Inhaled Corticosteroid-Long-Acting Beta-2 Agonist Fixed-Dose Combinations: Preferred Controller in 6- to 11-Year-Olds with Persistent Asthma

Asthma is a chronic inflammatory disease characterized by variable airway obstruction. Asthma treatment involves using inhaled corticosteroids (ICSs) for reducing inflammation and beta-2 agonists for bronchodilation [1, 2]. In recent years, there has been a change in the approach to asthma treatment. Currently, asthma guidelines recommend the combined use of ICS and beta-2 agonists even for mild asthma, starting from 6 years of age, because monotherapy with short-acting beta-2 agonists has been shown to increase the risk of severe asthma exacerbations and asthma-related deaths [1‒4].

ICSs containing therapies, whether as-needed or daily, are well known as the most effective treatment for preventing asthma exacerbations in all ages [5‒8]. In adolescents and adults, ICS-formoterol is now the single preferred option for both controller and reliever treatment due to its efficacy in preventing exacerbations [5‒7]. However, for children aged 6–11 years with persistent asthma, there are at least two preferred controller options: ICS monotherapy, ICS-long-acting beta-2 agonists (LABA), or ICS-formoterol fixed-dose combination therapies, except at step 2 [1, 2]. In studies cited in the guidelines for children aged 6–11 years with moderate to severe persistent asthma, comparisons have been made between fluticasone propionate (FP) and fluticasone propionate/salmeterol (FP/SAL), as well as between budesonide (BUD) and budesonide/formoterol (BUD/F) treatments [8‒12]. Furthermore, there are two published protocols but no completed studies on the use of either as-needed or daily ICS-formoterol for steps 1–4 for school-aged children [13, 14].

So far, there is no retrospective or prospective head-to-head comparison between ICS monotherapy (FP) and different types of fixed-dose combination treatments (FP/SAL and BUD/F) in children aged 6–11 years with persistent asthma. The primary objective of the study was to evaluate the impact of preferred treatments (either ICS monotherapy or ICS-LABA fixed-dose combination therapies) used in children aged 6–11 years with persistent asthma on the frequency of exacerbations requiring systemic corticosteroids (CS).

Patients aged 6–11 years with a diagnosis of persistent asthma who were followed up at our institution between January 2021 and January 2024 were included in the study. The hospital’s electronic database was used to retrospectively record asthma controller medication, the frequency of asthma exacerbations (requiring systemic CS, emergency department [ED] visit, and/or hospitalization), and pneumonia. Written, informed consent was obtained from the parent/legal guardian of the patients for participation in the study and publication of their medical details. The study was approved by the Gazi University Faculty of Medicine Clinical Research Ethics Committee (2024-420).

• Aged 6–11 years

• Patients diagnosed with mild to severe persistent asthma (step 2–4 asthma treatment)

• Patients prescribed a daily ICS-containing controller treatment

• A follow-up for at least 12 months with this treatment

• Aged <6 years or ≥12 years

• Patients undergoing step 5 asthma treatment

• Patients prescribed leukotriene receptor antagonists as the only controller treatment

• A follow-up for less than 12 months with ICS-containing controller treatment

Exacerbations of asthma are episodes characterized by a progressive increase in symptoms of shortness of breath, cough, wheezing, or chest tightness, as well as a progressive decrease in lung function [1, 2]. In this study, asthma exacerbation subtypes were defined as exacerbations requiring systemic CS and exacerbations requiring ED visit and/or hospitalization.

Patients with symptoms suggestive of pneumonia, diagnosed based on physical examination, laboratory, and imaging findings, and/or coded with J18.9 (unspecified pneumonia), J15.9 (bacterial pneumonia, unspecified), J12.9 (viral pneumonia, unspecified), according to the International Classification of Diseases (ICD)-10 by the clinician, were considered having pneumonia.

The primary objective of this study was to compare ICS monotherapy (FP) and ICS-LABA fixed-dose combination therapies (FP/SAL and BUD/F) based on the frequency of exacerbations requiring systemic CS.

The secondary objectives of this study were to compare these three treatments based on the frequency of all exacerbations, exacerbations requiring ED visit/hospitalization, and pneumonia.

The data were analyzed using SPSS version 25.0 statistical software. Descriptive statistics were provided as number and percentage for categorical variables: mean, standard deviation, minimum, and maximum values for numerical variables. The chi-square test was used to compare categorical variables between treatment groups. For comparing numerical variables between treatment groups, normal distribution assumptions were evaluated using the Kolmogorov-Smirnov and Shapiro-Wilk tests, followed by the Kruskal-Wallis test. Variables showing differences between treatment groups in univariate analyses were evaluated using logistic regression analysis. A significance level of p < 0.05 was considered, and 95% confidence intervals were calculated.

The medical records of 358 children aged 6–11 years, diagnosed with persistent asthma and followed up at our clinic, between January 2021 and January 2024, were retrospectively reviewed. After excluding patients who did not meet the study design criteria, 248 patients were analyzed (Fig. 1). Baseline characteristics of the patients were presented in Table 1.

All of our patients received metered-dose inhaler or dry-powder inhaler form of either FP (n = 122) or FP/SAL (n = 41), or BUD/F (n = 85) therapies as step 2–4 asthma treatment. No children were treated with BUD monotherapy in metered-dose inhaler or dry-powder inhaler due to its unavailability in our country, where the only available ICS monotherapy is FP. Among the patients using BUD/F, there were no patients using as-needed salbutamol; all of them followed maintenance and reliever therapy (MART). Patients using FP and FP/SAL, on the other hand, had as-needed salbutamol as a reliever treatment. The use of fixed-dose combinations increased with male gender, current age, age at diagnosis and the duration of follow-up (p = 0.006, p < 0.001, p < 0.001, p = 0.002, respectively).

Among the patients included in the study, 60 of them (24.2%) experienced at least one exacerbation (mean: 1.92, SD: 1.20, min: 1, max: 6) during the follow-up period. The frequency of exacerbations (mean ± SD) was higher in the FP group (0.85 ± 1.25) compared to the FP/SAL (0.51 ± 1.17) and BUD/F (0.22 ± 0.62) groups (p < 0.001).

The primary and secondary outcomes of the study were presented in Table 2. The frequency of all exacerbations, exacerbations requiring systemic CS and exacerbations requiring ED visit/hospitalization were significantly higher in the FP group compared to the FP/SAL and BUD/F groups (Fig. 2). There were no significant differences between the FP/SAL and BUD/F groups concerning all exacerbation parameters (p > 0.05). The incidence of pneumonia, as a secondary study parameter, was very low in fixed-dose combination groups; therefore, a statistical comparison could not be performed (Table 2).

Further analysis with logistic regression revealed that patients using FP had a 4.36 times higher risk of experiencing exacerbations compared to fixed-dose combination therapies (95% confidence interval, 1.49–12.78; p = 0.007). Male sex, current age, age at diagnosis, and duration of follow-up did not influence the frequency of asthma exacerbations requiring systemic CS (p > 0.05 for all). A statistical comparison between FP and fixed-dose combination therapies (FP/SAL or BUD/F) considering the primary and secondary study outcomes could not be made between patients at step 2, 3, or 4 of asthma treatment because of the insufficient number of patients in each group.

The US Food and Drug Administration (FDA) has reported that patients aged 6–11 years are the most at-risk group for serious asthma-related events, particularly hospitalization [15, 16]. Therefore, properly managing asthma treatment in this age group is critically important for reducing exacerbations. In this study, we found that overall exacerbations, exacerbations requiring systemic CS, and exacerbations requiring ED visit/hospitalization were higher in patients receiving ICS monotherapy, and we thought that ICS-LABA fixed-dose combination therapies are more effective in reducing asthma exacerbations in children aged 6–11 years with persistent asthma. However, due to our inability to reach a sufficient number of patients, we were unable to evaluate their effect on pneumonia.

To date, numerous studies have compared step 3 treatments, such as increasing the dose of FP versus FP/SAL fixed-dose combination therapy, in children aged 6–11 years, have shown that adding salmeterol to FP is at least as effective as increasing the dose of ICS for improving asthma control and lung function [9‒12]. In contrast to a sufficient number of studies in adolescents and adults [17‒19], there is only 1 study in patients aged 4–11 years with persistent asthma comparing the use of BUD/F as MART, with fixed-dose BUD/F (as-needed terbutaline) and a fourfold-higher maintenance dose of BUD (as-needed terbutaline) therapies [8]. This prospective study found that utilizing BUD/F as MART resulted in a longer time to the first exacerbation, fewer severe exacerbations compared to fixed-dose BUD/F (as-needed terbutaline), and higher dose BUD monotherapy, as well as greater growth in height compared to higher dose BUD monotherapy. In another study, in 5- to 11-year-old asthmatic children unresponsive to ICS monotherapy, the use of BUD/F therapy as MART was shown to be not only more cost-effective but also to lead to a better quality of life compared to maintenance BUD/F and as-needed albuterol use, based on asthma control and exacerbation status [20]. In a study by the same author comparing the use of BUD/F as MART in step 3 or 4 asthma patients aged 12 and older with the use of medium-to-high-dose ICS/LABA and as-needed short-acting beta-2 agonists, it was noted that the use of BUD/F as MART was more cost-effective when considering the cost of asthma exacerbations. However, this study does not specify which fixed combinations of ICS/LABA were used [21]. In partial similarity to our study, a study comparing three different treatment modalities (BUD/F as MART, fixed combination of BUD/F and fixed-dose BUD) in children aged 6- to 11-year-old with persistent asthma showed that BUD/F therapy as MART was more cost-effective than both the fixed combination of BUD/F and fixed-dose BUD, based on asthma control and outcomes [22]. Consequently, in the guidelines, all these options (medium-dose ICS monotherapy, or low-dose ICS-LABA, or very low-dose ICS-formoterol) are included among the preferred step 3 treatment choices for children aged 6–11 years. In our study, we found that ICS-LABA fixed-dose combination therapies were more effective than ICS monotherapy. Patients receiving FP/SAL and BUD/F showed fewer exacerbations, less need for systemic CS, and fewer ED visits/hospitalizations compared to FP. Therefore, we believe that ICS-LABA fixed-dose combination therapies could be the preferred controlled treatment in 6- to 11-year-old children with persistent asthma, with ICS monotherapy being an alternative treatment.

Because a statistical comparison between FP and fixed-dose combination therapies (FP/SAL or BUD/F) considering the primary and secondary study outcomes could not be made between patients at step 2, 3, or 4 of asthma treatment, we cannot currently comment on whether fixed-dose combination therapies could be the preferred treatment starting from step 2. We believe that the results of the recently published study protocols will answer this question [13, 14]. Studies comparing fixed-dose combination therapies (BUD/F versus FP/SAL) are limited to adolescents and adults and have concluded that neither of the two ICS-LABA fixed-dose combinations is superior to the other in terms of asthma exacerbations [23‒25]. A Cochrane review comparing the fixed-dose combinations of FP/SAL and BUD/F conducted over a decade also reported a lack of data for those under 12 years of age [24]. We have not encountered any prospective or retrospective studies that compare the effects of different ICS-LABA fixed-dose combinations in this age group afterward. Unfortunately, it is also not possible to determine whether one of these ICS-LABA fixed-dose combinations is superior to the other in our study. This comparison may be feasible with a larger sample size.

The limitations of our study include its retrospective design, the restriction of routine respiratory function tests for patients with persistent asthma during the COVID-19 pandemic, and the availability of only FP as ICS monotherapy in our country. Additionally, the small sample size restricted certain planned comparisons. On the other hand, our study has strong perspectives. There are no previous studies comparing these treatments in the 6- to 11-year-age group. The study, conducted at a tertiary center, ensured treatments were managed by pediatric allergy specialists according to guidelines, free from external interference in treatment selection.

We think that ICS-LABA fixed-dose combination therapies are more effective than ICS monotherapy in preventing asthma exacerbations in 6–11-year-old children with persistent asthma and, therefore, could be recommended as the preferred controllers. However, this finding needs confirmation with prospective controlled studies. In addition, there remains a gap in understanding which ICS-LABA fixed-dose combination therapies (FP/SAL or BUD/F) would prove more effective in managing persistent asthma among children aged 6–11 years. Future prospective head-to-head comparison studies are essentially needed to address this question.

Written, informed consent was obtained from the parent/legal guardian of the patients for participation in the study and publication of their medical details. The study was approved by the Gazi University Faculty of Medicine Clinical Research Ethics Committee (2024-420).

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Gizem Koken: conceptualization, investigation, visualization, methodology, data curation, software, formal analysis, writing – original draft, and writing – review and editing. Sinem Polat Terece and Ceren Varer Akpinar: methodology, data curation, software, and formal analysis. Hacer Ilbilge Ertoy Karagol and Arzu Bakirtas: methodology and writing – review and editing.

Edited by: H.-U. Simon, Bern.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.