The current guidelines state that low-dose inhaled corticosteroids (ICS) may be used primarily in children of all ages when maintenance therapy is needed and that LTRAs should be administered as an alternative treatment. If step-up treatment is required, the prescription of moderate-dose ICS or LTRAs in combination with low-dose ICS is recommended for children aged <6 years. For children aged ≥6 years, the use of low-dose ICS in combination with long-acting beta-2 agonists is recommended, while high- or low-dose ICS with LTRAs are recommended as alternative treatments [16,17].

A Cochrane review that analyzed 19 pediatric randomized controlled trials (RCTs) to compare the efficacy of montelukast to that of ICS revealed the superior efficacy of the latter [18]. A meta-analysis of RCTs in preschoolers with asthma or recurrent wheezing also reported that daily ICS use was more effective than montelukast treatment [19]. However, several studies showed different outcomes in real-life environments since the actual effects of a medication are determined by both medication efficacy and patient compliance. Ducharme et al. [20] examined the real-life effectiveness of montelukast versus ICS in children with mild or moderate asthma. Physicians prescribed medication for 62% of the follow-up period when prescribing ICS versus 97% of follow-up when prescribing montelukast. Patients purchased 51% versus 74% of the prescribed ICS and montelukast at pharmacies, respectively. As a result, children who were prescribed ICS used the medication for 24% of the follow-up period, while those who were prescribed montelukast used the medication for 38% of the follow-up period. There was no intergroup difference in the rates of oral corticosteroid use or emergency room visits, but the ICS prescription groups were the more frequently admitted and more frequently required rescue beta-2 agonists [20]. According to a study analyzing the Korean National Health Insurance claim database from 2010 to 2014, LTRAs including montelukast were the most prescribed in children of all ages with asthma. The rate of ICS prescriptions for asthmatic patients aged ≥6 years was <15% [21]. These results suggest that Korean pediatricians prefer to prescribe montelukast rather than ICS. In a recent survey of 1,838 pediatric patients currently receiving treatment for asthma in Korea and their parents, 38% of patients receiving inhaled treatment and 50% of those receiving LTRAs were taking the treatment as prescribed. Furthermore, 70% of LTRA users versus only 34% of inhaler users felt that their treatment modality was easy to use [22].

A randomized study comparing responses to fluticasone inhaler and montelukast treatment in school-aged children with mild to moderate asthma defined a response as a ≥7.5% improvement in forced expiratory volume in 1 second (FEV₁), and showed that 5% of the children responded to montelukast only, 23% responded to fluticasone only, 17% responded to both medications, and 55% responded to neither medication. Predictors of good response to fluticasone only were lower pulmonary function and provocative concentration causing a 20% drop in FEV₁, and higher FeNO levels, total eosinophil counts, serum eosinophil cationic protein (ECP), and total immunoglobulin E. Conversely, predictors of good response to montelukast were lower age and short duration of asthma [23].

In summary, although the efficacy of montelukast is inferior to that of ICSs and asthma management guidelines recommend that ICSs be prescribed primarily when starting maintenance therapy, both physicians and patients prefer montelukast to ICSs. In addition, some patients respond better to montelukast than to ICS, but additional studies are needed to determine which patients will respond better.

There are currently no specific tools or biomarkers available to diagnose asthma in preschool children. Therefore, it is important for physicians to recognize the various patterns of recurrent wheez ing in this population. The proposed phenotypes of recurrent wheezing in early childhood are as follows: transient wheezing, nonatopic wheezing, persistent asthma, and severe intermittent wheezing [24,25]. This classification is helpful in under standing childhood wheezing but is difficult to use clinically. Wheezing may be classified as an “episodic (viral) wheeze” (EVW) or “multipletrigger wheeze” (MTW) [26]. An EVW is defined as wheezing during discrete time periods, often in association with the clinical evidence of a viral cold, with an absence of wheezing between episodes. An MTW is defined as wheezing that shows discrete exacerbations but also symptoms between episodes.

A recent meta-analysis reported on the effects of montelukast treatment for the prevention of post-bronchiolitis wheezing [27]. The authors concluded that montelukast reduced the frequency of recurrent wheezing but did not reduce the incidence of recurrent wheezing, corticosteroid use, or number of symptom-free days in post-bronchiolitis infants; therefore, it was not appropriate for clinical use. However, in an RCT of post-bronchiolitis patients treated with montelukast for 3 months and followed up for 12 months, the serum eosinophil-derived neurotoxin (EDN) levels were significantly decreased and cumulative recurrent wheezing episodes were significantly decreased in the montelukast-treated group [28].

A Cochrane review of the effects of LTRA against EVW in preschool children reported that LTRA maintenance or intermittent therapy did not reduce the number of children experi encing one or more episodes requiring rescue medicine, emergency room visits, or hospital admissions [29,30]. However, the authors suggested that certain subgroups may respond to LTRA since children with EVW did not show homogeneous phenotypes and that they should be prescribed montelukast as a therapeutic trial and continue maintenance therapy if they respond well. The European Respiratory Society (ERS) recommended that, montelukast should be the first choice for daily maintenance therapy in children with EVW, while ICSs should be the first choice of maintenance therapy in children with MTW. However, the ERS highlighted that it is difficult to distinguish EVW from MTW in some children [31]. A recent meta-analysis of the effects of montelukast against both EVW and MTW in preschool children reported that montelukast was ineffective in preschool children with recurrent wheezing. The authors suggested that further studies should be conducted to investigate how to easily identify montelukast responders in clinical settings [32].

EDN may be a useful biomarker for the treatment and monitoring of preschool children with asthma or recurrent wheezing [33,34]. EDN is one of four major proteins secreted by activated eosinophils together with ECP, major basic protein, and eosinophil peroxidase. Unlike the other three, EDN has an isoelectronic point of 8.3, which is close to neutral; therefore, it is possible to measure accurately and reproducibly in the blood [35]. In a previous study, we compared the concentrations of serum EDN to asthma symptom scores in preschool children [36]. Serum EDN levels were the highest in children with acute asthma, followed by those with stable asthma and those in the control group, and the differences among the three groups were significant. Another study suggested that serum EDN levels 3 months after respiratory syncytial virus bronchiolitis were predictive of recurrent wheezing within 12 months. The serum EDN concentration cutoff value for predicting wheezing recurrence was 53 ng/mL (positive predictive value, 57%; negative predictive value, 76%; sensitivity, 72%; and specificity, 62%). The normal range of serum EDN concentration was 13–45 ng/mL [28]. Predictive value of EDN levels for asthma was based on clinical performance result. Using 44.2 ng/mL (median+1SD) as the cut off for an elevated EDN level compared to those found in Controls, the sensitivity was 81.3%, the specificity was 87.1%, the positive predictive value (PPV) of EDN level for asthma 90.7 %, and the negative predictive value (NPV) was 75.0% [35]. Another recent study compared the effects of montelukast and 0.5-mg budesonide inhalation suspension therapy for 12 weeks in symptomatic preschool children with asthma and serum EDN levels ≥53 ng/mL [37]. During the study period, asthma control days increased in both groups and there was no significant intergroup difference. However, serum EDN levels were significantly decreased only in the montelukast group. Therefore, based on several years of EDN-related research, we recommend starting maintenance therapy with montelukast when the EDN concentration is ≥53 ng/mL (1 SD of normal) and stopping when it decreases to <45 ng/mL (Fig. 2).

Current clinical practice guidelines recommended controller therapy for children experiencing daytime asthma symptoms more than once a week, with activity limitations, who require the use of a reliever more than once a week, or who have any nighttime symptoms [16]. However, a recent study compared the efficacy of montelukast maintenance therapy and as-needed β2-agonist therapy for 48 weeks in preschool children experiencing asthma symptoms more than once a month but less than once a week [38]. During the study, 28% of the montelukast group and 50% of the no-controller group experienced asthma exacerbations; 21% and 41% of the children, respectively, required increased treatment. Therefore, montelukast use should be considered as maintenance therapy in preschool children with intermittent asthma (Table 1).

The efficacy of LTRAs combined with antihistamines is often mentioned in clinical journals and guidelines. The combination of montelukast and 2nd-generation antihistamines may protect against seasonal decreases in lung function in patients with allergic rhinitis. Furthermore, LTRAs may be more effective at treating allergic rhinitis when combined with antihistamines since the agents have different efficacies. Recently, one such compound was developed and marketed for children in Korea [39].