Asthma is a heterogeneous lung disease and an important global public health problem affecting all age groups that is usually characterized by chronic airway inflammation (Global Initiative for Asthmam, 2019). Among asthma patients, the proportion with mild asthma should be 50–70% (Dusser et al., 2007). In general, patients with mild asthma have few or intermittent symptoms, so their treatment adherence is poor, especially with regard to the regular use of low-dose inhaled corticosteroids (ICS) as maintenance treatment (Rand et al., 2007). However, it should be noted that they still present with airway inflammation and have an increased risk of exacerbation and asthma-related death due to inadequate use of inhaled glucocorticoids (Fuhlbrigge et al., 2002; Barnes and Ulrik, 2015). For example, a study from the United States found that 3.6% of patients with mild asthma were hospitalized due to deterioration of their condition; 16.1% of patients with intermittent asthma and 28.4% of patients with mild asthma needed emergency treatment in the previous year (Fuhlbrigge et al., 2002). Short-acting β₂-agonist (SABA) is widely used to relieve the symptoms of mild asthma patients, and overuse is common (Belhassen et al., 2016). Previous studies have shown that the use of SABA may increase the risk of exacerbation, disease progression and death in patients with asthma (Suissa et al., 1994; Stanford et al., 2012). Therefore, whether there is a better alternative strategy for the treatment of mild persistent asthma has been the subject of concern in recent years.

Several recent studies have found that a combination of inhaled corticosteroids and formoterol [a fast- and long-acting β-agonist (LABA)] used as needed is an alternative treatment for mild persistent asthma. In the SYmbicort Given “as needed” in Mild Asthma (SYGMA) studies, compared with SABA used as needed, ICS-LABA can effectively reduce the risk of exacerbation and improve symptoms, and it was not inferior to low-dose ICS maintenance therapy in patients with mild asthma (Bateman et al., 2018; O’Byrne et al., 2018). Two studies published since then have yielded somewhat similar results (Beasley et al., 2019; Hardy et al., 2019). In these studies, it is worth noting that, although some of the results in these studies are significantly different, they are not close to the minimum absolute difference required for clinical significance. Additionally, there are still some differences between the results of these studies. The latest Global Initiative for Asthma (GINA) guidelines recommend that patients with mild asthma should follow as-needed treatment with ICS-LABA instead of SABA alone (Global Initiative for Asthmam, 2019), but there is still lack of systematic evidence, and no meta-analysis of the recently published literature has been conducted. Therefore, we conducted this study.

According to the results of this meta-analysis, compared with SABA used as needed, budesonide–formoterol used as needed can effectively reduce the risk of severe exacerbation of mild persistent asthma: that is, budesonide-formoterol used as needed resulted in a 54% lower rate of severe exacerbation (defined as worsening asthma leading to the prescription of systemic glucocorticoid treatment for ≥3 days, or hospitalization or an emergency department visit leading to systemic glucocorticoid treatment (Patel et al., 2013). In addition, budesonide–formoterol used as needed can effectively prolong the time to first severe exacerbation of mild persistent asthma patients in comparison to SABA used as needed. There was no difference in the risk of severe exacerbation or the time to first severe exacerbation between the budesonide–formoterol group and the budesonide group. Moreover, in SYGMA studies, the rate of adherence was good, and there was no significant difference between the groups (Bateman et al., 2018; O’Byrne et al., 2018). Interestingly, a recent study has shown that budesonide–formoterol used as needed in patients with mild asthma can effectively reduce medical costs (Elsisi et al., 2019). Thus, these findings may result in a series of favorable effects on mild persistent asthma patients; that is, if they are treated with budesonide–formoterol used as needed, patients’ medical compliance can be increased, and the cost burden and mortality can be decreased (Elsisi et al., 2019).

For the treatment and management of asthma, lung function improvement and symptom control are additional concerns. Three previous studies found that the ACQ-5 scores of patients in the budesonide–formoterol group were higher than those of the budesonide group (Bateman et al., 2018; O’Byrne et al., 2018; Beasley et al., 2019), but the latest study completed by Hardy et al. did not find similar results (Hardy, et al., 2019). The results of this meta-analysis showed that the ACQ-5 scores in the budesonide–formoterol group were higher than those of the budesonide group but lower than those of the SBAB group [WMD = −015, 95% CI = −0.19 to (−0.11), p < 0.001; WMD = 0.11, 95% CI = 0.08–0.15, p < 0.001; respectively]. It should be noted that these differences in ACQ-5 scores did not reach the minimum threshold of clinical significance. For FEV1, the meta-analysis showed that the budesonide–formoterol group experienced significantly greater improvement than the SABA group (WMD = 46.46, 95% CI = 24.92–68.0, p < 0.001), but there was no difference between the budesonide–formoterol group and the budesonide group (WMD = −19.86, 95% CI = −48.23 to 8.52, p = 0.17). Similarly, the absolute value of FEV1 improvement was limited for clinical value evaluation. There are differences between the results of our meta-analysis and the results of previous SYGMA studies (Bateman et al., 2018; O’Byrne et al., 2018), which may be related to the slightly different design methods and inclusion criteria used in the two later studies published in 2019. More studies may be needed in the future to assess whether budesonide–formoterol used as needed by mild persistent asthma patients can improve lung function and control symptoms.

Corticosteroid dose exposure is also a concern in asthma treatment and management. Previous studies have found that long-term inhaled corticosteroid may lead to a series of adverse events, although many findings may still be controversial. For example, long-term use of inhaled corticosteroid in asthma patients could increase risk of upper respiratory tract infection [odds ratio (OR) = 1.24, 95% CI = 1.08–1.42] (Yang et al., 2018), pneumonia (OR = 1.38, 95% CI = 1.36–1.41) (Kim et al., 2019), gastrointestinal events (HR = 1.26, 95% CI = 1.02–1.56) (Hansen et al., 2008) and so on. Differences in the daily dose of inhaled corticosteroid between the groups was reported in four published articles (Bateman et al., 2018; O’Byrne et al., 2018; Beasley et al., 2019; Hardy et al., 2019). This meta-analysis showed that the daily dose of inhaled corticosteroid in the budesonide–formoterol group was significantly lower than that in the budesonide group [WMD = −154.0, 95% CI = −206.87 to (−101.14), p < 0.001]. However, our meta-analysis did not find any significant difference in the incidence of adverse events, including upper respiratory tract infection, among the groups. It is worth noting that the treatment of asthma is a long-term process, and the risk of respiratory infection still exists and may be closely related to the age of the patients, the environment and occupational exposure, complications, the duration of inhaled drug use and the correct use of inhaled treatment measures (D’Amato et al., 2014; Job et al., 2016).

To summarize, our meta-analysis found that budesonide–formoterol used as needed for mild persistent asthma may significantly reduce severe exacerbations and prolong the time to first severe exacerbation compared with SABA used as needed, but there may be no clinically significant difference in symptom control and lung function improvement, which needs to be confirmed by further research. Thus, some concerns are should be considered. For instance, Domingo et al. contemplated their review whether reducing severe exacerbations or controlling symptoms was more important for asthma patients (Domingo et al., 2019). They arrived at no definite conclusion. In addition, long-term uncontrolled inflammation is one of the risk factors recognized for airway remodeling (Cohn et al., 2004). Although two studies found that the use of budesonide–formoterol used as needed can reduce the level of FeNO, which reflects that it may be beneficial to airway inflammation, the FeNO level was higher than that in the budesonide maintenance group (Novel START study: ratio of geometric means, 1.13; 95% CI, 1.02 to 1.25; PRACTICAL study: ratio of geometric means 1.13, 95% CI 1.07–1.21) (Beasley et al., 2019; Hardy et al., 2019). Due to the complexity of the pathogenesis of airway remodeling, whether budesonide–formoterol used as needed can fully improve airway inflammation in comparison to budesonide maintenance will have implications for future airway remodeling; thus, it deserves further attention. Moreover, although some patients with moderate asthma were included (Hardy et al., 2019), there were not enough patients and evidence to show that use of budesonide–formoterol as needed is definitely beneficial for patients with moderate asthma.

Although several reviews had evaluated the efficacy of budesonide–formoterol used as needed in patients with mild asthma (Bianco et al., 2020; Cloutier et al., 2020; Papi et al., 2021), it was still not comprehensive. In our meta-analysis, we not only showed that inhaled budesonide-formoterol used as needed may reduce severe exacerbations in patients with mild persistent asthma, but also emphasized that the evidence of budesonide-formoterol used as needed for improving clinically significant difference of symptoms and lung function may be insufficient, which needs to be further confirmed in the future. Different from other reviews (Bianco et al., 2020; Cloutier et al., 2020; Papi et al., 2021), we conducted quantitative analysis of published data of previous literatures, which is helpful for physicians to understand more vividly. It’s worth noting that there was a high degree of heterogeneity when comparing multiple outcomes (exacerbation, FEV1, inhaled glucocorticoid dose and adverse events) between the budesonide group and the budesonide-formoterol group in the present meta-analysis. This heterogeneity may be due to differences in study design, implementation strategy, patient baselines, patient composition, and sample size. Additionally, when we pooled the data, some of the results reflected the direct effects provided by the original research, so there may have been bias. Moreover, due to the limited data, some of the outcomes were not fully combined.

In summary, compared with SABA treatment used as needed, budesonide–formoterol used as needed may reduce severe exacerbations in adolescent/adult patients with mild persistent asthma; however, whether budesonide–formoterol can improve lung function and symptom control requires further verification. Additionally, it was difficult to confirm whether budesonide formoterol used as needed was not inferior to budesonide maintenance treatment for patients with mild persistent asthma at this stage.