Erick Forno

Serum Vitamin D Levels and Markers of Severity of Childhood Asthma in Costa Rica

RATIONALE Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood. OBJECTIVES To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood. METHODS We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses. MEASUREMENTS AND MAIN RESULTS Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log(10) unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004-0.71; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.18; 95% CI, 0.05-0.67; P = 0.01), and increased airway responsiveness (a < or =8.58-mumol provocative dose of methacholine producing a 20% fall in baseline FEV(1) [OR, 0.15; 95% CI, 0.024-0.97; P = 0.05]). CONCLUSIONS Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.

A Genome-Wide Association Study on African-Ancestry Populations For Asthma

BACKGROUND Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Decreased response to inhaled steroids in overweight and obese asthmatic children

BACKGROUND The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear. OBJECTIVES We sought to determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children. METHODS We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program trial. Participants were then stratified into overweight/obese and nonoverweight groups, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial. RESULTS There was a significant interaction between BMI and budesonide for prebronchodilator FEV(1)/forced vital capacity (FVC) ratio (P = .0007) and bronchodilator response (BDR; P = .049) and a nonsignificant trend for an interaction between BMI and budesonide on prebronchodilator FEV(1) (P = .15). Nonoverweight children showed significant improvement with inhaled budesonide in lung function (FEV(1), FEV(1)/FVC ratio, and BDR) during the early (years 1-2) and late (years 3-4) stages of the trial. Overweight/obese children had improved FEV(1) and BDR during the early but not the late stage of the trial and showed no improvement in FEV(1)/FVC ratio. When comparing time points at which both groups showed a significant response, the degree of improvement among nonoverweight children was significantly greater than in overweight/obese children at most visits. Nonoverweight children had a 44% reduction in the risk of emergency department visits or hospitalizations throughout the trial (P = .001); there was no reduction in risk among overweight/obese children (P = .97). CONCLUSIONS Compared with children of normal weight, overweight/obese children in the Childhood Asthma Management Program showed a decreased response to inhaled budesonide on measures of lung function and emergency department visits/hospitalizations for asthma.

Probiotic administration in early life, atopy, and asthma: a meta-analysis of clinical trials.

BACKGROUND AND OBJECTIVE: Probiotics may reduce the risk of atopy and asthma in children. However, results from clinical trials have been conflicting, and several of them may have been underpowered. We performed a meta-analysis of randomized, placebo-controlled trials to assess the effects of probiotic supplementation on atopic sensitization and asthma/wheeze prevention in children. METHODS: Random-effects models were used to calculate pooled risk estimates. Meta-regression was conducted to examine the effect of potential factors on probiotics efficacy. RESULTS: Probiotics were effective in reducing total immunoglobulin E (IgE) (mean reduction: –7.59 U/mL [95% confidence interval (CI): –14.96 to –0.22]; P = .044). Meta-regression showed that the reduction in IgE was more pronounced with longer follow-up. Probiotics significantly reduced the risk of atopic sensitization when administered prenatally (relative risk: 0.88 [95% CI: 0.78 to 0.99]; P = .035 for positive result on the skin prick test and/or elevated specific IgE to common allergens) and postnatally (relative risk: 0.86 [95% CI: 0.75 to 0.98]; P = .027 for positive result on skin prick test). Administration of Lactobacillus acidophilus, compared with other strains, was associated with an increased risk of atopic sensitization (P = .002). Probiotics did not significantly reduce asthma/wheeze (relative risk: 0.96 [95% CI: 0.85 to 1.07]). CONCLUSIONS: Prenatal and/or early-life probiotic administration reduces the risk of atopic sensitization and decreases the total IgE level in children but may not reduce the risk of asthma/wheeze. Follow-up duration and strain significantly modified these effects. Future trials for asthma prevention should carefully select probiotic strain and consider longer follow-up.

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.

Motor vehicle air pollution and asthma in children: A meta-analysis

BACKGROUND Asthma affects more than 17 million people in the United States;1/3 of these are children. Children are particularly vulnerable to airborne pollution because of their narrower airways and because they generally breathe more air per pound of body weight than adults, increasing their exposure to air pollutants. However, the results from previous studies on the association between motor vehicle emissions and the development of childhood wheeze and asthma are conflicting. Therefore, we conducted a meta-analysis to clarify their potential relationship. METHODS MEDLINE, Highwire, and The Cochrane Library databases were searched for relevant studies. Adjusted odds ratio (OR) with corresponding 95% confidence interval (CI) for the association between traffic air pollutants and wheeze or asthma were retrieved from individual studies and pooled to generate summary effect estimates (meta-OR) in STATA 11.1. RESULTS Nineteen studies were included in the meta-analysis. Exposure to nitrogen dioxide (meta-OR: 1.05, 95% CI: 1.00-1.11), nitrous oxide (meta-OR: 1.02, 95% CI: 1.00-1.04), and carbon monoxide (meta-OR: 1.06, 95% CI: 1.01-1.12) were positively associated with a higher prevalence of childhood asthma. Exposure to sulfur dioxide (meta-OR: 1.04, 95% CI: 1.01-1.07) was positively associated with a higher prevalence of wheeze in children. Exposure to nitrogen dioxide was positively associated with a higher incidence of childhood asthma (meta-OR: 1.14, 95% CI: 1.06-1.24), and exposures to particulate matter was positively associated with a higher incidence of wheeze in children (meta-OR: 1.05, 95% CI: 1.04-1.07). CONCLUSIONS Living or attending schools near high traffic density roads exposes children to higher levels of motor vehicle air pollutants, and increases the incidence and prevalence of childhood asthma and wheeze.

Asthma and Ethnic Minorities: Socioeconomic Status and Beyond

Purpose of reviewWe aim to discuss current insights into our understanding of the mechanisms by which socioeconomic status influences the prevalence and severity of asthma in ethnic minorities. In addition, we review potential risk factors for ethnic disparities in asthma that are not mediated by socioeconomic status. Recent findingsExposures and factors correlated with ethnicity through socioeconomic status (e.g. indoor and outdoor air quality, smoke exposure, and access to healthcare) are likely to explain a significant proportion of the observed ethnic differences in asthma morbidity. However, other factors correlated with ethnicity (e.g. genetic variation) can impact ethnic disparities in asthma independently of and/or interacting with socioeconomic status-related factors. SummarySocioeconomic status is a rough marker of a variety of environmental/behavioral exposures and a very important determinant of differences in asthma prevalence and severity among ethnic minorities in the United States. However, socioeconomic status is unlikely to be the sole explanation for ethnic disparities in asthma, which may also be due to differences in genetic variation and gene-by-environment interactions among ethnic groups.

Maternal Obesity in Pregnancy, Gestational Weight Gain, and Risk of Childhood Asthma

BACKGROUND AND OBJECTIVE: Environmental or lifestyle exposures in utero may influence the development of childhood asthma. In this meta-analysis, we aimed to assess whether maternal obesity in pregnancy (MOP) or increased maternal gestational weight gain (GWG) increased the risk of asthma in offspring. METHODS: We included all observational studies published until October 2013 in PubMed, Embase, CINAHL, Scopus, The Cochrane Database, and Ovid. Random effects models with inverse variance weights were used to calculate pooled risk estimates. RESULTS: Fourteen studies were included (N = 108 321 mother–child pairs). Twelve studies reported maternal obesity, and 5 reported GWG. Age of children was 14 months to 16 years. MOP was associated with higher odds of asthma or wheeze ever (OR = 1.31; 95% confidence interval [CI], 1.16–1.49) or current (OR = 1.21; 95% CI, 1.07–1.37); each 1-kg/m2 increase in maternal BMI was associated with a 2% to 3% increase in the odds of childhood asthma. High GWG was associated with higher odds of asthma or wheeze ever (OR = 1.16; 95% CI, 1.001–1.34). Maternal underweight and low GWG were not associated with childhood asthma or wheeze. Meta-regression showed a negative association of borderline significance for maternal asthma history (P = .07). The significant heterogeneity among existing studies indicates a need for standardized approaches to future studies on the topic. CONCLUSIONS: MOP and high GWG are associated with an elevated risk of childhood asthma; this finding may be particularly significant for mothers without asthma history. Prospective randomized trials of maternal weight management are needed.

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.

Predicting asthma exacerbations in children.

Purpose of review This review critically assesses recently published literature on predicting asthma exacerbations in children, while also providing general recommendations for future research in this field. Recent findings Current evidence suggests that every effort should be made to provide optimal treatment to achieve adequate asthma control, as this will significantly reduce the risk of severe disease exacerbations. Children who have had at least one asthma exacerbation in the previous year are at highest risk for subsequent exacerbations, regardless of disease severity and/or control. Although several tools and biomarkers to predict asthma exacerbations have been recently developed, these approaches need further validation and/or have only had partial success in identifying children at risk. Summary Although considerable progress has been made, much remains to be done. Future studies should clearly differentiate severe asthma exacerbations due to inadequate asthma control from those occurring in children whose asthma is well controlled, utilize standardized definitions of asthma exacerbations, and use a systematic approach to identify the best predictors after accounting for the multiple dimensions of the problem. Our ability to correctly predict the development of severe asthma exacerbations in an individual child should improve in parallel with increased knowledge and/or understanding of the complex interactions among genetic, environmental (e.g. viral infections) and lifestyle (e.g. adherence to treatment) factors underlying these events.