Leukotriene inhibitors for bronchiolitis in infants and young children.

Cochrane Database of Systematic Reviews

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) Liu F, Ouyang J, Sharma AN, Liu S, Yang B, Xiong W, Xu R

Liu F, Ouyang J, Sharma AN, Liu S, Yang B, Xiong W, Xu R. Leukotriene inhibitors for bronchiolitis in infants and young children. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010636. DOI: 10.1002/14651858.CD010636.pub2.

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Leukotriene inhibitors for bronchiolitis in infants and young children (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Montelukast versus placebo, Outcome 1 Length of hospital stay. . . . . Analysis 1.2. Comparison 1 Montelukast versus placebo, Outcome 2 All-cause mortality. . . . . . Analysis 1.3. Comparison 1 Montelukast versus placebo, Outcome 3 Clinical severity score (baseline). Analysis 1.4. Comparison 1 Montelukast versus placebo, Outcome 4 Clinical severity score (day 2). . Analysis 1.5. Comparison 1 Montelukast versus placebo, Outcome 5 Clinical severity score (day 3). . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Leukotriene inhibitors for bronchiolitis in infants and young children Fang Liu1 , Jing Ouyang1 , Atul N Sharma2 , Songqing Liu1 , Bo Yang1 , Wei Xiong3 , Rufu Xu4 1 Pharmacy

Department, First Affiliated Hospital of the Third Military Medical University, Chongqing, China. 2 Department of Emergency Medicine, California Emergency Physician (CEP) - Mercy San Juan Hospital, Carmichael, USA. 3 Department of Respiratory Diseases, First Affiliated Hospital of the Third Military Medical University, Chongqing, China. 4 Department of Military Epidemiology, Military Preventive Medical College, Third Military Medical University, Chongqing, China Contact address: Songqing Liu, Pharmacy Department, First Affiliated Hospital of the Third Military Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China. [email protected]. Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: New, published in Issue 3, 2015. Review content assessed as up-to-date: 6 May 2014. Citation: Liu F, Ouyang J, Sharma AN, Liu S, Yang B, Xiong W, Xu R. Leukotriene inhibitors for bronchiolitis in infants and young children. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010636. DOI: 10.1002/14651858.CD010636.pub2. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Bronchiolitis is an acute inflammatory illness of the bronchioles common among infants and young children. It is often caused by the respiratory syncytial virus (RSV). Management of bronchiolitis varies between clinicians, reflecting the lack of evidence for a specific treatment approach. The leukotriene pathway has been reported to be involved in the pathogenesis of bronchiolitis. Leukotriene inhibitors such as montelukast have been used in infants and young children with bronchiolitis. However, the results from limited randomised controlled trials (RCTs) are controversial and necessitate a thorough evaluation of their efficacy for bronchiolitis in infants and young children. Objectives To assess the efficacy and safety of leukotriene inhibitors for bronchiolitis in infants and young children. Search methods We searched CENTRAL (2014, Issue 5), MEDLINE (1946 to April week 4, 2014), EMBASE (1974 to May 2014), CINAHL (1981 to May 2014), LILACS (1982 to May 2014), Web of Science (1985 to May 2014), WHO ICTRP and ClinicalTrials.gov (6 May 2014). Selection criteria RCTs comparing leukotriene inhibitors versus placebo or another intervention in infants and young children under two years of age diagnosed with bronchiolitis. Our primary outcomes were length of hospital stay and all-cause mortality. Secondary outcomes included clinical severity score, percentage of symptom-free days, percentage of children requiring ventilation, oxygen saturation, recurrent wheezing, respiratory rate and clinical adverse effects. Data collection and analysis We used standard Cochrane Collaboration methodological practices. Two authors independently assessed trial eligibility and extracted data, such as general information, participant characteristics, interventions and outcomes. We assessed risk of bias and graded the quality of the evidence. We used Review Manager software to pool results and chose random-effects models for meta-analysis. Leukotriene inhibitors for bronchiolitis in infants and young children (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results We included five studies with a total of 1296 participants under two years of age hospitalised with bronchiolitis. Two studies with low risk of bias compared 4 mg montelukast (a leukotriene inhibitor) daily use from admission until discharge with a matching placebo. Both selected length of hospital stay as a primary outcome and clinical severity score as a secondary outcome. However, the effects of leukotriene inhibitors on length of hospital stay and clinical severity score were uncertain due to considerable heterogeneity between the study results and wide confidence intervals around the estimated effects (hospital stay: mean difference (MD) -0.95 days, 95% confidence interval (CI) -3.08 to 1.19, P value = 0.38, low quality evidence; clinical severity score on day two: MD -0.57, 95% CI 2.37 to 1.23, P value = 0.53, low quality evidence; clinical severity score on day three: MD 0.17, 95% CI -1.93 to 2.28, P value = 0.87, low quality evidence). The other three studies compared montelukast for several weeks for preventing post-bronchiolitis symptoms with placebo. We assessed one study as low risk of bias, whereas we assessed the other two studies as having a high risk of attrition bias. Due to the significant clinical heterogeneity in severity of disease, duration of treatment, outcome measurements and timing of assessment, we did not pool the results. Individual analyses of these studies did not show significant differences between the leukotriene inhibitors group and the control group in symptom-free days and incidence of recurrent wheezing. One study of 952 children reported two deaths in the leukotriene inhibitors group: neither was determined to be drug-related. No data were available on the percentage of children requiring ventilation, oxygen saturation and respiratory rate. Finally, three studies reported adverse events including diarrhoea, wheezing shortly after administration and rash. No differences were reported between the study groups. Authors’ conclusions The current evidence does not allow definitive conclusions to be made about the effects of leukotriene inhibitors on length of hospital stay and clinical severity score in infants and young children with bronchiolitis. The quality of the evidence was low due to inconsistency (unexplained high levels of statistical heterogeneity) and imprecision arising from small sample sizes and wide confidence intervals, which did not rule out a null effect or harm. Data on symptom-free days and incidence of recurrent wheezing were from single studies only. Further large studies are required. We identified one registered ongoing study, which may make a contribution in the updates of this review.

PLAIN LANGUAGE SUMMARY Leukotriene inhibitors for bronchiolitis in infants and young children Review question We reviewed the evidence regarding the effect of leukotriene inhibitors on clinical outcomes in infants and young children with bronchiolitis. Background One of the most common respiratory illnesses experienced by infants is bronchiolitis, an inflammation of the small airways in the lungs. Bronchiolitis can be caused by viruses such as the respiratory syncytial virus or influenza. Symptoms include rhinitis, wheezing, coughing and sneezing. It is associated with considerable morbidity and can result in hospitalisation. Leukotriene inhibitors are supposed to reduce airway inflammation, which means that they could help to reduce airway inflammation associated with bronchiolitis. We reviewed the evidence from randomised trials to see whether using leukotriene inhibitors is better than placebo in children under two years of age with bronchiolitis. Study characteristics This evidence is current to May 2014. We identified five randomised controlled trials (1296 participants under two years of age) comparing montelukast (a leukotriene inhibitor) with placebo in infants and young children hospitalised with bronchiolitis. Key results Our primary outcomes were length of hospital stay and all-cause mortality. Secondary outcomes included clinical severity score, percentage of symptom-free days, percentage of children requiring ventilation, recurrent wheezing, oxygen saturation, respiratory rate and clinical adverse effects. The effects of montelukast on length of hospital stay and clinical severity score were uncertain due to considerable heterogeneity (differences) between the study results and wide confidence intervals around the estimated effects. Data on symptom-free days and Leukotriene inhibitors for bronchiolitis in infants and young children (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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incidence of recurrent wheezing were from single studies only and individual analyses of these studies did not show significant differences between the intervention group and the control group. One study of 952 children reported two deaths in the leukotriene inhibitors group: neither was determined to be drug-related. No data were available on the percentage of children requiring ventilation, oxygen saturation and respiratory rate. Finally, three studies reported adverse events including diarrhoea, wheezing shortly after administration and rash. No differences were reported between the study groups. Quality of the evidence We assessed the quality of the evidence for length of hospital stay and clinical severity score as low due to inconsistency and imprecision arising from small sample sizes and wide confidence intervals, which did not rule out no effect or harm. Overall, the current evidence does not allow definitive conclusions to be made about the effect and safety of leukotriene inhibitors in infants and young children with bronchiolitis.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Montelukast versus placebo for bronchiolitis in infants and young children Patients or population: infants and young children with bronchiolitis Settings: inpatients Intervention: leukotriene inhibitors (montelukast) Comparison: placebo Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

Assumed risk

Corresponding risk

Control

Montelukast placebo

No of participants (studies)

Quality of the evidence (GRADE)

136 (2 studies)

⊕⊕

low1,2

952 (1 study)

See comment

136 (2 studies)

⊕⊕

low1,2

Comments

versus

Length of hospital stay

The mean length of hospital stay in the intervention groups was 0.95 lower (3.08 lower to 1.19 higher)

All-cause mortality See comment Deaths Follow-up: 0 to 6 months

See comment

Clinical severity score (day 2)

The mean clinical severity score (day 2) in the intervention groups was 0.57 lower (2.37 lower to 1.23 higher)

RR 2.51 (0.12 to 52.16)

One study of 952 children reported 2 deaths in the leukotriene group: neither was determined to be drug-related

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Clinical severity score (day 3)

Clinical adverse effects

The mean clinical severity score (day 3) in the intervention groups was 0.17 higher (1.93 lower to 2.28 higher) See comment

See comment

Not estimable

132 (2 studies)

⊕⊕

low2

1063 (3 studies)

See comment

3 studies reported adverse events. The most common adverse events were wheezing shortly after administration, diarrhoea and rash. There was no difference between the study groups

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. 1 Downgraded 2 Downgraded

one level due to inconsistency: high level of unexplained statistical heterogeneity. one level due to imprecision: small sample size and the confidence interval does not rule out a null effect or harm.

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BACKGROUND Description of the condition Bronchiolitis is a common acute inflammatory illness of the bronchioles, the smallest air passages of the lungs. It is often seen in children under two years of age, with the majority being aged between three and six months (Quintero 2007). The most common cause of bronchiolitis is the respiratory syncytial virus (RSV). However, parainfluenza, influenza, adenovirus and rhinovirus have also been implicated (Denny 1977; Hervas 2012). The onset and progression of bronchiolitis is similar to that of the common cold with patients experiencing low-grade fever, rhinorrhoea (also known as ’runny nose’, a condition where the nasal cavity is filled with a significant amount of mucous fluid), cough, sneezing and wheezing. Around 10% of children in high-income countries contract bronchiolitis in the first year of life and 2% to 3% of these will require hospitalisation (Koehoorn 2008). The risk of death for a healthy infant with bronchiolitis is less than 0.5%, but the risk has been shown to be much higher for children with congenital heart disease (3.5%) and chronic lung disease (3.45%) (figures from Canada) (Worrall 2008). The rate of hospitalisation for bronchiolitis has increased steadily in North America and Europe over the past 10 to 20 years (CDC 2003; Langley 2003; Shay 1999). Additionally, bronchiolitis has been linked with an increased incidence of asthma later in life (Mohapatra 2008). It is associated with a significant healthcare burden worldwide (Mansbach 2005).

Description of the intervention The management of bronchiolitis varies between clinicians, reflecting the absence of clear scientific evidence for a specific treatment approach. Bronchodilators, antibiotics and steroids are widely used but not routinely recommended (Fernandes 2013; Gadomski 2014; Farley 2014). A review on epinephrine for bronchiolitis has recently provided evidence that epinephrine is more effective than placebo for bronchiolitis in outpatients but there is no evidence to support its use for inpatients (Hartling 2011). Another review on nebulised hypertonic saline solution has shown that nebulised 3% saline may significantly reduce the length of hospital stay among infants hospitalised with non-severe acute viral bronchiolitis and improve the clinical severity score in both outpatient and inpatient populations, compared to those treated with nebulised 0.9% saline (Zhang 2013). However, although this is an effective treatment it is not a convenient one, therefore new treatment approaches are necessary. Leukotriene inhibitors, such as montelukast, have been widely used in asthma therapy. These are drugs that inhibit leukotrienes, which are fatty compounds produced by the immune system that cause inflammation in asthma, bronchitis and bronchiolitis, constricting the airways. Leukotriene inhibitors can decrease the concentration of leukotrienes and reduce the symptoms of wheezing

and coughing. They might therefore have a potential benefit in the treatment of bronchiolitis in children who present with wheezing (Halfhide 2008).

How the intervention might work The pathogenesis of bronchiolitis involves the stimulation of the 5lipoxygenase gene, a key player in the biosynthesis of leukotrienes (LTs), which increases the concentration of cysteinyl LTs (CysLTs) in the airways. CysLTs are known to cause obstruction of the airway and the alveoli, mucosal oedema and increased bronchial responsiveness. Therefore, CysLTs are a potential target in the treatment of bronchiolitis (Piedimonte 2005). Leukotriene inhibitors are either leukotriene receptor antagonists or leukotriene synthesis inhibitors, which can decrease the concentration of CysLTs by selectively blocking the binding of cysteinyl leukotrienes to CysLT receptors or inhibiting the synthesis of 5-lipoxygenase. As a result, leukotriene inhibitors may be a new treatment for bronchiolitis (Scow 2007). The leukotriene inhibitors currently available are montelukast (Singulair), zafirlukast (Accolate), pranlukast and zileuton (Zyflo). Montelukast, zafirlukast and pranlukast are leukotriene receptor antagonists that prevent leukotriene from binding to cell receptors and initiating the chain of events that leads to inflammation. Zileuton is a 5lipooxygenase pathway inhibitor that interferes with the synthesis of LTA4, LTC4, LTD4 and LTE4. Currently, montelukast is the only leukotriene inhibitor that has been approved by the US Food and Drug Administration (FDA) for use in children as young as two years of age.

Why it is important to do this review Leukotriene inhibitors such as montelukast have been used in infants and young children. However, the results from limited randomised controlled trials (RCTs) are controversial and necessitate a thorough evaluation of their efficacy for bronchiolitis in infants and young children.

OBJECTIVES To assess the efficacy and safety of leukotriene inhibitors for bronchiolitis in infants and young children.

METHODS

Criteria for considering studies for this review


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Types of studies We included RCTs comparing leukotriene inhibitors with control (placebo or other interventions). We did not include quasi-RCTs, cross-over trials or cluster-RCTs.

adapted the search strategy to search EMBASE (Appendix 2), CINAHL (Appendix 3), LILACS (Appendix 4) and Web of Science (Appendix 5). We did not use any language or publication restrictions.

Types of participants

Searching other resources

We included infants and children up to 24 months of age with physician-diagnosed bronchiolitis (inclusion was not restricted since the definition of bronchiolitis varies between countries and some bronchiolitis trial reports may not specify the clinical findings required for the diagnosis of the participants).

We searched Clinicaltrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (last searched 6 May 2014) to identify unpublished and ongoing studies. We carefully scrutinised the reference lists of the included studies and relevant review articles for additional references.

Types of interventions

Data collection and analysis

We included all types of leukotriene inhibitors (such as montelukast, zafirlukast and zileuton) compared with placebo or other interventions, irrespective of dosage, duration and route of administration. Types of outcome measures

Primary outcomes

1. Length of hospital stay. 2. All-cause mortality. Secondary outcomes

1. 2. 3. 4. 5. 6. 7.

Clinical severity score. Percentage of symptom-free days. Percentage of children requiring ventilation. Oxygen saturation. Recurrent wheezing. Respiratory rate. Clinical adverse effects.

Selection of studies Two review authors (JO, WX) independently assessed the titles and abstracts of all records identified by the searches. We classified these studies as ’included’, ’unclear’ and ’excluded’. We obtained the full articles when they were classified as included or unclear. Two review authors (JO, WX) independently assessed full articles classified as included and unclear for inclusion using a standardised form. We resolved any disagreements through discussion or, if required, adjudication from another review author (AS). Data extraction and management Two review authors (FL, JO) independently extracted data from the included studies using a standardised data extraction form. We extracted general information (study ID, date of extraction, title, authors and source of study if not published); study characteristics (study design, participants and inclusion/exclusion criteria used in the study); intervention (type of leukotriene inhibitors, dosage, treatment duration, comparison details, duration of follow-up) and outcomes (primary and secondary outcomes and adverse effects).

Search methods for identification of studies Assessment of risk of bias in included studies Electronic searches We searched CENTRAL (2014, Issue 5) (accessed 6 May 2014), which contains the Acute Respiratory Infections Group’s Specialised Register, MEDLINE (1946 to April week 4, 2014), EMBASE (1974 to May 2014), CINAHL (1981 to May 2014), LILACS (1982 to May 2014) and Web of Science (1985 to May 2014). We used the search strategy described in Appendix 1 to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE (Lefebvre 2011). We

We used the ’Risk of bias’ assessment tool and criteria set out in the Cochrane Handbook for Systematic Reviews of Interventions to assess the risk of bias in the included studies (Higgins 2011). The assessment tool includes seven domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other sources of bias. Three review authors (RX, SL, BY) independently assessed the risk of bias of the included studies as ’low risk’, ’unclear risk’ and ’high risk’ for each domain. We resolved any disagreement by consensus.


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Grading the body of evidence

We used the Evidence-Based Practice Centers Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, based on the standard GRADE system (GRADE 2009) to assess the domain-specific strength of evidence for four relevant outcomes: length of hospital stay, all-cause mortality, clinical severity score and clinical adverse effects. Two review authors (FL, RX) independently graded the body of evidence using adapted decision rules. We examined the following domains: risk of bias, consistency, directness and precision based on GRADE guidance (GRADE 2009). We graded the overall strength of evidence as ’high’, ’moderate’, ’low’ or ’very low’ based on the likelihood of further research changing our confidence in the estimate of effect. We resolved discrepancies by consensus between two review authors (FL, RX).

Measures of treatment effect We synthesised continuous data (such as length of hospital stay) using mean difference (MD) with 95% confidence interval (CI). We considered a measurement scale, i.e. clinical severity score, as continuous data and synthesised as mentioned above. If data were available, we would have utilised the risk ratio (RR) with 95% CI for dichotomous data, i.e. all-cause mortality. We also reported the type of clinical adverse effects in detail (Higgins 2011).

Unit of analysis issues We did not include quasi-RCTs, cross-over trials or cluster-RCTs as they were inappropriate. One study included three arms (Bisgaard 2008: montelukast 4 mg, montelukast 8 mg and placebo). The baseline characteristics are similar among these groups and the comparisons are independent. However, we did not include these data in a meta-analysis due to significant clinical heterogeneity among studies.

Dealing with missing data We contacted three trial authors to verify key study characteristics or obtain missing statistics (Amirav 2008; Bai 2010; Proesmans 2009). The author of Amirav 2008 provided us with the mean and standard deviations of clinical severity score. Proesmans 2009 provided us with the mean and standard deviations of numbers of symptom-free days. However, due to the significant heterogeneity, we did not utilise these data. Unfortunately, Bai 2010 failed to provide us with the raw data on incidence of recurrent wheezing.

Assessment of heterogeneity We assessed clinical heterogeneity before pooling. We would not combine data from clinically heterogeneous trials but would describe these separately. We evaluated statistical heterogeneity by

using the Chi2 test with a P value < 0.1 indicating significant heterogeneity. We used the I2 statistic to quantify statistical heterogeneity. The importance of heterogeneity depends on several factors, according to the Cochrane Handbook for Systematic Reviews of Interventions. A rough guide to interpretation, with some modification aiming to avoid overlap, is as follows: 0% to 30% might not be important; 31% to 50% may represent moderate heterogeneity; 51% to 75% may represent substantial heterogeneity and 76% to 100% represents considerable heterogeneity (Higgins 2011). Assessment of reporting biases To minimise the potential for reporting biases, we did not impose any language restrictions on the searches. We also searched the International Clinical Trial Registry Platform for unpublished and ongoing studies. If sufficient data were available, we would have used a funnel plot to detect publication bias. Notwithstanding, this was not necessary due to the small number of included studies. Data synthesis We pooled quantitative results within the different comparisons when studies were consistent on clinical grounds and had available outcome data. We combined results using random-effects models regardless of heterogeneity, due to expected differences in interventions, outcomes and measurement instruments. According to the Cochrane Handbook for Systematic Reviews of Interventions Chapter 9, when no heterogeneity exists both fixed-effect and random-effects models will give identical results. When heterogeneity exists, a random-effects model is more suitable as it incorporates two possible sources of heterogeneity (caused by sampling error or substantive variability) among the studies (Higgins 2011; Tania 2006). We used inverse variance methods to conduct meta-analyses for both dichotomous and continuous outcomes. Additionally, we combined dichotomous and continuous data into a standardised mean difference (SMD) whenever required (Higgins 2011). We reported all results with 95% confidence interval (CI). We used Review Manager software for data management and analysis (RevMan 2014). We also included a ’Summary of findings’ table using the GRADEpro software, considering outcomes such as length of hospital stay, all-cause mortality, clinical severity score and clinical adverse effects (GRADE 2009). Subgroup analysis and investigation of heterogeneity We planned to conduct the following subgroup analyses but due to insufficient data this was not possible. 1. Type of comparison (placebo/another active treatment). 2. Type of participants (outpatient/inpatient). 3. Bronchiolitis in patients with or without high risks (bronchopulmonary dysplasia, congenital heart disease).


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4. Type of leukotriene inhibitor. 5. Age group (younger than one month/older than one month if neonates are included). Sensitivity analysis We planned a sensitivity analysis but it was not undertaken because of the limited number of included trials.

RESULTS

Description of studies

Results of the search The electronic searches for this review were performed by the Trials Search Co-ordinator of the Cochrane Acute Respiratory infections (ARI) Group. Searches of CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS and Web of Science on 6 May 2014 identified 170 records; manual searches identified two records. After screening the titles and abstracts, we excluded 123 records and retained 49 potentially relevant records for full-text assessment, of which we excluded 37 records (33 studies), resulting in 12 records involving six studies. Finally, we excluded one further study because the investigators could not provide the original data (Bai 2010). Thus, we included five RCTs in this review (Figure 1). We identified one ongoing trial from the WHO International Clinical Trials Registry Platform, which meets our inclusion criteria (Wang 2013). It was registered in October 2013 and is still recruiting participants. See Characteristics of ongoing studies table.

Figure 1. Study flow diagram.


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Included studies All five studies were randomised, double-blind, parallel-group, controlled trials. Bisgaard 2008 is an international multi-centre trial with a large sample, which was conducted in both highincome and low-income countries involving Denmark, Mexico, Singapore, South Africa and the USA. Kim 2010 is a multi-centre study conducted in South Korea and Japan. The remaining three studies were conducted in Belgium (Proesmans 2009), Egypt (Zedan 2010), and Israel (Amirav 2008). Participants

We included a total of 1296 participants between the ages of one month to 24 months hospitalised with bronchiolitis. All studies clearly described the criteria for diagnosis of bronchiolitis and all studies included the first episode of bronchiolitis except for Bisgaard 2008, which included a small proportion with a second episode of bronchiolitis (about 10% in each group). RSV detection was available in all trials except for Zedan 2010.

Two studies selected length of hospital stay as the primary outcome and clinical severity scores as the secondary outcome (Amirav 2008; Zedan 2010). Both of them used the same validated score, which was initially described by Wang 1992; the score rated respiratory rate, wheezing, retraction and general condition from zero to three (the higher score corresponding to increased severity). The outcome measurements varied among studies when using montelukast for preventing post-bronchiolitis symptoms. Bisgaard 2008 selected percentage of symptom-free days during four weeks treatment as the primary outcome. Proesmans 2009 selected the number of symptom-free days over three months treatment as the primary outcome. Kim 2010 selected the serum eosinophilderived neurotoxin level as the primary outcome. Other outcome measures included percentage of bronchiolitis-free days, patients with exacerbations, patients with systemic corticosteroids use (Bisgaard 2008), the need for additional treatment after hospital discharge, the number of respiratory exacerbations, time to first exacerbation (Proesmans 2009), and serum eosinophil-derived neurotoxin level (Kim 2010).

Adverse effects Interventions

Two studies used 4 mg montelukast (a leukotriene inhibitor) or matching placebo daily from admission until discharge to treat acute bronchiolitis (Amirav 2008; Zedan 2010). The other three studies used 4 mg montelukast for several weeks for preventing post-bronchiolitis symptoms (Bisgaard 2008; Kim 2010; Proesmans 2009). Bisgaard 2008 used an additional dose (8 mg montelukast) to assess whether there is a dose-effect relationship. The treatment duration and follow-up period varied among these three studies. Kim 2010 and Proesmans 2009 used montelukast daily for three months with one year of follow-up. Bisgaard 2008 evaluated two different treatment durations including four weeks and the subsequent 20 weeks.

Outcome measures

Amirav 2008, Bisgaard 2008 and Proesmans 2009 reported adverse events and Bisgaard 2008 also reported two deaths in the intervention group during treatment, but neither of the deaths was determined to be drug-related.

Excluded studies We excluded 34 studies with reasons. The most common reasons for exclusion included type of publication, populations and study design (see Characteristics of excluded studies table).

Risk of bias in included studies Risk of bias in the included studies is detailed in Characteristics of included studies table and summarised in Figure 2 and Figure 3.


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Figure 2. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.


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Figure 3. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study.


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Allocation We considered sequence generation and allocation concealment to be clearly described in the included studies (Amirav 2008; Bisgaard 2008; Kim 2010; Proesmans 2009; Zedan 2010).

Selective reporting We would have used a funnel plot to detect reporting bias but this was not necessary due to the small number of included studies. Other potential sources of bias

Blinding For the purposes of our review, we considered blinding adequate in most of these included studies. Three studies clearly described the blinding of participants and personnel and the blinding of outcome assessment (Amirav 2008; Bisgaard 2008; Kim 2010). However, Proesmans 2009 only mentioned that the blinding code was broken only after all included patients had finished the trial follow-up; they did not mention whether the outcome assessor was blinded or not.

We did not identify any other potential sources of bias.

Effects of interventions See: Summary of findings for the main comparison Montelukast versus placebo for bronchiolitis in infants and young children Primary outcomes

1. Length of hospital stay

Incomplete outcome data Three included studies used flow diagrams to assess differential drop-out from the study groups (Amirav 2008; Bisgaard 2008; Zedan 2010). Possible attrition bias might be a factor in two studies because the percentage of loss to follow-up of participants was beyond 15%, which might lead to attrition bias (Kim 2010; Proesmans 2009).

Two studies reported the length of hospital stay from admission to discharge as a primary outcome. Zedan 2010 had a positive result while Amirav 2008 had negative result. The pooled results based on the two studies showed that there was no statistically significant difference between the intervention group and the control group (mean difference (MD) -0.95 days, 95% confidence interval (CI) -3.08 to 1.19, P value = 0.38, I2 statistic = 88%) (Analysis 1.1; Figure 4).

Figure 4. Forest plot of comparison: 1 Montelukast versus placebo, outcome: 1.1 Length of hospital stay.

2. All-cause mortality

Only one study reported deaths. “Two patients died during the study, neither was determined by the investigator to be drug related. One patient died of acute respiratory distress syndrome and sepsis while hospitalised for RSV-induced bronchiolitis. The other one died of thermal burns in a house fire”. There was no statistically significant difference between these groups (P value = 0.55) (Analysis 1.2).

Secondary outcomes

1. Clinical severity score

Two included studies reported the clinical severity score and utilised the same validated score system that was initially described by Wang 1992. We pooled data comparing clinical severity score on admission (defined as baseline) and the next two days after treatment (defined as day two and day three) because of the small


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number of remaining participants. The pooled results showed that there was no statistically significant difference between the intervention group and the control group (baseline: MD 0.11, 95% CI -0.51 to 0.74, P value = 0.72, I2 statistic = 0% (Analysis 1.3); day two: MD -0.57, 95% CI -2.37 to 1.23, P value = 0.53, I2 statistic = 81% (Analysis 1.4; Figure 5); day three: MD 0.17; 95% CI -1.93 to 2.28, P value = 0.87, I2 statistic = 84% (Analysis 1.5; Figure 6). Figure 5. Forest plot of comparison: 1 Montelukast versus placebo, outcome: 1.4 Clinical severity score (day 2).

Figure 6. Forest plot of comparison: 1 Montelukast versus placebo, outcome: 1.5 Clinical severity score (day 3).

2. Percentage of symptom-free days

Two studies selected symptom-free days as secondary outcomes but reported this differently (Bisgaard 2008; Proesmans 2009). Bisgaard 2008 reported the percentage of symptom-free days during two periods (four weeks or a total of 24 weeks of treatment) and defined the symptom-free days as a day with no daytime cough, wheeze, shortness of breath and no night-time cough. Data are presented as the means and standard deviations. The results showed that there was no significant trend for montelukast treatment compared with placebo during 24 weeks of treatment. Proesmans 2009 reported the number of symptom-free days during three months of treatment and defined symptom-free days as 24 hours during which the parent reported no daytime or night-time symptoms (symptoms included wheeze, cough and troubled breathing, and limited activities). Data are presented as median, interquartile

ranges and minimum/maximum. The results also demonstrated no significant difference between groups (P value = 0.415). Owing to the significant heterogeneity between studies, we did not pool the results. Results from individual studies were consistent with each other, which indicated that montelukast did not affect symptom-free days in patients with post-bronchiolitis when compared with placebo.

3.Percentage of children requiring ventilation

No relevant data were available on the percentage of children require ventilation.

4. Oxygen saturation

No relevant data were available on oxygen saturation.


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5. Recurrent wheezing

Only one study reported the incidence of recurrent wheezing during three months of treatment and one year of follow-up (Kim 2010). The results showed that montelukast treatment did not reduce the incidence of recurrent wheezing.

6. Respiratory rate

No relevant data were available on respiratory rate.

7. Clinical adverse effects

Three studies reported adverse events but none were determined to be drug-related (Amirav 2008; Bisgaard 2008; Proesmans 2009). Proesmans 2009 reported that five infants were withdrawn because of possible adverse events. Two for abdominal pain and vomiting, two for sleepless nights and one for rash. Amirav 2008 reported 10 clinical adverse events during the study. There were no sudden, unexpected, serious adverse reactions and no patients discontinued the study because of adverse effects. The most common adverse effects were wheezing shortly after administration, diarrhoea and rash. There was no difference between the study groups. Bisgaard 2008 reported that montelukast was generally well tolerated. There were no differences between the study groups.

DISCUSSION Summary of main results In this review, we evaluated the efficacy and safety of leukotriene inhibitors for bronchiolitis in infants and young children. The results are summarised in Summary of findings for the main comparison and Data and analyses. In brief, we included five randomised, double-blinded, placebocontrolled trials, which were conducted in both high-income and low-income countries. Two studies used 4 mg montelukast daily from admission until discharge and selected the same outcome measurements (length of hospital stay as primary outcome and clinical severity score as secondary outcome). Both had similar clinical statuses but with opposite results from individual studies. The pooled results did not show statistically significant differences in shortening the length of hospital stay (mean difference (MD) 0.95, 95% confidence interval (CI) -3.08 to 1.19, P value = 0.38) or decreasing the clinical severity score (day two: MD -0.57, 95% CI -2.37 to 1.23, P value = 0.53; day three: MD 0.17, 95% CI 1.93 to 2.28, P value = 0.87) when compared with placebo. The other three studies used montelukast in patients hospitalised with bronchiolitis for several weeks for preventing post-bronchiolitis symptoms. However, the outcome measurements, duration of treatment and follow-up period varied among the three studies,

which implied significant clinical heterogeneity between studies. Therefore, we did not pool results. Results from individual studies were consistent with each other, which indicated that montelukast did not affect symptom-free days in patients with post-bronchiolitis when compared with placebo. Only one study reported the incidence of recurrent wheezing during the three months treatment and one-year follow-up. The results showed that montelukast treatment did not reduce the incidence of recurrent wheezing. The cumulative recurrent wheezing was similar in the intervention and placebo group for the 12-month follow-up period. All-cause mortality was reported in one study only. Two patients died during treatment but neither death was drug-related. The analysis also showed no statistically significant difference between groups. Adverse events were reported in three included studies. We did not pool results given the heterogeneity. Individual trial analyses did not show significant differences between the leukotriene inhibitors group and the placebo group.

Overall completeness and applicability of evidence In this review, all included studies recruited participants hospitalised with mild bronchiolitis. All studies excluded premature children and children with chronic conditions. Lack of evidence for this subset of patients is problematic, since these patients might be especially susceptible to bronchiolitis. Therefore, caution should be taken when extrapolating the finding of this review to patients with chronic diseases or premature children. Furthermore, study designs differed too much between the studies when using leukotriene inhibitors to prevent post-bronchiolitis symptoms, especially in terms of severity of disease, outcome measures, duration of treatment and follow-up period, which might limit the applicability of the evidence for preventing post-bronchiolitis symptoms.

Quality of the evidence We assessed three included trials to be at low risk of bias for sequence generation, allocation concealment, blinding, incomplete outcome data and selective reporting. We assessed the other two studies as having a high risk of attrition bias due to the percentage of loss to follow-up of participants, which was above 15%. We assessed the quality of the evidence using the GRADE Working Group method (GRADE 2009). We judged the quality of the evidence for the effect on length of hospital stay and clinical severity score as low due to inconsistency (high level of unexplained statistical heterogeneity) and imprecision (small sample size and the CI does not rule out a null effect or harm). See Summary of findings for the main comparison.


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Potential biases in the review process We did not use funnel plots to assess publication bias due to the small number of included studies. We changed the outcomes shown in the ’Summary of findings’ table from all-cause mortality and admission, as specified in the published protocol, to all-cause mortality, length of hospital stay, clinical severity score and clinical adverse effects in this review, which might be a source of bias.

Agreements and disagreements with other studies or reviews To the best of our knowledge, there is no other systematic review assessing the short-term treatment efficacy and safety of leukotriene inhibitors for infants and young children under two years of age with acute bronchiolitis. Peng 2014 assessed the efficacy montelukast for preventing post-bronchiolitis wheezing and demonstrated results consistent with ours in that montelukast was not effective in preventing post-bronchiolitis wheezing.

and imprecision arising from small sample sizes and wide confidence intervals, which did not rule out a null effect or harm.

Implications for research More large randomised controlled trials (RCTs) are necessary to evaluate the efficacy and safety of leukotriene inhibitors in infants and young children with bronchiolitis. This is particularly important in preterm infants and high-risk patients (e.g. patients with bronchopulmonary dysplasia and congenital heart disease), who are especially susceptible to this illness. Research should focus on the first episode of wheezing in younger children so the results will be pertinent to infants with typical viral bronchiolitis. A second episode of bronchiolitis with recurrent wheezing might be due to other respiratory diseases such as asthma. Thus, it is necessary to identify simple, valid and universal tools to distinguish prospectively between these diseases in future studies.

ACKNOWLEDGEMENTS AUTHORS’ CONCLUSIONS Implications for practice The current evidence is based on limited included studies and does not allow definitive conclusions to be made about the effects of leukotriene inhibitors used for bronchiolitis in infants and young children. We downgraded the quality of the evidence to low due to inconsistency (unexplained high levels of statistical heterogeneity)

We wish to thank Sarah Thorning (Trials Search Co-ordinator) for help in defining the search strategy and in running the literature searches. We wish to thank Clare Dooley (Assistant Managing Editor, Cochrane Acute Respiratory Infections Group), Liz Dooley (Manage Editor, Cochrane Acute Respiratory Infections Group), Inge Axelsson and Chris Del Mar for providing ongoing assistance with this review. Finally, we wish to thank the following people for commenting on the drafts of this review: Deviprasad Mohapatra, Vishal Jatana, Federico Martinon-Torres, Kana R Jat, Sree Nair and Ravi Shankar.

REFERENCES

References to studies included in this review Amirav 2008 {published and unpublished data} Amirav I, Kruger N, Borovitch Y, Babai I, Miron D, Zuker M, et al. Double blind placebo controlled randomized trial of montelukast in acute RSV bronchiolitis [Abstract]. European Respiratory Journal 2007;30:499s. ∗ Amirav I, Luder AS, Kruger N, Borovitch Y, Babai I, Miron D, et al. A double-blind, placebo-controlled, randomized trial of montelukast for acute bronchiolitis. Pediatrics 2008;122:e1249–55. Amirav I, Luder AS, Kruger N, Borovitch Y, Babai I, Miron D, et al. A double-blind, placebo-controlled, randomized trial of montelukast for acute bronchiolitis. Pediatrics 2009; 123:604. Bisgaard 2008 {published data only} ∗ Bisgaard H, Flores-Nunez A, Goh A, Azimi P, Halkas A, Malice MP, et al. Study of montelukast for the treatment

of respiratory symptoms of post-respiratory syncytial virus bronchiolitis in children. American Journal of Respiratory and Critical Care Medicine 2008;178:854–60. Bisgaard H, Malice M, Marchal J, Reiss T, Knorr B. Randomized, placebo-controlled study of montelukast for treatment of post-RSV-bronchiolitic respiratory symptoms in children. Allergy 2007;62:127. Knorr B, Marchal JL, Malice MP, Bisgaard H, Reiss T. Post hoc analysis of the effect of montelukast in treating post RSV bronchiolitic respiratory symptoms in children [Abstract]. European Respiratory Journal 2007;30:461. Knorr B, Massaad R, Lu S, Newcomb K, Bisgaard H, Reiss T. Safety of montelukast in children with post RSV bronchiolitic respiratory symptoms [Abstract]. European Respiratory Journal 2007;30(Suppl 51):461s. Kim 2010 {published data only} ∗ Kim C-K, Choi J, Kim HB, Callaway Z, Shin BM, Kim JT, et al. A randomized intervention of montelukast for post-


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bronchiolitis: effect on eosinophil degranulation. Journal of Pediatrics 2010;156:749–54. Kim H, Choi J, Callaway Z, Shin B, Kim J, Fujisawa T, et al. A randomized intervention of montelukast for postbronchiolitis: effect on eosinophil degranulation. Journal of Allergy and Clinical Immunology 2010;125:AB65. Proesmans 2009 {published and unpublished data} Proesmans M, Sauer K, Govaere E, Raes M, De Bilderling G, De Boeck K. Montelukast does not prevent reactive airway disease in young children hospitalized for RSV bronchiolitis. Acta Paediatrica 2009;98:1830–4. Zedan 2010 {published data only} Zedan M, Gamil N, El-Assmy M, Fayez E, Nasef N, Fouda A, et al. Montelukast as an episodic modifier for acute viral bronchiolitis: a randomized trial. Allergy and Asthma Proceedings 2010;31:147–53.

References to studies excluded from this review Al-Hamdani 2010 {published data only} Al-Hamdani FY. Comparative clinical evaluation of ketotifen and montelukast sodium in asthmatic Iraqi patients. Saudi Pharmaceutical Journal 2010;18:245–9. Anonymous 2007 {published data only} Anonymous. Pre-school viral wheeze in primary care. Drug & Therapeutics Bulletin 2007;45(3):17–20. Bacharier 2008 {published data only} Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. Journal of Allergy & Clinical Immunology 2008; 122:1127–35.e8. Bai 2010 {published data only} Bai J, Xu PR. Montelukast in the treatment of bronchiolitis, a multi-center, randomized, three-blind, placebo-controlled trial. Chinese Journal of Evidence-Based Medicine 2010;10: 1011–5. Belcaro 2011 {published data only} Belcaro G, Luzzi R, Cesinaro Di Rocco P, Cesarone MR, Dugall M, Feragalli B, et al. Pycnogenol improvements in asthma management. Panminerva Medica 2011;53:57–64. Bisgaard 2003 {published data only} Bisgaard H. A randomized trial of montelukast in respiratory syncytial virus post bronchiolitis. American Journal of Respiratory and Critical Care Medicine 2003;167:379–83. Bisgaard H, Hermansen M, Vrang C, Andersen E, Dybmose G, Braendholt V, et al. Montelukast prevent post-RSVbronchiolitis wheeze. European Respiratory Journal 2002;20: 17. Bisgaard H, Hermansen M, Vrang C, Andersen EA, Dybmose G, Braendholt V, et al. Leukotriene receptor antagonist reduces lung symptoms following respiratory syncytial virus bronchiolitis in infants. American Journal of Respiratory and Critical Care Medicine 2002;165:B38. ∗ Bisgaard H, Study Group on Montelukast, Respiratory Syncytial Virus. A randomized trial of montelukast in

respiratory syncytial virus post bronchiolitis. American Journal of Respiratory and Critical Care Medicine 2003;167: 379–83. Bouzaher 2013 {published data only} Bouzaher A, Phipatanakul W. The effect of montelukast on respiratory symptoms and lung function in wheezy infants. Pediatrics 2013;132(Suppl):47–8. Bush 2009 {published data only} Bush A. Practice imperfect - treatment for wheezing in preschoolers. New England Journal of Medicine 2009;360: 409–10. Bush 2010 {published data only} Bush A. Pre-school wheezers: not small asthmatic children. Hong Kong Journal of Paediatrics 2010;15:24–34. Cook 1992 {published data only} Cook AJ, Sampson AP, Green CP, Spencer DA, Piper PJ, Price JF. Leukotrienes in infants with acute viral bronchiolitis [abstract]. British Journal of Clinical Pharmacology 1992;34: 155. Cowan 2010 {published data only} Cowan DC, Hewitt RS, Cowan JO, Palmay R, Williamson A, Lucas SJE, et al. Exercise-induced wheeze: fraction of exhaled nitric oxide-directed management. Respirology 2010;15:683–90. Goswami 2009 {published data only} Goswami P, Jones SM. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. Pediatrics 2009;124(Suppl):147–8. Helenius 2004 {published data only} Helenius I, Lumme A, Ounap J, Obase Y, Rytila P, Sarna S, et al. No effect of montelukast on asthma-like symptoms in elite ice hockey players. Allergy 2004;59:39–44. Ji 2007 {published data only} Ji JZ, Chen ZG, Chen YF, Chen FH, Chen H, Deng L. Effect of leukotriene receptor antagonist on the levels of Th1 and Th2 cytokines in sera of infants with respiratory syncytial virus pneumonia. Chinese Journal of Experimental & Clinical Virology 2007;21:132–4. Kearns 2008 {published data only} Kearns GL, Lu S, Maganti L, Li XS, Migoya E, Ahmed T, et al. Pharmacokinetics and safety of montelukast oral granules in children 1 to 3 months of age with bronchiolitis. Journal of Clinical Pharmacology 2008;48:502–11. Knorr 2006 {published data only} Knorr B, Maganti L, Ramakrishnan R, Tozzi CA, Migoya E, Kearns G. Pharmacokinetics and safety of montelukast in children aged 3 to 6 months. Journal of Clinical Pharmacology 2006;46:620–7. Kooi 2008 {published data only} Kooi EMW, Schokker S, Marike BH, de Vries TW, VaessenVerberne AAPH, van der Molen Thys, et al. Fluticasone or montelukast for preschool children with asthma-like symptoms: randomized controlled trial. Pulmonary Pharmacology & Therapeutics 2008;21:798–804.


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Kozer 2012 {published data only} Kozer E, Lotem Z, Elgarushe M, Torgovicky R, Cohen R, Cohen HA, et al. RCT of montelukast as prophylaxis for upper respiratory tract infections in children. Pediatrics 2012;129:E285–90. Nagao 2012 {published data only} Nagao M, Hiraguchi Y, Hosoki K, Tokuda R, Fujisawa T. Early intervention with pranlukast for infants with recurrent wheeze [Abstract]. American Journal of Respiratory and Critical Care Medicine 2012;185:A3349. Nanulescue 2004 {published data only} Nanulescue MV, Farcau M, Popescu L, Muresan M, Ichim GE. Efficacy of montelukast in recurrent wheezing infants and small children [abstract]. Journal of Allergy and Clinical Immunology 2004;113(Suppl):161. Neto 2009 {published data only} Neto HJC, Rosario NA. Recurrent wheezing treatment in infancy: are we treating asthma?. Journal of Allergy and Clinical Immunology 2009;123(Suppl):85. Ngamphaiboon 2005 {published data only} Ngamphaiboon J. Montelukast in general pediatric practices. Journal of the Medical Association of Thailand 2005;88(Suppl 4):348–51. Pelkonen 2013 {published data only} Pelkonen AS, Malmstrom K, Sarna S, Kajosaari M, Klemola T, Malmberg LP, et al. The effect of montelukast on respiratory symptoms and lung function in wheezy infants. European Respiratory Journal 2013;41:664–70. Peng 2014 {published data only} Peng WS, Chen X, Yang XY, Liu EM. Systematic review of montelukast’s efficacy for preventing post-bronchiolitis wheezing. Pediatric Allergy and Immunology 2014;25(2): 143–50. Piedimonte 2005 {published data only} Piedimonte G, Renzetti G, Auais A, Di Marco A, Tripodi S, Colistro F, et al. Leukotriene synthesis during respiratory syncytial virus bronchiolitis: influence of age and atopy. Pediatric Pulmonology 2005;40:285–91. Prapronik 2005 {published data only} ∗ Prapronik M, Bornic Beden A, Cerneic M, Macek V. Leukotriene receptor antagonist (LTRA) montelukast for the treatment of acute bronchiolitis in children under two years of age [abstract]. American Thoracic Society 2005 International Conference; 2005 May 20-25; San Diego, CA. 2005:C47 Poster A2. Praprotnik M, Macek V. Leukotriene receptor antagonist (LTRA) montelukast for the treatment of acute bronchiolitis in infants [abstract]. European Respiratory Journal 2004;24 (Suppl 48):504s. Rivera-Spoljaric 2009 {published data only} Rivera-Spoljaric K, Chinchilli VM, Camera LJ, Zeiger RS, Paul IM, Phillips BR, et al. Signs and symptoms that precede wheezing in children with a pattern of moderateto-severe intermittent wheezing. Journal of Pediatrics 2009; 154(6):877–81.e4.

Santanello 2005 {published data only} Santanello NC, Norquist JM, Nelsen LM, Williams VSL, Hill CD, Bisgaard H. Validation of a pediatric caregiver diary to measure symptoms of postacute respiratory syncytial virus bronchiolitis. Pediatric Pulmonology 2005; 40:31–8. Straub 2003 {published data only} Straub DA, Minocchieri S, Moeller A, Hamacher J, Sennhauser FH, Wildhaber JH. Nitric oxide and lung function measurement in wheezy infants following antiinflammatory treatment with montelukast [abstract]. American Thoracic Society 99th International Conference. 2003:A117. Straub 2005 {published data only} Straub DA, Moeller A, Minocchieri S, Hamacher J, Sennhauser FH, Hall GL, et al. The effect of montelukast on lung function and exhaled nitric oxide in infants with early childhood asthma. European Respiratory Journal 2005; 25:289–94. Valovirta 2010 {published data only} Valovirta E, Boza M, Robertson C, Verbruggen N, Smugar S, Knorr B, et al. Intermittent and daily montelukast versus placebo for treating episodic asthma in children 6 months to 5 years of age. Allergy: European Journal of Allergy and Clinical Immunology 2010;65:141. Wang 2011 {published data only} Wang YF, An SY, Zhang JL. Efficacy of montelukast in children with bronchiolitis. Chinese Journal of New Drugs 2011;20:1439–41. Widegren 2011 {published data only} Widegren H, Andersson M, Borgeat P, Flamand L, Johnston S, Greiff L. LTB4 increases nasal neutrophil activity and conditions neutrophils to exert antiviral effects. Respiratory Medicine 2011;105:997–1006. Zentz 2011 {published data only} Zentz SE. Care of infants and children with bronchiolitis: a systematic review. Journal of Pediatric Nursing 2011;26: 519–29.

References to ongoing studies Wang 2013 {unpublished data only} Add-on therapy with montelukast in treatment of bronchiolitis conducted in the First Affiliated Hospital with Nanjing Medical University. Ongoing study October 2013.

Additional references CDC 2003 Centers for Disease Control and Prevention. Bronchiolitisassociated outpatient visits and hospitalizations among American Indian and Alaska Native children - United States, 1990-2000. MMWR. Morbidity and Mortality Weekly Report 2003;52:707–10. Denny 1977 Denny FW, Collier AM, Henderson FW, Clyde WJ Jr. The epidemiology of bronchiolitis. Pediatric Research 1977;11: 234–6.


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Farley 2014 Farley R, Spurling GKP, Eriksson L, Del Mar CB. Antibiotics for bronchiolitis in children under two years of age. Cochrane Database of Systematic Reviews 2014, Issue 10. [DOI: 10.1002/14651858.CD005189.pub4] Fernandes 2013 Fernandes RM, Bialy LM, Vandermeer B, Tjosvold L, Plint AC, Patel H, et al. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD004878.pub4] Gadomski 2014 Gadomski AM, Brower M. Bronchodilators for bronchiolitis. Cochrane Database of Systematic Reviews 2014, Issue 6. [DOI: 10.1002/14651858.CD001266.pub4] GRADE 2009 GRADE. The GRADE Working Group, GRADE handbook for grading quality of evidence and strength of recommendation version 3.2. Available from http:// www.gradeworkinggroup.org 2009. Halfhide 2008 Halfhide C, Smyth RL. Innate immune response and bronchiolitis and preschool recurrent wheeze. Paediatric Respiratory Reviews 2008;9(4):251–62. Hartling 2011 Hartling L, Bialy LM, Vandermeer B, Tjosvold L, Johnson DW, Plint AC, et al. Epinephrine for bronchiolitis. Cochrane Database of Systematic Reviews 2011, Issue 6. [DOI: 10.1002/14651858.CD003123.pub3] Hervas 2012 Hervas D, Reina J, Yanez A, del Valle JM, Figuerola J, Hervas JA. Epidemiology of hospitalization for acute bronchiolitis in children: differences between RSV and non-RSV bronchiolitis. European Journal of Clinical Microbiology and Infectious Diseases 2012;31:1975–81.

Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Mansbach 2005 Mansbach JM, Emond JA, Camargo CA Jr. Bronchiolitis in US emergency departments 1992 to 2000: epidemiology and practice variation. Pediatric Emergency Care 2005;21: 242–7. Mohapatra 2008 Mohapatra SS, Boyapalle S. Epidemiologic, experimental, and clinical links between respiratory syncytial virus infection and asthma. Clinical Microbiology Reviews 2008; 21:495–504. Quintero 2007 Quintero DR, Gershan WM. Diagnosis and treatment of infants with bronchiolitis. Journal of Clinical Outcomes Management 2007;14:205–10. RevMan 2014 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. Scow 2007 Scow DT, Luttermoser GK, Dickerson KS. Leukotriene inhibitors in the treatment of allergy and asthma. American Family Physician 2007;75:65–70. Shay 1999 Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA 1999;282:1440–6. Tania 2006 Tania B, Huedo M, Julio SM, Fulgencio MM, Juan B. Assessing heterogeneity in meta-analysis: Q statistic or I squared index?. CHIP Documents 2006:paper 19. Wang 1992 Wang EE, Milner RA, Navas L, Maj H. Observer agreement for respiratory signs and oximetry in infants hospitalized with lower respiratory infections. American Review of Respiratory Disease 1992;145:106–9.

Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Chichester: Wiley–Blackwell.

Worrall 2008 Worrall G. Bronchiolitis. Canadian Family Physician 2008; 54(5):742–3.

Koehoorn 2008 Koehoorn M, Karr CJ, Demers PA, Lencar C, Tamburic L, Brauer M. Descriptive epidemiological features of bronchiolitis in a population-based cohort. Pediatrics 2008; 122:1196–203.

Zhang 2013 Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD006458.pub3]

Langley 2003 Langley JM, LeBlanc JC, Smith B, Wang EE. Increasing incidence of hospitalization for bronchiolitis among Canadian children, 1980-2000. Journal of Infectious Diseases 2003;188:1764–7.

References to other published versions of this review

Lefebvre 2011 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane

Liu 2013 Liu F, Ouyang J, Sharma AN, Liu S, Yang B, Xiong W, et al. Leukotriene inhibitors for bronchiolitis in infants and young children. Cochrane Database of Systematic Reviews 2013, Issue 7. [DOI: 10.1002/14651858.CD010636] ∗ Indicates the major publication for the study


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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Amirav 2008 Methods

Prospective, randomised, placebo-controlled, double-blind, parallel-group study

Participants

Setting: 2 medical centres in Israel Inclusion criteria: Participants age > 4 weeks and < 2 years (mean age 3.8 ± 3.5 months) with a respiratory symptom duration of < 4 days were included. Symptoms of bronchiolitis include prodromal rhinorrhoea and cough, followed by at least 2 of the following signs: chest retractions, tachypnoea, wheezing or rales. Additional inclusion criteria included first episode of wheezing or shortness of breath, randomisation within 12 hours of admission and informed consent Excluded criteria: Any previous hospital admissions with respiratory illnesses, had ever been treated with anti-asthma medications before the current illness, corticosteroid treatment in any form during current illness and underlying cardiopulmonary disease Randomly assigned: Group 1 (montelukast 4 mg): N = 24 Group 2 (placebo): N = 31 Completed: Group 1: N = 23, 1 patient withdrew consent Group 2: N = 30, 1 patient withdrew consent A nalysed: Group 1: N = 23 Group 2: N = 30 Age (months): Group 1: 3.2 ± 2.8 Group 2: 4.5 ± 4.2 Gender (male/female): Group 1: 15:8 Group 2: 14:16 Positive for RSV (%): Group 1: 74 Group 2: 80 Asthma in family (%): Group 1: 13.0 Group 2: 10.0 Bronchodilator therapy before (%): Group 1: 13.0 Group 2: 3.3 Antibiotics before admission (%): Group 1: 4.3 Group 2: 0.0


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Amirav 2008

(Continued)

Interventions

Group 1: montelukast group, 4 mg/day Group 2: matching placebo Starting in the evening of the admission day and continuing each evening until discharge. Patients were observed for 30 minutes after ingestion of granules. If vomiting occurred, 1 additional dose was given

Outcomes

Primary outcomes: Length of stay from admission to discharge Secondary outcomes: Clinical score (described by Wang 1992); change in cytokine levels in nasal lavage between admission and discharge days; the time until child was “medically fit for discharge”

Notes

Registered in Clinicaltrials.gov NCT00524693 2 medical centres: Ziv Hospital and Wolfson Medical Centre in Israel

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Assignment was conducted by using an online randomiser

Allocation concealment (selection bias)

Low risk

Allocation status was concealed in sealed envelopes

Blinding of participants and personnel Low risk (performance bias) All outcomes

Throughout the study, the investigators, nursing and medical staff, and parents were unaware of which treatment group infants were assigned. The difference between montelukast and placebo was undetectable by sight or smell

Blinding of outcome assessment (detection Low risk bias) All outcomes

Throughout the study, the investigators, nursing and medical staff and parents were unaware of which treatment group infants were assigned

Incomplete outcome data (attrition bias) All outcomes

Low risk

2 families withdrew their consent, 1 in the montelukast group and 1 in the placebo group

Selective reporting (reporting bias)

Low risk

The study protocol is available and all of the study’s outcomes have been reported

Other bias

Unclear risk

No information provided


21

Bisgaard 2008 Methods

Multi-centre, randomised, double-blind, placebo-controlled trial

Participants

Setting: 116 centres across 6 continents Inclusion criteria: RSV-positive participants were 3 to 24 months old and had been hospitalised for at least 24 hours for a first or second episode of physician diagnosed bronchiolitis. At least 2 of the following symptoms of bronchiolitis were required: respiratory rate greater than 40 breaths/minute; cough; wheezing; audible rales, crackles and/or rhonchi and paradoxical chest movements (retractions) Exclusion criteria: Patients whose bronchiolitic symptoms exceeded 8 days from onset and those who had experienced more than 1 episode of bronchiolitis before hospitalisation were not eligible Randomly assigned (N = 979) Group 1 (placebo group): N = 328 Group 2 (low-dosage montelukast, 4 mg): N = 327 Group 3 (high-dosage montelukast, 8 mg): N = 324 Treated (N = 952): Group 1: N = 318 Group 2: N = 315 Group 3: N = 319 Patients who did note receive any dose of study drug were excluded Completed (N = 745): Group 1: N = 261, 57 participants discontinued Group 2: N = 248, 67 participants discontinued Group 3: N = 236, 83 participants discontinued Analysed (N = 952): Group 1: N = 318 Group 2: N = 315 Group 3: N = 319 Age (months): Group 1: 7.4 ± 4.6 (2 to 23) Group 2: 7.8 ± 4.4 (2 to 23) Group 3: 8.1 ± 4.7 (2 to 23) Gender (male/female): Group 1: 189/129 Group 2: 185/130 Group 3: 184/135 First episode of bronchiolitis: Group 1: N = 274 (86.2%) Group 2: N = 264 (83.8%) Group 3: N = 262 (82.1%) Patients needing oxygen during hospitalisation: Group 1: N = 84 (26.5%) Group 2: N = 105 (33.4%) Group 3: N = 105 (33.0%) Patients receiving corticosteroids during hospitalisation: Group 1: N = 76 (23.9%) Group 2: N = 74 (23.5%) Group 3: N = 72 (22.6%)


22

Bisgaard 2008

(Continued)

Interventions

Group 1: placebo group Group 2: low-dosage montelukast, 4 mg/day Group 3: high-dosage montelukast, 8 mg/day A 4-week period I and a 20-week period II of extended treatment. About half the randomised participants were allowed treatment of bronchiolitis with corticosteroids during hospitalisation. 1 oral corticosteroid rescue per month was allowed in both treatment periods. Throughout the study, participants were permitted as needed short-acting βagonist therapy for treatment of respiratory symptoms and the use of oxygen, nutrition and intravenous fluids according to the investigator’s usual clinical practice

Outcomes

Primary outcome: Percentage of symptom-free days during period I Secondary outcomes: Percentage of bronchiolitis-free days during period I Percentage of participants with exacerbations during period I + II Average of individual daily symptom scores during period I + II Patients with exacerbations during period I + II Patients with systemic corticosteroid use during period I + II Patients with healthcare resource use during period I + II

Notes

ClinicalTrials.gov Identifier: NCT00076973 2 participants died, but none of them died because of the drug use. 1 (4 mg montelukast group) died of acute respiratory distress syndrome and sepsis while hospitalised for RSVinduced bronchiolitis. The other 1 (8 mg of montelukast) died of thermal burns in a house fire

Risk of bias Bias




Assignment was conducted according to a computer-generated randomised allocation schedule


Low risk

Allocation numbers were centrally assigned in sequential order via an interactive voice response system


All study personnel and participants remained blinded to treatment allocation throughout the study


The code was revealed to the researchers once recruitment, data collection and laboratory analyses were completed


They used ITT analysis

Low risk


23

Bisgaard 2008

(Continued)


Low risk

They evaluated the efficacy and safety of all participants that randomised to the 3 groups

Other bias

Unclear risk


Kim 2010 Methods

Randomised, double-blind, placebo-controlled, parallel group

Participants

Setting: multiple centres in Korea and Japan Inclusion criteria: Infants aged 6 to 24 months who were hospitalised with their first episode of RSV bronchiolitis were recruited Exclusion criteria: Patients who had a history of asthma symptoms or had ever used anti-asthma medications, including the occasional use of beta-agonists were excluded. Infants born before 36 weeks gestation or with known chronic diseases were also excluded Randomly assigned: Group 1 (montelukast 4 mg): N = 100 Group 2 (placebo): N = 100 Completed: Group 1: N = 79, 21 participants discontinued Group 2: N = 71, 29 participants discontinued Analysed: Group 1: N = 79 Group 2: N = 71 Age (months): Group 1: 13.2 (6 to 23) Group 2: 15.1 (7 to 24) Gender (male/female): Group 1: 54:25 Group 2: 46:25 Patients needing oxygen therapy: Group 1: 25% Group 2: 28% Patients receiving β-agonist therapy: Group 1: 71% Group 2: 67%

Interventions

Group 1: montelukast 4 mg/day Group 2: matching placebo Administered once daily in the evening for 12 weeks as the study treatment Follow-up data were collected for a total of 12 months

Outcomes

Primary outcome: Serum eosinophil-derived neurotoxin (EDN) levels Secondary outcome:


24

Kim 2010

(Continued)

Recurrent wheezing for 12 months Notes

-

Risk of bias Bias




Assessment was according to a computergenerated randomised allocation schedule


Low risk

Blinding of active and placebo granules was provided by the Inje University Sanggye Paik Hospital pharmacy according to a computer-generated randomised allocation schedule


All study investigators and participants remained blinded to group assignment for the entire study period


All study investigators and participants remained blinded to group assignment for the entire study period


High risk

“19 infants in the RSV-MONT group and 25 in the RSV-PLC group were lost to follow-up”. The percentage of participants who were lost to follow-up was beyond 15%, which might induce attrition bias


Unclear risk


Other bias

Unclear risk


Proesmans 2009 Methods

Randomised, double-blind, placebo-controlled trial

Participants

Setting: multiple centres in Belgium Inclusion criteria: Patients aged ≤ 24 months (range from 1 month to 8 months) hospitalised during at least 24 h with a first episode of RSV proven bronchiolitis were enrolled. Bronchiolitis was defined as a clinical syndrome of upper airway infection followed by signs of respiratory distress, cough, crepitations and/or wheeze in an infant with no previous history of wheeze. RSV detection was performed with the BinaxNOW RSV test. During their hospital stay participants were treated symptomatically according to the judgement of the treating physician (oxygen, nebulised bronchodilators or nebulised epinephrine, nu-


25

Proesmans 2009

(Continued)

trition, IV fluids). Inhaled steroids and systemic steroids were not prescribed as inpatient treatment Exclusion criteria: Children with a history of previous wheezing episodes were excluded as well as children with significant concomitant disease (neurological impairment, cyanogenic cardiopathy, immunological deficit). Prematurity and BPD were not exclusion criteria Randomly assigned (N = 83): Group 1: montelukast 4 mg Group 2: matching placebo Completed: Group 1: N = 31 Group 2: N = 27 25 participants dropped out Analysed: Group 1: N = 31 Group 2: N = 27 Age (months): Group 1: 3.5 (1.0 to 7.0) Group 2: 3.3 (1.0 to 8.0) Gender (male/female): No relevant reports Interventions

Group 1: montelukast 4 mg Group 2: matching placebo Administered during a period of 3 months Follow-up was planned after 2, 6 and 12 weeks during the 3-month treatment period and then after 6, 9 and 12 months during the follow-up

Outcomes

Primary outcome: Number of symptom-free days and disease-free days Secondary outcomes: Need for additional treatment after hospital discharge: use of bronchodilators and maintenance inhaled steroids as well as the time to start inhaled steroids Number of unscheduled doctor visits; the number of respiratory exacerbations; the time to first exacerbation

Notes

-

Risk of bias Bias




Participants were randomised by using a computer model


Canisters were randomised using a computer model and allocated to the patient sequentially

Low risk


26

Proesmans 2009

(Continued)


The blinding code was broken only after all included participants had finished the trial follow-up

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

They did not mention whether the outcome assessment was blinded or not


High risk

“Eighty three patients were randomised. Twenty five participants dropped out; nineteen because the diary card was not filled out”. The percentage of participants who dropped out was above 20% and the reason for missing outcome data is likely to be related to true outcome. It seems that they just reported those who completed the trials; data from those who dropped out were not collected


Unclear risk


Other bias

Unclear risk


Zedan 2010 Methods


Participants

Setting: multiple centres in Egypt Inclusion criteria: Infants aged 1 to 24 months of age, clinically diagnosed with first-episode viral bronchiolitis Exclusion criteria: Infants with a history of prematurity, previous hospital admissions due to respiratory illnesses, history of previous bronchodilator use before this illness and treatment with corticosteroids before the current illness, in addition to cases with probable immunodeficiency or underlying cardiopulmonary disease Randomly assigned: Group 1 (montelukast, 4 mg): N = 47 Group 2 (placebo): N = 38 Completed: Group 1: N = 46, 1 patient discontinued Group 2: N = 37, 1 patient discontinued Analysed: Group 1: N = 46 Group 2: N = 37 Age (months): Group 1: 3.5 ± 2.37 Group 2: 3.3 ± 2.36


27

Zedan 2010

(Continued)

Gender (male/female): Group 1: 30:16 Group 2: 22:15 Asthma in family: Group 1: N = 18 (39.1%) Group 2: N = 12 (32.4%) Breast-feeding: Group 1: N = 28 (60.9%) Group 2: N = 24 (64.9%) Interventions

Group 1: montelukast 4 mg Group 2: placebo Administered daily from the time of admission until discharge

Outcomes

Primary outcome: Length of hospital stay Secondary outcomes: Clinical severity scores; changes in plasma levels of interferon gamma and interleukin-4

Notes

-

Risk of bias Bias




Assignment was conducted by randomly permuted blocks using an online randomiser


Low risk

Allocation status was concealed in sealed envelopes in the pharmacy


Through the study, the investigators, nursing and medical staff and parents were unaware of which treatment group infants were assigned to. The physical difference between granules of montelukast and placebo was undetectable by sight or smell


Through the study, the investigators, nursing and medical staff, and parents were unaware of which treatment group infants were assigned to


Low risk

1 participant discontinued in each group


Low risk


28

Zedan 2010

(Continued)

Other bias

Unclear risk


BPD: bronchopulmonary dysphasia h: hour ITT: intention-to-treat IV: intravenous LOS: length of hospital stay N: number RSV: respiratory syncytial virus

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Al-Hamdani 2010

Population: clinical definition was not certain and recurrent wheezing

Anonymous 2007

Publication type: review

Bacharier 2008

Population: clinical definition was not certain and recurrent wheezing

Bai 2010

The published version of this study only showed the statistical results. We contacted the investigators for raw data, but unfortunately these data could not be provided. After negotiating with the editors, we decided to excluded this study

Belcaro 2011

Population: asthma patients

Bisgaard 2003

Population: this study included some children older than two years of age

Bouzaher 2013

Population: clinical definition of bronchiolitis was not certain and recurrent wheezing

Bush 2009


Bush 2010

Population: children with preschool wheezing

Cook 1992

Intervention: received either aerosolised ribavirin or placebo control

Cowan 2010


Goswami 2009

Population: 12 to 59 months of age with 2 episodes of wheezing

Helenius 2004

Population: adults

Ji 2007

Population: infants and young children with respiratory syncytial virus (RSV) pneumonia


29

(Continued)

Kearns 2008

Study design: not randomised

Knorr 2006


Kooi 2008

Population: children aged 2 to 6 years with asthma-like symptoms

Kozer 2012

Population: children aged 1 to 5 years with viruses causing upper respiratory tract infection

Nagao 2012

Publication type: abstract

Nanulescue 2004

Population and publication type: children with recurrent wheezing and only an abstract has been published

Neto 2009


Ngamphaiboon 2005


Pelkonen 2013

Population: clinical definition of bronchiolitis was not certain and recurrent wheezing

Peng 2014

Publication type: systematic review

Piedimonte 2005


Prapronik 2005

Unobtainable: meeting abstract without full text

Rivera-Spoljaric 2009

Population: parents of children age 12 to 59 months with moderate-to-severe intermittent wheezing

Santanello 2005


Straub 2003

Publication type: meeting abstract; population: wheezy infants without certain definition of bronchiolitis

Straub 2005


Valovirta 2010

Population: children aged 5 months to 6 years

Wang 2011

Other: we excluded this study because it did not report clinical outcomes

Widegren 2011


Zentz 2011


RCT: randomised controlled trial


30

Characteristics of ongoing studies [ordered by study ID] Wang 2013 Trial name or title

Add-on therapy with montelukast in treatment of bronchiolitis conducted in the First Affiliated Hospital with Nanjing Medical University

Methods


Participants

Male or female infants aged 2 months to 2 years and diagnosed with bronchiolitis

Interventions

Montelukast versus placebo

Outcomes

1. Clinical score 2. Adverse effects

Starting date

October 2013

Contact information

[email protected]

Notes

ChiCTR-TRC-13003735


31

DATA AND ANALYSES

Comparison 1. Montelukast versus placebo

Outcome or subgroup title

No. of studies

No. of participants

2 1 2 2 2

136 952 136 136 132

1 Length of hospital stay 2 All-cause mortality 3 Clinical severity score (baseline) 4 Clinical severity score (day 2) 5 Clinical severity score (day 3)

Statistical method

Effect size

Mean Difference (IV, Random, 95% CI) Risk Ratio (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

-0.95 [-3.08, 1.19] 2.51 [0.12, 52.16] 0.11 [-0.51, 0.74] -0.57 [-2.37, 1.23] 0.17 [-1.93, 2.28]

Analysis 1.1. Comparison 1 Montelukast versus placebo, Outcome 1 Length of hospital stay. Review:

Leukotriene inhibitors for bronchiolitis in infants and young children

Comparison: 1 Montelukast versus placebo Outcome: 1 Length of hospital stay

Study or subgroup

Leukotriene inhibitors

Mean Difference

Placebo

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

Amirav 2008

23

3.52 (1.77)

30

3.42 (1.22)

51.9 %

0.10 [ -0.74, 0.94 ]

Zedan 2010

46

3.34 (1.38)

37

5.42 (3.47)

48.1 %

-2.08 [ -3.27, -0.89 ]

100.0 %

-0.95 [ -3.08, 1.19 ]

Total (95% CI)

69

IV,Random,95% CI

IV,Random,95% CI

67

Heterogeneity: Tau2 = 2.10; Chi2 = 8.60, df = 1 (P = 0.003); I2 =88% Test for overall effect: Z = 0.87 (P = 0.38) Test for subgroup differences: Not applicable

-10

-5

Favours montelukast


0

5

10

Favours placebo

32

Analysis 1.2. Comparison 1 Montelukast versus placebo, Outcome 2 All-cause mortality. Review:


Comparison: 1 Montelukast versus placebo Outcome: 2 All-cause mortality


Study or subgroup

Placebo

Risk Ratio

Weight

Risk Ratio

n/N

n/N

IV,Random,95% CI

IV,Random,95% CI

Bisgaard 2008

2/634

0/318

100.0 %

2.51 [ 0.12, 52.16 ]

Total (95% CI)

634

318

100.0 %

2.51 [ 0.12, 52.16 ]

Total events: 2 (Leukotriene inhibitors), 0 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.60 (P = 0.55) Test for subgroup differences: Not applicable

0.001 0.01 0.1

1

Favours montelukast

10 100 1000 Favours placebo

Analysis 1.3. Comparison 1 Montelukast versus placebo, Outcome 3 Clinical severity score (baseline). Review:


Comparison: 1 Montelukast versus placebo Outcome: 3 Clinical severity score (baseline)

Study or subgroup


Mean Difference

Placebo

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

Amirav 2008

23

7.71 (2.22)

30

7.17 (2.36)

25.2 %

0.54 [ -0.70, 1.78 ]

Zedan 2010

46

8.65 (1.79)

37

8.68 (1.55)

74.8 %

-0.03 [ -0.75, 0.69 ]

100.0 %

0.11 [ -0.51, 0.74 ]

Total (95% CI)

69

IV,Random,95% CI

IV,Random,95% CI

67

Heterogeneity: Tau2 = 0.0; Chi2 = 0.61, df = 1 (P = 0.44); I2 =0.0% Test for overall effect: Z = 0.36 (P = 0.72) Test for subgroup differences: Not applicable

-10

-5

Favours montelukast


0

5

10

Favours placebo

33

Analysis 1.4. Comparison 1 Montelukast versus placebo, Outcome 4 Clinical severity score (day 2). Review:


Comparison: 1 Montelukast versus placebo Outcome: 4 Clinical severity score (day 2)

Study or subgroup


Mean Difference

Placebo

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

Amirav 2008

23

6.75 (2.59)

30

6.33 (2.14)

46.2 %

0.42 [ -0.89, 1.73 ]

Zedan 2010

46

4.66 (2.29)

37

6.08 (1.67)

53.8 %

-1.42 [ -2.27, -0.57 ]

100.0 %

-0.57 [ -2.37, 1.23 ]

Total (95% CI)

69

IV,Random,95% CI

IV,Random,95% CI

67


-10

-5

0

Favours montelukast

5

10

Favours placebo

Analysis 1.5. Comparison 1 Montelukast versus placebo, Outcome 5 Clinical severity score (day 3). Review:


Comparison: 1 Montelukast versus placebo Outcome: 5 Clinical severity score (day 3)

Study or subgroup


Mean Difference

Placebo

Weight

N

Mean(SD)

N

Mean(SD)

Amirav 2008

20

6.15 (2.43)

29

4.86 (2.23)

47.9 %

1.29 [ -0.05, 2.63 ]

Zedan 2010

46

3.64 (2.58)

37

4.5 (2.19)

52.1 %

-0.86 [ -1.89, 0.17 ]

100.0 %

0.17 [ -1.93, 2.28 ]

Total (95% CI)

66

IV,Random,95% CI

Mean Difference IV,Random,95% CI

66


-10

-5

Favours montelukast


0

5

10

Favours placebo

34

APPENDICES Appendix 1. MEDLINE (Ovid) search strategy MEDLINE (Ovid) 1 exp Bronchiolitis/ 2 bronchiolit*.tw. 3 wheez*.tw. 4 respiratory syncytial viruses/ or respiratory syncytial virus, human/ 5 Respiratory Syncytial Virus Infections/ 6 (respiratory syncytial virus* or rsv).tw. 7 or/1-6 8 Leukotriene Antagonists/ 9 exp Leukotrienes/ 10 (leukotrien* or leucotrien* or anti-leukotrien*).tw,nm 11 montelukast*.tw,nm. 12 zafirlukast*.tw,nm. 13 pranlukast*.tw,nm. 14 zileuton*.tw,nm. 15 (singulair or accolate or zyflo).tw,nm. 16 or/8-15 17 7 and 16

Appendix 2. EMBASE (Elsevier) search strategy #17 #6 AND #16 #16 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 #15 singulair:ab,ti OR accolate:ab,ti OR zyflo:ab,ti #14 montelukast*:ab,ti OR pranlukast*:ab,ti AND zafirlukast*:ab,ti OR zileuton*:ab,ti #13 ’zileuton’/de #12 ’pranlukast’/de #11 ’zafirlukast’/de #10 ’montelukast’/de #9 leukotrien*:ab,ti OR leucotrien*:ab,ti OR ’anti-leukotriene’:ab,ti OR ’anti-leukotrienes’:ab,ti #8 ’leukotriene’/exp #7 ’leukotriene receptor affecting agent’/exp #6 #1 OR #2 OR #3 OR #4 OR #5 #5 ’respiratory syncytial virus’:ab,ti OR ’respiratory syncytial viruses’:ab,ti OR rsv:ab,ti #4 ’respiratory syncytial pneumovirus’/de OR ’respiratory syncytial virus infection’/de #3 wheez*:ab,ti #2 bronchiolit*:ab,ti #1 ’bronchiolitis’/exp


35

Appendix 3. CINAHL (Ebsco) search strategy S25 S14 AND S24 S24 S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 S23 (MH “Quantitative Studies”) S22 TI placebo* OR AB placebo* S21 (MH “Placebos”) S20 (MH “Random Assignment”) S19 TI random* OR AB random* S18 TI ((singl* or doubl* or trebl* or tripl*) N1 (blind* or mask*)) OR AB ((singl* or doubl* or trebl* or tripl*) N1 (blind* or mask*)) S17 TI clinic* trial* OR AB clinic* trial* S16 PT clinical trial S15 (MH “Clinical Trials+”) S14 S7 AND S13 S13 S8 OR S9 OR S10 OR S11 OR S12 S12 TI (singulair or accolate or zyflo) OR AB (singulair or accolate or zyflo) S11 TI (montelukast* or zafirlukast* or pranlukast* or zileuton*) OR AB (montelukast* or zafirlukast* or pranlukast* or zileuton*) S10 TI (leukotrien* or leucotrien* or anti-leukotrien*) OR AB (leukotrien* or leucotrien* or anti-leukotrien*) S9 (MH “Leukotrienes”) S8 (MH “Leukotriene Antagonists+”) S7 S1 OR S2 OR S3 OR S4 OR S5 OR S6 3, S6 TI (respiratory syncytial virus* or rsv) OR AB (respiratory syncytial virus* or rsv) S5 (MH “Respiratory Syncytial Virus Infections”) S4 (MH “Respiratory Syncytial Viruses”) S3 TI wheez* OR AB wheez* S2 TI bronchiolit* OR AB bronchiolit* S1 (MH “Bronchiolitis+”)

Appendix 4. LILACS (BIREME) search strategy mh:“Leukotriene Antagonists” OR mh:leukotrienes OR mh:d10.251.355.255.100.450* OR mh:d23.469.050.175.450* OR leukotrien* OR leucotrien* OR “anti-leukotriene” OR “anti-leukotrienes” OR montelukast* OR zafirlukast* OR pranlukast* OR zileuton* OR singulair OR accolate OR zyflo AND db:(“LILACS”) AND type˙of˙study:(“clinical˙trials”)

Appendix 5. Web of Science (Thomson Reuters) search strategy

#5

99

#4 AND #3 Databases=SCI-EXPANDED, CPCI-S Timespan=All years

#4

1,383,818

Topic=(random* or placebo* or crossover* or “cross over” or allocat* or ((singl* or doubl*) NEAR/1 blind*)) OR Title=(trial) Databases=SCI-EXPANDED, CPCI-S Timespan=All years

#3

291

#2 AND #1 Databases=SCI-EXPANDED, CPCI-S Timespan=All years


36

(Continued)

#2

21,534

Topic=(leukotrien* or leucotrien* or anti-leukotrien* or montelukast* or zafirlukast* or pranlukast* or zileuton* or singulair or accolate or zyflo) Databases=SCI-EXPANDED, CPCI-S Timespan=All years

#1

28,027

Topic=(bronchiolit* or wheez* or “respiratory syncytial virus*” or rsv) Databases=SCI-EXPANDED, CPCI-S Timespan=All years

CONTRIBUTIONS OF AUTHORS Liu Songqing developed and co-ordinated the protocol, edited the subsequent draft review and participated in assessing risk of bias. Liu Fang participated in writing and editing the protocol, wrote the subsequent draft review and participated in data extraction and grading the body of evidence. Ouyang Jing participated in writing and editing the protocol, advised on the subsequent draft review, and participated in selection of studies and data extraction. Atul N Sharma edited the protocol and subsequent draft review, and participated in resolving disagreement between JO and WX. Yang Bo edited and advised on parts of the protocol and draft review, and participated in assessing risk of bias. Xiong Wei edited and advised on parts of the protocol and draft review, and participated in selection of studies. Xu Rufu edited and advised on parts of the protocol and draft review, and participated in assessing risk of bias and grading the body of evidence.

DECLARATIONS OF INTEREST Liu Songqing: none known. Liu Fang: none known. Ouyang Jing: none known. Atul N Sharma: none known. Yang Bo: none known. Xiong Wei: none known. Xu Rufu: none known.


37

DIFFERENCES BETWEEN PROTOCOL AND REVIEW We did not perform subgroup analyses or sensitivity analysis due to the limited number of included studies. We deleted the primary outcome (admission for outpatient studies) because no outpatients had been included. However, we will add this outcome measure if data are available in future updates of this review.

INDEX TERMS Medical Subject Headings (MeSH) Acetates [adverse effects; ∗ therapeutic use]; Bronchiolitis [∗ drug therapy]; Length of Stay; Leukotriene Antagonists [adverse effects; therapeutic use]; Quinolines [adverse effects; ∗ therapeutic use]; Randomized Controlled Trials as Topic

∗

MeSH check words Humans; Infant


38

Glucocorticoids for acute viral bronchiolitis in infants and young children.

Comparison of CPAP and HFNC in Management of Bronchiolitis in Infants and Young Children.

Effect of bronchodilators on respiratory resistance in infants and young children with bronchiolitis and wheezy bronchitis.

Hypertonic saline for bronchiolitis in infants.

Tracheostomy in infants and young children.

The electroretinogram in infants and young children.

Retropharyngeal masses in infants and young children.

Epidemic of bronchiolitis in infants.

Epidemic of bronchiolitis in infants.

Prenatal tobacco smoke exposure increases hospitalizations for bronchiolitis in infants.

Surfactant therapy for bronchiolitis in critically ill infants.

Acute bronchiolitis in infants, a review.

Latest options for treatment of bronchiolitis in infants.

Risk of urinary tract infection in infants and children with acute bronchiolitis.

Significance of intracranial bruits in neonates, infants, and young children.

Challenges in vaccination of neonates, infants and young children.

Management of severe hydroureteronephrosis in infants and young children.

Retinal Development in Infants and Young Children with Achromatopsia.

Does cesarean section pose a risk of respiratory syncytial virus bronchiolitis in infants and children?

Controversies Surrounding Clostridium difficile Infection in Infants and Young Children.

Determinants of sensitization to allergen in infants and young children.

Adenovirus type 21 bronchopneumonia in infants and young children.

Renal papillary morphology in infants and young children.

Retinal findings after head trauma in infants and young children.