Originally published: June 2018

McKeever T, et al.
Quadrupling inhaled glucocorticoid dose to abort asthma exacerbations.

N Engl J Med 2018;378(10):902–910.

Acute asthma exacerbations (or ‘asthma attacks’) are episodes where asthma symptoms, typically of cough, breathlessness and wheeze, worsen and require additional treatment. These exacerbations are responsible for morbidity and mortality in asthma patients, as well as significant healthcare utilisation and spending. Severe exacerbations are treated with high dose, oral steroids and can necessitate urgent medical review in the hospital setting. Minimising severe asthma exacerbations is a key goal of asthma treatment.

Personalised self-management plans are aimed at recognising and addressing worsening symptoms. Previous studies which have investigated doubling the dose of inhaled corticosteroids (ICS) when worsening symptoms are noticed have not shown any benefit in reducing acute asthma exacerbations.1

In March’s New England Journal of Medicine, McKeever and colleagues report the findings of their pragmatic, unblinded, randomised trial of 1,922 adolescent and adult participants with asthma. They investigated the effectiveness of quadrupling the ICS dose at the time of worsening symptoms to prevent acute asthma exacerbations, compared with increasing bronchodilator treatment as per a self-management plan.2

They showed that quadrupling the dose of ICS resulted in a lower rate of severe exacerbations: 45% compared with 52% in the control group. At the 12 month follow-up, the quadrupling group had received a higher total dose of inhaled steroid than the control group (385 mg versus 328 mg) but a lower oral steroid dose (121 mg versus 151 mg). The quadrupling group had a higher incidence of upper airways adverse events, particularly oral candidiasis, likely due to the local effects of high dose inhaled steroids (19 versus 7 events).

This trial showed a modest reduction in acute exacerbation events. The pragmatic design of the trial and the mostly primary care trial population means that the results may show real-world applicability to a wide proportion of asthma patients. The results do, however, need to be interpreted with caution. The unblinded nature of the trial means that there is the possibility of biased results. Also, the 19% reduction in exacerbations compared with the control group did not meet the author’s threshold of a 30% reduction, which they felt would be clinically meaningful. Finally, the systemic effects of very high dose ICS, as would be being delivered during quadrupling ICS dose, are poorly understood. Effects on adrenal suppression, bone health and diabetes control, for example, need to be further explored.

A study in the same issue of the New England Journal of Medicine showed that quintupling the dose of ICS in children did not prevent acute asthma exacerbations but did result in a trend towards lower growth rate, again emphasising the need to understand the systemic effects of high dose ICS.3

Dr Rahul Shrimanker is a clinical research fellow at the University of Oxford.

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