Respiratory Syncytial Virus-Associated Hospitalizations in Children <5 Years: 2016–2022

NVSN surveillance methods have been described elsewhere.^8,9 Briefly, we conducted active, prospective surveillance ≥5 days per week for hospitalized children with acute respiratory illness (ARI) at 7 pediatric medical centers in Nashville, Tennessee; Rochester, New York; Cincinnati, Ohio; Seattle, Washington; Houston, Texas; Kansas City, Missouri; and Pittsburgh, Pennsylvania. We enrolled children <18 years old hospitalized for ARI, defined as an illness with 1 or more of the following: fever, cough, earache, nasal congestion, runny nose, sore throat, vomiting after coughing, wheezing, shortness of breath, rapid or shallow breathing, apnea, apparent life-threatening event, brief resolved unexplained event, and/or myalgia. Data were collected through parent and guardian interviews, medical chart review, and systematic testing of respiratory specimens from all enrolled children for RSV and other respiratory viruses by reverse transcription polymerase chain reaction. Race and ethnicity were reported by the child’s parent or guardian. Institutional review board approval was obtained at each site and at Centers for Disease Control and Prevention (CDC) (CDC IRB#6770). We limited this analysis to children aged <5 years at the time of hospitalization.

Analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC). Characteristics of children hospitalized with RSV were compared between 4 prepandemic seasons (December 1, 2016–September 30, 2020)⁹ and calendar year 2021 or calendar year 2022 by χ-square for categorical variables or Wilcoxon rank sum for continuous variables. For population-based RSV-associated hospitalization rates, only residents of defined catchment area counties for the 7 sites were included; Nashville (Davidson County, TN); Rochester (Monroe County, NY); Cincinnati (Hamilton County, OH); Seattle (King County, WA); Houston (Brazoria, Chambers, Fort Bend, Galveston, Harris, Liberty, Montgomery, and Waller Counties, TX); Kansas City (Jackson County, MO); and Pittsburgh (Allegheny County, PA). County-specific population denominator data are from the 2020 US bridged-race population estimates.¹⁰ Population-based numerators were obtained by adjusting the observed number of hospitalizations at each site to account for weeks with <7 days of surveillance, the proportion of eligible children not enrolled (range 35% to 40%), sensitivity of RSV reverse transcription polymerase chain reaction testing compared with serology (87.6%, CDC unpublished data), and each site’s estimated market share of ARI hospitalizations. Rates were calculated per 1000 children and 95% bootstrap percentile confidence intervals (CI) were determined based on 1000 bootstrap samples for each rate. Bootstrap rate ratios, 95% bootstrap percentile CIs, and P values for the observed differences in rates were calculated.

In the 4 prepandemic seasons, RSV-associated hospitalizations peaked in NVSN surveillance sites in December and January; they peaked in July 2021 and November 2022 during these pandemic years (Fig 1). There was no significant difference in median age between prepandemic seasons and the 2021 season (6.0 months and 6.6 months, respectively; Table 1); however, the median age of children hospitalized with RSV was higher in 2022 than in prepandemic seasons or 2021 (9.6 months vs 6.0 months, P < .001) with a lower proportion of infants aged 0 to 2 months and a higher proportion of children aged 24 to 59 months compared with prepandemic seasons (P < .001). Even with a lower proportion of infants aged 0 to 2 months in 2022, RSV-associated hospitalization rates were consistently highest among the youngest infants in all years. In 2021, a slightly higher proportion of RSV-positive children were Black, Non-Hispanic, or Hispanic (any race) and fewer were white, Non-Hispanic than in prepandemic seasons, whereas in 2022, a higher proportion of RSV-positive children were Hispanic (P < .001 for both). There was no difference in prevalence of underlying medical conditions among RSV-positive hospitalized children between prepandemic seasons and 2021 or 2022 except for an increase in prevalence of neuromuscular disease in the 2021 season (P = .004). Overall, codetections were more common in 2022 than in prepandemic seasons (P = .003); however, codetections of rhinovirus and enterovirus were more common in 2021 and 2022 than in prepandemic seasons (P = .02 and P = .01, respectively), and other virus coinfections were less common. This is likely because of the atypical timing of the 2021 and 2022 RSV seasons abutting the late summer and early fall rhinovirus and enterovirus season. More RSV-positive hospitalized children received supplemental oxygen in 2022 than in prepandemic seasons (P < .001), but there was no difference in the proportion requiring mechanical ventilation or intensive care. In 2022, a higher proportion of children were hospitalized for 3 or more days but there was no difference in median length of stay (P = .07). One RSV-associated death was reported in 2021.

RSV-associated hospitalization rates were higher in 2021 and 2022 than the prepandemic seasonal average annual rates across all age groups and consistently highest among the youngest infants aged 0 to 2 months (Table 2). Rate ratios of 2021 age-specific rates to 2016 to 2020 average annual prepandemic rates ranged from 1.23 to 1.39 and were highest in children aged 24 to 59 months. Rate ratios of 2022 age-specific rates to 2016 to 2020 average annual prepandemic rates ranged from 1.15 to 2.31 and were also highest in children aged 24 to 59 months. Among children less than 2 years of age (0–2, 3–5, 6–11, and 12–23 months) there was no difference in hospitalization rates during 2021 and 2022; however, children aged 24 to 59 months had significantly higher rates of RSV-associated hospitalization in 2022 (rate ratio 1.68 [95% CI 1.37–2.00]). There was also considerable variability in RSV-associated hospitalization rates by enrollment site (Fig 2), with 1 site experiencing slightly lower than prepandemic average RSV-associated hospitalization rates in 2021 and 1 site in 2022.

After a period of very limited RSV circulation during March 2020 to May 2021, the United States experienced atypical RSV seasons in 2021 and 2022 with higher RSV-associated hospitalization rates in children aged <5 years. Although older children were more likely to be hospitalized in pandemic seasons compared with prepandemic seasons and likely contributed to the strain on healthcare systems in 2022, the overall hospitalization burden remained highest among the youngest infants. In fact, infants aged 0 to 2 months had more than 10 times the rate of RSV-associated hospitalizations than children aged 24 to 59 months in all surveillance years. Although the proportion of children who received supplemental oxygen increased in 2022, other measures of disease severity, including proportion admitted to the ICU, proportion requiring mechanical ventilation, and median hospital length of stay, did not differ from prepandemic seasons.

Lack of prior RSV exposure in children aged 12 to 23 months may have led to some increases in hospitalization rates in 2021 and 2022; however, the magnitude of the increase observed in older children in our analysis is substantially less than would have been expected if these same children had been exposed in infancy. The increased rate of 2.4 per 1000 children aged 24 to 59 months is much lower than prepandemic rates in infants that are 5 to 10 times higher. This finding is consistent with prior studies finding lower rates of lower respiratory tract disease in children with first RSV exposure in the second year of life.^7,11 RSV prevention products have demonstrated efficacy against RSV disease, not infection. Our findings are reassuring and suggest that even if these products did prevent—and effectively postpone primary RSV infection – we would not see substantial increases in hospitalization rates in children 12 to 23 months of age after the introduction of maternal vaccination or widespread immunoprophylaxis with long-acting monoclonal antibody products.

There are several limitations in this analysis. First, children hospitalized at the 7 pediatric medical centers of NVSN may not be representative of all hospitalized children across the United States. Second, there may be systematic differences in enrolled children and those who are not enrolled in NVSN, including critically ill children that may impact our assessment of disease severity over time. Third, differences in the use of masking and other nonpharmaceutical interventions by site during the pandemic period may have impacted rates. Likewise, differences in exposures and care-seeking patterns by race and ethnicity during the pandemic period may have impacted enrollment. Finally, this limited epidemiologic analysis found few differences in overall severity of hospitalizations that may be masked by aggregating children aged <5 years. We further assessed this by age 0 to 11 months and 12 to 59 months and did not see differences in severity in prepandemic and 2021 or 2022 seasons. Codetections of other respiratory viruses may impact RSV disease severity and may have contributed to increased hospitalization rates in children aged 24 to 59 months in 2022.

RSV continues to be the leading cause of hospitalization in infants and the atypical 2021 and 2022 RSV seasons resulted in higher hospitalization rates with similar disease severity to prepandemic seasons placing considerable strain on the health system. Newly approved RSV prevention products targeting infants have the potential to substantially reduce the burden of RSV-associated hospitalizations.