Childhood Asthma Management Program Trial Research Articles

Novel eosinophilic gene expression networks associated with IgE in two distinct asthma populations.

Asthma represents a significant public health burden; however, novel biological therapies targeting immunoglobulin E (IgE)-mediated pathways have widened clinical treatment options for the disease. In this study, we sought to identify gene transcripts and gene networks involved in the determination of serum IgE levels in people with asthma that can help inform the development of novel therapeutic agents. We analysed gene expression data from a cross-sectional study of 326 Costa Rican children with asthma, aged 6 to 12years, from the Genetics of Asthma in Costa Rica Study and 610 young adults with asthma, aged 16 to 25years, from the Childhood Asthma Management Program trial. We utilized differential gene expression analysis and performed weighted gene coexpression network analysis on 25060 genes, to identify gene transcripts and network modules associated with total IgE, adjusting for age and gender. We used pathway enrichment analyses to identify key biological pathways underlying significant modules. We compared findings that replicated between both populations. We identified 31 transcripts associated with total IgE that replicated between the two study cohorts. These results were notable for increased eosinophil-related transcripts (including IL5RA, CLC, SMPD3, CCL23 and CEBPE). Pathway enrichment identified the regulation of T cell tolerance as important in the determination of total IgE levels, supporting a key role for IDO1. These results provide robust evidence that biologically meaningful gene expression profiles (relating to eosinophilic and regulatory T cell pathways in particular) associated with total IgE levels can be identified in individuals diagnosed with asthma during childhood. These profiles and their constituent genes may represent novel therapeutic targets.

Genetic risk factors for decreased bone mineral accretion in children with asthma receiving multiple oral corticosteroid bursts

Long-term intermittent oral corticosteroid (OCS) use in children with asthma leads to significant decreases in bone mineral accretion (BMA). We aimed to identify genetic factors influencing OCS dose effects on BMA in children with asthma. We first performed a gene-by-OCS interaction genome-wide association study (GWAS) of BMA in 489 white participants in the Childhood Asthma Management Program trial who took short-term oral prednisone bursts when they experienced acute asthma exacerbations. We selected the top-ranked 2000 single nucleotide polymorphisms (SNPs) in the GWAS and determined whether these SNPs also had cis-regulatory effects on dexamethasone-induced gene expression in osteoblasts. We identified 2 SNPs (rs9896933 and rs2074439) associated with decreased BMA and related to the tubulin γ pathway. The rs9896933 variant met the criteria for genome-wide significance (P = 3.15 × 10(-8) in the GWAS) and is located on the intron of tubulin folding cofactor D (TBCD) gene. The rs2074439 variant (P = 2.74 × 10(-4) in the GWAS) showed strong cis-regulatory effects on dexamethasone-induced tubulin γ gene expression in osteoblasts (P = 8.64 × 10(-4)). Interestingly, we found that BMA worsened with increasing prednisone dose as the number of mutant alleles of the 2 SNPs increased. We have identified 2 novel tubulin γ pathway SNPs, rs9896933 and rs2074439, showing independent interactive effects with cumulative corticosteroid dose on BMA in children with asthma receiving multiple OCS bursts.

Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids

To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10(-5)), rs2388639 (combined P = 8.56 × 10(-9)), and rs10044254 (combined P = 9.16 × 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

Decreased response to inhaled steroids in overweight and obese asthmatic children

The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear. We sought to determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children. 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. 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). 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.

Pediatric Asthma Controller Therapy

The treatment of children with asthma has historically relied upon expert opinion using data extrapolated from adult studies. Over the past few years, landmark studies have been completed providing healthcare professionals with evidence on which a reasonable approach can be made for children suffering from this common and serious disease. Asthmatic phenotype in children, unlike adults, tends to differ according to age, which must be taken into account as well as triggers, severity, and level of control. The care of the child with asthma is complex, but accumulating data have demonstrated that we are on the right path for optimizing control while reducing the burden of side effects. The newest Global Initiative for Asthma (GINA) guidelines, as well as recent updates from the landmark CAMP (Childhood Asthma Management Program) study and information from the PACT (Pediatric Asthma Control Trial) and budesonide/formoterol controller and reliever studies, along with recent comparisons of higher dose inhaled corticosteroids (ICS), and ICS/long-acting β(2)-adrenoceptor agonist (LABA) combination and leukotriene receptor antagonist (LTRA) therapies in children have clarified a few of the big questions in pediatric asthma. For children with asthma aged 5 years and older, the CAMP trial demonstrated that regular use of ICS reduces the frequency of symptoms; however, height was adversely affected and there is no evidence for altering the natural history of asthma. In patients aged 6 years and over whose asthma is uncontrolled on ICS alone, combination therapy with ICS and a LABA has been recently compared with the use of higher dose ICS and the addition of an LTRA in pediatric patients. The addition of a LABA statistically will be of most benefit; however, some children will have optimal control with doubling the baseline dose of ICS or addition of an LTRA. Use of budesonide/formoterol as a controller and reliever therapy extends the time to first exacerbation versus contemporary use of this medication in patients aged 4 years and older. Ciclesonide, a newer ICS, has demonstrated acceptable efficacy but has the added benefit of not affecting growth. Certainly, with mounting evidence, the care-map in pediatric asthma control is becoming clearer.

Predictors of remitting, periodic, and persistent childhood asthma

The course of mild to moderate persistent asthma in children is not clearly established. To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence. The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by a 4-year observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent). Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all 3 asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting versus persistent asthma were lack of allergen sensitization and exposure to indoor allergens (odds ratio [OR], 3.23; P < .001), milder asthma (OR, 2.01; P = .03), older age (OR, 1.23; P = .01), less airway hyperresponsiveness (higher log methacholine FEV(1) PC(20) (OR, 1.39; P = .03), higher prebronchodilator FEV(1) percent predicted (OR, 1.05; P = .02), and lower forced vital capacity percent predicted (OR, 0.96; P = .04). Remission of asthma in adolescence is infrequent and not affected by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.

Development of a Pharmacogenetic Predictive Test in asthma: proof of concept

To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR). We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 microg/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population. The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n = 422) and 0.60 (n = 475) and 0.63 (n = 235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations. Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.

Long-term Budesonide or Nedocromil Treatment, Once Discontinued, Does Not Alter the Course of Mild to Moderate Asthma in Children and Adolescents

Strunk RC, Sternberg AL, Szefler SJ, et al. J Pediatr. 2009;154(5):682–687 PURPOSE OF THE STUDY. To determine whether long-term, continuous use of inhaled antiinflammatory medications affects asthma outcomes in children with mild-to-moderate asthma after use is discontinued. STUDY POPULATION. A total of 941 children, 5 to 12 years of age, who had previously participated in the Childhood Asthma Management Program (CAMP). METHODS. During the CAMP trial, subjects received treatment with budesonide, nedocromil, or placebo for 4.3 years. During the posttrial period, …

Effect of long-term corticosteroid use on bone mineral density in children: a prospective longitudinal assessment in the childhood Asthma Management Program (CAMP) study.

Systemic corticosteroids are known to induce osteoporosis and increase the risk for fractures in adults and children. Inhaled corticosteroids have been shown to increase the risk for osteoporosis and fractures in adults at risk; however, long-term prospective studies of children to assess risks of multiple short courses of oral corticosteroids and chronic inhaled corticosteroids have not been performed. Thus, we assessed the effects of multiple short courses of oral corticosteroids and long-term inhaled corticosteroids on bone mineral accretion over a period of years. This was a cohort follow-up study for a median of 7 years of children who had mild-to-moderate asthma and initially were randomly assigned into the Childhood Asthma Management Program trial. Serial dual-energy radiograph absorptiometry scans of the lumbar spine for bone mineral density were performed for all patients. Annual bone mineral accretion was calculated for 531 boys and 346 girls who had asthma and were aged 5 to 12 years at baseline (84% of the initial cohort). Oral corticosteroid bursts produced a dosage-dependent reduction in bone mineral accretion (0.052, 0.049, and 0.046 g/cm(2) per year) and an increase in risk for osteopenia (10%, 14%, and 21%) for 0, 1 to 4, and >or=5 courses, respectively, in boys but not girls. Cumulative inhaled corticosteroid use was associated with a small decrease in bone mineral accretion in boys but not girls but no increased risk for osteopenia. Multiple oral corticosteroid bursts over a period of years can produce a dosage-dependent reduction in bone mineral accretion and increased risk for osteopenia in children with asthma. Inhaled corticosteroid use has the potential for reducing bone mineral accretion in male children progressing through puberty, but this risk is likely to be outweighed by the ability to reduce the amount of oral corticosteroids used in these children.

Association of Hypothalamic-Pituitary-Adrenal Axis Function with Neuropsychological Performance in Children with Mild/Moderate Asthma

The present study examines the relationship between hypothalamic-pituitary-adrenal (HPA) axis function and child psychological/neuropsychological function in a group of children with mild to moderate asthma. The goal of the study was to determine whether child neuropsychological functioning and psychological functioning were associated with cortisol production in response to adrenocorticotropic hormone(ACTH) stimulation when assessed as area under the curve. Data for this study were gathered from 63 children who participated in an ancillary study within the Childhood Asthma Management Program (CAMP) during the pre-randomization phase of the CAMP trial. At 2 of the 8 CAMP clinical centers participants completed an ACTH stimulation test after an overnight stay in the General Clinical Research Center. Gender differences on baseline cortisol and change in cortisol 30 minutes after infusion of ACTH were present. Results further indicated significant associations between cortisol production and measures of child neuropsychological function. Stepwise multiple regression analysis revealed that cortisol change could be predicted by measures of gender, working memory, and arousal maintenance, providing support for the hypothesis that cortisol plays a modest role in the neuropsychological function of children with mild and moderate asthma. In contrast, cortisol production was not associated with child reports of psychological functioning. Limitations to the methods employed in this study are discussed.

Neurocognitive functioning in children with mild and moderate asthma in the Childhood Asthma Management Program

Background: The Childhood Asthma Management Program (CAMP) is a multicenter double-blind, randomized, placebo-controlled, clinical trial of two anti-inflammatory agents and placebo in children with mild and moderate asthma. Objective: The interrelationship between asthma severity and neurocognitive functioning among 1041 children (age range, 5-12 years) enrolled in the CAMP trial was examined. Methods: Asthma severity was established at baseline with a clinical history of asthma symptomatology and measures of lung function (spirometry and methacholine challenge). Diary cards were used in a screening to record nighttime awakenings and doctor contacts caused by asthma symptoms, symptom severity, and number of puffs from a rescue inhaler. All children received a comprehensive neurocognitive assessment at the end of the 28-day screening period (before randomization), including measures of intelligence, attention, memory, and academic achievement. Results: Significant differences were found between children with mild and moderate asthma on lung function and symptom outcome variables (logeFEV1PC20,ΔFEV1 percent predicted, change in peak flow percent predicted, nighttime awakenings caused by asthma, average symptom severity score, and average daily number of puffs from a rescue inhaler) but not on neurocognitive variables. Multiple regression analyses revealed that asthma outcomes could not be predicted by neurocognitive variables despite controlling for socioeconomic status. The prevalence of neurocognitive dysfunction, as indicated by the use of psychostimulant medication, was found to be consistent with that found in the existing literature. Conclusion: Mild and moderate asthma symptoms are not related to neurocognitive functioning in the children enrolled in CAMP. Mean performance on neurocognitive variables was found to be similar to that of national normative data. (J Allergy Clin Immunol 2000;105:717-24.)