Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.

Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS.

Author Summary

Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function before and after the administration of short-acting β2-agonists, common medications used for asthma treatment. We performed a genome-wide association study of BDR with 1,644 white asthmatic subjects from six drug clinical trials and attempted to replicate these findings in 1,051 white subjects from two independent cohorts. The most significant associated variant was near the SPATS2L gene. We knocked down SPATS2L mRNA in human airway smooth muscle cells and found that β2-adrenergic receptor levels increased, suggesting that SPATS2L may be a regulator of BDR. Our results highlight the promise of pursuing GWAS results that do not necessarily reach genome-wide significance and are an example of how results from pharmacogenetic GWAS can be studied functionally.

Background

The course of mild to moderate persistent asthma in children is not clearly established.

Objective

To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence.

Methods

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 4 years 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).

Results

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 three asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting vs. persistent asthma were lack of allergen sensitization and exposure to indoor allergens [OR=3.23, p<0.001], milder asthma [OR=2.01, p=0.03], older age [OR=1.23, p=0.01], less airway hyperresponsiveness (higher log methacholine FEV1 PC20 [OR=1.39, p=0.03]), higher pre-bronchodilator FEV1 % predicted [OR=1.05, p=0.02], and lower FVC % predicted [OR=0.96, p=0.04].

Conclusion

Remission of asthma in adolescence is infrequent and not impacted 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.

Background

Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.

Objective

We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-moderate persistent asthma.

Methods

In the 1,041 participants in the Childhood Asthma Management Program (CAMP), subjects with a change in FEV1 of 12% or greater (and 200mLs) after inhaled ß2 agonist at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR.

Results

We identified 52 children with consistent BDR over the 4-year trial. Multivariable logistic regression modeling demonstrated that baseline pre-bronchodilator FEV1 (OR=0.71, p<0.0001), log 10 IgE level (OR=1.97, p=0.002), and lack of treatment with inhaled corticosteroids (OR=0.31, p=0.009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (p=0.007), required more prednisone bursts (p=0.0007), had increased nocturnal awakenings due to asthma (p<0.0001), and missed more days of school (p=0.03) than non-responders during the 4-year follow-up.

Conclusions

We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.