EDITORIAL

Anti-inflammatory reliever therapy in asthma: The evidence

mounts but more is needed
Key words: asthma, anti-inflammatory reliever, adults. The finding that budesonide-formoterol MART at
step 3 or 4 is more effective in reducing severe exacer-
The Global Initiative for Asthma (GINA) strategy 2019 bations than increasing maintenance ICS-LABA plus
update recommended that short-acting beta2-agonists as-needed SABA to either step 4 or 5, respectively, has
(SABA) should not be used alone as sole therapy with- important clinical implications, as it suggests that for a
out inhaled corticosteroids (ICS), and that combination patient on maintenance ICS-LABA, switching across to
ICS-formoterol is preferred to SABA as reliever therapy budesonide-formoterol MART is preferred to the pro-
across the spectrum of asthma severity, in adults and gressive stepwise increase in treatment to higher steps
adolescents.1 It was proposed that these recommenda- as proposed by earlier GINA guidelines. That this bene-
tions represented the most important change in asthma fit can be achieved at a lesser steroid exposure is par-
management for over 30 years.2 Since this strategy was ticularly important to clinical practice as steroid-related
published, two additional studies of as-needed ICS- side effects are dose-dependent and cumulative.
formoterol have been published, reporting greater effi- The authors also reported that GINA-defined asthma
cacy of as-needed budesonide-formoterol in reducing control on budesonide-formoterol MART was similar with
severe exacerbation risk compared with as-needed those on the same or higher maintenance dose ICS-LABA
SABA or with maintenance ICS plus as-needed SABA in plus as-needed SABA. This finding indicates that the
mild asthma.3,4 These were open-label studies which greater efficacy of the MART regimen preferentially relates
investigated the way that patients would use as-needed to exacerbation reduction, rather than symptom control.
ICS-formoterol in real life, and included patients with As a result, although the most important consideration
baseline SABA use as infrequent as twice a month, across the spectrum of asthma severity is reducing the risk
thereby extending the evidence of efficacy to the mil- of severe exacerbations,1,5 for those in whom symptom
dest patients with very infrequent symptoms. control is the priority, both regimens have similar benefit
This evidence enabled GINA to strengthen its recom- in terms of this outcome measure.
mendations regarding the preferred use of ICS-formoterol As suggested by Jenkins et al., although their review pro-
rather than SABA reliever therapy in the 2020 update, and vides substantive evidence of the efficacy and safety of AIR
reiterate the key objectives of asthma management to therapy with ICS-formoterol, further research is urgently
reduce the risk of asthma-related exacerbations and death needed. One priority is to determine how to use ICS-
including in patients with so-called mild asthma, to provide formoterol reliever therapy according to a stepwise treat-
consistent messaging about the aims of treatment including ment-based algorithm. As recently proposed, an ICS-
prevention of exacerbations across the spectrum of asthma formoterol reliever therapy-based algorithm (Fig. 1) would
severity and to avoid establishing a pattern of patient reli- not only be more practical and simpler to follow than the
ance on SABA early in the course of the disease.5 It also traditional stepwise algorithm based on SABA reliever use,
led to the term ‘anti-inflammatory reliever’ (AIR) to but also likely to be superior as suggested by comparisons
describe the use of ICS-formoterol as a reliever therapy.6 of the different regimens at the individual steps of the algo-
While the recent focus has been on the use of ICS- rithms.6 With no requirement to add on or change inhalers,
formoterol reliever monotherapy in mild disease, in a it avoids often conflicting messages in asthma education,
recent review in Respirology, Jenkins et al. have reviewed focusing instead on the importance of concurrent symptom
published data from randomized controlled trials investi- control and risk reduction. It is also intuitive enough that
gating the efficacy and safety of as-needed budesonide- with the right education and support patients could take a
formoterol when used as part of the maintenance and more active role in their own management, and a practical
reliever therapy (MART) regimen in moderate-to-severe action plan based on the algorithm to facilitate such auton-
asthma.7 This review confirmed the findings of a recent omy has already been proposed,6 although studies are now
systematic review and meta-analysis that severe exacerba- needed to assess its utility in clinical practice.
tion rates are lower with ICS-formoterol MART compared Further research should focus on addressing the sig-
with the same or higher dose of maintenance ICS-long- nificant disconnect between the evidence base for
acting beta2−agonist (LABA) plus as-needed SABA.8 The asthma management in adults and children. In contrast
reduction in risk with budesonide-formoterol MART was to adults, a single study by Bisgaard et al. has provided
greater in those with worse asthma symptom control evidence for MART in children.9 At the milder end of
(higher Asthma Control Questionnaire (ACQ)-5 score) the asthma spectrum, there have been no studies of as-
suggesting that in addition to a history of a recent severe needed ICS-formoterol as sole therapy in children
exacerbation, poor asthma symptom control identifies a younger than 12 years; establishing the efficacy and
high-risk group who preferentially benefit from the safety of this regimen in this age group is another pri-
budesonide-formoterol MART regimen. ority as, if effective, it would mean that a single ICS-
© 2020 Asian Pacific Society of Respirology Respirology (2020) 25, 776–778
doi: 10.1111/resp.13889
Editorial 777

Figure 1 Prototype anti-inflammatory reliever (AIR) therapy algorithm in adult asthma based on budesonide-formoterol 200/6 μg
(Symbicort Turbuhaler, AstraZeneca). Alternative cut-off points could be used to guide transition between steps.
Reproduced with permission from Beasley et al. 2020.6

formoterol inhaler could be used to treat asthma across adolescent asthma. However, more evidence is
all ages and severities. required to guide the optimal use of this approach in
Finally, there is a need for research of the efficacy the management of asthma.
and safety of other ICS-formoterol products, and ICS-
SABA products, for each of which there is evidence of Pepa Bruce MBBS,1 Lee Hatter MBBS1 and
efficacy at one step, but not across the range of asthma Richard Beasley DSc1,2,3
1
severity, as would be required for their use in clinical Medical Research Institute of New Zealand, Wellington,
practice.10 A range of inhaler devices with ICS- New Zealand; 2Respiratory Medicine Department,
formoterol or ICS-SABA products, including low-cost Capital and Coast District Health Board, Wellington,
inhalers, would enhance the more widespread use of New Zealand; 3School of Biological Sciences, Victoria
this therapeutic approach globally. University Wellington, Wellington, New Zealand
AIR therapy with ICS-formoterol, either alone or with
regular maintenance use according to the MART regi-
men, has resulted in a paradigm shift in asthma man- Acknowledgement: The MRINZ receives Independent Research
agement, and the evidence is now sufficient to warrant Organisation funding from the Health Research Council of New
its use as the preferred reliever regimen in adult and Zealand.

Respirology (2020) 25, 776–778 © 2020 Asian Pacific Society of Respirology

778 Editorial

Disclosure statement: R.B. reports research funding from Health to moderate asthma (PRACTICAL): a 52-week, open-label,
Research Council of New Zealand, AstraZeneca, multicentre, superiority, randomised controlled trial. Lancet 2019;
GlaxoSmithKline and Genentech; and personal fees from 394: 919–28.
AstraZeneca, Theravance Biopharma and Avillion, outside the 5 Global Initiative for Asthma. Global Strategy for Asthma Manage-
submitted work. ment and Prevention, 2020 Update. 2020. [Accessed 4 May 2020.]
Available from URL: [Link]
6 Beasley R, Braithwaite I, Semprini A, Kearns C, Weatherall M,
REFERENCES Harrison TW, Papi A, Pavord ID. ICS-formoterol reliever therapy
stepwise treatment algorithm for adult asthma. Eur. Respir. J. 2020;
1 Global Initiative for Asthma. Global Strategy for Asthma Manage- 55: 1901407.
ment and Prevention, 2019 Update. 2019. [Accessed 4 May 2020.] 7 Jenkins C, Bateman ED, Sears M. What have we learnt about
Available from URL: [Link] asthma control from trials of budesonide-formoterol as mainte-
2 Reddel H, FitzGerald JM, Bateman ED, Bacharier LB, Becker A, nance and reliever? Respirology 2020; 25: 804–15.
Brusselle G, Buhl R, Cruz A, Fleming L, Inoue H et al. GINA 2019: a 8 Sobieraj DM, Weeda ER, Nguyen E, Coleman CI, White CM,
fundamental change in asthma management. Treatment of asthma Lazarus SC, Blake KV, Lang JE, Baker WL. Association of inhaled
with short-acting bronchodilators alone is no longer recommended for corticosteroids and long-acting beta-agonists as controller and
adults and adolescents. Eur. Respir. J. 2019; 53: 1901046. quick relief therapy with exacerbations and symptom control in
3 Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, persistent asthma: a systematic review and meta-analysis. JAMA
Hancox RJ, Harrison T, Houghton C, Oldfield K, Papi A et al. Con- 2018; 319: 1485–96.
trolled trial of budesonide-formoterol as needed for mild asthma. 9 Bisgaard H, Le Roux P, Bjamer D, Dymek A, Vermeulen JH,
N. Engl. J. Med. 2019; 380: 2020–30. Hultquist C. Budesonide/formoterol maintenance plus reliever ther-
4 Hardy J, Baggott C, Fingleton J, Reddel HK, Hancox RJ, apy: a new strategy in pediatric asthma. Chest 2006; 130: 1733–43.
Harwood M, Corin A, Sparks J, Hall D, Sabbagh D et al. 10 Beasley R, Bird G, Harper J, Weatherall M. The further paradoxes
Budesonide-formoterol reliever therapy versus maintenance of asthma management: time for a new approach across the spec-
budesonide plus terbutaline reliever therapy in adults with mild trum of asthma severity. Eur. Respir. J. 2018; 52: 1800694.

© 2020 Asian Pacific Society of Respirology Respirology (2020) 25, 776–778