Key messages

• Leukotriene inhibitors might not decrease mortality in patients with bronchiolitis, and it is unclear whether hospitalization length decreases because the certainty of the evidence is very low.
• Leukotriene inhibitors may decrease incidence of recurrent wheezing in patients with bronchiolitis, but the certainty of the evidence is low.
• Leukotriene inhibitors increase adverse effects in patients with bronchiolitis, although the magnitude of this increase is uncertain.

What is the evidence.
See evidence matrix  in Epistemonikos later

We found two systematic reviews [1],[2], including six randomized controlled trials, reported in 12 references [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14]. 

What types of patients were included

The six trials only included patients diagnosed with bronchiolitis [3],[4],[6],[7],[8],[9].

Regarding to age, the six trials included patients younger than 24 months [3],[4],[6],[7],[8],[9]. If this age group is subdivided, one trial included patients between 1 and 24 months [6], two trials included patients between 3 and 24 months [4],[9], one trial included patients between 4 and 24 months [8], one trial included patients between 6 and 24 months [3] and one trial included patients younger than 24 months [7].

Two trials included patients with a first episode of bronchiolitis of any etiology [6],[8], two trials included a first episode of bronchiolitis caused by respiratory syncytial virus [3],[7] and one trial included first or second episode of bronchiolitis caused by respiratory syncytial virus [9].

The six trials only included inpatient population [3],[4],[6],[7],[8],[9]. Of these, two trials required a minimum stay of 24 hours [7], [9].

No trial considered outpatient population.

What types of interventions were included

The six trials compared oral montelukast versus placebo [3],[4],[6],[7],[8],[9].

Regarding dosing, four trials used 4 mg/day [3],[4],[6],[7], one trial used 8 mg/day [8] and one trial used doses of 4 and 8 mg/day [9].

Regarding intervention duration, two trials administered montelukast since admission day until discharge [6],[8], two trials used it for three months [3],[7], one trial between 1 and 4 weeks [4] and one trial between 4 and 20 weeks [9].

What types of outcomes
were measured

The systematic reviews reported the following outcomes:

All cause-mortality, incidence of recurrent wheezing, length of hospital stay, clinical adverse effects, percentage of children requiring ventilation, percentage of symptom-free days, frequency of recurrent wheezing, serum eosinophil-derived neurotoxin levels, corticosteroids usage, clinical severity score, oxygen saturation and respiratory rate. 

Follow-up was one year in two trials [3], [7], six months in one [9] and 18 months in one [4]. In two trials the follow-up was not reported [6],[8].

To whom this evidence does and does not apply

• The evidence presented in this summary applies to patients with bronchiolitis, diagnosed in the context of upper respiratory symptoms (cough and/or rhinorrhea) followed by signs of respiratory distress (costal retraction and/or tachypnea) and added respiratory sounds (wheezing, audible rales, crackles and/or roncus). Regarding the etiology, it includes any type of virus, predominantly respiratory syncytial virus.
• It does not apply to children older than 24 months.
• None of the trials were conducted in the outpatient setting. However, it is reasonable to extrapolate the information presented in this summary to this context.

• For the summary of findings we selected the outcomes: mortality, lenght of hospital stay, incidence of recurrent wheezing, clinical adverse effects and ventilation requirements as they are critical for decision making on use of leukotriene inhibitors in bronchiolitis. This selection is based on the opinion of the authors of the summary, but generally agrees with the outcomes mentioned by the systematic reviews.
• The outcome ventilation requirements was considered important despite it was not reported by the primary studies.

• It is not possible to make an adequate balance because the certainty of the evidence about the benefits is low or very low.
• If there is indeed an effect, it would be a decrease in recurrence of wheezing, which should be weighed against mild adverse effects.
• Regarding adverse effects, the trials reported leukotriene inhibitors were in general well tolerated and reported adverse effects were considered mild. The most common adverse effect were abdominal pain, vomiting, diarrhea, insomnia and rash. None of them led to treatment discontinuation [7],[8],[9].
• Only one trial reported deaths. Neither of the two deaths was attributed by the investigators to the use of leukotriene inhibitors [9].

• Considering there is uncertainty and it is an intervention in which the balance between benefits and risks is not clear, most patients and caregivers should lean against their use.
• However, it is expected there would be variability in the decision, especially in scenarios without resource limitations. Those patients or caregivers who put more value on an uncertain benefit may tend to favor their use, and those who give a greater value to the certainty of the evidence, adverse effects or costs, will abstain from their use.
• It is important to note, as it is a tablet, it has advantages in terms of adherence compared to inhalers and aerocamera, which could influence the decision in some cases.

• It is not possible to make an appropriate balance between benefits and costs due to the existing uncertainty.
• The cost per dose of leukotriene inhibitors is greater than that of the most commonly used inhalation therapies. In spite of this, its use for a limited period of time as in the trials identified, could reduce expenses related to the treatment of recurrences.
• In scenarios with limited resources, it is unlikely to be a cost effective intervention.
• It is reasonable to do a formal economic assessment in scenarios where its use is being considered.

Differences between this summary and other sources

• The conclusions of this summary are consistent with those presented in the two identified systematic reviews in relation to the outcomes of mortality, hospitalization days and adverse effects [1],[2].
• Our summary suggests there may be a decrease in the incidence of recurrent wheezing, since the confidence interval is interpreted as one of the elements that decreases the certainty of the evidence (according to the GRADE methodology) and not in a dichotomous way only on the basis of statistical significance. This differs in part from the reviews identified, which indicated that it might not reduce the incidence of recurrent wheezing [2] or that montelukast did not reduce the incidence of recurrent wheezing compared to placebo [1].
• The guideline of the American Academy of Pediatrics on Diagnosis, management and prevention of bronchiolitis does not mention antileukotrienes amid possible treatments for bronchiolitis [15].

• The probability that future research changes the conclusions of this summary is high because of the existing uncertainty.
• We did not identify ongoing studies in the International Clinical Trials Registry Platform of the World Health Organization or published studies not included in any of the identified systematic reviews.