Deaths from RSV in young infants—the hidden community burden
Authors: Cheryl Cohen, Heather J Zar
Journal: The Lancet Global Health (2022)

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) in children. In 2015, the global burden in children under 5 years was estimated to be 33·1 million RSV-associated LRTI episodes, 3·2 million hospitalisations, and around 60 000 in-hospital deaths, but there were up to 118 200 estimated deaths when accounting for community-based mortality.1Shi T McAllister DA O'Brien KL et al.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 study.Lancet. 2017; 390: 946-958Summary Full Text Full Text PDF PubMed Scopus (1340) Google Scholar The Global Burden of Diseases, Injuries, and Risk Factors Study reported that in 2016, RSV accounted for 10·7 million LRTI episodes and more than 41 000 deaths in children younger than 5 years.2Troeger C Blacker B Khalil IA et al.Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Infect Dis. 2018; 18: 1191-1210Summary Full Text Full Text PDF PubMed Scopus (858) Google Scholar A more recent analysis of RSV-associated hospitalisations in 58 countries estimated that there were 2·5–4·1 million hospitalisations in children in 2019.3Li Y Johnson EK Shi T et al.National burden estimates of hospitalisations for acute lower respiratory infections due to respiratory syncytial virus in young children in 2019 among 58 countries: a modelling study.Lancet Respir Med. 2021; 9: 175-185Summary Full Text Full Text PDF Scopus (45) Google Scholar However, studies of the burden of RSV in infants have largely been done in health-care facilities, with a paucity of data from community settings, in part because of the difficulties of capturing community deaths and confirming RSV. Estimates of the overall burden of RSV-associated mortality have therefore mainly relied on modelling studies. In a study by Christopher Gill and colleagues in The Lancet Global Health,4Gill CJ Mwananyanda L MacLeod WB et al.Infant deaths from respiratory syncytial virus in Lusaka, Zambia from the ZPRIME study: a 3-year, systematic, post-mortem surveillance project.Lancet Glob Health. 2022; 10: e269-e277Scopus (10) Google Scholar the burden of RSV-associated mortality among infants younger than 6 months in Zambia, including community and facility-based deaths, was measured by post-mortem surveillance, predominantly at the morgue of the University Teaching Hospital in Lusaka, Zambia. RSV was detected using reverse transcriptase quantitative PCR on nasal samples. Over a 3-year period, samples were obtained from 2286 infants who had died, representing 79% of all deaths in infants younger than 6 months in the area. RSV was found in 7% of deaths, with higher detection among community deaths (9%) compared with early (4%; <48 h from admission) and late (5%; ≥48 h from admission) facility deaths. This finding represents a population-attributable fraction of 2·8% (95% CI 1·0–4·6) for all infant deaths. Most (72%) RSV-attributable deaths were in infants younger than 3 months. The pattern of RSV-associated mortality was seasonal and was highest in the most socioeconomically deprived communities. The final year of the study coincided with the SARS-CoV-2 pandemic, which was associated with reduced RSV circulation, and study activities were suspended during the time of the year that typically coincided with the peak RSV season, potentially leading to an underestimate of RSV-associated deaths. This study includes data from a single urban African city, Lusaka. Additional evidence for the high burden of RSV-associated community deaths has come from mortality surveillance studies in Argentina (in children <5 years), India (in children <2 years), and Pakistan (in infants <6 months).5Srikantiah P Vora P Klugman KP Assessing the full burden of respiratory syncytial virus in young infants in low- and middle-income countries: the importance of community mortality studies.Clin Infect Dis. 2021; 73: S177-S179Crossref PubMed Scopus (17) Google Scholar In all these settings, the burden of RSV-associated deaths predominated in the community and was highest in infants younger than 3 months. Additionally, the Child Health and Mortality Prevention Surveillance (CHAMPS) study (done in seven countries in sub-Saharan Africa and south Asia with high childhood mortality), post-mortem minimally invasive tissue sampling identified that RSV was an important cause of death in children younger than 5 years, with half of RSV-associated deaths occurring in infants younger than 6 months.6Blau DM Baillie VL Els T et al.Deaths attributed to respiratory syncytial virus in young children in high-mortality rate settings: report from child health and mortality prevention surveillance (CHAMPS).Clin Infect Dis. 2021; 73: S218-S228Crossref Scopus (11) Google Scholar Limitations of the current study include inclusion of infants only up to age 6 months, since RSV-associated LRTI can occur throughout early childhood.7O'Brien KL Baggett HC Brooks WA et al.Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study.Lancet. 2019; 394: 757-779Summary Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 8Zar HJ Barnett W Stadler A Gardner-Lubbe S Myer L Nicol MP Aetiology of childhood pneumonia in a well vaccinated South African birth cohort: a nested case-control study of the Drakenstein Child Health Study.Lancet Respir Med. 2016; 4: 463-472Summary Full Text Full Text PDF PubMed Scopus (136) Google Scholar Furthermore, the role of co-pathogens, including bacteria, was not investigated. Although case–control studies show that detection of RSV is strongly associated with LRTI, studies have also found that the cause of LRTI, especially severe disease, is frequently due to multiple organisms.7O'Brien KL Baggett HC Brooks WA et al.Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study.Lancet. 2019; 394: 757-779Summary Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 8Zar HJ Barnett W Stadler A Gardner-Lubbe S Myer L Nicol MP Aetiology of childhood pneumonia in a well vaccinated South African birth cohort: a nested case-control study of the Drakenstein Child Health Study.Lancet Respir Med. 2016; 4: 463-472Summary Full Text Full Text PDF PubMed Scopus (136) Google Scholar In the CHAMPS study, RSV with co-infections was common.6Blau DM Baillie VL Els T et al.Deaths attributed to respiratory syncytial virus in young children in high-mortality rate settings: report from child health and mortality prevention surveillance (CHAMPS).Clin Infect Dis. 2021; 73: S218-S228Crossref Scopus (11) Google Scholar Related to this finding, risk factors for mortality or vaccination status were not reported—immunisation with pneumococcal conjugate vaccine reduced subsequent hospitalisation for severe RSV-associated LRTI, indicating that bacterial RSV interaction might be important in severe disease. Additionally, swabs were taken after death, rather than at the time of acute illness, so some RSV-associated deaths might have been missed if the virus was no longer detectable in the nasopharynx. The development of new strategies to prevent RSV in infants—either immunisation of pregnant women or administration of a long acting monoclonal antibody to infants shortly after birth—offer much promise for prevention of RSV-associated LRTI and mortality.9Griffin MP Yuan Y Takas T et al.Single-dose nirsevimab for prevention of RSV in preterm infants.N Engl J Med. 2020; 383: 415-425Crossref PubMed Scopus (236) Google Scholar, 10Madhi SA Polack FP Piedra PA et al.Respiratory syncytial virus vaccination during pregnancy and effects in infants.N Engl J Med. 2020; 383: 426-439Crossref PubMed Scopus (191) Google Scholar The epidemiology of community-based deaths, with most deaths in infants under 3 months or in low socioeconomic status areas, suggests that such interventions might be highly effective in averting RSV-associated mortality, with the highest efficacy for preventive interventions in the first 90 days of life. Such interventions might be especially promising in communities that are the most disadvantaged or densely populated, and where there is suboptimal access to care. Programmes to deliver new interventions efficiently and effectively, either seasonally or annually, need to be developed. Ensuring affordable, equitable global access to new effective preventive interventions will be crucial, to reduce the substantial burden of RSV-associated mortality in infants in the community, as highlighted by the current study. CC reports grants to her institution from the US Centers for Disease Control and Prevention, the Programme of Advancement Through Health and Education, the Bill & Melinda Gates Foundation, the South African Medical Research Council, Wellcome Trust, and Sanofi Pasteur, outside the submitted work. HZ reports grants to her institution from the Gates Foundation, Pfizer, AstraZeneca, Novavax, MSD, and the South African Medical Research Council, outside the submitted work. Infant deaths from respiratory syncytial virus in Lusaka, Zambia from the ZPRIME study: a 3-year, systematic, post-mortem surveillance projectRSV was a major seasonal cause of overall infant mortality, particularly among infants younger than 3 months of age. Because most RSV deaths occurred in the community and would have been missed through hospital-based surveillance, the global burden of fatal RSV has probably been underestimated. Full-Text PDF Open Access