Background 

Acute viral bronchiolitis is the most common acute infection of the lower respiratory tract during the first year of life.(1) It is most often caused by the Respiratory Syncytial Virus (RSV), usually in a seasonal pattern.(2) The diagnosis is clinical, and findings include rhinorrhea, cough, low-grade fever, wheezing, and respiratory distress.(3) The disease causes a major clinical and economical health burden, with hospital admission rates up to 30/1.000 in developed countries, in addition to the impact in children and families cared for in community settings.(2,4) Hospitalizations have increased steeply during the last decades, and vulnerable populations (e.g. preterms) have increased morbidity.(5) Ongoing research has identified pre- and postnatal risk factors for bronchiolitis, and the link to recurrent wheezing and asthma is the focus of continuing research efforts.(6,7)

Treatment of bronchiolitis is an ever-controversial topic in pediatrics. There is wide practice variation worldwide, reflecting the variety of treatments and the absence of clear evidence for any single therapeutic approach.(8,9) Frequently used interventions, including bronchodilators and corticosteroids, have failed to show consistent and clinically relevant effects in previous meta-analyses of randomized clinical trials (RCTs).(9) A vaccine for RSV has proven elusive and an effective treatment to reduce post-bronchiolitis recurrent wheezing and later asthma is yet to be found. For clinicians on the frontline during every bronchiolitis season, the uncertainties of research findings are as striking as the burden of morbidity. It is disappointing, to say the least, that the best we can offer our patients is monitoring, respiratory support and adequate hydration, but these are the only effective measures routinely recommended by current clinical practice guidelines.(10)

As explained below, my ongoing PhD thesis is addressing some of the lingering questions in bronchiolitis treatment, from a synthesis and clinical trial research perspective. The main aim is to improve the design and conduct of clinical trials in this field, by reassessing current evidence and addressing the issue of outcome measures. International collaborations were set up with researchers from the Netherlands and Canada, enabling access to content and methodological expertise. Supervisors include Prof. Doutor J.C. Trindade and Prof. Doutora C. Sampaio (FML e IMM), and Martin Offringa, MD, PhD (Amsterdam Medical Center-AMC). Work is being developed under the auspices of the Gulbenkian Programme for Advanced Medical Education, and as an Institute of Molecular Medicine PhD student.

Corticosteroids and bronchodilators: revisiting old treatment strategies

The case of corticosteroids highlights the conflicting findings of research in this field. Their use dates back to the 1960s, in analogy of the clear benefits seen in children with acute asthma.(11) Inflammation plays a key role in the pathophysiology of bronchiolitis, but evidence is equivocal as to any positive clinical treatment effects of these anti-inflammatory drugs. While the previous Cochrane systematic review found no benefit for any of the outcomes analyzed, their use remains high.(8,12) Clarification of their effect is important given its well-known adverse effects.

The two largest multi-center RCTs in bronchiolitis were recently published and both assessed the use of corticosteroids.(13,14) Results from the CanBEST trial, conducted in Canada, unexpectedly suggested a relevant clinical benefit when combining corticosteroids and epinephrine. This has relaunched the debate surrounding the benefits and harms of these therapies, making it critical to incorporate these findings into the current body of evidence.

In collaboration with the Alberta Research Centre for Health Evidence, Department of Pediatrics, University of Alberta, Canada, in a project led by Lisa Hartling, we conducted a comprehensive systematic review and meta-analysis of corticosteroids, epinephrine and other bronchodilators. Our purpose was to analyze all evidence in light of the newest results, using new methodological tools to explore the comparative effectiveness and safety of all interventions, particularly combined therapy. This work led to the recent publication of a Cochrane review, showing the absence of a clinically relevant effect of stand-alone glucocorticoids on admissions or length of hospitalization in children with bronchiolitis.(15) Exploratory results for combined dexamethasone and epinephrine, including subgroup analyses, suggested benefit for outpatients, but safety data was limited. Results obtained using new methods of Bayesian network meta-analysis supported these findings, and ranked epinephrine and combined therapy as the most promising interventions.(16)

In search of adequate outcomes for bronchiolitis clinical trials

Conflicting research findings may relate to various shortcomings of RCTs in this field. One major issue which seriously hampers trial validity has been the heterogeneous and inadequate choice of outcome measures. Selection of appropriate outcomes is essential for study design, as ultimately, any study is only as credible as its endpoints.(17) Outcomes may encompass a spectrum of different health domains (e.g. biological, clinical), and the choice of health measurement instruments requires adequate knowledge of its measurement properties (i.e. validity, reliability, and responsiveness).(18) Research on outcomes for pediatric trials is scarce, and standardized core sets of scientifically sound and clinically relevant outcome measures for different conditions and interventions are needed.(19)

Failure to study and standardize outcomes may undermine the scientific, ethical and economic significance of RCTs. Frequently, bronchiolitis studies have used short-term and surrogate physiological outcomes, and many instruments were developed ad hoc and not studied adequately. The inconsistency in outcomes has limited the possibility for pooling of results in meta-analysis, and important health status domains have been forgotten, e.g. quality of life and symptoms.

Our ongoing projects use a comprehensive approach to improve outcome measurement for future clinical trials. In collaboration with the Department of Pediatric Clinical Epidemiology, AMC, with M. Offringa and J.H. Lee, we are conducting systematic reviews to identify and characterize the outcomes used in intervention studies, and their clinimetric properties. We are also using data from the CanBEST trial, led by A. Plint, to study the validity, reliability and responsiveness of a relevant instrument, the RDAI scale. The ultimate aim is to select a core set of standardized outcome measures for use in future trials, using consensus procedures with key stakeholders, i.e. clinicians, researchers, and patients.

Conclusion

The many challenges in bronchiolitis research span from assessing the most effective and safe treatment strategies for the acute short-term episode, to identifying its links with recurrent wheezing and asthma. In order to tackle these problems, it is imperative that the design and conduct of epidemiological and translational studies is adequate. Unmet needs in this area parallel the shortcomings found in other fields of pediatric research, and highlight the need to improve current research standards. Findings from these projects may help design better clinical trials, and ultimately to improve the treatment of this condition.

Ricardo M. R. M. Cunha Fernandes

Departamento da Criança e da Família, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte EPE
Laboratório de Farmacologia Clínica e Terapêutica, Faculdade de Medicina de Lisboa (FML) e Instituto de Medicina Molecular (IMM)
Programa Gulbenkian de Formação Médica Avançada
ricardocunhafernandes@clix.pt 
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