Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children

Abstract

Background Asthma exacerbations are a common cause of critical illness in children. Objective To determine factors associated with exacerbations in children with persistent asthma. Methods Regression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids, emergency or hospital care in the 48-week Pediatric Asthma Controller Trial (PACT) study. Children aged 6–14 with mild to moderate persistent asthma were randomized to receive either fluticasone propionate 100 mcg BID (FP monotherapy), combination fluticasone 100 mcg AM and salmeterol BID, or montelukast 5 mg once daily. Results Of the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio 2.10, p<0.001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast vs. FP monotherapy (OR 2.00, p=0.005), season (spring, fall, or winter vs. summer, p=<0.001), and average seasonal 5% reduction in AM peak expiratory flow (PEF) (OR 1.21, p=0.01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low PEF track together before an exacerbation, but have poor positive predictive value of exacerbation. Conclusion Children with mild to moderate persistent asthma with prior exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers, and diary card tracking are not reliable predictors of asthma exacerbations.

Predictors of Symptoms Are Different From Predictors of Severe Exacerbations From Asthma in Children

“…The results of our analysis are different from an analysis by Covar et al, 8 who found that the only predictor of exacerbations is a previous history of exacerbations. Reasons for our contrasting fi ndings could be that the Covar et al 8 study examined a shorter 48-week period, compared with our analysis, which examines a 4-year time frame.…”

“…Reasons for our contrasting fi ndings could be that the Covar et al 8 study examined a shorter 48-week period, compared with our analysis, which examines a 4-year time frame. Similar to our study, Covar et al 8 found that symptoms increased prior to exacerbations but had poor specifi city for predicting exacerbations. Our fi nding that lnPC 20 is associated exacerbations has been found in observational studies and are likely due to confounding by indication; thus, this study offers the strength of being able to assess whether treatment with inhaled corticosteroids decreases the risk of exacerbations because the treatment is randomized.…”

“…Younger age was also associated with severe exacerbations in the study by Covar et al 8 Previous studies have found that predictors of experiencing severe exacerbations are being treated with inhaled corticosteroids, 28 having had previous histories of ED visits or hospitalizations, 13,[29][30][31] or having had treatment in the past with oral corticosteroids. 30 The previous fi ndings that treatment with inhaled corticosteroids is a predictor of severe 2007 NAEPP recommendations for assessing risk and impairment separately.…”

“…7 Similarly, a 1-year pediatric trial found that symptom scores worsened before an exacerbation, but the best predictor of an exacerbation is a past history of an exacerbation. 8 Nevertheless, the relationship between symptoms and severe exacerbations from asthma in children is unknown over a longer time period, and scarce data are available to support the NAEPP guidelines for children. Children who are at risk for exacerbations from asthma may not experience greater asthma symptoms before the onset of the severe exacerbation.…”

“…[15][16][17][18][19] The strongest predictor for risk of exacerbations is a history of previous exacerbation. 8,16 The objectives of this study were (1) to assess the association of asthma symptoms with severe asthma exacerbations, and (2) to compare predictors of persistent asthma symptoms and predictors of severe exacerbations in children with asthma.…”