Respiratory syncytial virus (RSV) is the leading pathogen causing acute lower respiratory tract infection (LRTI) in the pediatric population, leading to almost 33.8 million episodes, 3.4 million hospitalizations, and 66,000–199,000 deaths among children under 5 years old (Di Mattia et al., 2021). RSV-induced LRTI in early childhood is a significant risk factor for the development of recurrent wheezing, asthma, and impaired lung function in later life (Young and Smitherman, 2021). Although some hopeful candidate vaccines and monoclonal antibodies are under development (PATH, 2021), there are yet no effective antiviral drugs or approved vaccines for RSV after 60 years of research (Jordan et al., 2021). A monoclonal antibody to the RSV F protein named palivizumab could reduce the rate and severity of RSV infections when administered preseasonally to children. But its use is limited to high-risk infants due to the high cost of medication (Boyoglu-Barnum et al., 2019). Therefore, the control of RSV transmission is still a tough problem globally.

RSV is an enveloped, single-stranded, negative-sense RNA virus. The RSV genome, which is around 15 kb, encodes at least 11 proteins, among which the attachment (G) protein and fusion (F) protein are key to mediating viral entry and inducing virus-neutralizing antibodies (Krishnamoorthy et al., 2012). The second hypervariable region (HVR2) of the G gene is highly genetically diverse and prone to be under selection pressure, which enabled it to be commonly used for the molecular classification of RSV (Lee et al., 2021). RSV has been classified as subgroups A and B based on genetic and immunological analyses, and further subclassified into at least 13 RSV A and 20 RSV B genotypes based on the sequences of the HVR2 of the G gene (Ma et al., 2021).

As a typical seasonal virus, RSV usually peaks in winter and declines by early spring in most temperate countries, with a median duration of 10–21 weeks (Staadegaard et al., 2021). However, the unexpected coronavirus disease 2019 (COVID-19) pandemic has exerted extraordinary changes to community behavior at a population level and remarkably restricted the prevalence of respiratory pathogens (Liu et al., 2021; Jia et al., 2022). However, along with the normalization of the COVID-19 epidemic control, an atypical reemergence of RSV was reported in various places (Agha and Avner, 2021; Foley et al., 2021; Government of Western Australia, 2021; Ujiie et al., 2021; Camporesi et al., 2022; Eden et al., 2022; Saravanos et al., 2022). Hence, we conducted this research to determine if RSV also resurged in Shanghai in the setting of COVID-19 pandemic and to demonstrate the differences between the resurgence with the previous RSV season.

In this study, we observed an unusual increase of the RSV detection rate in the summer of 2021 in Shanghai. Interestingly, the abnormal reemergence of RSV during COVID-19 was also observed during the summer months in both northern hemisphere countries including Japan, America, Canada, Israel, Italy (Public Health Agency of Canada, 2021; Ujiie et al., 2021; Weinberger Opek et al., 2021; Camporesi et al., 2022; The US Centers for Disease Control and Prevention, 2022), and southern hemisphere countries including Australia and New Zealand (Agha and Avner, 2021; Anglemyer et al., 2021; Foley et al., 2021, 2022; Dolores et al., 2022; Saravanos et al., 2022). Hence, our findings reflected a global phenomenon. The factors contributing to the “summer peak” of RSV in the post-COVID-19 phase were complicated, possibly including relaxation of restriction measures, increased social activities of children, extensive respiratory virus testing to rule out COVID-19, and possible changes in the environmental resistance of RSV strains. Continuous surveillance of RSV infection at both local and global scales is needed to provide more clues to explain the phenomenon.

RSV-A ON1 genotype and RSV B BA genotype have become the two predominant strains globally since their emergence in 2010 and 1999, respectively (Trento et al., 2003; Eshaghi et al., 2012). In China, ON1 became the major RSV A genotype during 2013–2015 (Song et al., 2017), while BA9 took the dominance during 2008–2014 (Chen et al., 2021). In our study, all RSV A strains were ON1 and all RSV B strains were BA9 either before or during COVID-19, which was consistent with the reports from other places of China and other countries in recent years (Chen et al., 2021; Lee et al., 2022; Sun et al., 2022). RSV A and B were reported to take dominance alternately, with a major prevalent pattern of “BBAA” most of the time (Luo et al., 2020; Sun et al., 2022). But RSV B is the main prevailing subtype in our study, although there was a co-circulation of both RSV A and B. Differently, a study in Australia showed that there was an overwhelming predominance of RSV A (>95% cases) from late 2020 to early 2021 and all of the RSV A viruses belonged to ON1-like genotype (Eden et al., 2022). Moreover, they found two genetically distinct RSV A clades circulating cryptically, which did not cluster with any other RSV A viruses sampled nationally or internationally to date for unknown reason (Eden et al., 2022). We did not observe distinct RSV A linages during COVID-19 in our data, possibly due to the small number of RSV A-positive cases. But it is interesting that although their prevailing subtype was different from ours, we both observed a similar summer upsurge of RSV, suggesting that people’s behavioral changes brought by COVID-19-associated nonpharmaceutical interventions (NPIs), e.g., strict quarantine policies, limited social activities, school closures and reopenings seemed to exert more effect on RSV transmission pattern than the virus properties.

Our study indicated that the severity of the delayed RSV seasons during COVID-19 in Shanghai was decreased, as evidenced by less frequent respiratory failure and severe LRTI cases than before, which was similar with the studies conducted in Australia and France, characterized by fewer hospitalizations and ICU admissions (Fourgeaud et al., 2021; Foley et al., 2022; Saravanos et al., 2022). However, the impacts of the delayed RSV season on patients might vary in different settings. For instance, studies in Italy indicated that the severity of RSV-associated disease was comparable with the previous season according to the respiratory support and PICU admissions (Stera et al., 2021; Camporesi et al., 2022). Also, a study in the United States of America (USA) indicated more severe RSV-related diseases in infants during COVID-19 pandemic (Agha and Avner, 2021). As for explanations, the studies from Australia tended to attribute milder clinical presentations during COVID-19 to the lowered threshold for respiratory virus testing (Sullivan et al., 2020; Foley et al., 2022; Saravanos et al., 2022), while the study from the USA proposed that the increased severity might be associated with diminished immunity from a lack of exposure to RSV in the previous season (Agha and Avner, 2021). According to the multivariate analysis in our study, we did not find risk factors for severe LRTI cases among the widely accepted predictors for RSV-induced severe cases including age, gestational age at birth, underlying diseases and co-infections (Malosh et al., 2017; Ghazaly and Nadel, 2018; Lee and Goh, 2021), which prompted us to look for clues in people’s behavioral changes during COVID-19. In the setting of COVID-19, parents in China tended to take their children, particularly infants, into hospitals immediately once they showed signs of respiratory infection to rule out COVID-19, rather than waiting for a self-healing as most parents did before the pandemic. Moreover, the government has deployed more personnel and resources to facilitate the diagnosis and treatment of respiratory diseases, leading to better care of the patients. Hence, we assume that the timely diagnosis and sufficient medical resources might contribute to the decreased RSV-associated disease severity during COVID-19, which deserves further assessment and exploration.

Apart from the external factors, the genetic changes of RSV themselves might also play a role in the clinical outcomes of RSV-infected patients during COVID-19. In our study, we found some amino acid substitutions which were more frequently seen in RSV B BA9 strains during COVID-19 than before the pandemic, including A269V, T274A, and T300I. As reported, certain alterations could change the virulence of RSV. For instance, a study from China reported that the severity score was lower in RSV A-positive cases with a set of 5 substitutions (T113I, V131D, N178 G, H258Q, and H266 L) of G gene compared with other RSV A-positive cases, suggesting a possible causative relationship (Li et al., 2020). Also, a study from the Netherlands found that 8 substituted amino acids (S102F, K216N, P256S, H258Y, S270Y, E271K, P300S, and T306I) of G gene were associated with higher disease severity with a more frequent need for extra oxygen (Vos et al., 2019). The mechanism of how these amino acid alterations affect the outcomes of the disease is still unclear. We did not find the above-mentioned substitutions in our results, but it deserves further assessment about the role of the genetic changes of RSV strains in our study or other unknown changes in RSV genome in the changed clinical features during the pandemic.

There are some limitations of our study. First, the period and number of the samples collected were not enough to show more comprehensive and precise epidemiological features of RSV before and during COVID-19. Moreover, no dual infections of RSV A and B were detected in the 403 samples, possibly due to the limited sample number and the unusually low level of RSV A-positive cases from February 2020 to July 2021. Second, as with other similar studies, the medical records we acquired usually could not fully reflect the overall conditions of the patients, leading to possible deviations in our analyses. Last but not least, since we only focused on RSV in this study, we were unable to comprehensively assess the epidemiological features of other common respiratory pathogens including human rhinoviruses, influenza A and B viruses, and parainfluenza virus before and during COVID-19, which will be a promising topic in our future study.

Conclusively, our study displayed epidemiological features and phylogenetic information of RSV before and during COVID-19 in Shanghai. It is clear that COVID-19 affected the transmission pattern of RSV since 2020 and the patients in our study showed certain demographic and clinical changes in the context of COVID-19. These findings provides a timely warning to the countries suffering from COVID-19 that other respiratory viruses, such as RSV, still deserve full attention to avoid unusual rebound and unexpected impacts, and further necessitates the continuous surveillance of the epidemiological and evolutionary dynamics of RSV both spatially and temporally.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

This study was approved by the Ethics Committee of the Children’s Hospital of Fudan University in February 2020 (Approval Number: 202027). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

RJ and JX conceived and designed the experiments, analyzed the data, and wrote the paper. RJ, LL, LS, MX, PL, and LC collected the nasopharyngeal aspirates from patients. RJ, ZL, DG, and HL collected the clinical data of patients. RJ, LL, ZL, DG, and HL performed the experiments. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the Key Development Program of Children’s Hospital of Fudan University (grant no. EK2022ZX05).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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