Impact of previous SARS-CoV-2 infection on the severity of respiratory syncytial virus infection in hospitalized children

This study investigated the association between prior SARS-CoV-2 exposure, determined serologically by the presence of specific IgG, IgA, and IgM antibodies, and the clinical severity of RSV infection in children under five years of age during the 2023/2024 epidemic season. Elucidation of whether such a relation exists is crucial given that both viruses are common agents causing respiratory disease in overlapping time frames, particularly in autumn and winter seasons in temperate climates^15,16. Therefore, it is plausible that over the course of a particular epidemic season, children will first be infected with SARS-CoV-2, followed by subsequent RSV infection.

Such exacerbation of the clinical severity of RSV infection could potentially result from antibody-dependent enhancement (ADE), a phenomenon in which the humoral immune response to one viral infection contributes to a more severe course of another¹⁷. For instance, prior exposure to the Zika virus is associated with a more severe course of dengue and an increased risk of fatal outcomes, largely due to cross-reactive non-neutralizing antibodies^18,19. More recently, in vitro and in vivo studies have demonstrated that antibodies generated in response to SARS-CoV-2 can enhance dengue virus infection²⁰ , though such an effect on the clinical level, at least in children, is contested²¹. Nevertheless, all of these observations raise theoretical concerns about similar effects with other respiratory viruses. Beyond ADE, SARS-CoV-2 infection may influence the severity of RSV infection through broader alterations in the immune system. In children, SARS-CoV-2 has been shown to induce long-term changes in both innate and adaptive immunity, including skewed cytokine responses, lymphopenia, and dysregulation of interferon signalling pathways^22,23. These effects could, in theory, impair viral clearance or exacerbate inflammation during subsequent infections such as RSV. Particularly in infants, who rely heavily on the early development of mucosal and systemic immune balance, such perturbations might increase susceptibility to more severe respiratory disease²⁴. Furthermore, SARS-CoV-2-related disruption of epithelial integrity and tissue-resident immunity in the airways could compromise frontline defence mechanisms²⁵, potentially facilitating enhanced RSV replication or tissue damage.

However, our findings do not support a clinically significant immunopathological interaction of this nature, at least within the humoral compartment detectable by current serological assays. This observation is particularly important in light of the global increase in pediatric RSV hospitalizations following the COVID-19 pandemic. For example, in Poland during the waning phase of the pandemic, hospital admission rates for children aged < 12 months, 12–24 months, and 25–60 months were approximately 2-, 4-, and fivefold higher than pre-pandemic levels, respectively²⁶. Similar trends have been reported in other countries^27,28,29. These patterns are consistent with what has been termed a “post-pandemic compensatory epidemic”, also in relation to other respiratory infections^30,31. RSV, a virus with strong seasonality, typically circulates from late fall through early spring, and annual exposure helps maintain a degree of population-level immunity. However, prolonged pandemic-related restrictions, including lockdowns, school closures, and reduced social contact, substantially limited RSV transmission³². As a result, many infants and toddlers missed their first natural exposure, leading to a larger pool of immunologically naïve children³³. A similar phenomenon was also observed in relation to other viral infections³⁴. Therefore, the post-pandemic resurgence of RSV likely reflects this accumulation of susceptible individuals, rather than enhanced disease severity due to prior SARS-CoV-2 exposure.

In line with our observations, clinical evidence in children suggests that there is no significant increase in the risk of RSV infection following a SARS-CoV-2 infection. A large cohort study involving children under five years old found that, after adjusting for coinfections and seasonal variations, the short-term rise in RSV cases was primarily due to coinfections rather than a true elevated risk post-COVID-19³⁵. Additionally, case series in infants indicate that coinfection with RSV and SARS-CoV-2 does not exacerbate the severity of COVID-19 symptoms³⁶. Interestingly, in vitro experiments suggest that SARS-CoV-2 infection can actually reduce RSV replication, suggesting possible viral interference rather than enhancement³⁷. Consequently, in animal models, prior SARS-CoV-2 exposure does not worsen RSV disease; in fact, it may even reduce RSV replication in the lower respiratory tract³⁸.

Nevertheless, the elevated proportion of children requiring oxygen following recent SARS‑CoV‑2 infection, though not statistically significant, suggests subtle, short‑term alterations in pulmonary or immune function. Functional imaging and lung function studies in pediatrics have documented persistent ventilation–perfusion mismatch and mild inflammatory changes several months post-infection, even in non-hospitalized cases^39,40,41. Mechanistically, delayed interferon signalling and impaired epithelial regeneration following SARS‑CoV‑2 have been demonstrated in respiratory models, pointing to slower mucosal repair processes that could heighten susceptibility to hypoxia during RSV coinfection. Moreover, mild obstructive patterns and diffusion impairments observed in follow-up pulmonary function tests in children indicate ongoing airway inflammation and mucosal dysfunction^42,43. Collectively, these data raise the possibility that recent SARS‑CoV‑2 exposure may transiently compromise respiratory resilience, thereby increasing oxygen support needs during subsequent RSV infection. Although our sample size limits definitive conclusions, this trend underscores the importance of longitudinal studies to explore temporal dynamics of recovery and vulnerability in pediatric mucosal immunity post-SARS‑CoV‑2.

The strength of the present study is the comprehensive serological profiling using a validated immunoblot microarray targeting multiple SARS-CoV-2 antigens, which allowed us to distinguish between recent and past infections with greater granularity than single-antigen assays. Furthermore, all children included in the analysis were hospitalized with confirmed RSV infection, allowing for robust comparisons of clinical severity parameters. However, the study also has limitations. First, while serological markers provide important evidence of past exposure, they cannot determine the exact timing of infection, and waning antibody levels may lead to underestimation of prior infections. Second, cellular immunity, which plays a crucial role in modulating responses to respiratory viruses, was not assessed. Third, all children included in the study were not vaccinated against SARS-CoV-2, and were not born to mothers vaccinated against RSV during pregnancy. Therefore, the results do not imply how vaccine-induced immunity, either through direct pediatric vaccination or transplacental maternal antibodies^44,45, might interact with the severity of RSV infections. Fourth, the relatively small number of children classified as recently infected with SARS-CoV-2 limited the statistical power to detect subtle differences in clinical outcomes and may have masked associations of potential relevance—further studies targeting this group are required. The study cohort was drawn from a single hospital, which may limit generalizability to broader populations with differing sociodemographic or healthcare characteristics. Moreover, RSV infection was confirmed primarily based on rapid antigen testing, not routine PCR, and no PCR testing for SARS-CoV-2 infection was performed. Finally, it is essential to interpret our findings in light of the evolving epidemiology of SARS-CoV-2. The study was conducted during the Omicron-dominant era, when the clinical image of COVID-19 differed from earlier pandemic phases, during which variants such as Alpha or Delta were associated with more systemic complications⁴⁶, including the now rarely observed multisystem inflammatory syndrome in children⁴⁷. Moreover, Omicron appears to continue towards lower clinical significance⁴⁸. Accordingly, the risk profile of RSV/COVID-19 coinfections may have shifted over time. In addition, it would be of interest to establish whether interactions between SARS-CoV-2 and RSV impact the clinical severities in other age groups, including the elderly, who constitute another risk group for both viral infections⁴⁹.