This is a comprehensive study examining the demographic and clinical characteristics of children hospitalized with moderate-to-severe RSV infection in Okinawa over a four-year period starting in April 2017. During the study period, the global COVID-19 pandemic led to the implementation of nationwide nonpharmaceutical interventions (NPIs), including physical distancing, mask use, and school closures, in Japan [17, 18]. These measures are likely to have played a major role in altering the epidemiology of moderate-to-severe RSV infections in Okinawa, particularly with respect to the timing of peak incidence and the age distribution of patients. However, it should be noted that other factors, such as climate variation, differences in circulating viral genotypes, and additional unknown influences, may also have contributed to these changes.
Our study identified several important factors associated with severe RSV infection among hospitalized children in Okinawa. Consistent with prior reports, younger age was a strong predictor of severe RSV infection. This is likely due to the combination of an immature immune system and anatomically narrower airways in infants, which have been demonstrated to contribute significantly to disease severity [19, 20]. The presence of siblings was also an independent risk factor, likely indicating increased exposure to RSV at home through older children [19, 20]. Nursery school attendance was less common among severe cases in the univariate analysis, but this association did not remain after adjustment in the multivariate model (Table 1 and Table 2). This indicates that the effect of nursery school exposure may be influenced by other factors such as age or sibling exposure. Among the 1,541 hospitalized children, 148 (9.6%) were preterm: 46 at ≤ 28 weeks, 76 at 29–35 weeks, and 26 at 36 weeks. Severe cases occurred in 2 (4.3%), 3 (3.9%), and 5 (11.4%) children in these groups, respectively. Although previous studies have shown that preterm infants are at higher risk of severe RSV disease [20], preterm birth was not identified as an independent predictor in our study. This may be partly explained by the limited number of extremely preterm infants and the potential protective effects of prophylaxis, although information on palivizumab or nirsevimab administration was not available in this study. In Japan, infants born at ≤ 28 weeks are generally considered eligible for palivizumab up to 12 months of age, and those born at 29–35 weeks up to 6 months. Moreover, under international recommendations, the majority of preterm infants would have been eligible for nirsevimab prophylaxis, although in Japan its use remains restricted to HRG infants. Underlying diseases were found to significantly increase the risk of severe RSV infection in our study. Although the overall prevalence of underlying diseases did not differ significantly in univariate analysis, the presence of multiple comorbidities was more common among severe cases (Table 1). Multivariate analysis confirmed that both overall and multiple underlying diseases independently increased the risk of severe disease (Table 2). This emphasizes the importance of careful clinical monitoring and prophylactic strategies for children with comorbidities, particularly those with multiple conditions.
The epidemiological pattern of RSV infection in Okinawa differs substantially from that observed in mainland Japan [21,22,23]. According to the nationwide sentinel surveillance, RSV epidemics in mainland Japan exhibited an annual peak from September to November during the 2012–2015 seasons. In contrast, Okinawa demonstrated broader or bimodal peaks, generally occurring between June and August, approximately six months earlier than in mainland Japan [21]. Between 2016 and 2019, the peak RSV outbreak season in mainland Japan moved from November to around September of the same year [21, 24]. Meanwhile, the timing of the peak in Okinawa remained largely unchanged; however, the peak magnitude gradually increased, resulting in an overlap of the epidemic peaks between Okinawa and mainland Japan [21].
In this study, we analyzed the monthly distribution of moderate-to-severe RSV cases based on medical records from four hospitals between April 2017 and March 2021. From 2017 to 2019, the total cases from the four hospitals showed a clear seasonal peak during the summer months (June–August). In contrast, in 2020, coinciding with the onset of the COVID-19 pandemic, these prominent peaks disappeared (Fig. 2). The temporal trends of moderate-to-severe cases closely matched the overall RSV activity reported for Okinawa, regardless of disease severity [21]. This agreement suggests that moderate-to-severe cases represent a relatively stable portion of the total RSV burden; therefore, monitoring severe cases may serve as a reliable proxy for broader epidemiological patterns and help guide targeted prevention strategies.
Taiwan is located approximately 650 km from the mainland of Okinawa and even closer to the Yaeyama Islands. These regions share similar latitudes, a subtropical to tropical oceanic climate, and comparable patterns in infectious disease epidemiology [25]. In Taiwan, RSV showed no clear seasonality between 1997 and 1999 [26], but from 2015 to 2020, a broad summer peak, especially from July to September, was observed, followed by a winter decline [27]. This pattern closely resembles that of Okinawa, where RSV also peaks in summer [21]. Studies in Thailand from 2015 to 2019 revealed a seasonal trend in RSV-associated ALRTIs, with the highest incidence from August to October during the rainy season [28]. This peak coincides with the peak in hospitalized cases observed in the present study in Okinawa (Fig. 2). Since the seasonal pattern of RSV in Okinawa more closely resembles that of Southeast Asia than mainland Japan, establishing cross-border information-sharing networks should be a priority in regional public health policy to improve the effectiveness of RSV control strategies in Okinawa.
Most hospitalizations for moderate-to-severe RSV infection in this study occurred in infants under 12 months, with a clear peak in the 0–2 month age group—consistent with findings from Europe and other regions [2]—and a secondary peak at 9–11 months (Fig. 3), possibly due to decreasing maternal antibodies and exposure to older siblings. Although hospitalizations decreased after 12 months, a considerable number of cases still required admission up to 24 months (Fig. 3), highlighting the need for continued attention to RSV infection beyond infancy. The age distribution of hospitalized moderate-to-severe RSV cases was consistent across all four study sites, including the remote Miyako and Yaeyama islands, indicating minimal regional variation in severe disease burden within Okinawa Prefecture.
In many countries, the widespread implementation of NPIs during the COVID-19 pandemic has been reported to have markedly suppressed the circulation of respiratory viruses, including RSV [29, 30]. Despite focusing only on hospitalized moderate-to-severe RSV cases, the study found a similar trend: the average annual number of cases declined from 456 pre-pandemic to 172 during the pandemic, about 40% of the previous level (Fig. 4). During the pandemic, the proportion of cases in infants under 6 months increased significantly, while that in the 6–12 months group decreased (Fig. 4). One possible explanation for the observed reduction and age shift during the pandemic is the widespread implementation of NPIs, such as masking, social distancing, and school closures, which significantly suppressed RSV circulation worldwide [29, 31, 32]. At the same time, the continued presence of cases in very young infants indicates that household transmission played a comparatively larger role during this period, leading to the shift in age distribution. Therefore, NPIs may have reduced the overall burden of RSV while indirectly increasing the relative share of infections among younger infants. However, epidemiological changes are rarely attributable to a single factor. Other mechanisms may also have contributed, including temporary reductions in population immunity caused by decreased viral circulation [33], shifts in circulating viral genotypes [22, 34], climatic variations, and region-specific behavioral factors [31]. Although these findings have been reported for RSV infections overall, it is reasonable to assume that the same mechanisms also influenced the subset of children who developed moderate-to-severe disease requiring hospitalization, as observed in our cohort. Taken together, these reports suggest that the unusual RSV epidemic patterns observed in Okinawa during the COVID-19 era were likely influenced by multiple interacting factors, with NPIs playing a key role.
Regarding respiratory support, nearly two-thirds of moderate cases required standard oxygen therapy, while the majority of severe cases required high-flow oxygen or mechanical ventilation. Since ICU admission criteria included the need for advanced respiratory support, these findings reflect the definitions applied for severity classification rather than representing independent associations (Table 3). Overall, 99.8% of patients recovered without any complications, and there were no fatalities (Table 3). Only three patients—all from the severe group—experienced complications: two required prolonged mechanical ventilation, and one developed AESD with developmental delays. The occurrence of these severe outcomes in patients without underlying diseases highlights the potential severity of RSV infection.
Palivizumab has long been the standard method for preventing severe RSV infection; however, it requires monthly injections and is limited to HRG infants [11, 12]. In recent years, nirsevimab has been approved in several countries [13, 14, 35]. As a long-acting monoclonal antibody, it provides season-long protection with a single injection administered before the RSV season and is indicated for all infants regardless of risk status; however, in Japan, insurance coverage is currently limited to infants in HRGs [14]. In parallel, maternal RSV vaccination is being established as a preventive strategy, in which antibodies generated in the mother are transferred to the fetus via the placenta [36]. Taken together, nirsevimab and maternal vaccination are expected to become the primary approaches for preventing severe RSV infection in infants.
Our findings underscore the distinctive epidemiology of RSV in Okinawa, where subtropical climate conditions result in patterns that differ from mainland Japan and more closely resemble Southeast Asia. The comprehensive, entire-prefecture dataset strengthens these observations. By focusing specifically on moderate-to-severe cases, we identified risk factors of direct clinical importance. Additionally, the influence of the COVID-19 pandemic on case numbers and age distribution further emphasizes the need for locally tailored prevention strategies, including considerations for prophylaxis policies such as palivizumab and nirsevimab.
This multicenter epidemiological study covering the entire Okinawa prefecture provides a valuable foundation for understanding the regional burden and characteristics of moderate-to-severe RSV infections.
Limitations include the lack of data on preventive measures such as palivizumab, nirsevimab, and maternal RSV vaccination, as well as the absence of subtype or genotype analysis, since diagnosis depended on rapid antigen testing. Additionally, no standardized research protocol was applied across the four hospitals; although each site followed national standard clinical practices, some variability in diagnostic and clinical procedures cannot be entirely ruled out. Nonetheless, detailed information on seasonality, age distribution, household composition, childcare facility use, and underlying diseases is expected to provide important insights for improving preventive strategies and serve as a basis for assessing and enhancing the implementation of RSV prevention efforts.
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