US, UK Studies Examine Whether Increasing Glucocorticoid Reduces Asthma Exacerbations

Tricia McKeever, PhD

A study in US children and a concurrently published UK study in adults and adolescents examined whether substantially increasing dose of inhaled glucocorticoid for early asthma symptoms can avert full-blown exacerbation.

The studies differed in design (including quintupling a specified low dose in the US, versus quadrupling a previous maintenance dose in the UK) and populations, and they produced different results. While there was no reduction of asthma exacerbations found with high-dose glucocorticoid in the US children, some benefit was evidenced in the adult and adolescent population in the UK.

The study in 254 children aged 5-11 years of age was reported by lead author Daniel Jackson, MD, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, and colleagues at multiple sites in the US including representatives from the National Heart, Lung and Blood Institute AsthmaNet. It was originally presented at the 2018 American Academy of Allergy, Asthma, and Immunology/ World Allergy Organization (AAAAI/WAO) Joint Congress in Orlando, FL.

"In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes," Jackson and colleagues wrote.

The rate of severe asthma exacerbations was the primary outcome in the US study, and time to the first severe exacerbation was the primary measure in the UK study. Tricia McKeever, PhD, Department of Epidemiology and Public Health, University of Nottingham, Nottingham, UK, and colleagues reported that among the approximate 1,900 participants, 45% in the high dose ICS group experienced a severe asthma exacerbation in the year after randomization compared to 52% receiving standard dose, with the corresponding adjusted hazard ratio of 0.81.

Daniel Jackson, MD

"Our trial involving adults and adolescents showed that a temporary quadrupling of the dose of inhaled glucocorticoids at the time of worsening asthma control resulted in a lower rate of severe exacerbations of asthma than no increase in the dose (45% vs 52%),” McKeever and colleagues reported.

The children in the US study had mild-to-moderate persistent asthma and had experienced at least 1 asthma exacerbation treated with systemic glucocorticoid in the previous year. They received 48 weeks of maintenance fluticasone propionate (Flovent), 2 inhalations of 44mcg/inhalation twice daily, and randomly assigned to either 44 mcg or the quintupled dose of 220 mcg/inhalationations twice daily for 7 days at the early signs of loss of asthma control.

Jackson and colleagues found no difference between the groups in the number of exacerbations, or in secondary measures including time to first exacerbation, rate of treatment failure, and symptom scores. The only notable difference between the groups, they point out, was that the high dose group was exposed to a greater amount of glucocorticoid without apparent benefit.

The UK study compared time to first severe exacerbation after randomization to one of 2 self-management plans for episodes of decreased asthma control, that maintained or quadrupled their previous glucocorticoid dose in addition to increasing bronchodilator medication. Although the increased bronchodilator could have confounded distinguishing between glucocorticoid dose effects, McKeever and colleagues attribute the difference in exacerbations to the temporary quadrupling of inhaled glucocorticoid.

In an editorial accompanying the studies, Philip Bardin, PhD, Monash Lung and Sleep Unit and Hudson Institute of Medical Research, Monash University and Medical Centre, Melbourne, Australia questioned whether the level of benefit found in the UK study warranted exposure to additional glucocorticoid.

"Given the adrenal suppression caused by quadrupling the dose of inhaled glucocorticoids, equivalent to a regular course of prednisolone, it will be difficult to convince clinicians that an exacerbation-prevention strategy involving high doses of inhaled glucocorticoids is merited," Bardin wrote.

The study of quintupling inhaled glucocorticoid dose in children and the study of quadrupling the dose in adults and adolecents to determine whether asthma exacerbations can be prevented were published online in the New England Journal of Medicine this month.