Bronquiolitis

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.
www.cochranelibrary.com
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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 32
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Leukotriene inhibitors for bronchiolitis in infants and young children (Review) i

[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. songqingliu@hotmail.com.
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.
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) 1
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
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.

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 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 No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Control Montelukast versus

placebo
Length of hospital stay The mean length of hos- 136 ⊕⊕

pital stay in the interven- (2 studies) low1,2
tion groups was
0.95 lower
(3.08 lower to 1.19
higher)
All-cause mortality See comment See comment RR 2.51 952 See comment One study of 952 chil-
Deaths (0.12 to 52.16) (1 study) dren reported 2 deaths in
Follow-up: 0 to 6 months the leukotriene group: nei-
ther was determined to be
drug-related
Clinical severity score The mean clinical severity 136 ⊕⊕

(day 2) score (day 2) in the inter- (2 studies) low1,2
vention groups was
0.57 lower
(2.37 lower to 1.23
higher)
4
Leukotriene inhibitors for bronchiolitis in infants and young children (Review)
Clinical severity score The mean clinical severity 132 ⊕⊕

(day 3) score (day 3) in the inter- (2 studies) low2
vention groups was
0.17 higher
(1.93 lower to 2.28
higher)
Clinical adverse effects See comment See comment Not estimable 1063 See comment 3 studies reported ad-
(3 studies) verse events. The most
common adverse events
were wheezing shortly af-
ter administration, diar-
rhoea and rash. There
was no difference be-
tween 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 one level due to inconsistency: high level of unexplained statistical heterogeneity.
2 Downgraded one level due to imprecision: small sample size and the confidence interval does not rule out a null effect or harm.
5
BACKGROUND and coughing. They might therefore have a potential benefit in the
treatment of bronchiolitis in children who present with wheezing
(Halfhide 2008).
Description of the condition
Bronchiolitis is a common acute inflammatory illness of the bron-
chioles, the smallest air passages of the lungs. It is often seen in chil- How the intervention might work
dren under two years of age, with the majority being aged between
The pathogenesis of bronchiolitis involves the stimulation of the 5-
three and six months (Quintero 2007). The most common cause
lipoxygenase gene, a key player in the biosynthesis of leukotrienes
of bronchiolitis is the respiratory syncytial virus (RSV). However,
(LTs), which increases the concentration of cysteinyl LTs (CysLTs)
parainfluenza, influenza, adenovirus and rhinovirus have also been
in the airways. CysLTs are known to cause obstruction of the
implicated (Denny 1977; Hervas 2012). The onset and progres-
airway and the alveoli, mucosal oedema and increased bronchial
sion of bronchiolitis is similar to that of the common cold with
responsiveness. Therefore, CysLTs are a potential target in the
patients experiencing low-grade fever, rhinorrhoea (also known as
treatment of bronchiolitis (Piedimonte 2005).
’runny nose’, a condition where the nasal cavity is filled with a sig-
Leukotriene inhibitors are either leukotriene receptor antagonists
nificant amount of mucous fluid), cough, sneezing and wheezing.
or leukotriene synthesis inhibitors, which can decrease the con-
Around 10% of children in high-income countries contract bron-
centration of CysLTs by selectively blocking the binding of cys-
chiolitis in the first year of life and 2% to 3% of these will require
teinyl leukotrienes to CysLT receptors or inhibiting the synthe-
hospitalisation (Koehoorn 2008). The risk of death for a healthy
sis of 5-lipoxygenase. As a result, leukotriene inhibitors may be
infant with bronchiolitis is less than 0.5%, but the risk has been
a new treatment for bronchiolitis (Scow 2007). The leukotriene
shown to be much higher for children with congenital heart disease
inhibitors currently available are montelukast (Singulair), zafir-
(3.5%) and chronic lung disease (3.45%) (figures from Canada)
lukast (Accolate), pranlukast and zileuton (Zyflo). Montelukast,
(Worrall 2008). The rate of hospitalisation for bronchiolitis has
zafirlukast and pranlukast are leukotriene receptor antagonists that
increased steadily in North America and Europe over the past 10
prevent leukotriene from binding to cell receptors and initiating
to 20 years (CDC 2003; Langley 2003; Shay 1999). Addition-
the chain of events that leads to inflammation. Zileuton is a 5-
ally, bronchiolitis has been linked with an increased incidence of
lipooxygenase pathway inhibitor that interferes with the synthesis
asthma later in life (Mohapatra 2008). It is associated with a sig-
of LTA4, LTC4, LTD4 and LTE4. Currently, montelukast is the
nificant healthcare burden worldwide (Mansbach 2005).
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.
Description of the intervention
The management of bronchiolitis varies between clinicians, re-
flecting the absence of clear scientific evidence for a specific
Why it is important to do this review
treatment approach. Bronchodilators, antibiotics and steroids are
widely used but not routinely recommended (Fernandes 2013; Leukotriene inhibitors such as montelukast have been used in in-
Gadomski 2014; Farley 2014). A review on epinephrine for bron- fants and young children. However, the results from limited ran-
chiolitis has recently provided evidence that epinephrine is more domised controlled trials (RCTs) are controversial and necessitate
effective than placebo for bronchiolitis in outpatients but there a thorough evaluation of their efficacy for bronchiolitis in infants
is no evidence to support its use for inpatients (Hartling 2011). and young children.
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 vi-
ral bronchiolitis and improve the clinical severity score in both OBJECTIVES
outpatient and inpatient populations, compared to those treated
with nebulised 0.9% saline (Zhang 2013). However, although this To assess the efficacy and safety of leukotriene inhibitors for bron-
is an effective treatment it is not a convenient one, therefore new chiolitis in infants and young children.
treatment approaches are necessary.
Leukotriene inhibitors, such as montelukast, have been widely
used in asthma therapy. These are drugs that inhibit leukotrienes, METHODS
which are fatty compounds produced by the immune system that
cause inflammation in asthma, bronchitis and bronchiolitis, con-
stricting the airways. Leukotriene inhibitors can decrease the con- Criteria for considering studies for this review
centration of leukotrienes and reduce the symptoms of wheezing

Types of studies search strategy to search EMBASE (Appendix 2), CINAHL (Ap-
We included RCTs comparing leukotriene inhibitors with control pendix 3), LILACS (Appendix 4) and Web of Science (Appendix
(placebo or other interventions). We did not include quasi-RCTs, 5). We did not use any language or publication restrictions.
cross-over trials or cluster-RCTs.
Searching other resources
Types of participants We searched Clinicaltrials.gov and the World Health Organization
We included infants and children up to 24 months of age with (WHO) International Clinical Trials Registry Platform (ICTRP)
physician-diagnosed bronchiolitis (inclusion was not restricted (last searched 6 May 2014) to identify unpublished and ongoing
since the definition of bronchiolitis varies between countries and studies. We carefully scrutinised the reference lists of the included
some bronchiolitis trial reports may not specify the clinical find- studies and relevant review articles for additional references.
ings required for the diagnosis of the participants).
Types of interventions Data collection and analysis

We included all types of leukotriene inhibitors (such as mon-
telukast, zafirlukast and zileuton) compared with placebo or other
interventions, irrespective of dosage, duration and route of admin- Selection of studies
istration. 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
Types of outcome measures the full articles when they were classified as included or unclear.
Two review authors (JO, WX) independently assessed full articles
Primary outcomes
classified as included and unclear for inclusion using a standardised
form. We resolved any disagreements through discussion or, if
1. Length of hospital stay. required, adjudication from another review author (AS).
2. All-cause mortality.
Data extraction and management

Secondary outcomes
Two review authors (FL, JO) independently extracted data from
1. Clinical severity score.
the included studies using a standardised data extraction form. We
2. Percentage of symptom-free days.
extracted general information (study ID, date of extraction, title,
3. Percentage of children requiring ventilation.
authors and source of study if not published); study characteristics
4. Oxygen saturation.
(study design, participants and inclusion/exclusion criteria used
5. Recurrent wheezing.
in the study); intervention (type of leukotriene inhibitors, dosage,
6. Respiratory rate.
treatment duration, comparison details, duration of follow-up)
7. Clinical adverse effects.
and outcomes (primary and secondary outcomes and adverse ef-
fects).
Search methods for identification of studies

Assessment of risk of bias in included studies
We used the ’Risk of bias’ assessment tool and criteria set out in the
Electronic searches Cochrane Handbook for Systematic Reviews of Interventions to assess
We searched CENTRAL (2014, Issue 5) (accessed 6 May 2014), the risk of bias in the included studies (Higgins 2011). The assess-
which contains the Acute Respiratory Infections Group’s Spe- ment tool includes seven domains: random sequence generation
cialised Register, MEDLINE (1946 to April week 4, 2014), EM- (selection bias), allocation concealment (selection bias), blinding
BASE (1974 to May 2014), CINAHL (1981 to May 2014), of participants and personnel (performance bias), blinding of out-
LILACS (1982 to May 2014) and Web of Science (1985 to May come assessment (detection bias), incomplete outcome data (attri-
2014). tion bias), selective reporting (reporting bias) and other sources of
We used the search strategy described in Appendix 1 to search bias. Three review authors (RX, SL, BY) independently assessed
MEDLINE and CENTRAL. We combined the MEDLINE search the risk of bias of the included studies as ’low risk’, ’unclear risk’
with the Cochrane Highly Sensitive Search Strategy for identifying and ’high risk’ for each domain. We resolved any disagreement by
randomised trials in MEDLINE (Lefebvre 2011). We adapted the consensus.

Grading the body of evidence using the Chi2 test with a P value < 0.1 indicating significant het-
We used the Evidence-Based Practice Centers Grading of Recom- erogeneity. We used the I2 statistic to quantify statistical hetero-
mendations Assessment, Development and Evaluation (GRADE) geneity. The importance of heterogeneity depends on several fac-
approach, based on the standard GRADE system (GRADE 2009) tors, according to the Cochrane Handbook for Systematic Reviews of
to assess the domain-specific strength of evidence for four rele- Interventions. A rough guide to interpretation, with some modifi-
vant outcomes: length of hospital stay, all-cause mortality, clinical cation aiming to avoid overlap, is as follows: 0% to 30% might not
severity score and clinical adverse effects. be important; 31% to 50% may represent moderate heterogene-
Two review authors (FL, RX) independently graded the body of ity; 51% to 75% may represent substantial heterogeneity and 76%
evidence using adapted decision rules. We examined the following to 100% represents considerable heterogeneity (Higgins 2011).
domains: risk of bias, consistency, directness and precision based
on GRADE guidance (GRADE 2009). We graded the overall Assessment of reporting biases
strength of evidence as ’high’, ’moderate’, ’low’ or ’very low’ based
To minimise the potential for reporting biases, we did not impose
on the likelihood of further research changing our confidence in
any language restrictions on the searches. We also searched the
the estimate of effect. We resolved discrepancies by consensus be-
International Clinical Trial Registry Platform for unpublished and
tween two review authors (FL, RX).
ongoing studies. If sufficient data were available, we would have
used a funnel plot to detect publication bias. Notwithstanding,
Measures of treatment effect this was not necessary due to the small number of included studies.
We synthesised continuous data (such as length of hospital stay)
using mean difference (MD) with 95% confidence interval (CI). Data synthesis
We considered a measurement scale, i.e. clinical severity score, as We pooled quantitative results within the different comparisons
continuous data and synthesised as mentioned above. If data were when studies were consistent on clinical grounds and had available
available, we would have utilised the risk ratio (RR) with 95% CI outcome data.
for dichotomous data, i.e. all-cause mortality. We also reported We combined results using random-effects models regardless of
the type of clinical adverse effects in detail (Higgins 2011). heterogeneity, due to expected differences in interventions, out-
comes and measurement instruments. According to the Cochrane
Handbook for Systematic Reviews of Interventions Chapter 9, when
Unit of analysis issues
no heterogeneity exists both fixed-effect and random-effects mod-
We did not include quasi-RCTs, cross-over trials or cluster-RCTs as els will give identical results. When heterogeneity exists, a ran-
they were inappropriate. One study included three arms (Bisgaard dom-effects model is more suitable as it incorporates two possible
2008: montelukast 4 mg, montelukast 8 mg and placebo). The sources of heterogeneity (caused by sampling error or substantive
baseline characteristics are similar among these groups and the variability) among the studies (Higgins 2011; Tania 2006). We
comparisons are independent. However, we did not include these used inverse variance methods to conduct meta-analyses for both
data in a meta-analysis due to significant clinical heterogeneity dichotomous and continuous outcomes. Additionally, we com-
among studies. bined 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
Dealing with missing data
Manager software for data management and analysis (RevMan
We contacted three trial authors to verify key study characteristics 2014).
or obtain missing statistics (Amirav 2008; Bai 2010; Proesmans We also included a ’Summary of findings’ table using the GRADE-
2009). The author of Amirav 2008 provided us with the mean pro software, considering outcomes such as length of hospital stay,
and standard deviations of clinical severity score. Proesmans 2009 all-cause mortality, clinical severity score and clinical adverse ef-
provided us with the mean and standard deviations of numbers of fects (GRADE 2009).
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. Subgroup analysis and investigation of heterogeneity
We planned to conduct the following subgroup analyses but due
to insufficient data this was not possible.
Assessment of heterogeneity 1. Type of comparison (placebo/another active treatment).
We assessed clinical heterogeneity before pooling. We would not 2. Type of participants (outpatient/inpatient).
combine data from clinically heterogeneous trials but would de- 3. Bronchiolitis in patients with or without high risks
scribe these separately. We evaluated statistical heterogeneity by (bronchopulmonary dysplasia, congenital heart disease).

4. Type of leukotriene inhibitor. Results of the search
5. Age group (younger than one month/older than one month The electronic searches for this review were performed by the Tri-
if neonates are included). als Search Co-ordinator of the Cochrane Acute Respiratory in-
fections (ARI) Group. Searches of CENTRAL, MEDLINE, EM-
Sensitivity analysis BASE, CINAHL, LILACS and Web of Science on 6 May 2014
identified 170 records; manual searches identified two records. Af-
We planned a sensitivity analysis but it was not undertaken because
ter screening the titles and abstracts, we excluded 123 records and
of the limited number of included trials.
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 be-
cause the investigators could not provide the original data (Bai
RESULTS 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
Description of studies 2013). It was registered in October 2013 and is still recruiting
participants. See Characteristics of ongoing studies table.
Figure 1. Study flow diagram.

Two studies selected length of hospital stay as the primary out-
Included studies come and clinical severity scores as the secondary outcome (Amirav
2008; Zedan 2010). Both of them used the same validated score,
All five studies were randomised, double-blind, parallel-group, which was initially described by Wang 1992; the score rated respi-
controlled trials. Bisgaard 2008 is an international multi-centre ratory rate, wheezing, retraction and general condition from zero
trial with a large sample, which was conducted in both high- to three (the higher score corresponding to increased severity).
income and low-income countries involving Denmark, Mexico, The outcome measurements varied among studies when using
Singapore, South Africa and the USA. Kim 2010 is a multi-cen- montelukast for preventing post-bronchiolitis symptoms. Bisgaard
tre study conducted in South Korea and Japan. The remaining 2008 selected percentage of symptom-free days during four weeks
three studies were conducted in Belgium (Proesmans 2009), Egypt treatment as the primary outcome. Proesmans 2009 selected the
(Zedan 2010), and Israel (Amirav 2008). number of symptom-free days over three months treatment as
the primary outcome. Kim 2010 selected the serum eosinophil-
Participants derived neurotoxin level as the primary outcome. Other out-
We included a total of 1296 participants between the ages of one come measures included percentage of bronchiolitis-free days, pa-
month to 24 months hospitalised with bronchiolitis. All studies tients with exacerbations, patients with systemic corticosteroids
clearly described the criteria for diagnosis of bronchiolitis and use (Bisgaard 2008), the need for additional treatment after hos-
all studies included the first episode of bronchiolitis except for pital discharge, the number of respiratory exacerbations, time to
Bisgaard 2008, which included a small proportion with a second first exacerbation (Proesmans 2009), and serum eosinophil-de-
episode of bronchiolitis (about 10% in each group). RSV detection rived neurotoxin level (Kim 2010).
was available in all trials except for Zedan 2010.
Adverse effects
Interventions Amirav 2008, Bisgaard 2008 and Proesmans 2009 reported ad-
verse events and Bisgaard 2008 also reported two deaths in the
Two studies used 4 mg montelukast (a leukotriene inhibitor)
intervention group during treatment, but neither of the deaths
or matching placebo daily from admission until discharge to
was determined to be drug-related.
treat acute bronchiolitis (Amirav 2008; Zedan 2010). The other
three studies used 4 mg montelukast for several weeks for pre-
venting post-bronchiolitis symptoms (Bisgaard 2008; Kim 2010;
Proesmans 2009). Bisgaard 2008 used an additional dose (8 mg Excluded studies
montelukast) to assess whether there is a dose-effect relationship.
We excluded 34 studies with reasons. The most common reasons
The treatment duration and follow-up period varied among these
for exclusion included type of publication, populations and study
three studies. Kim 2010 and Proesmans 2009 used montelukast
design (see Characteristics of excluded studies table).
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. 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
Outcome measures
3.

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

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

Allocation
Selective reporting
We considered sequence generation and allocation concealment to We would have used a funnel plot to detect reporting bias but this
be clearly described in the included studies (Amirav 2008; Bisgaard was not necessary due to the small number of included studies.
2008; Kim 2010; Proesmans 2009; Zedan 2010).
Other potential sources of bias

We did not identify any other potential sources of bias.
Blinding
For the purposes of our review, we considered blinding adequate Effects of interventions
in most of these included studies. Three studies clearly described
See: Summary of findings for the main comparison
the blinding of participants and personnel and the blinding of
Montelukast versus placebo for bronchiolitis in infants and young
outcome assessment (Amirav 2008; Bisgaard 2008; Kim 2010).
children
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 Primary outcomes
was blinded or not.
1. Length of hospital stay

Two studies reported the length of hospital stay from admission to
Incomplete outcome data
discharge as a primary outcome. Zedan 2010 had a positive result
Three included studies used flow diagrams to assess differential while Amirav 2008 had negative result. The pooled results based
drop-out from the study groups (Amirav 2008; Bisgaard 2008; on the two studies showed that there was no statistically significant
Zedan 2010). Possible attrition bias might be a factor in two studies difference between the intervention group and the control group
because the percentage of loss to follow-up of participants was (mean difference (MD) -0.95 days, 95% confidence interval (CI)
beyond 15%, which might lead to attrition bias (Kim 2010; -3.08 to 1.19, P value = 0.38, I2 statistic = 88%) (Analysis 1.1;
Proesmans 2009). Figure 4).
Figure 4. Forest plot of comparison: 1 Montelukast versus placebo, outcome: 1.1 Length of hospital stay.
Secondary outcomes
2. All-cause mortality
Only one study reported deaths. “Two patients died during the
study, neither was determined by the investigator to be drug re- 1. Clinical severity score
lated. One patient died of acute respiratory distress syndrome and Two included studies reported the clinical severity score and
sepsis while hospitalised for RSV-induced bronchiolitis. The other utilised the same validated score system that was initially described
one died of thermal burns in a house fire”. There was no statisti- by Wang 1992. We pooled data comparing clinical severity score
cally significant difference between these groups (P value = 0.55) on admission (defined as baseline) and the next two days after
(Analysis 1.2). treatment (defined as day two and day three) because of the small
number of remaining participants. The pooled results showed that
there was no statistically significant difference between the inter-
vention 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).
ranges and minimum/maximum. The results also demonstrated

2. Percentage of symptom-free days
no significant difference between groups (P value = 0.415). Owing
Two studies selected symptom-free days as secondary outcomes to the significant heterogeneity between studies, we did not pool
but reported this differently (Bisgaard 2008; Proesmans 2009). the results. Results from individual studies were consistent with
Bisgaard 2008 reported the percentage of symptom-free days dur- each other, which indicated that montelukast did not affect symp-
ing two periods (four weeks or a total of 24 weeks of treatment) and tom-free days in patients with post-bronchiolitis when compared
defined the symptom-free days as a day with no daytime cough, with placebo.
wheeze, shortness of breath and no night-time cough. Data are pre-
sented as the means and standard deviations. The results showed
that there was no significant trend for montelukast treatment com- 3.Percentage of children requiring ventilation
pared with placebo during 24 weeks of treatment. Proesmans 2009 No relevant data were available on the percentage of children re-
reported the number of symptom-free days during three months quire ventilation.
of treatment and defined symptom-free days as 24 hours dur-
ing which the parent reported no daytime or night-time symp-
toms (symptoms included wheeze, cough and troubled breathing, 4. Oxygen saturation
and limited activities). Data are presented as median, interquartile No relevant data were available on oxygen saturation.
5. Recurrent wheezing which implied significant clinical heterogeneity between studies.
Only one study reported the incidence of recurrent wheezing dur- Therefore, we did not pool results. Results from individual studies
ing three months of treatment and one year of follow-up (Kim were consistent with each other, which indicated that montelukast
2010). The results showed that montelukast treatment did not did not affect symptom-free days in patients with post-bronchioli-
reduce the incidence of recurrent wheezing. tis when compared with placebo. Only one study reported the in-
cidence of recurrent wheezing during the three months treatment
and one-year follow-up. The results showed that montelukast
6. Respiratory rate treatment did not reduce the incidence of recurrent wheezing. The
No relevant data were available on respiratory rate. 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
7. Clinical adverse effects died during treatment but neither death was drug-related. The
analysis also showed no statistically significant difference between
Three studies reported adverse events but none were determined to
groups.
be drug-related (Amirav 2008; Bisgaard 2008; Proesmans 2009).
Adverse events were reported in three included studies. We did not
Proesmans 2009 reported that five infants were withdrawn because
pool results given the heterogeneity. Individual trial analyses did
of possible adverse events. Two for abdominal pain and vomiting,
not show significant differences between the leukotriene inhibitors
two for sleepless nights and one for rash. Amirav 2008 reported
group and the placebo group.
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
Overall completeness and applicability of
rash. There was no difference between the study groups. Bisgaard
evidence
2008 reported that montelukast was generally well tolerated. There
were no differences between the study groups. In this review, all included studies recruited participants hospi-
talised 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
DISCUSSION should be taken when extrapolating the finding of this review to
patients with chronic diseases or premature children.
Summary of main results Furthermore, study designs differed too much between the stud-
In this review, we evaluated the efficacy and safety of leukotriene in- ies when using leukotriene inhibitors to prevent post-bronchiolitis
hibitors for bronchiolitis in infants and young children. The results symptoms, especially in terms of severity of disease, outcome mea-
are summarised in Summary of findings for the main comparison sures, duration of treatment and follow-up period, which might
and Data and analyses. limit the applicability of the evidence for preventing post-bron-
In brief, we included five randomised, double-blinded, placebo- chiolitis symptoms.
controlled 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
Quality of the evidence
clinical severity score as secondary outcome). Both had similar We assessed three included trials to be at low risk of bias for se-
clinical statuses but with opposite results from individual studies. quence generation, allocation concealment, blinding, incomplete
The pooled results did not show statistically significant differences outcome data and selective reporting. We assessed the other two
in shortening the length of hospital stay (mean difference (MD) - studies as having a high risk of attrition bias due to the percentage
0.95, 95% confidence interval (CI) -3.08 to 1.19, P value = 0.38) of loss to follow-up of participants, which was above 15%. We
or decreasing the clinical severity score (day two: MD -0.57, 95% assessed the quality of the evidence using the GRADE Working
CI -2.37 to 1.23, P value = 0.53; day three: MD 0.17, 95% CI - Group method (GRADE 2009). We judged the quality of the ev-
1.93 to 2.28, P value = 0.87) when compared with placebo. idence for the effect on length of hospital stay and clinical severity
The other three studies used montelukast in patients hospitalised score as low due to inconsistency (high level of unexplained statis-
with bronchiolitis for several weeks for preventing post-bronchi- tical heterogeneity) and imprecision (small sample size and the CI
olitis symptoms. However, the outcome measurements, duration does not rule out a null effect or harm). See Summary of findings
of treatment and follow-up period varied among the three studies, for the main comparison.

Potential biases in the review process and imprecision arising from small sample sizes and wide confi-
dence intervals, which did not rule out a null effect or harm.
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
Implications for research
and admission, as specified in the published protocol, to all-cause More large randomised controlled trials (RCTs) are necessary to
mortality, length of hospital stay, clinical severity score and clinical evaluate the efficacy and safety of leukotriene inhibitors in infants
adverse effects in this review, which might be a source of bias. and young children with bronchiolitis. This is particularly impor-
tant in preterm infants and high-risk patients (e.g. patients with
bronchopulmonary dysplasia and congenital heart disease), who
are especially susceptible to this illness.
Agreements and disagreements with other
studies or reviews Research should focus on the first episode of wheezing in younger
children so the results will be pertinent to infants with typical viral
To the best of our knowledge, there is no other systematic review as-
bronchiolitis. A second episode of bronchiolitis with recurrent
sessing the short-term treatment efficacy and safety of leukotriene
wheezing might be due to other respiratory diseases such as asthma.
inhibitors for infants and young children under two years of age
Thus, it is necessary to identify simple, valid and universal tools to
with acute bronchiolitis. Peng 2014 assessed the efficacy mon-
distinguish prospectively between these diseases in future studies.
telukast for preventing post-bronchiolitis wheezing and demon-
strated results consistent with ours in that montelukast was not
effective in preventing post-bronchiolitis wheezing.
ACKNOWLEDGEMENTS
We wish to thank Sarah Thorning (Trials Search Co-ordinator)
for help in defining the search strategy and in running the liter-
AUTHORS’ CONCLUSIONS
ature searches. We wish to thank Clare Dooley (Assistant Man-
aging Editor, Cochrane Acute Respiratory Infections Group), Liz
Implications for practice Dooley (Manage Editor, Cochrane Acute Respiratory Infections
The current evidence is based on limited included studies and does Group), Inge Axelsson and Chris Del Mar for providing ongoing
not allow definitive conclusions to be made about the effects of assistance with this review. Finally, we wish to thank the following
leukotriene inhibitors used for bronchiolitis in infants and young people for commenting on the drafts of this review: Deviprasad
children. We downgraded the quality of the evidence to low due to Mohapatra, Vishal Jatana, Federico Martinon-Torres, Kana R Jat,
inconsistency (unexplained high levels of statistical heterogeneity) Sree Nair and Ravi Shankar.
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bronchiolitis in children: differences between RSV and squared index?. CHIP Documents 2006:paper 19.
non-RSV bronchiolitis. European Journal of Clinical Wang 1992
Microbiology and Infectious Diseases 2012;31:1975–81. Wang EE, Milner RA, Navas L, Maj H. Observer agreement
Higgins 2011 for respiratory signs and oximetry in infants hospitalized
Higgins JPT, Green S (editors). Cochrane Handbook with lower respiratory infections. American Review of
for Systematic Reviews of Interventions. Version 5.1.0 Respiratory Disease 1992;145:106–9.
[updated March 2011]. The Cochrane Collaboration, Worrall 2008
2011. Available from www.cochrane-handbook.org. Worrall G. Bronchiolitis. Canadian Family Physician 2008;
Chichester: Wiley–Blackwell. 54(5):742–3.
Koehoorn 2008 Zhang 2013
Koehoorn M, Karr CJ, Demers PA, Lencar C, Tamburic Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP.
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bronchiolitis in a population-based cohort. Pediatrics 2008; in infants. Cochrane Database of Systematic Reviews 2013,
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Langley 2003
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Langley JM, LeBlanc JC, Smith B, Wang EE. Increasing
incidence of hospitalization for bronchiolitis among Liu 2013
Canadian children, 1980-2000. Journal of Infectious Diseases Liu F, Ouyang J, Sharma AN, Liu S, Yang B, Xiong W, et
2003;188:1764–7. al. Leukotriene inhibitors for bronchiolitis in infants and
Lefebvre 2011 young children. Cochrane Database of Systematic Reviews
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∗
for studies. In: Higgins JPT, Green S (editors). Cochrane Indicates the major publication for the study

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 respira-
tory 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

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 Assignment was conducted by using an on-
bias) line randomiser
Allocation concealment (selection bias) Low risk Allocation status was concealed in sealed
envelopes
Blinding of participants and personnel Low risk Throughout the study, the investigators,
(performance bias) nursing and medical staff, and parents were
All outcomes unaware of which treatment group in-
fants were assigned. The difference between
montelukast and placebo was undetectable
by sight or smell
Blinding of outcome assessment (detection Low risk Throughout the study, the investigators,
bias) nursing and medical staff and parents were
All outcomes unaware of which treatment group infants
were assigned
Incomplete outcome data (attrition bias) Low risk 2 families withdrew their consent, 1 in the
All outcomes 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

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
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)
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%)

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 ran-
domised 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 β-
agonist 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 RSV-
induced bronchiolitis. The other 1 (8 mg of montelukast) died of thermal burns in a
house fire
Risk of bias
Random sequence generation (selection Low risk Assignment was conducted according to
bias) a computer-generated randomised alloca-
tion schedule
Allocation concealment (selection bias) Low risk Allocation numbers were centrally assigned
in sequential order via an interactive voice
response system
Blinding of participants and personnel Low risk All study personnel and participants re-
(performance bias) mained blinded to treatment allocation
All outcomes throughout the study
Blinding of outcome assessment (detection Low risk The code was revealed to the researchers
bias) once recruitment, data collection and lab-
All outcomes oratory analyses were completed
Incomplete outcome data (attrition bias) Low risk They used ITT analysis
All outcomes

Bisgaard 2008 (Continued)
Selective reporting (reporting bias) Low risk They evaluated the efficacy and safety of
all participants that randomised to the 3
groups
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
Completed:
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)
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

Administered once daily in the evening for 12 weeks as the study treatment
Follow-up data were collected for a total of 12 months

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

Kim 2010 (Continued)
Recurrent wheezing for 12 months
Notes -
Risk of bias
Random sequence generation (selection Low risk Assessment was according to a computer-
bias) generated randomised allocation schedule
Allocation concealment (selection bias) Low risk Blinding of active and placebo granules
was provided by the Inje University Sang-
gye Paik Hospital pharmacy according to
a computer-generated randomised alloca-
tion schedule
Blinding of participants and personnel Low risk All study investigators and participants re-
(performance bias) mained blinded to group assignment for
All outcomes the entire study period
Blinding of outcome assessment (detection Low risk All study investigators and participants re-
bias) mained blinded to group assignment for
All outcomes the entire study period
Incomplete outcome data (attrition bias) High risk “19 infants in the RSV-MONT group and
All outcomes 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
Selective reporting (reporting bias) Unclear risk No information provided
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 respi-
ratory 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-

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
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)
No relevant reports
Interventions Group 1: montelukast 4 mg

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

Number of symptom-free days and disease-free days
Secondary outcomes:
Need for additional treatment after hospital discharge: use of bronchodilators and main-
tenance 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
Random sequence generation (selection Low risk Participants were randomised by using a
bias) computer model
Allocation concealment (selection bias) Low risk Canisters were randomised using a com-
puter model and allocated to the patient
sequentially

Proesmans 2009 (Continued)
Blinding of participants and personnel Low risk The blinding code was broken only after all
(performance bias) included participants had finished the trial
All outcomes follow-up
Blinding of outcome assessment (detection Unclear risk They did not mention whether the out-
bias) come assessment was blinded or not
All outcomes
Incomplete outcome data (attrition bias) High risk “Eighty three patients were randomised.
All outcomes Twenty five participants dropped out; nine-
teen because the diary card was not filled
out”. The percentage of participants who
dropped out was above 20% and the rea-
son for missing outcome data is likely to be
related to true outcome. It seems that they
just reported those who completed the tri-
als; data from those who dropped out were
not collected
Selective reporting (reporting bias) Unclear risk No information provided
Zedan 2010
Participants Setting: multiple centres in Egypt

Inclusion criteria:
Infants aged 1 to 24 months of age, clinically diagnosed with first-episode viral bronchi-
olitis
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 immunode-
ficiency or underlying cardiopulmonary disease
Randomly assigned:
Group 1 (montelukast, 4 mg): N = 47
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

Zedan 2010 (Continued)
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

Length of hospital stay
Secondary outcomes:
Clinical severity scores; changes in plasma levels of interferon gamma and interleukin-4
Notes -
Risk of bias
Random sequence generation (selection Low risk Assignment was conducted by randomly
bias) permuted blocks using an online ran-
domiser
Allocation concealment (selection bias) Low risk Allocation status was concealed in sealed
envelopes in the pharmacy
Blinding of participants and personnel Low risk Through the study, the investigators, nurs-
(performance bias) ing and medical staff and parents were
All outcomes unaware of which treatment group in-
fants were assigned to. The physical differ-
ence between granules of montelukast and
placebo was undetectable by sight or smell
Blinding of outcome assessment (detection Low risk Through the study, the investigators, nurs-
bias) ing and medical staff, and parents were
All outcomes unaware of which treatment group infants
were assigned to
Incomplete outcome data (attrition bias) Low risk 1 participant discontinued in each group
All outcomes
Selective reporting (reporting bias) Low risk

Zedan 2010 (Continued)
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 Publication type: review
Bush 2010 Population: children with preschool wheezing
Cook 1992 Intervention: received either aerosolised ribavirin or placebo control
Cowan 2010 Publication type: review
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

(Continued)
Kearns 2008 Study design: not randomised
Knorr 2006 Study design: not randomised
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 Publication type: review
Ngamphaiboon 2005 Publication type: review
Pelkonen 2013 Population: clinical definition of bronchiolitis was not certain and recurrent wheezing
Peng 2014 Publication type: systematic review
Piedimonte 2005 Study design: not randomised
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 Publication type: review
Straub 2003 Publication type: meeting abstract; population: wheezy infants without certain definition of bronchiolitis
Straub 2005 Study design: not randomised
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 Study design: not randomised
Zentz 2011 Publication type: review
RCT: randomised controlled trial

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
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 kad-yc@163.com
Notes ChiCTR-TRC-13003735

DATA AND ANALYSES
Comparison 1. Montelukast versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Length of hospital stay 2 136 Mean Difference (IV, Random, 95% CI) -0.95 [-3.08, 1.19]
2 All-cause mortality 1 952 Risk Ratio (IV, Random, 95% CI) 2.51 [0.12, 52.16]
3 Clinical severity score (baseline) 2 136 Mean Difference (IV, Random, 95% CI) 0.11 [-0.51, 0.74]
4 Clinical severity score (day 2) 2 136 Mean Difference (IV, Random, 95% CI) -0.57 [-2.37, 1.23]
5 Clinical severity score (day 3) 2 132 Mean Difference (IV, Random, 95% CI) 0.17 [-1.93, 2.28]
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.

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


Bronquiolitis

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Cochrane Database of Systematic Reviews

Leukotriene inhibitors for bronchiolitis in infants and young

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 (Review)

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) i

Leukotriene inhibitors for bronchiolitis in infants and young

Editorial group: Cochrane Acute Respiratory Infections Group.

PLAIN LANGUAGE SUMMARY

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 3

Montelukast versus placebo for bronchiolitis in infants and young children

Patients or population: infants and young children with bronchiolitis

Assumed risk Corresponding risk

Control Montelukast versus

Length of hospital stay The mean length of hos- 136 ⊕⊕

Clinical severity score The mean clinical severity 136 ⊕⊕

Clinical severity score The mean clinical severity 132 ⊕⊕

GRADE Working Group grades of evidence

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 6

Types of interventions Data collection and analysis

Data extraction and management

Search methods for identification of studies

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 7

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 8

Figure 1. Study flow diagram.

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 9

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 10

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 11

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 12

Other potential sources of bias

1. Length of hospital stay

ranges and minimum/maximum. The results also demonstrated

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 15

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 18

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 19

Characteristics of included studies [ordered by study ID]

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

Participants Setting: 2 medical centres in Israel

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 20

Interventions Group 1: montelukast group, 4 mg/day

Outcomes Primary outcomes:

Notes Registered in Clinicaltrials.gov NCT00524693

Bias Authors’ judgement Support for judgement

Other bias Unclear risk No information provided

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 21

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

Participants Setting: 116 centres across 6 continents

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 22

Interventions Group 1: placebo group

Outcomes Primary outcome:

Notes ClinicalTrials.gov Identifier: NCT00076973

Bias Authors’ judgement Support for judgement

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 23

Other bias Unclear risk No information provided

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

Participants Setting: multiple centres in Korea and Japan

Interventions Group 1: montelukast 4 mg/day

Outcomes Primary outcome:

Leukotriene inhibitors for bronchiolitis in infants and young children (Review) 24

Recurrent wheezing for 12 months

Bias Authors’ judgement Support for judgement

Selective reporting (reporting bias) Unclear risk No information provided

Other bias Unclear risk No information provided