The age profile of respiratory syncytial virus burden in preschool children of low- and middle-income countries: A semi-parametric, meta-regression approach

Author summary Why was this study done? Respiratory syncytial virus (RSV) is the most common cause of acute pulmonary infections in children. The RSV disease burden is high, especially in the nearly 600 million children under 5 living in 121 low-income (LIC) and middle-income countries (MICs) on which this study focuses.Evidence on the age distribution of RSV infections in these countries is based on sparse data using age breakdowns that are not always comparable.Different pharmaceutical products are becoming available that can reduce the RSV burden. Given that the immunity these products confer differs and wanes over time, it is essential to understand well at which months of age RSV infections drive the RSV disease burden.This study uses improved statistical models to estimate in depth the age profile of RSV cases, hospitalizations, and in-hospital deaths in young children. What did the researchers do and find? We calculated the distributions of the age of infection, hospitalization, and in-hospital deaths. Depending on whether we use hospital-based or community-based incidence studies to inform our methods, we estimate the peak age of infection at 2.6 to 4.8 months, the mean age at 15.8 to 18.9, and the median age at 11.6 to 14.7 months.We estimate that on an average year, there are 28.23 to 31.34 million cases of RSV, 2.95 to 3.35 million hospitalizations, and 34,114 to 46,485 deaths in children under 5 in LICs and MICs. About half the deaths occur in the community, outside of hospital settings.More severe outcomes, such as hospitalizations and in-hospital deaths have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths. What do these findings mean? Our results support strategies using passive immunity products, such as maternal vaccines and monoclonal antibodies, to protect infants and active vaccination strategies for children over one, who also bear a large proportion of the burden.These results improve the choice of strategies offering the best value for money from a given budget.This study may enable modelers to make improved estimates thus allowing policymakers to gain a better understanding of the potential impact that new pharmaceutical products could have. BackgroundRespiratory syncytial virus (RSV) infections are among the primary causes of death for children under 5 years of age worldwide. A notable challenge with many of the upcoming prophylactic interventions against RSV is their short duration of protection, making the age profile of key interest to the design of prevention strategies. Methods and findingsWe leverage the RSV data collected on cases, hospitalizations, and deaths in a systematic review in combination with flexible generalized additive mixed models (GAMMs) to characterize the age burden of RSV incidence, hospitalization, and hospital-based case fatality rate (hCFR). Due to the flexible nature of GAMMs, we estimate the peak, median, and mean incidence of infection to inform discussions on the ideal "window of protection" of prophylactic interventions. In a secondary analysis, we reestimate the burden of RSV in all low- and middle-income countries. The peak age of community-based incidence is 4.8 months, and the mean and median age of infection is 18.9 and 14.7 months, respectively. Estimating the age profile using the incidence coming from hospital-based studies yields a slightly younger age profile, in which the peak age of infection is 2.6 months and the mean and median age of infection are 15.8 and 11.6 months, respectively. More severe outcomes, such as hospitalization and in-hospital death have a younger age profile. Children under 6 months of age constitute 10% of the population under 5 years of age but bear 20% to 29% of cases, 28% to 39% of hospitalizations, and 38% to 50% of deaths.On an average year, we estimate 28.23 to 31.34 million cases of RSV, between 2.95 to 3.35 million hospitalizations, and 16,835 to 19,909 in-hospital deaths in low, lower- and upper middle-income countries. In addition, we estimate 17,254 to 23,875 deaths in the community, for a total of 34,114 to 46,485 deaths. Globally, evidence shows that community-based incidence may differ by World Bank Income Group, but not hospital-based incidence, probability of hospitalization, or the probability of in-hospital death (p & LE; 0.01, p = 1, p = 0.86, 0.63, respectively). Our study is limited mainly due to the sparsity of the data, especially for low-income countries (LICs). The lack of information for some populations makes detecting heterogeneity between income groups difficult, and differences in access to care may impact the reported burden. ConclusionsWe have demonstrated an approach to synthesize information on RSV outcomes in a statistically principled manner, and we estimate that the age profile of RSV burden depends on whether information on incidence is collected in hospitals or in the community. Our results suggest that the ideal prophylactic strategy may require multiple products to avert the risk among preschool children.