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 children born prematurely are a high-risk group for severe respiratory syncytial virus (RSV) acute lower respiratory infection (ALRI). Here, we assess the global disease burden of and risk factors for RSV-associated ALRI in preterm-born [<37 weeks gestational age (wGA)] young children.

Methods
We conducted a systematic analysis of aggregated data from published studies (between 1 Jan 1995 and 31 Dec 2021, identified from MEDLINE, Embase, and Global Health) and individual participant data shared by an investigator group on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children under two years of age born preterm. We conducted two-stage random-effects meta-regression analyses accounting for chronologic age groups, gestational age bands (early preterm: <32 wGA; late preterm: 32–<37 wGA), and time trend. 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 oxygen and mechanical ventilation or intensive care unit admission) by estimating pooled odds ratios (OR) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis).

Findings
We included 47 studies from the literature and 17 studies with individual-participant-level data. We estimated that globally in 2019, there were 1·64 million (95% uncertainty range: 1·35–1·99) RSV-associated ALRI episodes, 533,000 (385,000–730,000) hospital admissions, 3,050 (1,080–8,620) in-hospital deaths, and 26,760 (11,190–46,240) overall deaths in preterm infants. Among early preterm infants, 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 all infants (of any gestational age). In the second year of life, early preterm children had a comparable incidence rate but still significantly higher hospitalisation rate (RR=2·26, 1·27–3·98) compared to all children. Although late preterm children had RSV-associated ALRI incidence rate comparable to all children, they had higher RSV-associated ALRI hospitalisation rate in the first six months (RR= 1·93, 1·11–3·26). Overall, preterm infants accounted for 25% [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. While most factors identified to be associated with RSV-associated ALRI incidence were perinatal and sociodemographic characteristics, factors associated with severe outcomes were mainly underlying medical conditions including congenital heart disease, tracheostomy, broncho-pulmonary dysplasia, chronic lung disease, or Down syndrome (range of ORs: 1·40 to 4·23).

Interpretation
Preterm infants carry a disproportionately high RSV disease burden, with 10% of population accounting for 25% of RSV hospitalisation burden. Early preterm children have noteworthy RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV will likely have a significant public health impact for preventing RSV-associated ALRI and severe outcomes in preterm children.

Funding
EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU)