Determining the burden of respiratory syncytial virus disease: the known and the unknown
Authors: Ruth A Karron, Robert E Black
Journal: The Lancet (2017)

60 years ago, respiratory syncytial virus (RSV) was identified in children admitted to hospital in Baltimore, MD, USA, with bronchiolitis or pneumonia.1Chanock RM Finberg L Recovery from infants with respiratory illness of a virus related to chimpanzeecoryza agent (CCA). II. Epidemiological aspects of infection in infants and young children.Am J Hygiene. 1957; 66: 291-300PubMed Google Scholar Since that time, RSV has been established as a leading cause of acute lower respiratory illness (ALRI) in infants and children living in all regions of the world.2Nair H Nokes DJ Gessner BD et al.Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.Lancet. 2010; 375: 1545-1555Summary Full Text Full Text PDF PubMed Scopus (1950) Google Scholar, 3Lozano R Naghavi M Foreman K et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128Summary Full Text Full Text PDF PubMed Scopus (9860) Google Scholar, 4Rudan I O'Brien KL Nair H et al.Epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries.J Glob Health. 2013; 3: 010401Crossref PubMed Google Scholar, 5Stein RT Bont LJ Zar H et al.Respiratory syncytial virus hospitalization and mortality: systematic review and meta-analysis.Pediatr Pulmonol. 2017; 52: 556-569Crossref PubMed Scopus (165) Google Scholar As the widespread use of Haemophilus influenzae type b and pneumococcal conjugate vaccines decreases the burden of bacterial pneumonia in children, the proportional contribution of RSV to childhood ALRI will continue to increase. Substantial effort is being put into RSV disease prevention; more than 15 RSV vaccines and vaccine-like monoclonal antibodies (mAbs) are currently being assessed in clinical trials.6PATHRSV Vaccine snapshot—PATH Vaccine Resource Library.http://www.path.org/vaccineresources/details.php?i=1562Date: 2017Google Scholar The burden of RSV disease in children—both in hospital and in the community—has been well described in many high-income settings.7Hall CB Weinberg GA Iwane MK et al.The burden of respiratory syncytial virus infection in young children.N Engl J Med. 2009; 360: 588-598Crossref PubMed Scopus (1440) Google Scholar, 8Taylor S Taylor RJ Lustig RL et al.Modelling estimates of the burden of respiratory syncytial virus infection in children in the UK.BMJ Open. 2016; 6: e009337Google Scholar However, our understanding of the age-specific incidence of RSV disease and its contribution to paediatric mortality in low-income and middle-income countries (LMICs) has lagged behind. In 2010, Nair and colleagues2Nair H Nokes DJ Gessner BD et al.Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.Lancet. 2010; 375: 1545-1555Summary Full Text Full Text PDF PubMed Scopus (1950) Google Scholar published an estimate of what the global RSV morbidity and mortality had been in children younger than 5 years during 2005; this study was an important contributor to our understanding of the global impact of RSV, but had limitations associated with non-uniform case definitions and a broad range for estimated mortality (66 000–199 000 deaths, with no point estimate possible). Moreover, this study was not able to provide RSV morbidity and mortality estimates by narrow age strata in the first year of life, which is important to plan future passive and active RSV immunisation strategies. In The Lancet, Ting Shi and colleagues9Shi T McAllister DA O'Brien KL et al.for RSV Global Epidemiology NetworkGlobal, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.Lancet. 2017; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1170) Google Scholar present new global estimates of the incidence, hospital admission rates, and deaths for RSV-associated ALRI based on a literature review in all languages, including Chinese, an extensive search for unpublished data, and application of standardised case definitions. They estimate that in 2015, 33·1 million (uncertainty range [UR] 21·6–50·3) episodes of RSV-ALRI resulted in about 3·2 million (2·7–3·8) hospital admissions and 59 600 (48 000–74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, they estimate that 1·4 million (1·2–1·7) hospital admissions, and 27 300 (20 700–36 200) in-hospital deaths were due to RSV-ALRI. And they estimate that overall RSV-ALRI mortality could be as high as 118 200 (94 600–149 400). These data substantially increase the quality and quantity of information available to make RSV disease burden estimates, yet some remaining gaps limit their certainty and our ability to prioritise efforts to develop effective interventions. The most substantial data are available for overall RSV hospital admissions; less information is available for hospital admissions by age, especially in neonates, and for RSV illness and mortality in the community. The estimated deaths from RSV-associated ALRI of 118 200 (94 000–149 400) would constitute 8·2% of the estimated 1·438 million deaths classified as sepsis or pneumonia in 2015.10Liu L Oza S Hogan D et al.Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals.Lancet. 2016; 388: 3027-3035Summary Full Text Full Text PDF PubMed Scopus (1723) Google Scholar The uncertainty is probably greater than that reflected in the range given, which is based on the data used. The proportion of RSV-associated ALRI and deaths that occur outside of hospitals in LMICs is unknown and likely to be high. Estimation of RSV-associated ALRI deaths, including those that occurred at home, is based only on data from sites in rural Bangladesh, urban slums in Argentina, and rural hamlets in Indonesia where the excess ALRI mortality during RSV season was used to calculate the ratio between community and in-hospital deaths in each site. The mean of these three ratios was used to inflate the estimated in-hospital deaths in LMICs to estimate the total RSV deaths, adjusted for the co-occurrence of influenza. The possible effect of several factors, including the variation by place and time in RSV infection rates, the limited information available to allow attribution of excess deaths to RSV versus influenza or other infections with overlapping seasonality, a risk relationship of RSV with pneumococcal infections,11Madhi SA Klugman KP A role for Streptococcus pneumoniae in virus-associated pneumonia.Nat Med. 2004; 10: 811-813Crossref PubMed Scopus (317) Google Scholar and possible alterations of hospital admission rates or hospital case fatality rates in research sites, suggest that available data might limit our ability to accurately assess global RSV mortality. Additional studies of community-based RSV mortality are needed, with a particular focus on mortality in the first months of life and possible amelioration of mortality through introduction of pneumococcal conjugate vaccines. What are the implications of this study for RSV prevention strategies? Contrary to data from many previous epidemiological studies, this study finds a substantial RSV disease burden in neonates, with estimates of 40 episodes per 1000 neonates per year (95% CI 2·5–635·7). These data, along with the substantial rate of disease in the 1–5 month age group, suggest the necessity of passive protection against RSV infection at birth, either through maternal immunisation or administration of a birth dose of an extended half-life mAb.6PATHRSV Vaccine snapshot—PATH Vaccine Resource Library.http://www.path.org/vaccineresources/details.php?i=1562Date: 2017Google Scholar However, this study also finds a substantial RSV disease burden in older infants and young children: more than 80% of RSV-ALRI (about 27·5 of about 33 million cases) and more than half of all RSV in-hospital deaths (about 32 000 of about 60 000 deaths) are estimated to have occurred in infants older than 6 months of age, well beyond the reach of protection likely to be afforded by maternal immunisation.12Nunes MC Cutland CL Jones S et al.Duration of infant protection against influenza illness conferred by maternal immunization: secondary analysis of a randomized clinical trial.JAMA Pediatr. 2016; 170: 840-847Crossref PubMed Scopus (84) Google Scholar These data suggest the importance of developing vaccines for active infant immunisation to provide durable protection against RSV disease. Finally, as this and previous studies have shown,2Nair H Nokes DJ Gessner BD et al.Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.Lancet. 2010; 375: 1545-1555Summary Full Text Full Text PDF PubMed Scopus (1950) Google Scholar, 3Lozano R Naghavi M Foreman K et al.Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.Lancet. 2012; 380: 2095-2128Summary Full Text Full Text PDF PubMed Scopus (9860) Google Scholar, 9Shi T McAllister DA O'Brien KL et al.for RSV Global Epidemiology NetworkGlobal, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.Lancet. 2017; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1170) Google Scholar the overwhelming burden of RSV disease is in LMICs. The development of vaccines and mAbs for RSV disease prevention that are affordable and globally available must be a public health priority. RB declares no competing interests. RAK has received a consulting fee from Regeneron for a Scientific Advisory Board meeting that was convened to discuss RSV F mAb REGN2222 and has received funding through National Institutes of Health contract HHSN272200900010C for research on live viral vaccines, including RSV vaccines. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling studyGlobally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group. Full-Text PDF Open Access