Seasonality of respiratory syncytial virus infection in children hospitalized with acute lower respiratory tract infections in Hunan, China, 2013–2022

Globally, respiratory syncytial virus (RSV) is a prevalent cause of acute lower respiratory tract infections (ALRTIs) in childhood, and contributes significantly to hospital admissions among young children. This places a substantial burden on healthcare services. Nearly half of the worldwide disease burden associated with RSV occurs in just five countries: Pakistan, India, Nigeria, Indonesia, and China. In China, the estimated annual hospitalizations for infants and young children due to RSV infection range from 215,000 to 500,000 [1].

RSV activity exhibits a seasonal pattern in most regions, and its seasonal epidemics are a leading cause of hospitalization and mortality globally, particularly due to bronchiolitis and pneumonia [2, 3]. The RSV season is typically characterized by an RSV rate exceeding the defined threshold for a specific duration. RSV infection incidence peaks during winter and spring in temperate regions and during rainy seasons in tropical regions. The RSV season commences between March and June in countries in the Southern hemisphere and between September and December in the Northern hemisphere [4]. A study reported the long-term time-series data of medically attended first-time RSV infection among young children. From 2010 to 2019, the monthly incidence rate of medically attended RSV infection in children aged 0–5 years of the United States followed a consistent seasonal pattern: rising from September to November, peaking from December to January, then dropping from February to April, with sustained low rate during May to August [5]. Another study found that states with colder, drier weather and a large seasonal swing in potential evapotranspiration tended to experience an alternating pattern of ‘‘early-big’’ RSV epidemics one year followed by a ‘‘late-small’’ epidemic the next year [6]. In China, the incidence of RSV infection typically peaks between November and February of the following year [7].

Several RSV vaccine candidates and monoclonal antibodies are currently in the advanced clinical development stage [8]. Therefore, prevention of RSV transmission remains a promising strategy to control seasonal epidemics. Prior to the COVID-19 pandemic, RSV epidemiology adhered to a seasonal pattern worldwide [3]. Interestingly, the COVID-19 pandemic has significantly influenced RSV epidemiology, with many countries experiencing an absence of RSV infections during the first pandemic winter [9]. A delayed summer epidemic was observed in various locations worldwide [10‐12]. The success in preventing RSV infections was attributed to the strict implementation of non-pharmacological public health interventions targeting COVID-19. Concerns have been raised regarding potential severe RSV epidemics in the future due to “immunity debt,” a term that describes reduced protective immunity resulting from prolonged periods of low exposure to a pathogen, rendering a greater proportion of the population susceptible to the disease [13, 14].

China bears a significant burden of RSV infection [15], but few studies have assessed the seasonality or trends of RSV infections. Furthermore, during the COVID-19 outbreak, limited availability of epidemiological surveillance data for other respiratory viruses could have impeded the implementation of therapy and prophylactic interventions for RSV. The present study retrospectively examined available surveillance data for RSV in children hospitalized with ALRTI in Hunan, China, between 2013 and 2022. It evaluated seasonal changes in RSV infections both before and after the COVID-19 pandemic.

The present study explored the surveillance data for RSV-related ALRTI in Hunan, China, and assessed the seasonality of RSV. On average, the RSV season initiated around the calendar week 44 (mid-October) and spanned 27 weeks, concluding by week 17 of the following year (late April). This seasonal pattern was consistent with that reported in Beijing, China [7]. A global overview of RSV seasonality indicated that, in the majority of countries, the commencement, conclusion, and peak of RSV activity typically varied by only 1–3 weeks from season to season [20]. The United States exhibited RSV season patterns, beginning in October, peaking in December or early February, and lasting a median of 27–31 weeks before concluding in March-April, a pattern consistent with our study [21]. Another study found that some states (e.g. Colorado, Iowa, California in the 1990s) exhibited biennial patterns of alternating ‘‘early-big’’ epidemics in/around January of even-numbered years and ‘‘late-small’’ epidemics in/around February of odd-numbered years [6]. The impact of RSV subgroup on seasonal severity remains a subject of controversy [22]. Monitoring data for Beijing, China, revealed that RSV infection prevalence was highest in winter and spring among children in northern China from 2007 to 2015. China reported that RSV seasons occurred 3–5 weeks earlier and lasted 6 weeks longer in RSV subgroup A-dominant years compared to subgroup B-dominant years [7].

China, a northern hemisphere country, exhibits a well-established RSV circulation pattern with peak incidences in winter months and declines in early spring [7]. However, the emergence and spread of SARS-CoV-2 and subsequent mitigation measures have led to widespread social disruption, influencing the seasonal circulation patterns of respiratory viruses [9, 23‐25]. In our study, the total number of children hospitalized for ALRTIs decreased significantly starting in 2020. Despite similar overall detection rates of RSV compared to before, RSV decreased significantly after the outbreak, reaching historically low levels in the spring of 2020. A previous study reported that the monthly incidence rate of first-time medically attended RSV infection in children aged 0–5 years followed a consistent seasonal pattern from 2010 to 2019. The seasonal variation disappeared in 2020 and returned in 2021 but started earlier and reached a historically high rate of 2182 cases per 10,000 000 person-days in November 2022 [5]. A similar trend has been observed in several countries [9, 25, 26]. During the COVID-19 era, the interaction between RSV and SARS-CoV-2 has been widely discussed, with a viral interference effect and the implementation of NPIs proposed as explanations for these findings [25‐28]. During the 2009 influenza pandemic, where large-scale NPIs were not implemented, there was an associated delay in the onset of the RSV season by an average of 0.58 months [29]. In Hongkong, with the occurrence of pandemic influenza A (H1N1) 2009 virus during the traditional summer peak for RSV in 2009, the RSV summer peak was not observed. In March 2010, the spring peak returned, the summer peak was again absent subsequently, and abnormal early rise of RSV activity was observed in the winter of 2010 that remained until the summer of 2011 [30]. A previous study [27] suggested that rhinovirus may have delayed the introduction of the pandemic virus into Europe, and conversely, the pandemic virus may have interfered with RSV epidemics. In March 2019, an adenovirus outbreak in Hunan Province concluded the RSV season nearly 1 month earlier than in previous years. These findings collectively suggest potential interference between viruses.

As public health and social measures were gradually lifted, the resurgence of RSV became a significant concern, drawing attention from experts globally. Modeling studies in the US have initiated exploration into the impact of increased population susceptibility due to minimal RSV and influenza virus infections in 2020–2021 on the magnitude of subsequent seasons [31]. Lina et al. in Tokyo, Japan, also expressed similar concerns using an epidemic model [32]. The abnormal reemergence of RSV during the COVID-19 era was also observed during the summer months in 2021 in northern hemisphere countries, including America [21], Israel [28], England [9], Japan [33], and China (Beijing, Shanghai) [34, 35]. Compared to these countries and cities, the summer peak of RSV in the post-COVID-19 phase occurred earlier and persisted longer in Hunan, China. Following the nationwide lockdown on January 23, 2020, there was a drop in the RSV detection rate. Even after the easing of the national lockdown on May 10, 2020, RSV detection remained low compared to the previous year. Approximately 2 weeks after the concurrent reopening of state primary and secondary schools in early September, there was a sharp increase in RSV detections, lasting for 87 weeks and concluding in the spring of 2022. Through continuous surveillance, it was observed that the RSV detection rates surpassed the historical levels of 2013–2019. In addition, the median age of RSV-infected children during the recovery phase was higher, with a greater number of children aged 24–59 months.

Several factors contribute to RSV seasonality and resurgence. First, the NPIs was lifted or relaxed. With the unblocking of Wuhan on April 8, 2020, the implementation of the national NPIs policy and the gradual migration of the population may have promoted the spread of the RSV virus. Li et al. [36] suggested that the full reopening of schools was the predominant risk factor for RSV rebound, increasing the risk by as much as 23-fold. Second, immunity debt may also be one of the important reasons. In the absence of an RSV vaccine, partial and transient immunity is naturally and spontaneously achieved each year by two mechanisms: infection or transplacental transfer of maternal RSV antibodies. Because of a widespread lack of exposure to RSV, particularly in younger cohorts, resulting in the build-up of an increased pool of susceptible. We also found that the median age of RSV-infected children during the recovery phase was elder, with the number of children aged 24 to 59 months, which may be the cumulative effect of susceptible groups. Waning maternal immunity due to low RSV exposure and the consequent decrease in transplacental RSV antibody transfer may have contributed to increased RSV infections also. Third, other factors may also be involved. The infection pattern of RSV resurgence remains different from that prior to 2019 and importantly significantly higher, suggesting the possibility that COVID-19 or COVID-related risk factors including lasting impact on immune systems that may partially account for high RSV incidence rates in young children. The observed resurgence reported by Foley et al. occurred following months of relaxed social distancing measures (not immediately following relaxation of measures) [10]. The studies showed that, in the context of reinforced public health measures in adults, maintaining children’s communities open (with reinforcement of social distancing and mandatory face masks since 6 years old) had low impact on RSV infections. Other factors which are believed to influence the epidemiology of respiratory viruses such as temperature, humidity, crowding in school classrooms and viral co-infections or superinfections may also influence the chances of RSV epidemics. High temperatures decrease the risk for RSV rebound, with every 5 °C increase reducing the risk by 37%. The full reopening of schools could override the counter-effect of high temperatures, explaining the out-of-season RSV epidemics during the COVID-19 pandemic seen in our study. The increase in numbers and the change in median age suggest that the expanded cohort of RSV-naïve patients, including an increased number of older children coupled with waning population immunity [37], may have contributed to the resurgence. Our data underline the greater fragility of RSV control in the population: a slight relaxation of public health measures was concomitant to the resurgence of RSV in Hunan.

The present study observed a significant increase in RSV-related hospital admissions during 2020–21 and 2021–22 compared to preceding years. Despite the substantial surge in case numbers, the outcomes for hospitalized RSV cases during the COVID-19 outbreak appeared to be less severe. Analysis of data on ICU admission, and the incidence of severe pneumonia revealed a descend in the severity of ALRTI caused by RSV. Studies in Italy have reported that the severity of RSV-associated disease during the delayed season was comparable to that during the previous season based on respiratory support and PICU admissions [38]. Similarly, studies from Shanghai [34], Beijing [35], and Western Australia [12] have reported a decrease in the severity of the delayed RSV seasons during COVID-19 compared to previous seasons. Conversely, a study from the USA reported more severe RSV-related disease in infants during the COVID-19 pandemic [39]. As for the decrease in the severity of the disease in this study, it may be related to the older median age of infected children, who have larger airways and better immune function. In addition, the descent of co-infection may also help to reduce the severity of the disease.

This study also had some limitations. First, it focused exclusively on ALRTI inpatients who had undergone a nasopharyngeal examination. Second, it is a single-center study, and it would be more convincing if the data were from different centers. Third, we did not analyze the link between other viral or bacterial co-infections and RSV resurgence. The circulation of multiple respiratory viruses may have resulted in a high level of interactions between viruses, including an increase in viral co-infections or superinfections. In addition, RSV typing was absent and we failed to explore the mechanism of changes in clinical characteristics and epidemic trend of RSV infection after the epidemic, which was limited by our laboratory testing methods and the fact that the study was retrospective.

We enrolled 49,658 hospitalized children diagnosed with ALRTIs over a 9-year period, spanning both before and during the COVID-19 epidemic, to assess RSV prevalence. COVID-19 has influenced the transmission pattern of RSV since 2020, and the patients in our study exhibited distinct demographic and clinical changes in the context of COVID-19. RSV seasonality was disrupted during the COVID-19 pandemic, and the season exhibited an unusually prolonged duration. Despite these observations, RSV still warrants great attention to prevent unusual rebounds and unexpected impacts. In addition to future investigations and the development of passive and active immunization, thorough surveillance of RSV variation remains crucial as we transition into the post-COVID-19 era.