Review
Lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics

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Summary

Respiratory syncytial virus (RSV) is a major worldwide cause of morbidity and mortality in children under five years of age. Evidence-based management guidelines suggest that there is no effective treatment for RSV lower respiratory tract infection (LRTI) and that supportive care, ie, hydration and oxygenation, remains the cornerstone of clinical management. However, RSV treatments in development in the past decade include 10 vaccines and 11 therapeutic agents in active clinical trials. Maternal vaccination is particularly relevant because the most severe disease occurs within the first 6 months of life, when children are unlikely to benefit from active immunisation. We must optimise the implementation of novel RSV therapeutics by understanding the target populations, showing safety, and striving for acceptable pricing in the context of this worldwide health problem. In this Review, we outline the limitations of RSV LRTI management, the drugs in development, and the remaining challenges related to study design, regulatory approval, and implementation.

Introduction

Respiratory syncytial virus (RSV) bronchiolitis contributes greatly to mortality in children under 5 years of age,1 and has implications for long-term respiratory health.2 Nearly all children in the world will be infected with RSV by 2 years of age.3

Several evidence-based guidelines for the management of bronchiolitis exist, with differing recommendations, but all agree on supportive management in the inpatient setting. A guideline published by the American Academy of Pediatrics4 reported insufficient evidence for any intervention except respiratory support and hydration. In view of the paucity of therapeutic alternatives, it is essential to understand the existing challenges to the development of prevention and treatment options for RSV.

Section snippets

Burden of disease

In the USA, RSV is the leading cause of hospital admission in children under 1 year of age, causes about 150 000 hospital admissions per year in children under 2 years of age, and accounts for 18% of all emergency department visits in children under 5 years of age.5, 6, 7 Beyond the substantial disease burden during acute infection, evidence suggests that RSV bronchiolitis plays a causal part in the development of recurrent wheeze, and is associated with the development of asthma and subsequent

Clinical management: less is more

Bronchiolitis is a variable but usually self-limiting disease, and it is estimated to resolve in 90% of children about 21 days after symptom onset.23, 24 However in the case of severe disease (defined by respiratory distress or dehydration) children need to be managed with intravenous fluids and supplemental oxygen as inpatients.

The American Academy of Pediatrics (AAP) bronchiolitis guideline4 restricts the use of therapeutic interventions that are not evidence based. Moreover, the Cochrane

New therapeutics

RSV is a negative-sense single-stranded RNA virus encoding 11 proteins. RSV mainly infects the ciliated airway epithelial cells of the respiratory tract and causes both damage and inflammation of the bronchioles. Two surface proteins (G and F) play a part in RSV binding and fusion respectively. The RSV viral envelope protein, SH (small hydrophobic), is an ion channel whereas the inner envelope is formed by the M (matrix) protein. Inside the viral envelope, four proteins make up the

Remaining challenges

Although the investment in RSV therapeutics has injected new hope in emerging RSV pharmaceuticals, challenges remain for their clinical development and implementation—namely absence of consensus on the most clinically relevant outcomes, the definitions of clear target populations, and barriers to drug access.

Consensus among academics, developers, and regulators is needed on clinical trial design, including identifying relevant endpoints and criteria of vaccine and therapy efficacy. In the

Conclusion

RSV bronchiolitis represents a worldwide health problem, with a substantial disease burden in children less than 5 years of age and 66 000–199 000 estimated deaths worldwide per year. Beyond the acute disease, RSV is implicated in the pathogenesis of recurrent wheeze and possibly in the development of asthma. Evidence-based guidelines offer no obviously effective therapeutic interventions, leaving the standard management of RSV bronchiolitis dependent on adequate hydration and respiratory

Search strategy and selection criteria

References for this Review were identified through a search of PubMed and the Cochrane Library for original research and reviews, with no date or language restrictions, on Aug 1, 2015. We did not intend to do a systematic review of the literature with evidence grading. No inclusion or exclusion criteria were used. Instead, we selected articles that were most relevant to the subheadings used in this Review. We searched for original research and reviews using the terms “respiratory syncytial

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