Respiratory syncytial virus mortality among young children
Authors: Geoffrey A Weinberg
Journal: The Lancet Global Health (2017)

Acute lower respiratory infection (ALRI) continues to be one of the leading causes of morbidity and mortality in children younger than 5 years across the globe.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; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1189) Google Scholar However, significant challenges remain in determining the epidemiology and aetiology of, and risk factors for, ALRI, severe ALRI, and death. These challenges include addressing a number of biases in clinical diagnosis (with variable clinical and radiological definitions of ALRI), microbiological diagnosis (with known insensitivity of bacterial blood culture and nasopharyngeal viral immunofluorescence and culture, and increased sensitivity but reduced specificity by PCR analyses of nasopharyngeal specimens), and case and control ascertainment in the hospital and community.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; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1189) Google Scholar, 2Deloria Knoll M Fu W Shi Q et al.Bayesian estimation of pneumonia etiology: epidemiologic considerations and applications to the Pneumonia Etiology Research For Child Health (PERCH) study.Clin Infect Dis. 2017; 64: S213-S227Crossref PubMed Scopus (22) Google Scholar, 3O'Brien KL Baggett HC Brooks WA et al.Introduction to the epidemiologic considerations, analytic methods, and foundational results from the Pneumonia Etiology Research For Child Health study.Clin Infect Dis. 2017; 64: S179-S184Crossref PubMed Scopus (15) Google Scholar During the past 30 years, several complex multicentre studies have grappled with these challenges to better define the epidemiology and natural history of ALRI among young children in low-income, middle-income, and high-income countries.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; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1189) Google Scholar, 2Deloria Knoll M Fu W Shi Q et al.Bayesian estimation of pneumonia etiology: epidemiologic considerations and applications to the Pneumonia Etiology Research For Child Health (PERCH) study.Clin Infect Dis. 2017; 64: S213-S227Crossref PubMed Scopus (22) Google Scholar, 3O'Brien KL Baggett HC Brooks WA et al.Introduction to the epidemiologic considerations, analytic methods, and foundational results from the Pneumonia Etiology Research For Child Health study.Clin Infect Dis. 2017; 64: S179-S184Crossref PubMed Scopus (15) Google Scholar, 4Bénet T Sánchez Picot V et al.Microorganisms associated with pneumonia in children <5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study.Clin Infect Dis. 2017; 65: 604-612PubMed Google Scholar, 5Jain S Williams DJ Arnold SR et al.Community-acquired pneumonia requiring hospitalization among US children.N Engl J Med. 2015; 372: 835-845Crossref PubMed Scopus (940) Google Scholar, 6Bale JR Creation of a research program to determine the etiology and epidemiology of acute respiratory tract infection among children in developing countries.Rev Infect Dis. 1990; 12: S861-S866Crossref PubMed Scopus (27) Google Scholar, 7Selwyn BJ The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries. Coordinated Data Group of BOSTID Researchers.Rev Infect Dis. 1990; 12: S870-S888Crossref PubMed Scopus (304) Google Scholar Differing methods of patient ascertainment, changes in laboratory diagnostic methods, and the introduction of conjugate vaccines against Haemophilus influenzae type b and Streptococcus pneumoniae have made synthesis of the data into global estimates of ALRI mortality difficult. Nevertheless, it is estimated that the most commonly identified viral pathogen in children with ALRI—respiratory syncytial virus (RSV)—causes 33·1 million episodes, 3·2 million hospital admissions, and 59 600 in-hospital deaths annually among children younger than 5 years.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; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1189) Google Scholar In The Lancet Global Health, Nienke Scheltema and colleagues8Scheltema NM Gentile A Lucion F et al.Global RSV-associated mortality in young children: a retrospective case series.Lancet Glob Health. 2017; 5: 984-991Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar present a novel retrospective case series analysis of RSV-ALRI mortality among hospitalised children younger than 5 years in 23 countries across six continents during 1995–2015. This analysis is notable for both its breadth and coverage across low-income, middle-income, and high-income countries, and for its attempts to recognise, if not counter, biases in variable case ascertainment and microbiological diagnostic methods. The study, termed RSV-GOLD, obtained patient data from both a comprehensive literature search and direct communication with ALRI, pneumonia, and RSV research networks, and then synthesised the data in a customised, online study questionnaire instrument to produce analyses of mortality by income level of country, paediatric comorbidity, and clinical characteristics.8Scheltema NM Gentile A Lucion F et al.Global RSV-associated mortality in young children: a retrospective case series.Lancet Glob Health. 2017; 5: 984-991Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar The results contribute to the knowledge base of RSV-ALRI mortality among young children, 99% of which occurs in low-income and middle-income countries. Scheltema and colleagues found that a substantial proportion (70%) of RSV-ALRI in-hospital deaths in high-income countries were in children with medical comorbidities; a smaller proportion of deaths in children in middle-income and low-income countries were also associated with medical comorbid conditions (28%). Children in low-income countries dying with in-hospital RSV-ALRI had a lower median age at death than did those in high-income countries (5·0 months [IQR 2·3–11·0] vs 7·0 months [3·6–16·8], respectively). As we move closer to the development of safe and effective RSV vaccines,9Graham BS Modjarrad K McLellan JS Novel antigens for RSV vaccines.Curr Opin Immunol. 2015; 35: 30-38Crossref PubMed Scopus (78) Google Scholar, 10Shaw CA Ciarlet M Cooper BW et al.The path to an RSV vaccine.Curr Opin Virol. 2013; 3: 332-342Crossref PubMed Scopus (35) Google Scholar these data again suggest that to effectively prevent RSV-associated mortality in young children, maternal immunisation (with passive transfer of maternal antibodies) will likely be required, perhaps along with additional interventions for children suffering comorbidities. Scheltema and colleagues note some limitations of their work, which will require further study to refine the characterisation of children dying with RSV-ALRI. First, although their RSV-GOLD study appears to be the largest case series of in-hospital RSV-ALRI young child deaths reported to date, only half or fewer of all paediatric RSV-ALRI deaths globally occur in hospital, and children dying in the community may have different characteristics.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; (published online July 6.)http://dx.doi.org/10.1016/S0140-6736(17)30938-8Summary Full Text Full Text PDF Scopus (1189) Google Scholar The study drew data from 23 countries over a 20 year period, but a few countries contributed proportionally greater amounts of data than did their neighbours on the same continents, potentially leading to biases in the validity of the estimates. More importantly, the introduction of H influenzae and S pneumoniae conjugate vaccines over time, and the movement away from viral culture and immunofluorescence towards PCR diagnostic methods, likely add to both secular variation in ALRI aetiological attributable fraction and case ascertainment. An incomplete response rate among queried ALRI researchers may also have led to some decreased precision and accuracy of the data. Despite such limitations, Scheltema and colleagues are to be commended for performing this important first-pass effort in the characterisation of global RSV-ALRI mortality among hospitalised young children. The approach can be refined as microbiological methods are improved, and case and control ascertainment is stratified. This approach may be relevant for other potentially vaccine-preventable causes of paediatric ALRI as well, such as human parainfluenza viruses.11Weinberg GA Hall CB Iwane MK et al.Parainfluenza virus infection of young children: estimates of the population-based burden of hospitalization.J Pediatr. 2009; 154: 694-699Summary Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 12Abedi GR Prill MM Langley GE et al.Estimates of parainfluenza virus-associated hospitalizations and cost among children aged less than 5 years in the United States, 1998-2010.J Pediatric Infect Dis Soc. 2016; 5: 7-13Crossref PubMed Scopus (37) Google Scholar From the initial BOSTID respiratory disease studies of the 1980s,6Bale JR Creation of a research program to determine the etiology and epidemiology of acute respiratory tract infection among children in developing countries.Rev Infect Dis. 1990; 12: S861-S866Crossref PubMed Scopus (27) Google Scholar, 7Selwyn BJ The epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries. Coordinated Data Group of BOSTID Researchers.Rev Infect Dis. 1990; 12: S870-S888Crossref PubMed Scopus (304) Google Scholar through the ongoing analyses by the PERCH,2Deloria Knoll M Fu W Shi Q et al.Bayesian estimation of pneumonia etiology: epidemiologic considerations and applications to the Pneumonia Etiology Research For Child Health (PERCH) study.Clin Infect Dis. 2017; 64: S213-S227Crossref PubMed Scopus (22) Google Scholar, 3O'Brien KL Baggett HC Brooks WA et al.Introduction to the epidemiologic considerations, analytic methods, and foundational results from the Pneumonia Etiology Research For Child Health study.Clin Infect Dis. 2017; 64: S179-S184Crossref PubMed Scopus (15) Google Scholar GABRIEL,4Bénet T Sánchez Picot V et al.Microorganisms associated with pneumonia in children <5 years of age in developing and emerging countries: the GABRIEL pneumonia multicenter, prospective, case-control study.Clin Infect Dis. 2017; 65: 604-612PubMed Google Scholar EPIC,5Jain S Williams DJ Arnold SR et al.Community-acquired pneumonia requiring hospitalization among US children.N Engl J Med. 2015; 372: 835-845Crossref PubMed Scopus (940) Google Scholar and NVSN13Hall 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 (1447) Google Scholar, 14Hall CB Weinberg GA Blumkin AK et al.Respiratory syncytial virus-associated hospitalizations among children less than 24 months of age.Pediatrics. 2013; 132: e341-e348Crossref PubMed Scopus (354) Google Scholar study groups, and now the RSV-GOLD group,8Scheltema NM Gentile A Lucion F et al.Global RSV-associated mortality in young children: a retrospective case series.Lancet Glob Health. 2017; 5: 984-991Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar a more accurate and precise estimate of the burden of global RSV infection is being formed. The world's children deserve no less. I declare no competing interests. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case seriesThis study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries. Full-Text PDF Open Access