No reduction in asthma exacerbation with temporary glucocorticoid dose increase
A temporary increased dose of inhaled glucocorticoids did not reduce the rate of exacerbations in children with mild-to-moderate asthma, according to a study presented at the 2018 AAAAI/WAO congress held in Orlando, Florida, US.
“These findings suggest that a short-term increase to high-dose inhaled steroids should not be routinely included in asthma treatment plans for children with mild-moderate asthma who are regularly using low-dose inhaled corticosteroids,” said study lead author Dr Daniel Jackson from the University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, US.
“Low-dose inhaled steroids remain the cornerstone of daily treatment in affected children,” he said.
Participants in the multicentre, double-blind STICS* study were 254 children aged 5–11 years with mild-to-moderate persistent asthma who experienced ≥1 exacerbations in the previous year that was treated with systemic glucocorticoids. All participants received maintenance low-dose inhaled fluticasone propionate (two inhalations twice daily at 44 µg per inhalation) for 48 weeks and were randomized 1:1 to continue receiving the same low dose or a quintupled dose (two inhalations twice daily at 220 µg per inhalation) for 7 days each time there were early signs of loss of asthma control (yellow zone). The final assessment included 192 participants, 94 and 98 in the high- and low-dose group, respectively.
The rate of severe asthma exacerbations during the trial period was similar between children given high-dose or low-dose inhaled glucocorticoids (0.48 vs 0.37 exacerbations per year, relative rate, 1.3, 95 percent confidence interval [CI], 0.8–2.1; p=0.30). [N Engl J Med 2018;378:891-901]
There was also no significant between-group difference observed pertaining to time to first severe asthma exacerbation (p=0.20), rate of emergency department visit due to asthma (p=0.30), treatment failure (p=0.70), total symptom burden at time of asthma control loss (p=0.30), or albuterol use during yellow-zone episodes (p=0.30).
Children in the high-dose group had a 16 percent higher total exposure to glucocorticoids compared with those in the low-dose group over the trial period.
There was a trend towards a lower growth rate in children on high-dose compared with low-dose glucocorticoids (5.43 vs 5.65 cm growth per year, difference -0.23 cm per year; p=0.06), with a dose-response relationship observed in children <8 years (0.12 cm lower growth per year per yellow-zone episode in the high-dose vs low-dose group; p=0.02).
According to Jackson and co-authors, certain strategies recommend a short-term increase in the dose of inhaled corticosteroids during the yellow zone, though research evaluating this strategy has not produced evidence to back this up.
“One potential explanation for this apparent discrepancy is that, even without intervention beyond the use of a short-acting beta-agonist, a substantial proportion of yellow-zone episodes do not progress to severe exacerbations that lead to the use of systemic glucocorticoids,” they said.
“Increasing the dose of inhaled steroids at early signs of asthma worsening along with using quick relief medicines to relieve symptoms is a common practice,” said study author Dr Kristie Ross from Case Western Reserve University School of Medicine, Cleveland, Ohio, US.
“Our study shows that this is no more effective at preventing progression to more serious asthma exacerbations than the use of quick relief medicines alone, such as albuterol inhalers,” said Ross.
The authors cautioned that the STICS findings pertain only to children with mild-to-moderate asthma who are adherent to maintenance low-dose inhaled glucocorticoids, highlighting previous studies that have indicated a potential benefit of intermittent high-dose inhaled glucocorticoids during yellow-zone episodes in other age groups undergoing different treatment strategies for mild asthma. [N Engl J Med 2005;352:1519-1528; N Engl J Med 2009;360:339-353]
Potential benefit in adults with asthma?
In a separate multicentre, unblinded study, 1,922 adults and adolescents (mean age 57 years, 68 percent female) with asthma receiving any dose of inhaled glucocorticoids and who had experienced ≥1 exacerbations requiring systemic glucocorticoids in the previous year were randomized to continue with the same dose of inhaled glucocorticoids (n=965) or a quadrupled dose (n=957) with or without add-on medication at the early signs of loss of asthma control.
Fewer patients on the quadrupled dose of inhaled glucocorticoids experienced episodes of severe asthma exacerbation compared with those using the regular dose over 1 year following randomization (45 percent vs 52 percent, hazard ratio for time to first severe exacerbation, 0.81, 95 percent CI, 0.71–0.92; p=0.002). [N Engl J Med 2018;378:902-910]
Patients using the quadrupled dose also had fewer unscheduled healthcare consultations due to asthma (41 percent vs 47 percent) and were less likely to use systemic glucocorticoids (33 percent vs 40 percent) than those using the regular dose.
Within 14 days of loss of asthma control, nonserious adverse events (AEs) were more common among patients on the quadrupled than regular dose (n=56 vs 13) while serious AEs were more common among those on the regular compared with the quadrupled dose (n=32 vs 11).
In an accompanying commentary, Professor Philip Bardin from Monash University and Medical Centre, Melbourne, Victoria, Australia, pointed out that the unblinded study design may have introduced bias, while the allowance for use of long-acting beta-agonists may have lowered the reporting of exacerbations. [N Engl J Med 2018;378:950-952]
“Evidence indicates that substantial escalation of regularly used inhaled glucocorticoids, even by a factor of 4 or 5, fails to prevent most asthma exacerbations. A small subgroup of adults and adolescents with asthma may have a response to an escalation strategy; however, their baseline and exacerbation characteristics remain to be defined,” said Bardin.