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Medwave 2018 May-Jun;18(3):e7206 doi: 10.5867/medwave.2018.03.7206

�Deben utilizarse corticoides sist�micos en la bronquiolitis?

Should systemic corticosteroids be used for bronchiolitis?

Gonzalo Alarc�n-Andrade, Lorena Cifuentes

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Abstract

INTRODUCTION
Bronchiolitis is an acute small airways inflammation mainly caused by a viral infection. It is frequent in children under two years of age, particularly under 12 months. The use of systemic corticosteroids has been proposed for bronchiolitis, especially for severely ill patients. However, its efficacy is still controversial.

METHODS
To answer this question we gathered information using Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data from primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

RESULTS AND CONCLUSIONS
We identified four systematic reviews, including 20 randomized trials overall. We concluded the use of systemic corticosteroids has no benefit for the treatment of bronchiolitis, even for patients with mechanical ventilation.

Problem

Bronchiolitis is an acute small airways inflammation mainly caused by a viral infection, being respiratory syncytial virus one of the most important etiologies. It is highly frequent in children under two years of age, particularly under 12 months, being an important cause of hospital admission in this age group. Given its antiinflammatory effects and its efficacy in other respiratory conditions like asthma, the use of systemic corticosteroids has been proposed for patients presenting with bronchiolitis, especially for those severely ill.

The present summary aims to review if systemic corticosteroids are useful as an alternative treatment for patients presenting with an episode of bronchiolitis.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

Systemic corticosteroids do not substantially reduce the clinical score in patients with bronchiolitis.
Systemic corticosteroids probably do not reduce length of stay for inpatients without mechanical ventilation, and might not reduce it for patients with mechanical ventilation.
Systemic corticosteroids might not reduce the duration of mechanical ventilation.
Systemic corticosteroids might not reduce mortality in patients with mechanical ventilation.

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	Four systematic reviews were identified [1],[2],[3],[4]. They included 20 randomized trials overall [5],[6],[7],[8],[9],[10],[11],[12],[13], [14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24].
What types of patients were included*	All trials included patients presenting with bronchiolitis. Regarding age, 18 trials included patients less than 24 months [5],[6], [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[21],[23], [24]. Among them, four trials included patients less than 12 months [11],[13],[19],[23], one trial included patients less than 15 months [10], and two trials included patients less than 18 months [5],[21]. On the other hand, two trials included patients less than 36 months [20],[22]. Mean age was 7.4 months, with a range from four to 17 months. Six trials included only patients with confirmed respiratory syncytial virus [6],[8],[14],[15],[16],[17]. In the remaining trials, respiratory syncytial virus was confirmed in 28 to 71% of patients [5],[9],[10],[11],[12],[18],[19],[21],[22]. Five trials did not report viral etiology [7],[13],[20],[23],[24]. Patients were excluded if they presented with: previous wheezing in nine trials [8],[9],[10],[11],[12],[13],[20],[21],[22], chronic respiratory disease in 11 trials [5],[8],[9],[10],[11],[12],[19],[20],[21],[22],[24], cardiac disease like congenital cardiopathies in ten trials [5],[8],[9],[10],[11],[12],[19],[21],[22],[23], neurological disease in four trials [9],[10],[12],[22], prematurity in six trials [8],[9],[12],[17],[19],[24], immunodeficiency in seven trials [6],[8],[9],[10],[12],[19],[22], previous use of systemic corticosteroids in 13 trials [5],[6],[10],[12],[14],[15],[16],[17],[19],[20],[21],[22],[24], and assisted ventilation in eight trials [5],[9],[11],[12],[19],[21],[22],[24]. Four trials included patients with mechanical ventilation [6],[14],[15],[16]. Six trials did not report if they included patients with mechanical ventilation [7],[8],[10],[13],[18],[20]. Fifteen trials were conducted in inpatient setting [6],[7],[8],[10],[11],[13],[14],[15],[16],[17],[18],[21],[22],[23],[24]. The remaining five trials were conducted in an outpatient setting (emergency department) [5],[9],[12],[19],[20]. Six trials were multicenter studies [6],[16],[17],[19],[21],[24].
What types of interventions were included*	All trials compared systemic corticosteroids versus placebo. Nine trials used dexamethasone [6],[8],[10],[11],[12],[16],[19],[23],[24], one used prednisone [5], one used methylprednisolone [7], seven used prednisolone [9],[14],[15],[18],[20],[21],[22], one used either prednisolone or methylprednisolone [17], and one used an initial course of hydrocortisone followed by prednisone [13]. In eleven trials the corticosteroid was administered orally [5],[9],[10],[12],[14],[15],[18],[19],[20],[21],[22], in three it was intravenous [6],[8],[16], in four it was intramuscular [7],[11],[23],[24], in one it was either oral or intravenous [17], and in one it was initially intravenous and then oral [13]. In 11 trials, intervention lasted on average four days, with a range from two to ten days [5],[6],[7],[8],[9],[10],[11],[12],[14],[15], [16],[17],[18],[19],[20],[21],[22],[23],[24]. In one trial, intervention was administered until 3 days after hospital discharge [13].
What types of outcomes were measured	Systematic reviews reported the following outcomes: length of stay in hospital, length of stay in intensive care unit, duration of invasive mechanical ventilation, death of patients with mechanical ventilation, clinical score and duration of symptoms. Follow up was seven days or less in six trials [8],[9],[10],[14],[21],[23], two to four weeks in eight trials [6],[7],[11],[12],[13],[16],[20],[24], two months in one trial [22], a year in one trial [17], two years in one trial [5], and five years in one trial [14].

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of Findings

The information regarding the effects of systemic corticosteroids was based on ten randomized trials, including 580 patients [5],[6],[7],[8],[9],[10],[12],[13],[14],[15].Ten trials had no extractable data from the identified systematic reviews [4],[11],[17],[18],[19],[20],[21],[22],[23],[24].Three trials reported clinical score [7],[10],[12], five trials reported length of stay in hospital for patients without mechanical ventilation [6],[7],[9],[12],[13] and two reported length of stay for patients with mechanical ventilation [13],[15]. Three trials assessed the duration of mechanical ventilation [5],[13],[15] and three trials reported mortality in patients with mechanical ventilation [5],[13],[15]. Regarding adverse effects, four trials assessed them [8],[10],[13],[14]. The summary of findings is as follows:

The use of systemic corticosteroids does not relevantly reduce clinical score for patients with bronchiolitis. The certainty of the evidence is high.
The use of systemic corticosteroids probably does not reduce length of stay for patients without mechanical ventilation presenting with bronchiolitis. The certainty of the evidence is moderate.
The use of systemic corticosteroids might result in little or no reduction in length of stay for patients with mechanical ventilation presenting with bronchiolitis. The certainty of the evidence is low.
The use of systemic corticosteroids might result in little or no reduction of the duration of mechanical ventilation for patients presenting with bronchiolitis. The certainty of the evidence is low.
The use of systemic corticosteroids might result in little or no reduction of mortality in patients with mechanical ventilation presenting with bronchiolitis. The certainty of the evidence is low.
Probably, there are no significant adverse effects related to the use of systemic corticosteroids for bronchiolitis.

Follow the link to access the interactive version of this table (Interactive Summary of Findings – iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply

The evidence presented in this summary applies to patients under 24 months presenting with bronchiolitis at hospital and ambulatory settings. Some results only apply to patients with mechanical ventilation.
Even though respiratory syncytial virus predominates, it is reasonable to extrapolate the results to a different viral etiology of bronchiolitis.

About the outcomes included in this summary

Selected outcomes were clinical score, length of stay at hospital (for patients with and without mechanical ventilation), duration of mechanical ventilation, mortality (for patients with mechanical ventilation) and adverse effects, because they were considered critical outcomes for decision-making. This selection is based on the opinion of authors.

Balance between benefits and risks, and certainty of the evidence

The present summary shows that neither relevant decrease in clinical score exists, nor are benefits observed in terms of length of stay for patients without mechanical ventilation.
For patients with mechanical ventilation, systemic corticosteroids might not decrease length of stay, duration of mechanical ventilation or mortality.
Regarding adverse effects, in those trials that assessed them, none were observed relating systemic corticosteroids.
Supporting the conclusion above, a systematic review regarding systemic corticosteroids for asthma exacerbations indicates there is no significant increase in adverse effects with short courses, even when used several times a year [25]. Even though these results apply to patients with asthma, it is possible to extrapolate them to the similar duration use of systemic corticosteroids for bronchiolitis.

Resource considerations

Systemic corticosteroids, especially in short courses, do not imply a high cost, but if we consider the absence of significant benefits, it would not be a cost-effective measure.

What would patients and their doctors think about this intervention

Considering there is neither relevant reduction in clinical score nor in length of stay for patients without mechanical ventilation, most caregivers and physicians should oppose their use.
Even though no adverse effects were reported, given cost and difficulty of administration orally or parenterally in children less than 24 months, it is more probable that they oppose their use.
For patients with mechanical ventilation, given the low certainty of evidence against their use and the scarcity of therapeutic alternatives, some caregivers and physicians might be in favor of systemic corticosteroids.

Differences between this summary and other sources

The present summary yields conclusions which are consistent with included systematic reviews.
The guideline about diagnosis, management and prevention of bronchiolitis from the American Academy of Pediatrics strongly recommends against the use of systemic corticosteroids for any type of patient with bronchiolitis [26].
Similarly, the guideline from the National Institute for Health and Care Excellence (NICE) in United Kingdom, recommends against their use [27].

Could this evidence change in the future?

Given the certainty of the evidence, the probability of future research changing the conclusion from this summary is low for patients without mechanical ventilation and moderate for patients with mechanical ventilation.
During the conduction of this summary, two additional systematic reviews on the use of corticosteroids for bronchiolitis were identified [28],[29]. These were not included, because they did not differentiate inhalatory from systemic routes (oral, intravenous or intramuscular). Related to these reviews, six additional randomized trials were found and not included in the present summary [30],[31],[32],[33],[34],[35]. The systematic reviews analyzed in this summary did not include these trials, because of publication date was beyond the search period, or patients did not meet the inclusion criteria.
We did not identify ongoing trials in International Clinical Trials Registry of the World Health Organization regarding the use of systemic corticosteroids for bronchiolitis.
An ongoing systematic review was identified including the use of systemic corticosteroids for bronchiolitis [36] in PROSPERO International prospective register of systematic reviews.

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Systemic corticosteroids for bronchiolitis

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

● Given the certainty of the evidence, the probability of future research changing the conclusion from this summary is low for patients without mechanical ventilation and moderate for patients with mechanical ventilation.

● During the conduction of this summary, two additional systematic reviews on the use of corticosteroids for bronchiolitis were identified [28],[29]. These were not included, because they did not differentiate inhalatory from systemic routes (oral, intravenous or intramuscular). Related to these reviews, six additional randomized trials were found and not included in the present summary [30],[31],[32],[33],[34],[35]. The systematic reviews analyzed in this summary did not include these trials, because of publication date was beyond the search period, or patients did not meet the inclusion criteria.

● We did not identify ongoing trials in International Clinical Trials Registry of the World Health Organization regarding the use of systemic corticosteroids for bronchiolitis.

An ongoing systematic review was identified including the use of systemic corticosteroids for bronchiolitis [36] in PROSPERO International prospective register of systematic reviews.

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