Respiratory syncytial virus: return of a familiar foe

AN unanticipated by-product of the COVID-19 public health mitigation strategies (prolonged lockdowns, increased hand hygiene measures, international and national border closures) has been a disruption in transmission of other seasonal respiratory viruses, particularly respiratory syncytial virus (RSV), which disappeared for many months early in the pandemic. Upon relaxation of public health measures, RSV infections rapidly re-emerged in many Australian states, leading to an uncharacteristic peak in the spring/summer months and unexpected pressure on health care systems (here and here).

In children, the terms RSV bronchiolitis, pneumonia, pneumonitis, and acute lower respiratory tract infection (ALRI) are sometimes used interchangeably and refer to the syndrome of lower airway inflammation associated with RSV infection.

The clinical syndrome of bronchiolitis (most common in children under 12 months of age) is classically characterised by increased work of breathing, hyperinflation, cough and wheeze with or without fever and dehydration. In very young infants (eg, under the age 3 months) apnoeas or reduced feeding are frequent and may be the sole presenting feature. As with most respiratory viruses, there is a spectrum of clinical severity ranging from a mild upper respiratory tract illness to respiratory failure. While RSV is the commonest cause of viral bronchiolitis, a range of other respiratory viruses (eg, parainfluenza virus, human metapneumovirus, adenovirus and coronaviruses) can cause a similar clinical picture.

The management is usually supportive irrespective of the causative virus — with the exception of influenza, for which effective antiviral therapies exist.

Supportive therapy includes hydration (via nasogastric or intravenous routes) and/or oxygen support (eg, low or high flow oxygen therapy) or ventilation (non-invasive or invasive). Very rarely extracorporeal membrane oxygenation (ECMO) is needed.

Antibiotics are reserved for children in whom secondary bacterial infection is present or suspected. This may be indicated by a clinical deterioration, progression of radiological findings and/or abnormal blood parameters (eg, elevated procalcitonin).

Historically, in some states, nasopharyngeal sampling for viral pathogen identification has been avoided as it rarely impacts on patient management. However, the COVID-19 pandemic has highlighted the need to consider factors beyond individual patient care.

In pre-COVID-19 times, we witnessed the rapid worldwide spread of a newly emerged ON1 variant of RSV in 2009–2010 associated with increased clinical severity in many countries. RSV infections became notifiable in Australia in mid-2021, signifying its public health importance and ahead of expected preventive strategies being registered and available. While testing paradigms may differ across settings, notification of RSV will facilitate systematic surveillance for new variants and greater accuracy in population‐based estimates of incidence.

Understanding which children are at increased risk of severe RSV disease has also been the subject of study. In a large study of children under 2 years of age hospitalised for RSV infections at the Royal Children’s Hospital in Melbourne, prematurity and younger age remained the strongest predictors of severe RSV, but most hospitalised children (79%) were healthy with no known risk factors or comorbid conditions.

Genetics, environment, and innate immune factors likely play an important role in disease susceptibility. In addition to the acute effects of RSV, severe RSV has been linked to longer term effects of recurrent wheeze and asthma (here, here and here). Although causality has not been established, one follow-up study showed 48% of children hospitalised with RSV had a subsequent diagnosis of asthma before age 7.

RSV hospitalisation rates in Australia are highest in infants 0-2 months of age, estimated in 2019 at 2778 per 100 000 population. A recently published paper in The Lancet shed light on the global burden of RSV, reporting ≈33 million infections and 101 400 deaths per year attributable to RSV globally, with the largest burden in low and middle-income countries.

While mortality in Australia is thankfully low, worldwide one in every 28 deaths in those aged 28 days to < 6 months is attributable to RSV. Studies from Australia and the UK show that the health burden of RSV exceeds that of influenza both in children and adults with the excess burden of RSV in Australian children aged less than 5 years to be eight times higher than influenza (accepted for publication).

Furthermore, a recently published RSV economic analysis estimated a mean cost of AU$17 120 per child under the age of 5 years hospitalised (2018 data) and a combined annual health service cost of approximately AU$59–$121 million. A population-based study in Western Australia using linked routine microbiology testing data with clinical data in the years prior to when RSV was notifiable, developed a statistical prediction model to estimate the true burden. Results indicated that current testing practices are likely underestimating RSV hospitalisation incidence by 30–57% in those aged less than 6 months.

Traditionally, severe RSV has been considered a disease of young children and even though RSV rarely causes severe disease in healthy adults, it is an important pathogen in susceptible subgroups such as the elderly, those with chronic lung disease and individuals with immunocompromising conditions (eg, transplant recipients).

Although RSV has a high global burden of disease, no RSV vaccine is currently available and prevention of RSV is limited to one licensed passive immunisation monoclonal antibody (mAb) palivizumab (Synagis, Abbott laboratories). In Australia, this product is expensive and reserved for children considered most at-risk of severe outcomes (eg, those with underlying complex congenital heart disease or chronic lung disease).

The rapid advancement in mRNA vaccine technology for the COVID-19 pandemic has further fuelled an active RSV vaccine development pipeline (here and here). Currently, there are several paediatric and maternal RSV vaccines in development and passive infant immunisation with long-acting RSV mAbs are in late-phase trials.

Nirsevimab (AstraZeneca and Sanofi) is an mAb that has been shown to be highly effective in reducing medically attended RSV-associated ALRI and hospitalisations in ex-premature infants. It had a similar safety profile to palivizumab. It has also been shown to be effective at preventing RSV disease in healthy late-preterm and term infants. Nirsevimab has been granted Breakthrough Therapy Designation by the US Food and Drug Administration and Priority Medicine status by the European Medicines Agency. It is still not known if Nirsevimab will be marketed within a reachable price range for low-income and middle-income countries and which strategy will be used (targeted to all versus only high-risk infants).

The COVID-19 pandemic has taught us many important lessons.

Unprecedented surges in RSV infections and other respiratory viruses across Australia and globally have emphasised the need for systematic enhanced epidemiological and molecular surveillance. This is crucially important to inform health service preparedness, resource allocation and to identify emergence of new variants that may be associated with increased RSV severity. Genomic surveillance has become standard practice for COVID-19 and it may also be appropriate for RSV.

As preventive therapies for RSV move closer to clinical translation, research is needed to better understand the risk factors for severe disease to enable interventions to be targeted to children at highest risk. Research into antiviral therapies, including for neonates and infants, is urgently needed. Public health campaigns with enhanced community and parental awareness are currently lacking. A nationwide collaborative approach to better understand RSV transmission dynamics, molecular epidemiology and immune factors that confer susceptibility to severe RSV disease in children is needed to reduce both the local and global burden of RSV.

Dr Danielle Wurzel is a respiratory physician at The Royal Children’s Hospital (RCH), Melbourne; Head of Childhood Infections and Bronchiectasis Research program at Allergy Lung Health Unit, University of Melbourne and Honorary Research Fellow in the Respiratory Diseases Group of Murdoch Children’s Research Institute (MCRI).

Dr Lien Anh Ha Do is Senior Research Officer in the New Vaccines Group at MCRI. She is also an Honorary Fellow in the Department of Paediatrics at the University of Melbourne.

Associate Professor Nigel Crawford is Director of Surveillance of Adverse Events Following Vaccination in the Community at MCRI and the Head of the Immunisation Service at The RCH. He is also Principal Research Fellow, Department of Paediatrics, University of Melbourne.

Associate Professor Paul Licciardi is Immunology Team Leader and Senior Research Fellow in the New Vaccines Group at MCRI. He is also a Principal Research Fellow in the Department of Paediatrics at the University of Melbourne.

Associate Professor Hannah Moore is Program Head, Infections and Vaccines at the Telethon Kids Institute and Co-Head of the Infectious Disease Epidemiology team within the Wesfarmers Centre of Vaccines and Infectious Diseases (WCVID) at the Telethon Kids Institute in Perth. She also Associate Professor with the School of Population Health at Curtin University.

Professor Chris Blyth is a clinical academic, NHMRC Emerging Leadership Fellow and Director of WCVID. He is Professor of Paediatrics with the School of Medicine, University of Western Australia, a paediatric infectious diseases physician at Perth Children’s Hospital and a Clinical Microbiologist with PathWest Laboratory.

Prof Kim Mulholland is Group Leader of the New Vaccines research group at MCRI, and Professor of Child Health and vaccinology at London School of Hygiene and Tropical Medicine, UK. He is also a current member of the WHO Strategic Advisory Group of Experts on Immunization.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated. 

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