Response: The most fundamental change in asthma management in 30 years?

From the author:

I. Amirav and M.T. Newhouse have commented on the April 2019 recommendations by the Global Initiative for Asthma (GINA) that, for safety, adults and adolescents with asthma should not be treated with short-acting bronchodilators alone, and that instead, to reduce the risk of serious exacerbations, they should receive either symptom-driven (in mild asthma) or daily ICS-containing treatment (www.ginasthma.org/reports). The background evidence and rationale for the GINA recommendations were further explained in an editorial published in the European Respiratory Journal [1].

While discussion about the GINA recommendations is welcomed, an error in the authors' opening sentence must be corrected. The key changes in GINA 2019 are not about the “management of exacerbations of asthma” or “acute asthma” as stated, but about treatment of day-to-day asthma symptoms to prevent exacerbations. These recommendations were also integrated by GINA into home-based management of worsening asthma, but there is inadequate evidence to date about treatment of acute asthma with ICS–formoterol, with only two studies in emergency departments [2, 3]. In such settings, short-acting β₂-agonists (SABAs) are still recommended [4].

The evidence supporting the new GINA recommendations for adults and adolescents was not, as claimed by I. Amirav and M.T. Newhouse, limited to “a few studies that have used ‘as needed’ ICS/LABA for acute asthma”. Instead, as described in the European Respiratory Journal editorial [1], it included decades of evidence about the risks of treating asthma only with SABA, the substantial reduction in this risk with low dose ICS in population studies and randomised controlled trials even when symptoms were infrequent [5], and two large studies in over 8000 patients with mild asthma showing that the benefits of as-needed low dose ICS–formoterol were obtained without the need for daily treatment, and with <25% of an already low comparator ICS dose [6, 7]. GINA also took into account poor adherence with ICS in mild asthma, and the confusion (from the patient's perspective) in promoting SABA for symptom relief in Step 1 but then in Step 2 recommending regular ICS treatment in order to reduce use of SABA. Two additional randomised controlled trials of as-needed low dose ICS–formoterol in mild asthma have been published subsequently [8, 9].

The authors stated their concerns that most of the data about as-needed ICS–LABA were obtained with a specific dry powder device. However, in patients with moderate to severe asthma, a similar reduction in risk of severe exacerbations was found [10] in studies that instead used a pressurised metered-dose inhaler to deliver budesonide–formoterol [11] or beclometasone–formoterol [12], suggesting that neither the device nor the specific ICS is crucial to this benefit. Globally, several low dose ICS–formoterol formulations and devices are available that may be suitable for an as-needed regimen in mild asthma.

With regard to patients' ability to use inhalers, there was no evidence in the recent studies [8, 9] of differential outcomes between younger and older adults. There is an obvious evidence gap for children with mild or intermittent asthma, for whom, to reduce the risks of SABA-only treatment, GINA suggests considering a strategy used in several studies of taking a low dose ICS inhaler whenever they use their SABA inhaler [13, 14].

The authors raised concerns about potential conflicts of interest by GINA members, but in the context of their criticism of a dry powder device, one author notably failed to declare, until requested by the Editors, that he is employed by a manufacturer of aerosol delivery devices. All members of the GINA Science Committee and Board are active asthma researchers and, as described in the European Respiratory Journal editorial [1], the studies of as-needed low dose ICS–formoterol were initiated by GINA members rather than by a manufacturer. Before the 2019 recommendations were developed, the GINA Board undertook a careful review of processes for handling potential conflicts of interest; information about methodology is available on the GINA website (https://ginasthma.org/about-us/methodology/). The randomised controlled trials contributing to the GINA recommendations have already been reviewed by independent experts, including by national guideline bodies and regulatory authorities in several countries.

Finally, to the issue of medication access, the authors rather puzzlingly claim that, due to “the extremely high cost of albuterol pressurised metered-dose inhaler and formoterol DPI units”, the GINA recommendations would cause potential hardship for patients in the USA if off-label therapies were not covered. The GINA report is a global strategy and GINA strongly supports efforts to improve global medication access, including for patients in low- and middle-income regions. However, GINA's recommendations, particularly about safety, as in the present case, cannot wait for access to be achieved in every country. It is for each country and jurisdiction to determine at a local level the options best suited to their resources and needs in order to reduce the burden of asthma exacerbations and mortality, including in mild asthma.

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