Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data.

Background: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation.
Methods: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742.
Findings: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23).
Interpretation: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants.
Funding: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe.
Competing Interests: Declaration of interests YM and ES were affiliated with the University of Edinburgh when this work was conducted. YM is currently affiliated to the School of Public Health, Wuhan University, Wuhan, China and ES is employed by University College Hospital, University College Hospitals NHS Foundation Trust, London, UK. XW reports grants from GSK to their institution and personal fees from Pfizer, outside the submitted work. YL reports grants from Wellcome Trust, WHO, and GSK paid to their institution, and personal fees from Pfizer, outside the submitted work. TS reports grants from Royal Society of Edinburgh outside the submitted work. LJB reports regular interactions with AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, MeMed Diagnostics, and Janssen but has not received personal fees or other personal benefits; being the founding chairman of the ReSViNET Foundation; their affiliation (University Medical Centre Utrecht) has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics; major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation; major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi; major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer; and minor funding (€1000–€25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, and Janssen. HYC reports consulting for Ellume, Pfizer, and the Gates Foundation; serving on advisory boards for Vir, Merck, and AbbVie; conducting continuing medical education teaching with Medscape, Vindico, Cataylst CME, and Clinical Care Options; research funding from Gates Ventures; and receiving support and reagents from Ellume and Cepheid, all outside of the submitted work. HJZ reports grants from the Gates Foundation, AstraZeneca, MSD, and Pfizer paid to their institution outside the submitted work, and serving on advisory boards for MSD. TH reports personal fees from Janssen, Sanofi, Enanta, MSD, and Moderna, all outside of the submitted work. MHJ reports personal fees from AstraZeneca, OM-Pharma, Chiesi, GSK, and Boehringer Ingelheim, outside the submitted work. MCN reports grants from the Gates Foundation, European & Developing Countries Clinical Trials Partnership, Pfizer, AstraZeneca, and Sanofi; and serving on advisory boards for Sanofi, all outside the submitted work. BR received honoraria due to lectures from AbbVie, Germania, Sanofi, AstraZeneca, Milupa, Nestle, and Fresenius, outside the submitted work; and travel support from AbbVie, Chiesi, AstraZeneca, Sanofi, and Nestle. HN reports grants from the Innovative Medicines Initiative related to the submitted work; grants from WHO, the National Institute for Health Research, Pfizer, and Icosavax; and personal fees from the Gates Foundation, Pfizer, ReViral, GSK, Merck, Icosavax, Sanofi, Novavax, and AbbVie, outside the submitted work. CFY reports grants from National Medical Research Council Singapore and Wellcome Trust, and funding to attend conferences and honorarium from Sanofi, Pfizer, and Takeda, outside the submitted work. All other authors declare no competing interests.
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