Pediatric Asthma: Where Has Montelukast Gone?

Abstract

At its introduction in the management of pediatric asthma, montelukast was regarded as a potentially revolutionary drug due to its mechanism of action and easy clinical applicability. Nevertheless, its use in daily practice and evidence from clinical trials have shown that, rather than a radical change in the approach to asthmatic children, montelukast more likely represents a second-line medication that is useful when inhaled steroids alone fail in providing adequate symptom control. Furthermore, increasingly reported side effects have raised concerns regarding its safety. In the last decade, several studies have tried to better define the strengths and drawbacks of montelukast both in preschool wheezing and school-age asthma. The present review summarizes the literature published on this topic since 2010, highlighting the often-controversial results and the unanswered questions regarding the role of montelukast in pediatric asthma. Moreover, advances in the understanding of the mechanisms of action of montelukast are reported. The main finding emerging from the present analysis is that montelukast application is likely to be useful in a subset of asthmatic children rather than in large groups of patients. Future studies should focus on the identification of biomarkers able to predict which patients will benefit from montelukast to achieve a more tailored prescription.

1. Introduction

When the Food and Drug Administration (FDA) approved its application for the treatment of asthma in 1998, montelukast raised great interest and hope as a potentially revolutionary drug for the management of this condition, representing the most common chronic respiratory disease in childhood. Montelukast is the most powerful among the leukotriene receptor antagonists (LTRAs) and it acts by blocking the cysteinyl leukotriene 1 receptor (CysLTR₁), which is localized on cell membranes, mainly in the pulmonary macrophages and smooth muscle cells, and in the peripheral blood monocytes [1,2]. When, following immune or non-immune stimuli, polymorphonuclear leukocytes, macrophages, and mast cells are activated, the cytosolic enzymes phospholipase A2 and 5-lipoxygenase lead to the synthesis of leukotrienes B₄ (LTB₄) and C₄ (LTC₄), which are then transported in the extracellular space where LTD₄ and LTE₄ are also produced. Both LTC₄ and LTD₄ and, with lower affinity, LTE₄, can activate the CysLTR₁, thus inducing an inflammatory cascade, which has been involved in the pathogenesis of several allergic diseases [3,4]. A reduction in the respiratory cilia activity, bronchoconstriction, promotion of eosinophil migration into the airways, increased venopermeability, and mucus secretion are among the main effects induced by leukotriene receptors activation, thus making their role pivotal in the allergic response and in exercise-induced bronchospasm [5,6,7].

Montelukast’s application in clinical practice and growing evidence from the literature have progressively improved the definition of its role in pediatric asthma. Indeed, montelukast has been shown to represent a useful add-on option rather than a real alternative to the traditional maintenance therapy for asthma, which still largely relies on inhaled corticosteroids (ICSs). Due to the relevant body of literature that has been produced on this topic in the last decade, the role of montelukast in pediatric asthma and preschool wheeze has been partially re-defined, and possible answers to the doubts raised by its use in clinical practice are starting to be proposed. The present review focuses on the novelties arising from studies published in the last 12 years regarding montelukast use in children with wheezing disorders to analyze its strengths and limitations toward a more informed and aware application in clinical practice.

2. Search of the Relevant Literature

We carried out an electronic keyword literature search for English articles published on this topic since 2010 in the PubMed database. The terms “montelukast and children” were used as keywords in combination, and the studies obtained were evaluated to select the relevant literature. Available studies assessing the effects of other LTRAs, namely, zafirlukast and pranlukast, on pediatric asthma are limited [8,9]. Therefore, we did not include these drugs in the present review, and only focused on montelukast, which is by far the most widely used and studied LTRA in children. A total of 399 studies provided by the initial search were assessed for relevant content, with particular attention to aspects of novelty, but only part of them was ultimately taken into account for the review and included in the reference list.

3. Biological Mechanisms and Effects

Recent advances in the understanding of the molecular mechanisms underlying montelukast activity have shown that its anti-inflammatory effects in asthmatic subjects derive from increased interferon levels and a decreased concentration of pro-inflammatory cytokines interleukin-3 and interleukin-4, also associated with a concomitant reduction in the number of inflammatory cells in the peripheral blood [10,11]. In addition, a reduced production of the reactive oxygen species, both in the whole blood and in isolated neutrophils, has been reported in asthmatic children following treatment with montelukast [12]. Nevertheless, a significant inter-individual variability in the patients’ response to montelukast is commonly observed in clinical practice, and the role of genetic factors has therefore been investigated. In particular, a genome-wide association study recently identified previously unreported genetic loci that seemed to be associated with montelukast responsiveness. These loci reside in an intronic region of the gene MRPP3, which, even though not directly involved in asthma, has a crucial role in the processing and maturation of transfer RNAs, and may alter their post-transcriptional modification in leukotriene-producing cells [13].

Interestingly, the increasing understanding of its biological interactions may lead to the application of montelukast in other conditions (Figure 1) [14]. Indeed, due to its anti-inflammatory properties and the beneficial effects shown on cardiovascular damage, a possible role of montelukast in the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related symptoms has been proposed, particularly for the prevention and treatment of respiratory distress [15,16,17,18]. Furthermore, both CysLTR1 and CysLTR2 have been shown to be widely expressed in several brain regions, particularly after activation by pathological stimuli that ultimately determine neuroinflammation [19], and this has stimulated investigations concerning the application of montelukast in several neurodegenerative conditions, namely, Alzheimer’s disease [20,21], Parkinson’s disease [22,23,24], and Huntington’s disease [25,26]. In the context of Alzheimer’s disease, for instance, 5-lipoxygenase expression has been shown to be elevated in the hippocampus and was found in the microglia and neurons of murine models of the condition [27]. Significant production of leukotrienes in the brain, particularly in microglia, leads to blood–brain barrier disruption, neurodegeneration, and decreased neurogenesis, which may be at least partially mitigated by inhibition of the signaling at the receptor level. Evidence from both animal models [20] and clinical studies [28,29] has demonstrated that montelukast may realize this attenuation, ultimately inducing an improvement in cognitive function. Despite not yet being fully understood, the mechanism of action of montelukast seems to involve both the immune system in the brain, by downregulating the activity of glial cells, and the adaptive immunity, by reducing the number of CD8+ T-cells infiltrating the brain parenchyma, which negatively correlate with the patients’ cognitive scores [30].

4. Montelukast in Pediatric Asthma

4.1. Montelukast’s First Steps in Asthma Treatment

The first evidence in support of montelukast’s usefulness in asthma management was provided by well-designed trials in adult subjects demonstrating its efficacy in improving asthma control and in providing protection against exercise-induced bronchoconstriction [31,32]. This soon led toward the evaluation of montelukast applicability in the pediatric population, also due to some of its main features, which made it particularly attractive. First, oral administration in one or two daily doses represented a substantial advantage for children, virtually neutralizing the relevant issues related to poor compliance or inadequate technique with ICSs, which are still the cornerstone of maintenance therapy for pediatric asthma. Furthermore, the concerns associated with the adverse effects on growth, bone mineralization, and adrenal axis, associated with long-term steroid therapy [33], were not raised by montelukast, which is a non-steroidal anti-inflammatory agent.

Montelukast’s efficacy in school-aged [34] and preschool children [35,36] was first reported in studies published between the end of the 1990s and the early 2000s. In addition to its efficacy, montelukast was soon found to be superior to other drugs such as mast-cell stabilizers. School-aged children with mild-to-moderate asthma showed a significant improvement in their nocturnal symptoms and in the use of beta-agonists after a 4-week treatment with montelukast compared to inhaled nedocromil [37]. Similarly, when compared to inhaled cromolyn, montelukast led to a greater reduction in albuterol use, to higher adherence, and the satisfaction of both the parents and patients [38]. Data from these trials contributed to the progressive reduction in the use of chromones until their exclusion from pediatric asthma guidelines, and further strengthened the evidence regarding montelukast’s efficacy. Therefore, since its first mention as a possible therapeutic option in the 2002 Global Initiative for Asthma (GINA) Report [39], further studies have progressively improved the definition of the role of montelukast in the therapeutic management of children with asthma. Given the clinical benefit observed in asthmatic children older than 5 years, which is generally lower than that derived from low-dose ICSs [40], montelukast has soon found its application as an add-on treatment in children with poor asthma control despite low-dose ICSs. Such an indication was also confirmed in 2012 by the GINA Report [41]. Nevertheless, combination therapy (montelukast + ICS) proved less effective in controlling symptoms in school-aged children with moderate-persistent asthma than increasing from low to moderate doses of ICSs [42], and montelukast was demonstrated to be an ineffective ICS sparing alternative in these subjects [43].

With regard to preschool children, also in 2012, GINA recommended the use of leukotriene modifiers to reduce viral induced asthma exacerbations in children with a history of intermittent asthma [44]. Nevertheless, more detailed indications were provided by the 2008 European Respiratory Society (ERS) Task Force, proposing a new classification of preschool wheeze, with the definition of the two phenotypes “episodic viral wheeze” and “multiple-trigger wheeze” [45]. Such definitions not only had diagnostic and prognostic implications, but more importantly, entailed a different therapeutic approach. Indeed, ICSs were recommended as the first-choice maintenance treatment for multiple-trigger wheeze [46], and montelukast, to be started at the first symptoms of a viral cold, was recommended for episodic wheeze [47].

4.2. Adverse Reactions

Despite being traditionally considered as safe, with well-described anti-inflammatory and bronchoprotective activities [48], montelukast may determine adverse events that are mild in most cases [49]. However, the mechanisms and clinical aspects of montelukast-related adverse reactions represent one of the main issues the literature has focused on in the last decade. Many reports have particularly highlighted the occurrence of neuropsychiatric effects ranging from nightmares and sleep disorders to hallucinations, aggressiveness, anxiety, and suicidal ideation [50,51,52,53,54,55,56,57,58]. Such manifestations are more common in 4- to 6-year-old children and typically occur within the first ten days after first administration [59]. A detailed characterization of the adverse drug reactions following montelukast therapy was recently provided by a systematic review analyzing 13 studies and almost 7000 treated patients, which confirmed hyperactivity, irritability, anxiety, and sleep disorders as the most widely reported psychiatric manifestations [60]. The increasing awareness of these adverse reactions, their higher frequency in children rather than adults, and the documented negative impact on the patients’ quality of life [61] led the FDA to strengthen the existing warnings in 2020 by requiring montelukast to have a boxed warning about serious mental health side effects [62].

The observation of neuropsychiatric events not only during treatment, but also occasionally after montelukast discontinuation [63], and the report of cases with persisting symptoms after drug withdrawal, has stimulated researchers toward the identification of the involved mechanisms. A recent study analyzing montelukast metabolic pathways both in vitro and in mouse models has stressed the role of a metabolite, a montelukast-glutathione conjugate, that might be responsible for the decreased glutathione levels in the brain tissue, with a reduction in its protective effect against oxidative stress [64]. Furthermore, montelukast administration in mice has been shown to determine a hypothalamic–pituitary–adrenal axis dysregulation, ultimately entailing altered levels of neurotransmitters, which might induce the observed neuropsychiatric disorders [64]. Although not validated in an experimental model, some drug–gene interactions have also been hypothesized. A wide analysis of 1144 genes interacting with montelukast recently showed that some of them are related to mood disorders. Genes encoding neuropeptide precursors such as hypocretin, affecting depression or serotonin receptors and associated with schizophrenia and suicidality, might be involved in the pathogenesis of neuropsychiatric manifestations [65].

Despite being less frequently reported, several other organs and systems may be involved by adverse reactions following treatment with montelukast. An Italian review of published case reports provided a summary of the potentially harmful effects associated with its administration, even though most of them had been observed in adults [66]. Gastrointestinal symptoms, namely, abdominal pain, nausea, and vomiting may be associated with montelukast administration [60], and a case of hepatotoxicity in a 5-year-old child has been reported [67]. Skin may also be occasionally involved: an 8-year-old girl who had received montelukast for five months developed a widespread erythematous and bullous skin rash, mostly localized at her lower extremities, associated with striking blood and tissue eosinophilia [68]. The authors ultimately hypothesized the diagnosis of pemphigus, similar to other drug-induced reported cases [69]. Furthermore, Trayer and coworkers described an 11-year-old asthmatic child who presented with spontaneous lower limb bruising while on treatment with montelukast [70]. Such lesions were related to montelukast therapy both because a similar clinical pattern had previously been reported in a young woman [71] and because the resolution of the lesions was observed within a month after drug discontinuation. In these cases, even though not completely understood, an impaired platelet function induced by the altered balance in the circulating leukotrienes is likely. Finally, eosinophilic granulomatosis with polyangiitis (EGPA), previously referred to as Churg–Strauss syndrome, represents a further concern related to montelukast use, as a 4.5-fold increased risk for this condition has been estimated during therapy [72]. Nevertheless, rather than an adverse event related to a direct causative role of montelukast, EGPA has been suspected to be an underlying disease whose manifestations are unmasked as an indirect effect of montelukast administration [73]. Indeed, in most reported patients, EGPA onset was not only associated with the addition of montelukast to the therapeutic regimen, but also with the concomitant tapering of both systemic and inhaled steroids, which was likely possible due to the better asthma control achieved after LTRAs were started [74].

4.3. Preschool Wheezing

In 2014, six years after its publication, the ERS classification of preschool wheeze in episodic viral and multiple-trigger phenotypes [45] was partially reconsidered by its own authors, who acknowledged some limits of such categories in real-life clinical practice. Namely, the frequent overlap of wheeze patterns and their variation over time or with treatment made the wheeze category unclear in many patients. Furthermore, in terms of treatment indications, ICSs were confirmed as the preferred therapeutic approach for multiple-trigger wheeze, but were also indicated as a reasonable choice in episodic viral wheeze, particularly with frequent or severe episodes [75]. These considerations, representing a partial resizing of the role of montelukast in early-life wheezing, are supported by several studies. Indeed, Szefler and coworkers showed that children 2 to 4 years with mild persistent asthma achieved similar symptom control with ICSs and montelukast, even though a significantly greater benefit in terms of a lower rate of exacerbations requiring oral steroids or additional asthma medications was observed for patients receiving inhaled budesonide [76]. Similarly, a study from Pakistan comparing montelukast and ICSs in asthmatic preschoolers reported a more frequent need for step-up therapy in patients receiving LTRAs [77]. Furthermore, a cost-effective analysis of a double low-dose inhaled budesonide versus the association of low-dose ICS and montelukast in preschoolers with persistent asthma suggested that the first therapeutic strategy was associated with fewer exacerbations and lower costs [78]. Even when compared to the placebo, montelukast, administered intermittently to preschool children with >2 wheezing episodes, did not significantly reduce the number of unscheduled medical attendances for acute respiratory symptoms [79].

The mentioned findings were further strengthened by several metanalyses and reviews that analyzed the available literature on the topic. A large systematic review involving more than 3000 preschool children with asthma or recurrent wheezing concluded that ICSs represented a better option than LTRAs to control daily symptoms [80]. Interestingly, one of the most feared drawbacks of ICS therapy, the linear growth impairment, did not result in being more relevant in children receiving daily or as-needed ICSs than in those treated with montelukast [81]. In addition, two meta-analyses showed that compared to the placebo, montelukast was not more effective in reducing exacerbations in preschoolers with wheezing disorders (mean difference, 0.07, 95% confidence interval [CI], −0.14–0.29, p = 0.5), [82] nor in those with episodic viral wheeze (odds ratio 0.77, 95% CI 0.48–1.25) [83].

On the other hand, findings in contrast to the conclusions achieved by the mentioned meta-analyses have been reported. A Japanese study enrolling 93 patients aged 1–5 years with wheezing symptoms more than once a month but less than once a week showed less exacerbations and less need for step-up treatment in children receiving montelukast than in those under no controller therapy [84]. Moreover, Krawiec and coworkers found no significant differences between preschoolers with a history of one to three wheezing episodes randomized to receive montelukast, fluticasone, or no treatment for 12 weeks [85]. With a similar study design, but larger population, a Chinese study randomized 239 preschool children with recurrent wheeze to receive fluticasone propionate, oral montelukast, or budesonide suspension for 12 weeks. After comparing the number of wheezing episodes, the emergency visits, and the treatment costs between groups, the authors concluded that the three preventive treatments were equally effective, with the fluticasone propionate being the less expensive drug [86]. Nevertheless, the latter two studies, both comparing montelukast to other controller options and concluding for a similar efficacy of the different strategies, present some features that make their results difficult to generalize. Indeed, Krawiec and coworkers not only evaluated a quite limited study population, but included patients at their first up to their third wheezing episode, so likely selected subjects with relatively mild symptoms and a limited risk of recurrence [85]. Similarly, the study by Ding and coworkers, even though assessing a wider population, lacked a detailed patient characterization and a precise definition of how symptomatic relief was evaluated [86].

Table 1. Studies published since 2010 comparing montelukast to other controller options in preschool wheezing.

Study	Age (years)	No. of Patients	Comparison	Main Findings
Szefler, 2013 [46]	2–4	105 vs. 97	BUD vs. MK	No difference in time to first additional medication over 52 weeks. BUD associated with lower % of patients requiring oral steroids, lower rate of additional medications, or oral steroids
Jehan, 2014 [77]	0.5–5	2400	ICSs vs. MK	MK associated with more frequent need for step-up treatment
Nwokoro, 2014 [79]	0.8–5	669 vs. 677	Intermittent MK vs. placebo (at the onset of each viral cold)	No difference in no. of children who had unscheduled medical attendances and in the no. or duration of wheeze episodes. Increased time to first hospital admission in the MK group
Fitzpatrick, 2016 [81]	1–5	300	Daily FLUT vs. daily MK vs. as-needed FLUT plus albuterol	Daily FLUT associated with more asthma control days, fewer rescue albuterol inhalations, and fewer exacerbations
Nagao, 2018 [84]	1–5	47 vs. 46	MK vs. no controller	Fewer exacerbations and lower cumulative incidence of step-up treatment in the MK group
Krawiec, 2015 [85]	0.5–3	23 vs. 23 vs. 24	Low-dose FLUT vs. MK vs. no controller	No difference between groups in wheezing episodes over 1 year
Ding, 2019 [86]	2.5 ± 0.8	82 vs. 80 vs. 77	FLUT vs. MK vs. BUD	Lower costs of FLUT, higher adherence with MK

BUD: budesonide; MK: montelukast; ICSs: inhaled corticosteroids; FLUT: fluticasone.

summarizes the main findings from the studies regarding montelukast’s application in preschool wheezing published since 2010.

These partially conflicting results seem to support the role of montelukast in preschool wheeze as a useful second choice option in cases with absent or incomplete response to ICSs. However, the circumstance that may drive clinicians toward an earlier use of montelukast as an alternative to ICSs to achieve better control of respiratory symptoms is the inadequate adherence to ICS treatment. This issue, more relevant in preschoolers but not limited to them, raises the problem of the best therapeutic alternative able to combine easy use and adequate efficacy. Pressurized metered-dose inhalers (pMDIs) represent widely used devices in both preschoolers and older children. Even though errors such as too fast inhalation are common, repeated training and the use of spacers generally also allow for the good lung deposition of ICSs in less compliant patients [87]. On the other hand, the use of dry-powder inhalers (DPIs) has been associated with better patient adherence and good symptom control [88,89]. Nevertheless, as these devices require an inhalation as forceful as the patient can achieve, they are generally suitable for older children and adolescents [85]. Further steps toward an improved adherence to ICSs have been made with the introduction of new steroids such as ciclesonide and mometasone, whose efficacy in comparison to fluticasone or budesonide has been well-demonstrated [90,91]. The possibility of a single daily dose makes these steroids attractive alternatives, even though, as ciclesonide is licensed in Europe from the age of 12 years and mometasone from the age of 4 years, their use in preschool children is still limited. Furthermore, long-term superiority trials to identify their usefulness and safety in comparison to traditional ICSs are still needed to make their use widespread [92].

In this setting, a better compliance to an oral therapy such as montelukast rather than to inhaled drugs is somewhat intuitive and has been formally documented in a recent study [86]. Therefore, as, particularly in preschoolers, incorrect administration of ICSs due to poor inhalation technique may result in worse control of respiratory symptoms [93], the easy, once-daily orally administered montelukast may represent a reasonable and attractive alternative for symptom control.

4.4. School-Age Asthma

The analysis of the literature produced in the last decade regarding montelukast application in pediatric asthma provides a quite heterogeneous picture dominated by several studies highlighting the usefulness of LTRAs as a controller option in monotherapy [94,95,96,97] or as an add-on treatment [97,98,99,100,101], and, on the other hand, by evidence supporting the superiority of ICSs over montelukast (

Table 2. Studies published since 2010 comparing montelukast to other controller options in school-age asthma.

Study	Age (years)	No. of Patients	Comparison	Main Findings
Chen, 2021 [94]	2–14	153 vs. 240	BUD vs. MK	Lower% of children with symptoms or need for reliever medications more than twice a week in the MK group
Shin, 2019 [95]	2–17	1145 vs. 1145	BUD vs. MK	Higher adherence with MK, BUD patients more likely to have visits requiring asthma control medications
Shah, 2013 [96]	2–18	60 vs. 60	BUD vs. MK	More significant improvement in FEV1/FVC and daytime symptoms in the BUD group
Bérubé, 2014 [97]	2–14	76 vs. 252	MK vs. MK + ICSs	Significant improvement in asthma control in both groups
Jin, 2022 [98]	3–12	40 vs. 46	Routine therapy + BUD vs. Routine therapy + BUD + MK	Higher expiratory flow rate and lower levels of inflammatory markers in the BUD + MK group
Zhang, 2019 [99]	7.4 ± 2.5	45 vs. 45 vs. 45	MK vs. BUD vs. BUD + MK	Improved lung function, decreased inflammatory markers, shorter symptoms disappearance time in the BUD + MK group
Stelmach, 2015 [100]	6–14	39 vs. 37	ICSs + MK vs. ICS + placebo	Lower frequency of exacerbations, lower frequency of positive exercise challenge test in the MK group
Lemanske, 2010 [101]	6–17	165	High dose FLUT vs. FLUT + LABA vs. FLUT + MK	LABA step-up most likely to provide the best response (exacerbations, asthma control days, FEV1)

BUD: budesonide; MK: montelukast; ICSs: inhaled corticosteroids; FLUT: fluticasone; FEV₁/FVC: forced expiratory flow in 1 s/forced vital capacity; LABA: long-acting beta-agonist.

). Already a decade ago, a very rigorous Cochrane review concluded that the addition of anti-leukotrienes to ICSs was not associated with a significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICSs in children and adolescents with mild to moderate asthma [102]. Shortly afterward, a systematic review reported that four out of eight studies found a superiority of ICSs compared with montelukast, whereas no differences between the two therapeutic regimens emerged from the others [103].

These conclusions were modified a few years later, as, in the updated Cochrane review, the authors added that, for asthmatic adolescents receiving daily ICSs with suboptimal symptom control, adding anti-leukotrienes may decrease the incidence of moderate and severe exacerbations (50% reduction in the number of patients with exacerbations requiring oral corticosteroids, risk ratio 0.50, 95% CI 0.29–0.86) and improve lung function (FEV₁ mean change from baseline: 0.11 L, 95% CI 0.03–0.19 higher) and asthma control (asthma symptom score reduction: −0.15, 95% CI −0.26 to −0.05 lower) compared with the same dose of ICS. Nevertheless, they also stressed that available evidence did not allow them to determine whether the addition of LTRA was superior, inferior, or equivalent to a higher dose of ICSs [8]. This positive effect of montelukast seems to also extend to children with cough variant asthma, one of the most prominent causes of chronic cough in children, which manifests as an exacerbating cough, particularly in the morning and evening. Cough variant asthma, whose incidence is progressively increasing, may determine a significant impact on the learning skills, physical, and mental health of the affected children, and approximately 30–54% of cases progress toward the development of typical bronchial asthma [104]. In these patients, respiratory symptoms [105,106], lung function [105,106,107], and serum inflammatory markers [105] have been shown to improve more significantly with the association of montelukast and budesonide in comparison to budesonide alone.

On the other hand, a recent systematic review and meta-analysis from China stated that in the stepwise approach of pediatric asthma therapy, better symptom control (mean difference in asthma control test score: 2.30; 95% CI 1.39–3.21, p < 0.001) and lung function improvement (mean difference in peak expiratory flow% predicted: 5.45; 95% CI 1.57–9.34, p = 0.006) were achieved by adding salmeterol rather than montelukast to inhaled fluticasone [108]. Such conclusions are only apparently in contrast to those achieved by Chauhan and coworkers. The combination of these findings supports the role of montelukast as a valuable add-on option in children with suboptimal asthma control with daily ICSs, even though evidence is still insufficient to make it the first choice when compared to salmeterol.

As a surrogate outcome of the therapeutic effects of montelukast, some authors have recently analyzed the consequences of its withdrawal in children with asthma. The assessment of lung function, fraction of exhaled nitric oxide (FeNO), and the asthma control test did not significantly differ between the placebo and montelukast groups within 2 weeks after withdrawal [109]. A systematic review confirmed and extended these findings, concluding that only limited and short-term effects of deprescribing montelukast have been reported in the literature [110].

Despite the experience of large variability in clinical response when administered to asthmatic children, there is growing evidence of beneficial effects determined by montelukast on several biomarkers. Particularly, montelukast has been shown to regulate the T helper 1 (Th1)/Th2 balance, to increase the expression of CD4+CD25+ regulatory T cells, and to decrease the airway inflammation typical of asthma [111]. In addition, the observation that treatment with montelukast is associated with the reduction in the eosinophil count and of markers of airway remodeling in induced sputum supports its possible role in the modulation of asthma-related airway modifications and in the reduction in eosinophilic inflammation [11,112].

A possible explanation of these discrepancies is not difficult to hypothesize and is perceived, even if not proven, by many clinicians: montelukast may be of help in some individuals, but completely useless in others. Unfortunately, we do not know how to differentiate them prospectively [113]. Evidence in support of this statement is starting to emerge as, for instance, montelukast has been shown to be a better controller medication in obese rather than in lean patients with early-onset atopic asthma [114]. Indeed, in obese patients with asthma, relative corticosteroid resistance has been reported [115], and body mass index seems to correlate with leukotriene synthesis [116], thus making anti-leukotrienes the potentially ideal medication for this category of subjects. A further step in delineating which patients are more likely to benefit from montelukast therapy has been proposed by a Polish study [117]. To identify potential risk factors for respiratory exacerbations, the authors analyzed inflammatory markers in children with mild asthma during the 12 months following the change from ICS to montelukast therapy. Their findings showed that in 75% of patients, asthma control was adequately maintained, and that high induced sputum eosinophils (>2.5%) and raised levels of FeNO (>20 ppb) represented the most important predictors of exacerbations after switching from ICSs to montelukast [117]. More interestingly, a recent study demonstrated that genetic variation in LTA4H, a gene involved in the leukotriene pathway, may contribute to variability in montelukast response. Indeed, the presence of a specific regulatory variant, likely upregulating LTA4H activity, was found to be related to an increased risk of exacerbations under montelukast treatment, thus supporting a precision medicine approach for the use of montelukast in asthma management [118]. Additionally, transforming growth factor beta 1 (TGFB1), a cytokine involved in asthma pathogenesis and associated with treatment response, has been related to montelukast activity [119]. Indeed, the presence of a specific polymorphism in the TGFB1 promoter has been shown to modulate the effects of montelukast on TGFB1 gene expression, thus suggesting a synergistic effect of this drug and TGFB1 gene variants on the expression of this modulator, whose role seems to be crucial in airway remodeling of asthmatic subjects [119,120].

5. Conclusions and Future Directions

At the beginning of its use in pediatric wheezing disorders, montelukast raised great expectations and hopes that were partially betrayed by its application in daily clinical practice. Nevertheless, the strengths and limitations of this therapeutic alternative have been progressively highlighted by published studies, thus better delineating its role and indications. The present review provides an overview of what the literature has proposed on this topic during the last twelve years. The emerging picture appears heterogeneous due to the often conflicting results regarding the efficacy of montelukast for both preschool and school-aged children with asthma. However, as indicated by the current guidelines, the data seem to support the role of montelukast as an effective second-line therapy that, rather than replace ICSs, may be added to them to improve symptom control in selected patients.

Nevertheless, whereas several adult studies have directly compared the benefits of different second-line medications when used in addition to ICSs [121,122,123,124], the pediatric literature relatively lacks such trials. Indeed, very few studies on asthmatic children have assessed the benefits deriving from ICSs plus montelukast in direct comparison to ICSs plus other second-line medications. Similar trials would likely allow for a further delineation of the role of montelukast in pediatric asthma and could help clinicians in the choice of the more appropriate drug when a step-up approach in asthma treatment is required.

In addition, growing evidence is providing new insights into montelukast’s mechanisms of action, paving the way for the identification of potential biomarkers able to select subjects with a higher probability of therapeutic response. Indeed, as supported by recent findings, the most relevant issue in the evaluation of montelukast efficacy is more likely related to the selection of patients eligible for treatment than to the drug itself. Research efforts aimed at identifying reliable biomarkers will hopefully allow for a more personalized approach in montelukast prescription. The consequent decrease in the incidence of potentially harmful adverse reactions and the optimization of its beneficial effects will likely lead to a more reasoned and fruitful application of montelukast in daily practice.