Abstract
The GINA recommendation to use as-required ICS-formoterol in symptomatic mild asthma is applicable to smokers with a low cumulative smoking history, but evidence is lacking for its effectiveness in smokers with medium and high tobacco use http://bit.ly/2Xqqluu
To the Editor:
The Global Initiative for Asthma (GINA) 2019 report makes a major change in asthma management by recommending that adults and adolescents with mild symptomatic asthma (Step 1) receive as-needed low-dose inhaled corticosteroid (ICS)–formoterol rather than a short-acting β2-agonist alone [1]. At step 2, daily low-dose ICS is recommended, and GINA 2019 considers low-dose ICS–formoterol reliever as an alternative “preferred controller”. The main evidence supporting these recommendations is provided by two large randomised controlled trials of inhaled budesonide–formoterol as-needed in mild asthma (SYGMA 1 and 2) [2, 3] and from two “real-life” open label randomised controlled trials (Novel START and PRACTICAL) [4, 5]. The strategy is considered generalisable across the spectrum of mild to moderate asthma, based on consistent findings from analysis of subgroups related to age, gender, smoking status and other factors [5].
How good is the evidence for the effectiveness of the low-dose ICS–formoterol reliever strategy in current and former smokers with mild asthma? There are several reasons to believe that further studies are required. Firstly, the proportion of participants with a smoking history recruited to low-dose budesonide–formoterol reliever trials is much lower than the general population. In the SYGMA 1 and 2 studies, <3% and ≤13% were current and former smokers, respectively, and in the Novel START and PRACTICAL trials, <8% and ≤25% were current and former smokers, respectively. The prevalence rates for cigarette smoking amongst the 300 million people in the world with asthma match those in the general population of many countries [6, 7]. In some high-income countries almost one quarter of the population are current smokers and a further quarter are former smokers. Several low-income and middle-income countries are at risk of worsening tobacco epidemics [8]. Secondly, participants with a smoking history enrolled in the trials had a low pack-year history, indicating a low intensity and short duration of exposure to tobacco smoke. The SYGMA 1 and 2 studies do not report the pack-year history of participants, but this is likely to be low, since smokers with a smoking history of ≥10 pack-years were excluded [2, 3]. The Novel START and PRACTICAL trials used less stringent exclusion criteria relating to smoking status: self-reported >20 pack-years smoking history, or the onset of respiratory symptoms after the age of 40 years in current or ex-smokers with ≥10 pack-years smoking history [4, 5]. Despite these more relaxed criteria, the median pack-year history in the Novel START treatment groups was only around 3 (interquartile range 0.5–9) and in the PRACTICAL study groups was around 3 (1–8). Thirdly, the doses of budesonide administered in the budesonide–formoterol reliever strategy trials were 17% [2] to 50% [5] lower than budesonide–formoterol (budesonide 400 μg daily) maintenance treatment groups. Current smokers with mild to moderate asthma have impaired short-term responses to ICS compared to never smokers with asthma and may require higher doses of ICS to overcome corticosteroid insensitivity [7, 9, 10]. The dose of ICS used in the budesonide–formoterol reliever strategy trials may be insufficient to improve clinical outcomes in smokers with asthma, particularly in individuals with a higher intensity and longer duration of exposure to cigarette smoke (>10 pack-year history).
The influence of exposure to tobacco smoke on the clinical features, immunopathology and response to treatment of asthma is complex and poorly understood [7]. Smokers with asthma have worse asthma control, more exacerbations and a greater reduction in lung function over time than non-smokers with asthma [7]. The most effective drug therapies for many asthma patients with a smoking history are uncertain, since most asthma trials exclude current or former smokers with >10 pack-year history due to concerns about including patients with COPD. Both smoking and asthma associated factors influence the response to drug therapies in asthma patients with a history of smoking, including differences between current smokers and former smokers and between individuals with a high intensity and long duration of exposure to tobacco smoke and those with a low cumulative smoking history (table 1).
In conclusion, the new GINA report recommendation on the use of as-required ICS–long-acting β2-agonist in symptomatic mild or moderate asthma is applicable to current or former smokers with a low cumulative smoking history, but evidence is lacking for its effectiveness in current or former smokers with medium and high tobacco use, as is also the case for most other asthma treatment recommendations. Large “real-life” clinical trials of ICS–formoterol reliever therapy are required in moderate and heavy smokers with asthma and studies should include participants from low- and medium-income countries where the prevalence of cigarette smoking is often high. These studies will provide an evidence base for recommendations on drug treatment for the different subgroups of symptomatic current and former smokers with asthma.
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Footnotes
Author contributions: Conception, drafting the manuscript for important intellectual content, manuscript revision and final approval: all authors.
Conflict of interest: N.C. Thomson has nothing to disclose.
Conflict of interest: R. Chaudhuri has nothing to disclose.
- Received October 17, 2019.
- Accepted November 13, 2019.
- Copyright ©ERS 2020