Global, Regional, and National Disease Burden Estimates of Acute Lower Respiratory Infections Due to Respiratory Syncytial Virus in Young Children in 2019: A Systematic Analysis

Abstract

Background: Respiratory syncytial virus (RSV) is the predominant cause of acute lower respiratory infection (ALRI) in young children. We previously estimated that globally in 2015, 33·1 million episodes of RSV-associated ALRI occurred in children aged 0–<60 months, resulting in a total of 118,200 community and in-hospital deaths. Since then, several community surveillance studies have been conducted to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated ALRI morbidity and mortality at global, regional and national levels in children aged 0–<60 months for 2019.

Methods: We expanded our global RSV disease burden dataset by obtaining new data from an updated systematic literature review (including papers published between 1^st January 2017 and 31^st December 2020) as well as unpublished data from 51 high-quality studies. Generalised linear mixed-effects model (GLMM) was applied to estimate RSV-associated ALRI incidence, hospital admission and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. Country-level RSV-associated ALRI incidence was estimated through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality (i.e., in-hospital and out-of-hospital / community).

Findings: We estimated that globally in 2019, there were 33·0 million (uncertainty range, UR: 25·4–44·6) RSV-associated ALRI episodes, 3·6 million (2·9–4·6) RSV-associated ALRI hospital admissions, 26300 (15100–49100) RSV-associated ALRI in-hospital deaths, and 101400 (84500–125200) RSV-attributable overall deaths in 0–<60 months. In infants aged 0–<6 months, there were 6·6 million (4·6–9·7) RSV-associated ALRI episodes, 1·4 million (1·0–2·0) RSV-associated ALRI hospital admissions, 13300 (6800–28100) RSV-associated ALRI in-hospital deaths, and 45700 (38400–55900) RSV-attributable overall deaths. 2·0% (1·6–2·4) of overall deaths in 0–<60 months and 3·6% (3·0–4·4) of overall deaths in 28 days–<6 months were attributable to RSV. Low- and middle-income countries (LMICs) accounted for more than 95% of RSV-associated ALRI episodes and more than 97% of RSV-attributable deaths across all age bands.

Interpretation: RSV represents substantial morbidity and mortality burden globally in 0–<60 months, especially during the first six months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease, with one in every 50 deaths in 0–<60 months and one in every 28 deaths in 28 days–<6 months being attributable to RSV globally. RSV passive immunisation programmes targeting protection during the first six months of life could have a substantial effect on reducing RSV disease burden.

Funding: European Union Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Declaration of Interest: YL reports grants from Wellcome Trust and WHO, outside the submitted work. MTC reports grants from BMGF related to the submitted work; and grants from MITS Surveillance Alliance, and support for attending the RSVVW meeting from ReSViNET, outside the submitted work. SAM reports grants from Pfizer, Minervax, GSK, BMGF, and South African Medical Research Council, honoraria from BMGF, and participation on data safety monitoring boards for PATH and CAPRISA, outside the submitted work. SBO reports grants from BMGF, outside the submitted work. EAFS reports grants, personal fees, and travel fees from AstraZeneca, Merck, Regeneron, Pfizer, and Roche; consultation, lecture fees, travel support, and data and safety monitoring board fees from Abbvie; data and safety monitoring board fees from GSK; consultation fees from Alere; grants from Johnson and Johnson; and grants and travel support from Novavax, outside the submitted work. HC reports grants from BMGF, outside the submitted work. AGordon reports grants from NIAID and CDC related to the submitted work, and participation on an advisory board for Janssen, outside the submitted work. TH reports personal fees from Janssen and Sanofi Pasteur, outside the submitted work. AK reports grants from CDC, and honoraria from CDC and WHO, outside the submitted work. AMI reports grants from FISABIO-Public Health, Sanofi Pasteur and CIBER-ESP (ISCIII) related to the submitted work; and honoraria from MSD as a speaker in a vaccine research course, and travel grants for attending meetings sponsored by Sanofi, outside the submitted work. HCM reports grants from National Health and Medical Research Council related to the submitted work; and honoraria from MSD for participation on an expert input forum, outside the submitted work. DJN reports grants from Wellcome Trust related to the submitted work. OE reports receipt of PhD scholarship from DAAD (German Academic Exchange Service) Government of Ghana scholarship, outside the submitted work. CR reports grants from CDC in collaboration with U.S. Naval Medical Research Unit Nօ. 6 related to the submitted work, and grants from South America Influenza Initiative, outside the submitted work. AS reports grants from University of Colorado, outside the submitted work. RS reports grants from Merck, outside the submitted work. SKS reports salaries from GSK for working on the data abstraction, leading the prospective cohort study from which the data were abstracted and for providing input for the manuscript development, related to the submitted work; and stock in GSK, outside the submitted work. AvG reports grants from CDC, outside the submitted work. DW reports grants from Murdoch Children’s Research Institute related to the submitted work, and honoraria from MSD for participation on an expert input forum, outside the submitted work. LMY reports grants from Japan Agency for Medical Research and Development related to the submitted work, and honoraria for a lecture from MSD KK. HJZ reports grants from BMGF, South African Medical Research Council, NIH and AstraZeneca, and participation on WHO Technical Advisory Group with no payment, outside the submitted work. HN reports grants from the Innovative Medicines Initiative related to the submitted work; and consulting fees from BMGF, Pfizer, and Sanofi, honoraria from Abbvie, support from Sanofi for attending meetings, and participation on advisory boards from Sanofi, Janssen, Novavax, Reviral, Resvinet, and WHO, outside the submitted work.

Ethical Approval: The study protocol was approved by the Naval Medical Research Unit Number Six Institutional Review Board in compliance with all applicable Federal regulations governing the protection of human subjects. Some

Keywords: Respiratory Syncytial Virus, disease burden, global burden, acute lower respiratory infection, children, pneumonia, bronchiolitis, epidemiology, mortality