted linear or logistic regression models to evaluate associations between several analytical steps of omics data, including genome-wide (GW) genotype data, GW methylation, GW expression profiling, cytokine levels, asthma-intermediate phenotypes, and asthma status. At each point, only the top genes/single-nucleotide polymorphisms/probes/cytokines were carried forward for subsequent analysis. In step 1, asthma modified the gene expression-protein level association for 1,645 genes; pathway analysis showed an enrichment of these genes in the cytokine signaling system (n = 269 genes). In steps 2-3, expression levels of 40 genes were associated with intermediate phenotypes (asthma onset age, forced expiratory volume in 1 second, exacerbations, eosinophil counts, and skin test reactivity); of those, methylation of seven genes was also associated with asthma. Of these seven candidate genes, IL5RA was also significant in analytical steps 4-8. We then measured plasma IL-5 receptor α levels, which were associated with asthma age of onset and moderate-severe exacerbations. In addition, in silico database analysis showed that several of our identified IL5RA single-nucleotide polymorphisms are associated with transcription factors related to asthma and atopy. This approach integrates several analytical steps and is able to identify biologically relevant asthma-related genes, such as IL5RA. It differs from other methods that rely on complex statistical models with various assumptions.

Cockroach allergen exposure and plasma cytokines among children in a tropical environment.

BACKGROUND: Little is known about the effects of socioeconomic status or cockroach allergen on immune responses in school-age children, particularly in tropical environments. OBJECTIVE: To examine whether cockroach allergen and/or socioeconomic status is associated with plasma cytokine levels in Puerto Rican children. METHODS: This was a cross-sectional study of 532 children (6-14 years old) with (n = 272) and without (n = 260) asthma in San Juan (Puerto Rico). House dust allergens (cockroach [Bla g 2], dust mite [Der p 1], cat dander [Fel d 1], dog dander [Can f 1], and mouse urinary protein [Mus m 1]) were quantified using monoclonal antibody arrays. A panel of 14 cytokines (interleukin [IL]-1ß, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon-γ, and tumor necrosis factor-α) was measured in plasma samples. Low household income was defined as less than $15,000 per year (below the median income for Puerto Rico in 2008-2009). Linear regression was used for the analysis of cockroach allergen and plasma cytokines. RESULTS: In a multivariable analysis adjusting for low income and other allergen levels, cockroach allergen was significantly associated with decreased IL-17A and with increased levels of 8 cytokines (IL-4, IL-10, IL-17F, IL-21, IL-25, IL-31, interferon-γ, and tumor necrosis factor-α). After stratifying this analysis by cockroach allergy (ie, having a cockroach positive immunoglobulin E reaction), our findings remained largely unchanged for children sensitized to cockroach but became weaker and statistically nonsignificant for non-sensitized children. CONCLUSION: Cockroach allergen has broad effects on adaptive immune responses in school-age children in a tropical environment, particularly in those sensitized to cockroach.

Stress and Bronchodilator Response in Children with Asthma.

RATIONALE: Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). OBJECTIVES: To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma. METHODS: This was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids. MEASUREMENTS AND MAIN RESULTS: High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the ß2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). CONCLUSIONS: High child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.

Diet, interleukin-17, and childhood asthma in Puerto Ricans.

BACKGROUND: Dietary patterns might influence the pathogenesis of asthma in Puerto Ricans, the ethnic group most affected by this disease in the United States. OBJECTIVE: To examine the association among diet, T-helper cell type 17 cytokines, and asthma in Puerto Rican children. METHODS: As part of a case-control study of 678 Puerto Rican children 6 to 14 years old in San Juan, participants completed a 75-item questionnaire on the child's food consumption in the prior week. Foods were aggregated into 7 groups: fruits, vegetables, grains, protein foods, dairy, fats, and sweets. Logistic regression was used to evaluate consumption frequency of each group, plasma T-helper cell type 17 cytokine levels, and asthma. Based on this analysis, a food score (range -2 [unhealthy diet: high consumption of dairy products and sweets, low consumption of vegetables and grains] to +2 [healthy diet: high consumption of grains and vegetables, low consumption of dairy and sweets]) was created to identify dietary patterns. RESULTS: High consumption of grains was associated with lower odds of asthma (adjusted odds ratio [aOR] 0.52, 95% confidence interval [CI] 0.33-0.82), whereas frequent consumption of dairy products (aOR 1.93, 95% CI 1.32-2.84) or sweets (aOR 1.82, 95% CI 1.08-2.72) was associated with higher odds of asthma. A healthier diet (each 1-point increment in food score) was associated with lower levels of interleukin-17F (ß = -1.48 pg/mL, 95% CI -1.78 to -1.20) and with 36% decreased odds of asthma (aOR 0.64, 95% CI 0.53-0.77). CONCLUSION: A healthy diet, with frequent consumption of vegetables and grains and low consumption of dairy products and sweets, was associated with lower levels of interleulin-17F and decreased odds of childhood asthma in Puerto Ricans.

Obesity and adiposity indicators, asthma, and atopy in Puerto Rican children.

BACKGROUND: Whether adiposity indicators other than body mass index (BMI) should be used in studies of childhood asthma is largely unknown. The role of atopy in "obese asthma" is also unclear. OBJECTIVES: To examine the relationship among adiposity indicators, asthma, and atopy in Puerto Rican children, and to assess whether atopy mediates the obesity-asthma association. METHODS: In a study of Puerto Rican children with (n = 351) and without (n = 327) asthma, we measured BMI, percent of body fat, waist circumference, and waist-to-hip ratio. The outcomes studied included asthma, lung function, measures of atopy, and, among cases, indicators of asthma severity or control. We performed mediation analysis to assess the contribution of atopy to the relationship between adiposity and asthma. RESULTS: BMI, percent of body fat, and waist circumference were associated with increased odds of asthma. Among cases, all 3 measures were generally associated with lung function, asthma severity/control, and atopy; however, there were differences depending on the adiposity indicator analyzed. Atopy considerably mediated the adiposity-asthma association in this population: allergic rhinitis accounted for 22% to 53% of the association with asthma, and sensitization to cockroach mediated 13% to 20% of the association with forced vital capacity and 29% to 42% of the association with emergency department visits for asthma. CONCLUSIONS: Adiposity indicators are associated with asthma, asthma severity/control, and atopy in Puerto Rican children. Atopy significantly mediates the effect of adiposity on asthma outcomes. Longitudinal studies are needed to further investigate the causal role, if any, of adiposity distribution and atopy on "obese asthma" in childhood.

Prematurity, atopy, and childhood asthma in Puerto Ricans.

BACKGROUND: Puerto Rican children share a disproportionate burden of prematurity and asthma in the United States. Little is known about prematurity and childhood asthma in Puerto Rican subjects. OBJECTIVE: We sought to examine whether prematurity is associated with asthma in Puerto Rican children. METHODS: We performed a case-control study of 678 children aged 6 to 14 years with (n = 351) and without (n = 327) asthma living in San Juan, Puerto Rico. Prematurity was defined by parental report for our primary analysis. In a secondary analysis, we only included children whose parents reported prematurity that required admission to the neonatal intensive care unit. Asthma was defined as physician-diagnosed asthma and wheeze in the prior year. We used logistic regression for analysis. All multivariate models were adjusted for age, sex, household income, atopy (≥1 positive IgE level to common allergens), maternal history of asthma, and early-life exposure to environmental tobacco smoke. RESULTS: In a multivariate analysis there was a significant interaction between prematurity and atopy on asthma (P = .006). In an analysis stratified by atopy, prematurity was associated with a nearly 5-fold increased odds of asthma in atopic children (adjusted odds ratio, 4.7; 95% CI, 1.5-14.3; P = .007). In contrast, there was no significant association between prematurity and asthma in nonatopic children. Similar results were obtained in our analysis of prematurity requiring admission to the neonatal intensive care unit and asthma. CONCLUSIONS: Our results suggest that atopy modifies the estimated effect of prematurity on asthma in Puerto Rican children. Prematurity might explain, in part, the high prevalence of atopic asthma in this ethnic group.

Mouse allergen exposure and decreased risk of allergic rhinitis in school-aged children.

BACKGROUND: Little is known about exposure to mouse allergen (Mus m 1) and allergic rhinitis (AR). OBJECTIVE: To evaluate the association between mouse allergen exposure and AR in children. METHODS: We examined the relation between mouse allergen level in house dust and AR in 511 children aged 6 to 14 years in San Juan, Puerto Rico. Study participants were chosen from randomly selected households using a multistage probability sample design. The study protocol included questionnaires, allergy skin testing, and collection of blood and dust samples. AR was defined as current rhinitis symptoms and skin test reactivity to at least one allergen. RESULTS: In the multivariate analyses, mouse allergen level was associated with a 25% decreased odds of AR in participating children (95% confidence interval, 0.62-0.92). Although endotoxin and mouse allergen levels were significantly correlated (r = 0.184, P < .001), the observed inverse association between Mus m 1 and AR was not explained by levels of endotoxin or other markers of microbial or fungal exposure (peptidoglycan and glucan). CONCLUSION: Mouse allergen exposure is associated with decreased odds of AR in Puerto Rican school-aged children.

ADCYAP1R1 and asthma in Puerto Rican children.

RATIONALE: Epigenetic and/or genetic variation in the gene encoding the receptor for adenylate-cyclase activating polypeptide 1 (ADCYAP1R1) has been linked to post-traumatic stress disorder in adults and anxiety in children. Psychosocial stress has been linked to asthma morbidity in Puerto Rican children. OBJECTIVES: To examine whether epigenetic or genetic variation in ADCYAP1R1 is associated with childhood asthma in Puerto Ricans. METHODS: We conducted a case-control study of 516 children ages 6-14 years living in San Juan, Puerto Rico. We assessed methylation at a CpG site in the promoter of ADCYAP1R1 (cg11218385) using a pyrosequencing assay in DNA from white blood cells. We tested whether cg11218385 methylation (range, 0.4-6.1%) is associated with asthma using logistic regression. We also examined whether exposure to violence (assessed by the Exposure to Violence [ETV] Scale in children 9 yr and older) is associated with cg11218385 methylation (using linear regression) or asthma (using logistic regression). Logistic regression was used to test for association between a single nucleotide polymorphism in ADCYAP1R1 (rs2267735) and asthma under an additive model. All multivariate models were adjusted for age, sex, household income, and principal components. MEASUREMENTS AND MAIN RESULTS: EACH 1% increment in cg11218385 methylation was associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.0-1.6; P = 0.03). Among children 9 years and older, exposure to violence was associated with cg11218385 methylation. The C allele of single nucleotide polymorphism rs2267735 was significantly associated with increased odds of asthma (adjusted odds ratio, 1.3; 95% confidence interval, 1.02-1.67; P = 0.03). CONCLUSIONS: Epigenetic and genetic variants in ADCYAP1R1 are associated with asthma in Puerto Rican children.

Vitamin D insufficiency and severe asthma exacerbations in Puerto Rican children.

RATIONALE: Vitamin D insufficiency (a serum 25(OH)D <30 ng/ml) has been associated with severe asthma exacerbations, but this could be explained by underlying racial ancestry or disease severity. Little is known about vitamin D and asthma in Puerto Ricans. OBJECTIVES: To examine whether vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, and time outdoors. METHODS: A cross-sectional study was conducted of 560 children ages 6-14 years with (n = 287) and without (n = 273) asthma in San Juan, Puerto Rico. We measured plasma vitamin D and estimated the percentage of African racial ancestry among participants using genome-wide genotypic data. We tested whether vitamin D insufficiency is associated with severe asthma exacerbations, lung function, or atopy (greater than or equal to one positive IgE to allergens) using logistic or linear regression. Multivariate models were adjusted for African ancestry, time outdoors, atopy, and other covariates. MEASUREMENTS AND MAIN RESULTS: Vitamin D insufficiency was common in children with (44%) and without (47%) asthma. In multivariate analyses, vitamin D insufficiency was associated with higher odds of greater than or equal to one severe asthma exacerbation in the prior year (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.5-4.9; P = 0.001) and atopy, and a lower FEV(1)/FVC in cases. After stratification by atopy, the magnitude of the association between vitamin D insufficiency and severe exacerbations was greater in nonatopic (OR, 6.2; 95% CI, 2-21.6; P = 0.002) than in atopic (OR, 2; 95% CI, 1-4.1; P = 0.04) cases. CONCLUSIONS: Vitamin D insufficiency is associated with severe asthma exacerbations in Puerto Rican children, independently of racial ancestry, atopy, or markers of disease severity or control.

African ancestry and lung function in Puerto Rican children.

BACKGROUND: Puerto Rican and African American subjects share a significant proportion of African ancestry. Recent findings suggest that African ancestry influences lung function in African American adults. OBJECTIVE: We sought to examine whether a greater proportion of African ancestry is associated with lower FEV(1) and forced vital capacity (FVC) in Puerto Rican children independently of socioeconomic status, health care access, or key environmental/lifestyle factors. METHODS: We performed a cross-sectional case-control study of 943 Puerto Rican children aged 6 to 14 years with (n= 520) and without (n= 423) asthma (defined as physician-diagnosed asthma and wheeze in the prior year) living in Hartford, Connecticut (n= 383), and San Juan, Puerto Rico (n= 560). We estimated the percentage of African racial ancestry in study participants using genome-wide genotypic data. We tested whether African ancestry is associated with FEV(1) and FVC using linear regression. Multivariate models were adjusted for indicators of socioeconomic status and health care and selected environmental/lifestyle exposures. RESULTS: After adjustment for household income and other covariates, each 20% increment in African ancestry was significantly associated with lower prebronchodilator FEV(1) (-105 mL; 95% CI, -159 to -51 mL; P< .001) and FVC (-133 mL; 95% CI, -197 to -69 mL; P< .001) and postbronchodilator FEV(1) (-152 mL; 95% CI, -210 to -94 mL; P< .001) and FVC (-145 mL; 95% CI, -211 to -79 mL; P< .001) in children with asthma. Similar but weaker associations were found for prebronchodilator and postbronchodilator FEV(1) (change for each 20% increment in African ancestry, -78 mL; 95% CI, -131 to -25 mL; P= .004) and for postbronchodilator FVC among children without asthma. CONCLUSIONS: Genetic factors, environmental/lifestyle factors, or both correlated with African ancestry might influence childhood lung function in Puerto Rican subjects.

Factors associated with disparities in emergency department use among Latino children with asthma.

BACKGROUND: Significant disparities in emergency department (ED) rates exist for Latinos; however, few studies have investigated the factors that may account for these disparities. OBJECTIVES: To examine individual/family and health system factors among Latino and non-Latino white (NLW) children with asthma to explain disparities in ED rates. METHODS: The study was carried out in Puerto Rico (PR) and Rhode Island (RI) with the same design: a cross-sectional, observational approach with repeated measurements of selected variables. RESULTS: The sample was composed of 804 children ages 7 to 15 years, with 405 from PR and 399 from RI. Latino children from both sites had significantly higher rates of ED use as compared with NLWs from RI. Regression analyses showed site, asthma control, parental reported severity of asthma and public insurance to be significantly associated with ED use. CONCLUSION: Latino ethnicity and public insurance were among the most important factors related to frequent ED use. Revisions of the policies driving public insurance to assure better access to specialists, preventive education, and evidence-based treatment are needed. The results also suggest the need for the development of interventions in the ED that are geared toward educating families on how best to use emergency services.

A genome-wide study of DNA methylation in white blood cells and asthma in Latino children and youth.

Latinos are heavily affected with childhood asthma. Little is known about epigenetic mechanisms of asthma in Latino youth. We conducted a meta-analysis of two epigenome-wide association studies (EWAS) of asthma, using DNA from white blood cells (WBCs) from 1,136 Latino children and youth aged 6 to 20 years. Genes near the top CpG sites in this EWAS were examined in a pathway enrichment analysis, and we then assessed whether our results replicated those from publicly available data from three independent EWAS conducted in non-Latino populations. We found that DNA methylation profiles differed between subjects with and without asthma. After adjustment for covariates and multiple testing, two CpGs were differentially methylated at a false discovery rate (FDR)-adjusted P < 0.1, and 193 CpG sites were differentially methylated at FDR-adjusted P < 0.2. The two top CpGs are near genes relevant to inflammatory signalling, including CAMK1D (Calcium/Calmodulin Dependent Protein Kinase ID) and TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains). Moreover, 25 genomic regions were differentially methylated between subjects with and without asthma, at Sidák-corrected P < 0.10. An enrichment analysis then identified the TGF-beta pathway as most relevant to asthma in our analysis, and we replicated some of the top signals from publicly available EWAS datasets in non-Hispanic populations. In conclusion, we have identified novel epigenetic markers of asthma in WBCs from Latino children and youth, while also replicating previous results from studies conducted in non-Latinos.

Under-diagnosis of atopic dermatitis in Puerto Rican children.

BACKGROUND: Little is known about atopic dermatitis (AD) among children in Puerto Rico. OBJECTIVE: To examine risk factors and identify approaches to better diagnose AD in Puerto Rican children. METHODS: Case-control study of AD among 540 children aged 6-14 years in San Juan, Puerto Rico. AD was defined as: 1) physician-diagnosed AD, 2) RAST-AD: AD symptoms plus ≥1 positive IgE to allergens, and 3) STR-AD: AD-symptoms and skin test reactivity to ≥1 allergen. Logistic regression was used for the multivariable analysis. We also evaluated the diagnostic performance of various approaches by comparing their sensitivity, specificity, positive predicted value [PPV], negative predictive value [NPV], and area under curve [AUC]). RESULTS: Of the 70 children with STR-AD, only 5 (7.1%) had PD-AD. In children without asthma, a positive IgE to Dermatophagoides (D.) pteronyssinus and signs of mold/mildew at home were significantly associated with 3.3 and 5 times increased odds of STR-AD, respectively. Among children with asthma, private/employer-based health insurance and a positive IgE to D. pteronyssinus were each significantly associated with approximately twofold increased odds of STR-AD. A combination of current eczema symptoms and a positive IgE to D. pteronyssinus yielded a sensitivity ≥ 70%, specificity and NPV ≥ 95%, PPV ≥ 88%, and an AUC ≥ 0.85 for STR-AD. Replacing a positive IgE to D. pteronyssinus with a positive IgE to ≥1 allergen slightly increased sensitivity without affecting other parameters. CONCLUSIONS: AD is markedly under-diagnosed by physicians in Puerto Rico. This could be improved by assessing eczema symptoms and measuring IgEs to common allergens.

DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study.

BACKGROUND: Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children. METHODS: We did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts. FINDINGS: DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%). INTERPRETATION: We identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants. FUNDING: US National Institutes of Health.

Diet, Lung Function, and Asthma Exacerbations in Puerto Rican Children.

Changes in dietary patterns may partly explain the epidemic of asthma in industrialized countries. The objective of this study was to examine the relationship between dietary patterns and lung function and asthma exacerbations in Puerto Rican children. This is a case-control study of 678 Puerto Rican children (ages 6-14 years) in San Juan (Puerto Rico). All participants completed a respiratory health questionnaire and a 75-item food frequency questionnaire. Food items were aggregated into 7 groups: fruits, vegetables, grains, protein, dairy, fats, and sweets. Logistic regression was used to evaluate consumption frequency of each group and asthma. Based on the results, a dietary score was created [range from -2 (unhealthy diet: high consumption of dairy and sweets, low consumption of vegetables and grains) to 2 (healthy diet: high consumption of vegetables and grains and low consumption of dairy and sweet)]. Multivariable linear or logistic regression was used to assess the relationship between dietary score and lung function or asthma exacerbations. After adjustment for covariates, a healthier diet (each 1-point increment in dietary score) was associated with significantly higher %predicted forced expiratory volume in the first second (FEV1) and %predicted forced vital capacity (FVC) in control subjects. Dietary pattern alone was not associated with asthma exacerbations, but children with an unhealthy diet and vitamin D insufficiency (plasma 25(OH)D <30 ng/mL) had higher odds of ≥1 severe asthma exacerbation [odds ratio (OR) = 3.4, 95% confidence interval (CI) = 1.5-7.5] or ≥1 hospitalization due to asthma (OR = 3.9, 95% CI = 1.6-9.8, OR = 3.4, 95% CI = 1.5-7.5) than children who ate a healthy diet and were vitamin D sufficient. A healthy diet, with frequent consumption of vegetables and grains and low consumption of dairy products and sweets, was associated with higher lung function (as measured by FEV1 and FVC). Vitamin D insufficiency, together with an unhealthy diet, may have detrimental effects on asthma exacerbations in children.