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Three Part Question

In [infants with bronchiolitis] does [treatment with leukotriene receptor antagonists] reduce the [clinical severity in acute phase of illness]?

Clinical Scenario

A 7 month old male infant is admitted with acute bronchiolitis. On clinical examination he is noticed to have obvious respiratory distress with wheezing and crepitations all over the chest. Initially he is managed conservatively, aiming to maintain hydration by parenteral fluid supplementation and oxygenation (oxygen saturations above 92%) by head box oxygen administration. Persistent wheezing, troublesome cough and feed intolerance lead to empirical trial of various combinations of inhaled beta-2 agonists, anticholinergics and steroids without any clinical response. You remember that a leukotriene receptor antagonist Montelukast is increasingly being used in management of children with wheezing but you are not sure what their role is in acute brochiolitis and you decide to find out more.

Search Strategy

Medline (1951-2004) via Dialog DATAstar. Embase and Pubmed
(same search strategies used). Cochrane and BestBETS.
Bronchiolitis and Montelukast OR Bronchiolitis and Leukotriene receptor antagonists OR Bronchiolitis and antileukotrienes OR RSV infection and Montelukast OR RSV infection and ukotriene receptor antagonists.

Search Outcome

Total papers - 6 papers found (2 relevant). All retrieved via Medline

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bisgaard et al 2003 Denmark	130 infants with acute RSV bronchiolitis (3-36 month). Randomised to 5 mg Montelukast vs. Placebo for 28 days	Randomised double blind multicentre placebo controlled trial (Level 1 b)	Clinical symptoms during the 4 weeks treatment period	Infants on Montelukast were free of any symptoms on 22 % (Quartiles:4-39) of days and nights compared with 4% (Quartiles:0-29) on placebo(p=0.015). Significantly reduced day time cough on active treatment (p=0.04). Significantly delay in time to exacerbations (withdrawal due to symptom severity or hospitalization due to lung symptoms) on active treatment (p=0.044).	Children up to 36 months were included. Median age of study population was 9 months.
			Clinical symptoms during a further 4 week period starting 4 weeks after the end of treatment	No significant difference in treatment groups during follow up 4 weeks after stopping treatment
Ng et al 2000 Japan	3 infants (5-20 months old) with virus associated brochiolitis/ wheezing	Case series (Level 4)	Improvement in respiratory distress and wheezing	In all these cases addition of Montelukast was associated with marked clinical improvement within 1 week	Small sample size Lack of controls Heterogenous sample

Comment(s)

Bronchiolitis is a common illness which most often affects infants between 2 to 12 months of age. Respiratory Syncytial Virus (RSV), accounts for the majority of pathogens isolated during clinical disease, although Adenovirus (types 3, 7, 21), Parainfluenza virus (type 3), Rhinovirus etc. have also been implicated as causative infectious agent of bronchiolitis. Epidemics of bronchiolitis are almost always linked to RSV infection. Cysteinyl leukotrienes (LTC4, D4, E4) are released during RSV airway infection in infants and their levels are significantly higher in the nasopharyngeal secretion of infants with RSV bronchiolitis than that found in infants with RSV upper respiratory tract infections only(Volvitz). Cysteinyl leuktrienes are known to cause bronchial obstruction, mucosal edema, increased mucous secretion and bronchial responsiveness. Thus one can assume that antagonists of receptors for Cysteinyl leukotrienes like Montelukast might be an effective treatment for acute bronchiolitis particularly caused by RSV. Bisgaard's study was designed to evaluate the efficacy of Montelukast on RSV post bronchiolitis symptoms, i.e., airway symptoms after the acute phase of illness rather than the acute bronchiolitis itself and treatment with Montelukast was delayed by a median of 3 days from admission and up to 7 days from the onset of first symptom. The trial showed significant increase in number of days and nights free of any symptoms and significant reduction in day time cough during the 4 weeks period of treatment with Montelukast. The separation of effects in the treatment group from control group only became apparent during the last 2 weeks of the treatment period. There were no significant differences between treatment groups in any of the outcomes during follow up 4 weeks after stopping treatment. However this study included infants from 3-36 months of age with median age of 9 months whereas median age of infants typically suffers from RSV bronchiolitis is 3 months and possibility of any other lung condition e.g. post RSV reactive airway disease, that responds to Montelukast in older children confounding the results can not be excluded. Ng's study was a case series reporting 3 cases with virus associated brochiolitis/wheezing who responded poorly to inhaled steroids and bronchiodilators but addition of Montelukast was associated with marked clinical improvement within one week but these cases were very heterogenous, differed from simple virus induced acute bronchiolitis and use of multiple drugs including montelukast did not enable any firm conclusions.

Clinical Bottom Line

Currently, no studies are available specifically designed to look at the efficacy of leukotriene receptor antagonists in reducing the clinical severity in acute phase of bronchiolitis. Leukotriene receptor antagonists if given in the early part of illness may be effective in reducing short term post bronchiolitic cough and wheezing, although there is no enough evidence to derive a firm conclusion and further trials are warranted.

References

1. Volovitz B, Welliver RC, De Castro G, Krystofik DA,Ogra PL. The release of leukotrienes in the respiratory tract during infection with respiratory syncytial virus: role in obstructive airway disease. Pediatr Res. 1988;24(4):504-7.
2. Bisgaard H. Study Group on Montelukast and Respiratory Syncytial Virus. A randomized trial of montelukast in respiratory syncytial virus post bronchiolitis. Am J respire Crit Care Med 2003;167(3):379-383.
3. Ng DK, Law AK, Chau K-W, Chan H-K. Use of montelukast in the treatment of early childhood wheezing from clinical experience with three cases. Respirology 2000;5(4):389-392.