Efficacy and safety of montelukast adjuvant therapy in adults with cough variant asthma: A systematic review and meta‐analysis

Abstract Background Montelukast is a highly selective and specific cysteinyl leukotriene receptor antagonist used in the treatment of asthma. Whether montelukast as adjuvant therapy can significantly and safely treat adults with cough variant asthma (CVA) remains inconclusive. Aims This meta‐analysis systematically evaluated the efficacy and safety of montelukast as an adjuvant treatment for adults with CVA. Materials and methods Randomized controlled trials (RCTs) on montelukast combined with inhaled corticosteroids (ICS) and long‐acting β2 agonists (LABAs) to treat CVA in adults, from inception to March 6, 2023, were retrieved from the CNKI, Wanfang, VIP, CBM, PubMed, Embase, Cochrane Library, and Web of Science databases and Clinical Trials website. Review Manager (version 5.4) and Stata (version 15.0) were used to conduct the meta‐analysis. Results A total of 15 RCTs were ultimately included in the meta‐analysis. It was established that montelukast as adjuvant therapy raised the total effective rate (RR = 1.20, 95% confidence interval [CI] [1.13, 1.27], P < 0.01) and improved the FEV1% (SMD = 0.91, 95% CI [0.40, 1.41], P < 0.01), PEF% (SMD = 0.63, 95% CI [0.38, 0.88], P < 0.01), FEV1 (SMD = 1.15, 95% CI [0.53, 1.77], P < 0.01), PEF (SMD = 0.64, 95% CI [0.42, 0.86], P < 0.01), and FEV1/FVC% (SMD = 0.76, 95% CI [0.51, 1.01], P < 0.01) and reduced the recurrence rate (RR = 0.28, 95% CI [0.15, 0.53], P < 0.01). The incidence of adverse reactions was higher in the montelukast auxiliary group compared to the control group but with no statistical difference (RR = 1.32, 95% CI [0.89, 1.96], P = 0.17). Conclusion Existing evidence indicated that the use of montelukast as an adjuvant therapy had therapeutic efficacy superior to ICS + LABA alone for the treatment of adult patients with CVA. However, further research is needed, especially a combination of high‐quality long‐term prospective studies and carefully designed RCTs.

needed, especially a combination of high-quality long-term prospective studies and carefully designed RCTs.
K E Y W O R D S cough variant asthma, meta-analysis, montelukast, randomized controlled trial

| INTRODUCTION
Cough variant asthma (CVA), which is primarily characterized by cough, is an atypical form of asthma.The cough is irritating and dry, mild during the day, and severe at night.There is airway hyperresponsiveness, but symptoms or signs such as shortness of breath or wheezing are absent, and treatment with anti-asthmatic drugs is beneficial in patients with CVA. 1 Epidemiological studies have shown that CVA is the leading cause of chronic cough in China, accounting for about 32-34%. 2,3t is the second most common cause after upper airway cough syndrome in Europe and the United States. 4everal studies have shown that CVA accounts for about 25-32.6% of chronic cough in adults 2,5 and about 30-35.7% of patients with CVA eventually develop typical asthma. 6The principles for the treatment of CVA are similar to those for asthma. 1 Treatment with inhaled corticosteroids (ICS) or inhaled corticosteroids combined with long-acting β2 agonists (ICS + LABA) is recommended for more than 8 weeks.
Treatment with ICS + LABA therapy provides rapid and effective cough relief.However, in patients with poor ICS or severe airway inflammation, a combination of leukotriene receptor antagonists may be used. 7Montelukast is a highly selective and specific cysteinyl leukotriene receptor antagonist (CysLTRA).It can relieve bronchospasms and airway mucosal edema by binding to leukotriene receptors, thereby reducing inflammatory cell infiltration and mucus secretion and promoting disease improvement. 8,9linical studies on montelukast as adjuvant therapy versus ICS + LABA in the treatment of adult CVA have been conducted, but the results are controversial. 10,11No meta-analyses are currently available on this topic.Our study systematically integrated the related randomized controlled trials (RCTs) published at home and abroad on montelukast used as an adjuvant in combination with ICS + LABA for treating adults with CVA.

| MATERIALS AND METHODS
This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement 12 and registered in PROS-PERO (No. CRD42021289588).Ethical approval and patient consent were not required, as all analyses were based on previously published studies.

| Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) patients aged 18 years or older who were diagnosed with CVA, regardless of gender or race; (2) intervention treatments that included montelukast combined with ICS + LABA versus ICS + LABA for at least 8 weeks; and (3) RCTs, without any restrictions on language or publication type.
The primary outcomes were as follows: (1) the total effective rate and (2) lung function indicators: forced expiratory volume in the first second as a percentage of the predicted value (FEV1%), peak expiratory flow expressed as a percentage of the predicted value (PEF%).The secondary outcomes included (1) lung function indicators: forced expiratory volume in the first second (FEV1), peak expiratory flow (PEF), ratio of the forced expiratory volume in the first second to the forced vital capacity expressed as a percentage (FEV1/FVC%); (2) the recurrence rate; and (3) the incidence of adverse reactions.
Repetitive studies, studies with insufficient data available, animal experiments, literature reviews, metaanalyses, conference abstracts, case reports, and studies without explicit randomization methods were excluded from our analysis.

| Data extraction and quality assessment
Data extraction was conducted by two independent researchers (QX and TTL). 13,14It included the first author, publication year, baseline characteristics, intervention measures, treatment course, and outcomes.][17] The methodological quality assessment of included trials was independently evaluated by the two authors (QX and TTL) based on the Cochrane Collaboration risk of bias assessment tool (ROB). 18The evaluation domains were as follows: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases.Each domain was rated as low, unclear, or high risk of bias.

| Statistical analysis
Dichotomous outcomes are expressed as the relative risk (RR) with a 95% confidence interval (CI), while continuous outcomes are presented by the standardized mean difference (SMD) with 95% CI.Heterogeneity was evaluated using the Chi-square and I 2 statistics.Only when the P value was >0.1 or I 2 was ≤50% was the fixed-effects model performed to combine effect sizes.In all other cases, the random-effects model was adopted.Subgroup analysis was conducted according to cough symptoms and recurrence and cough symptoms and bronchial provocation tests in the studies, which were included in the analysis.Sensitivity analysis was also performed to further identify potential sources of heterogeneity.Data analysis was performed by Review Manager (version 5.4), and Stata (version 15.0) was applied to detect publication bias.A P value of less than 0.05 was considered to indicate a statistically significant difference.

| Publication bias
The result of Begg's test showed that the total effective rate of this study had no publication bias (P = 0.079) (Figure 4), which to some extent supported the reliability of the research results.

| DISCUSSION
CVA is the leading cause of chronic cough in China and is the second most common cause of chronic cough in European and American countries.It also accounts for about 25-32.6% of chronic cough in adults.Irritant dry cough is the main clinical symptom of CVA.A positive bronchial provocation test is still essentially the gold standard for diagnosis, and effective anti-asthma treatment is a necessary diagnostic condition. 34It is worth noting that uncontrolled and recurrent CVA may lead to the development of classic asthma, 35 which in turn further leads to worsening lung function.Hence, early intervention and standardized CVA treatment are crucial.Domestic and international guidelines 1,4 recommend treatment with ICS or ICS + LABA for the management of CVA.Leukotriene receptor antagonists can be used in patients who cannot use hormones or whose hormonal therapy is ineffective.Currently, airway inflammation, remodeling, and airway hyperresponsiveness are widely recognized to play a critical role in the pathogenesis of CVA. 36Studies found that although the clinical symptoms of CVA patients were milder compared to those with typical asthma, increases in the degree of eosinophilia in the central airway mucosal tissue biopsy and bronchoalveolar lavage fluid were the same. 37Cysteinyl leukotrienes (CysLTs), which are closely related to airway inflammation of CVA, are mainly produced by eosinophils.CysLTs mainly include LTC4, LTD4, LTE4, and LTF4, which can lead to bronchial smooth muscle contraction, mucosal edema, and mucus secretion.Montelukast is a cysteinyl leukotriene receptor (CysLTR) antagonist, which can selectively block the CysLT1R to inhibit inflammation of the airway.Leukotrienes are also involved in CVA airway remodeling.Studies suggested that LTC4 and LTD4 are the primary leukotrienes that mediate airway remodeling.Both of them have a high affinity for CysLT1R. 38Montelukast can inhibit airway remodeling by blocking CysLT1R.Some scholars 39 compared the LTC4 concentration and LTC4/PGE2 ratio in induced sputum of CVA, typical asthma, and eosinophilic bronchitis and suggested that high LTC4 concentrations and high LTC4/PGE2 ratios are the inflammatory basis of airway hyperresponsiveness.Montelukast can inhibit airway hyperresponsiveness by preventing LTC4 from binding to CysLT1R.
Fifteen studies were eventually included in our analysis.All these studies were based on the use of ICS + LABA combined with montelukast for adjuvant treatment of CVA in adults for at least 8 weeks.Meta-analysis suggested that montelukast adjuvant therapy increased the total response rate, improved lung function indicators (FEV1%, PEF%, FEV1, PEF, and FEV1/FVC%), and reduced the recurrence rate.Although the incidence of adverse reactions in the montelukast adjuvant group was higher, they were alleviated spontaneously or after symptomatic treatment.There was moderate heterogeneity when analyzing the total effective rate based on cough symptoms combined with recurrence.When Ye and Feng's study was excluded, heterogeneity was significantly decreased.Studying the original text of Ye and Feng 28 found that the patients were 19-57 years old, the course of the disease was 3-23 months, and the montelukast treatment cycle reached 12 weeks.Due to the moderate heterogeneity in FEV1%, sensitivity analysis was conducted, which indicated that the study by Wang and Li 26 may have been the cause of the heterogeneity.In their study, patients were aged 20-55 and had a disease course of 2-25 months.All the patients received 10 mg of montelukast before bedtime for 8 weeks.In the process of analyzing FEV1 attributed to the high heterogeneity, a sensitivity analysis was also carried out, which found that heterogeneity decreased after removing the research by Guo. 22Analysis of the original study found that patients in the study by Guo 22 were 19-60 years old and had a disease duration of 2-24 months.Montelukast was given at 10 mg once a day for an unlimited medication time, and the treatment course was 8 weeks.Considering the actual situation, all the above had the potential to produce heterogeneity.
A meta-analysis confirmed that montelukast combined with budesonide significantly increased the total effective rate; improved FEV1, FEV1%, and PEF; and reduced the recurrence rate in the treatment of children with CVA compared to budesonide alone. 40A study by Feng et al. 41 found that a treatment regimen of montelukast given with a combination of salmeterol-ticasone had a higher total response rate and apparent efficiency, shorter cough duration, and lower recurrence rate without limitations on the age of CVA patients compared to when salmeterol-ticasone was given alone.The above studies were consistent with our results.In addition, our study limited the inclusion of adults with CVA, and the treatment of montelukast combined with ICS + LABA was used for at least 8 weeks.The results confirmed that the standardized treatment of montelukast was effective for adult CVA patients.Furthermore, reliable indicators like PEF% and FEV1/FVC%, which also reflect lung function, were added to the outcome and showed improvement, further verifying the effectiveness of montelukast in improving lung function.
Our study had several strengths.First, this is the first study, to the best of our knowledge, that conducted a systematic review and meta-analysis of montelukast as an adjunctive treatment for adults with cough variant asthma.Second, data screening, extraction, and quality evaluation were all individually completed by two researchers to ensure the reliability of the data.Additionally, subgroup analysis was also carried out to further investigate the source of heterogeneity.Our study also had some limitations.First, blinding was not mentioned in all included studies, which in turn might have led to implementation bias.Second, although the dose of montelukast in all included studies was 10 mg, the frequency and duration of use were not consistent across all the studies.Third, the small number of included studies and small sample size might have impacted the reliability of the results of this systematic review.Therefore, future studies should clarify the implementation of blinding methods when conducting relevant studies, standardize the application of montelukast according to guidelines, and conduct large-scale multicenter RCTs to improve the reliability of the research results.
Existing evidence indicated that the use of montelukast as an adjuvant therapy had therapeutic efficacy superior to that of ICS + LABA alone for the treatment of adult patients with CVA.However, based on the above limitations, further research is needed, especially a combination of high-quality long-term prospective studies and carefully designed RCTs.

F
I G U R E 1 PRISMA flow diagram of the study selection process.T A B L E 1 Characteristics of the included studies

F I G U R E 2
Assessment of risk of bias: (A) risk of bias graph; (B) risk of bias summary.F I G U R E 3 Forest plots with montelukast adjuvant group versus the control group: (A) total effective rate; (B) FEV1%; (C) PEF%; (D) FEV1; (E) PEF; (F) FEV1/FVC%; (G) recurrence rate; (H) incidence of adverse reactions.