Epidemiology of Moderate-to-Severe Respiratory Syncytial Virus Infections in Children in Subtropical Okinawa, Japan: A Four-Year Retrospective Study

Epidemiology of Moderate-to-Severe Respiratory Syncytial Virus Infections in Children in Subtropical Okinawa, Japan: A Four-Year Retrospective Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Epidemiology of Moderate-to-Severe Respiratory Syncytial Virus Infections in Children in Subtropical Okinawa, Japan: A Four-Year Retrospective Study Kahoru Fukuoka-Araki, Kotaro Araki, Hiromi Fukuoka, Yoshiaki Cho, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7316076/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Tropical Medicine and Health → Version 1 posted 11 You are reading this latest preprint version Abstract Background: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections (ALRTIs) in infants and young children worldwide. While its epidemiology is well-characterized in temperate climates, data from subtropical regions such as Okinawa, Japan, remain limited. This study aimed to describe the clinical and demographic characteristics, risk factors, and seasonality of moderate-to-severe RSV infections in children under five years across Okinawa. Methods: This retrospective, multicenter study analyzed pediatric cases of laboratory-confirmed RSV infection requiring hospitalization between April 2017 and March 2021. Data were collected from four core hospitals across Okinawa Prefecture. Patients were categorized as having moderate or severe disease based on ICU admission status. Demographic variables, underlying medical conditions, household and childcare characteristics, and seasonal trends were assessed. Results: A total of 1,541 hospitalized RSV cases were included, of which 117 (7.6%) were classified as severe. Approximately 60% of cases were in infants under 12 months, with the highest burden in the 0–2 month age group. The severe group had a significantly lower median age and higher proportion of children with siblings. Nursery school attendance was more common in the moderate group, likely reflecting the younger age of severe cases. While the prevalence of individual comorbidities did not differ between groups, having multiple underlying conditions was significantly associated with disease severity. RSV activity peaked during summer (June–August) in 2017–2019 but shifted to winter in 2020–2021, coinciding with the COVID-19 pandemic and a 62% reduction in cases. Conclusions: This study offers the first region-wide assessment of moderate-to-severe pediatric RSV infections in a subtropical setting in Japan. Despite not including data on the use of palivizumab, nirsevimab, or maternal vaccination, the findings provide essential baseline data to guide the implementation of new preventive strategies tailored to local epidemiology. Respiratory syncytial virus COVID-19 Respiratory infection Pediatric infectious disease Okinawa islands Subtropical region Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Respiratory syncytial virus (RSV), a member of the genus Orthopneumovirus in the family Pneumoviridae, is an enveloped, non-segmented, negative-sense RNA virus and a leading cause of acute lower respiratory tract infections (ALRTIs) in infants and young children worldwide ( 1 , 2 ). Globally, RSV is responsible for approximately 33 million ALRTIs episodes annually, leading to more than 3 million hospitalization and an estimated 118,200 deaths among children under five years of age, with the majority occurring in low- and middle-income countries ( 2 ). High-risk groups (HRGs) for moderate-to-severe RSV infection include preterm infants, children with chronic lung disease or congenital heart disease, immunocompromised individuals, and those with genetic conditions such as Down syndrome ( 3 ). Severe RSV infection in early infancy has also been associated with long-term respiratory sequelae, including recurrent wheezing and increased risk of asthma in childhood ( 4 , 5 ). The prevalence and seasonality of RSV infection are strongly influenced by climatic factors. In temperate regions, RSV epidemics typically peak during the winter months, from September to January in the northern hemisphere, coinciding with cold and dry conditions ( 6 , 7 ). In contrast, tropical and subtropical regions, characterized by high humidity and rainfall, often experience year-round RSV activity with less distinct seasonal peaks ( 6 ). In Japan, RSV is a major cause of pediatric hospitalization due to acute respiratory infections. The annual incidence is estimated at 1,761 per 100,000 children, with 19–36 deaths reported each year ( 8 , 9 ). The country’s pronounced climatic gradient between northern and southern regions ( 10 ) results in substantial variation in RSV epidemic timing nationwide. Consequently, continuous monitoring of regional RSV activity and issuing timely, region-specific public health alerts are considered critical for effective disease control. In Japan, RSV surveillance is carried out through sentinel pediatric sites across the country, which report weekly case and demographic data to health authorities. The Japan Institute for Health Security (JHIS) collects and analyzes this data ( 11 ), although clinical severity and outcomes are not included. Until recently, palivizumab was the only approved preventive option for infants, but its use was limited to HRGs and required monthly injections during the RSV season ( 12 , 13 ). In recent years, nirsevimab—a long-acting monoclonal antibody that offers season-long protection with a single dose for all infants ( 14 , 15 )—and maternal RSV vaccination have emerged as promising preventive strategies ( 16 ). To support the successful implementation of these measures, detailed data on seasonality, age groups, household structure, childcare attendance, and underlying diseases are essential for identifying high-risk populations and tailoring prevention strategies to regional needs. Okinawa Prefecture is separated from mainland Japan and consists of the main Okinawa Island as well as the Miyako and Yaeyama islands. It has a subtropical to tropical climate. Due to its geographical isolation, most residents receive medical care within the prefecture, and inter-prefectural patient transfer is uncommon, making Okinawa an ideal setting for comprehensive regional epidemiological studies. This study represents the first report to analyze detailed demographic and clinical characteristics, including annual incidence, hospitalization outcomes, oxygen therapy use, preterm birth status, and underlying conditions, of moderate-to-severe RSV cases requiring hospitalization in Okinawa Prefecture over a four-year period beginning in April 2017. Notably, the study period overlapped with the global COVID-19 pandemic, allowing us to examine the potential impact of nationwide infection control measures on the age distribution and severity profile of moderate-to-severe RSV cases. Methods Study setting and population Okinawa Prefecture, located approximately 1,600 km southwest of Tokyo, comprises the Okinawa main island and multiple remote islands, including the Miyako and Yaeyama island groups situated about 300 km and 400 km further southwest, respectively (Fig. 1 ). The region has a subtropical to tropical oceanic climate, with an average maximum temperature of 29.1°C in July and an average minimum of 17.3°C in January, and total annual precipitation of 2,161 mm over the five-year period beginning in 2020 ( 10 ). The prefecture has a total population of approximately 1.5 million, including approximately 76,800 children under 5 years of age. Population distribution is concentrated on the main island of Okinawa and its surrounding islands, which account for 92.4% of the residents, while the Miyako and Yaeyama Islands comprise 3.81% and 3.75%, respectively ( 17 ). For healthcare administration, Okinawa Prefecture is divided into five medical service areas (MSAs) based on clusters of municipalities. On the main island, three MSAs—Northern, Central, and Southern—cover 9–16 adjacent municipalities each. The Miyako and Yaeyama MSAs correspond to the Miyako and Yaeyama Islands, respectively. Study design and participating hospitals This is a retrospective, chart-based epidemiological study conducted over a four-year period from April 2017 to March 2021 at four regional core hospitals in Okinawa Prefecture: Okinawa Nanbu Medical Center & Children’s Medical Center (ONMC), Chubu Hospital, Miyako Hospital, and Yaeyama Hospital. ONMC (444 beds), located near Naha City, serves the Southern MSA, which accounts for approximately 54.5% of the main island population. Chubu Hospital (559 beds), located in Uruma City, serves the Central MSA, covering approximately 38.0% of the main island population. Miyako Hospital (276 beds) and Yaeyama Hospital (302 beds) are the sole core hospitals serving the Miyako and Yaeyama MSAs, respectively (Fig. 1 ). Patient enrollment and case classification Children under 5 years of age hospitalized for laboratory-confirmed RSV infection were eligible for inclusion. Patients admitted exclusively to a general pediatric ward were classified as moderate cases, whereas those requiring intensive care unit (ICU) management were classified as severe cases. Data collection Clinical and demographic data were extracted from medical records, including age, sex, presence of siblings, nursery school attendance, preterm birth (gestational age < 37 weeks), underlying diseases, ICU admission, type of respiratory support, and discharge outcomes. Respiratory support modalities were recorded cumulatively, as individual patients could receive multiple interventions during hospitalization. Ethics approval This study was approved by the Clinical Research Review Committee of Okinawa Chubu Hospital, Okinawa, Japan (Approval No. 2020-68). Patient data were anonymized prior to analysis. Statistical analysis Continuous variables were summarized as medians with interquartile ranges (IQRs) and compared using the Mann–Whitney U test. Categorical variables were expressed as counts and percentages and analyzed using the chi-square test or Fisher’s exact test as appropriate. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical interface for R. A two-sided p-value of < 0.05 was considered statistically significant. Results Patients A total of 1,561 records of children under 5 years of age with moderate-to- severe RSV infection were initially enrolled. After excluding 20 cases due to failure to meet the case definition or duplication, 1,541 cases were included in the final analyses. Of the 1,541 cases, 548 were reported from ONMC, 522 from Chubu Hosp., 169 from Miyako Hosp., and 302 from Yaeyama Hosp. (Fig. 2). The 1,541 children hospitalized with RSV infection were classified into two groups: those with severe cases requiring ICU care and those with moderate cases not requiring ICU admission. A comparative analysis was conducted between the two groups regarding demographic characteristics, sibling status, nursery school attendance, and the presence and type of underlying diseases (Table 1). The median age was significantly lower in the severe group than in the moderate group. The proportion of children with siblings was significantly higher in the severe group. In contrast, the rate of nursery school attendance was significantly lower in the severe group. No significant differences were observed between the two groups in terms of female ratio or the proportion of preterm births (Table 1). Underlying diseases were present in 14.8% of all cases, with 14.5% in the moderate group and 18.8% in the severe group. The higher occurrence in severe cases was not statistically significant. When analyzing individual diseases, cardiovascular disease was found in 3.4% of severe cases (4/117) and 1.6% of moderate cases (23/1,424), with no significant difference. No other disease categories showed significant variation by severity. However, the proportion of patients with two or more underlying diseases was significantly greater in the severe group than in the moderate group (6.0% [7/117] vs. 2.6% [37/1,424], p < 0.05) （Table 1）. Seasonal and regional distribution of moderate-to-severe RSV infections Figure 3 illustrates the seasonal distribution of moderate-to-severe RSV infection cases across four hospitals in Okinawa Prefecture from April 2017 to March 2021. During this four-year surveillance period, seasonal peaks consistently occurred in the summer months, June to August, from 2017 through 2019. In contrast, RSV activity was minimal between December and February throughout the study period. This seasonal pattern was observed uniformly across the regions of Okinawa Prefectures (Fig. 3). The peak incidence of RSV infections gradually increased from 2017 to 2019. However, in 2020, coinciding with the onset of the COVID-19 pandemic, the peak incidence markedly decreased and shifted from summer to winter. Additionally, the peak became broader in distribution, with the timing of peak months varying across the four hospitals: ONMC observed its peak from September to November, Chubu around December, and Yaeyama in February. In contrast, Miyako did not exhibit a distinct seasonal peak during this period (Fig. 3). Age distribution of moderate-to-severe RSV infections in children under 24 months Among the 1,541 patients with moderate-to-severe RSV infection, 89.0% (n = 1,373) were under 24 months of age. The age distribution in three-month intervals is shown in Figure 4. The largest subgroup was the 0–2-month age group, accounting for 26% (n = 360) of cases. The number of cases dropped sharply in the 3–5-month group, increased again in the 6–11-month groups with a secondary peak at 9–11 months, and then declined steadily through 21–23 months. These patterns were consistent across all regions, with no notable regional differences observed (Figure 4). Comparison of age-specific proportions of moderate-to-severe RSV cases before and during COVID-19 The age-stratified distribution of children under 5 with moderate-to-severe RSV infection was analyzed for the periods before and during the pandemic. From April 2017 to March 2020, 1,369 cases were reported (approximately 456 annually), whereas only 172 cases occurred during April 2020–March 2021, representing a statistically significant 62% decrease from the pre-pandemic average. In both periods, infants aged <6 months accounted for the largest proportion of cases; this proportion increased significantly in the pandemic period, while the proportion of infants aged 6 to <12 months decreased significantly. There were no significant differences between periods for children aged ≥12 months (Figure 5). Respiratory support and clinical outcomes in patients with moderate-to- severe RSV Infection Of the 1,541 patients with moderate-to-severe RSV infection, 1,039 (67.4%) required some form of respiratory support. Normal flow oxygen support via facial mask or nasal cannula was the most frequently used modality, administered to 998 patients (64.8%), including 898 moderate cases (63.1%) and 100 severe cases (85.5%). High-flow nasal cannula was used in 314 patients (20.3%), comprising 204 moderate cases (14.3%) and 110 severe cases (94.0%). Mechanical ventilation was provided to 51 patients (3.3%), including 3 moderate cases (0.2%) and 48 severe cases (41.0%). Respiratory support was not required in 502 patients (32.6%), consisting of 501 moderate cases (35.2%) and 1 severe case (0.9%). Overall, 1,538 patients (99.8%) recovered without complications. Complications occurred in three patients, all in the severe group. Of these, two required long-term mechanical ventilation, and one developed RSV encephalopathy with subsequent developmental delay. None of the three patients with complications had underlying diseases. No deaths were reported (Table 2). Discussion Okinawa Prefecture, located in the East China Sea between mainland Japan and Taiwan, comprises more than 150 islands, 38 of which are inhabited. It is the only prefecture in Japan characterized by a subtropical to tropical climate. This retrospective epidemiological study was conducted using medical records from four prefectural hospitals in Okinawa: ONMC, Chubu Hospital, Miyako Hospital, and Yaeyama Hospital. The first two are located in the main island of Okinawa and serve over 90% of its population, while the latter two are situated on Miyako and Yaeyama Islands, respectively, functioning as the primary referral centers in their respective regions. This is the first study to examine 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 non-pharmaceutical interventions (NPIs), including physical distancing, mask use, and school closures, in Japan ( 18 , 19 ). These circumstances offered a unique opportunity to examine how such measures affected the epidemiology of moderate-to-severe RSV infections in Okinawa, focusing on changes in the timing of peak incidence and the age distribution of patients. In our analysis, the severe group had a median age of 3 months, significantly younger than the moderate group — and previous reports indicate that being under 3 months of age increases the need for respiratory support ( 20 ). In the severe group, 88.3% had siblings, suggesting that transmission from older children may contribute to severity. Previous studies have also identified having siblings as a risk factor for severe RSV infection ( 20 ). While nursery school attendance has been identified as a risk factor for severe RSV infection in previous studies ( 20 , 21 ), a higher attendance rate was observed among moderate cases in the present study (Table 1 ). This discrepancy may be explained by the younger age distribution of the severe group, as many of these children had not yet reached the typical age for nursery enrollment. Earlier studies have reported that chronic lung disease, congenital heart disease, and immunodeficiency are risk factors for severe RSV infection ( 22 – 24 ). In our study, however, the prevalence of each individual underlying diseases did not differ significantly between the moderate and severe groups. In contrast, the proportion of patients with two or more underlying diseases was significantly higher in the severe group compared to the moderate group (Table 1 ). The epidemiological pattern of RSV infection in Okinawa differs substantially from that observed in mainland Japan ( 25 – 27 ). According to the nationwide sentinel surveillance, RSV epidemics in mainland Japan exhibited a sharp annual peak from October 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 ( 25 ). Between the 2016 and 2019 seasons, the peak timing of RSV epidemics in mainland Japan shifted earlier, from November to around September ( 25 , 28 ). 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 ( 25 ). During the four-year study period from April 2017 to March 2021, analysis of medical records from four participating hospitals revealed that the number of moderate-to-severe RSV cases peaked between June and August (Fig. 3 ). This timing coincided with the peak of overall RSV infections—regardless of severity—reported in Okinawa Prefecture through the nationwide sentinel hospital-based surveillance ( 25 ). In 2020, following the implementation of NPIs against COVID-19, the typical seasonal peak of RSV infections disappeared nationwide, while in Okinawa, the peak was delayed by about six months, occurring between September and December ( 25 ). 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 ( 29 ). In Taiwan, RSV showed no clear seasonality between 1997 and 1999 ( 30 ), but from 2015 to 2020, a broad summer peak—especially from July to September—was observed, followed by a winter decline ( 31 ). This pattern closely resembles that of Okinawa, where RSV also peaks in summer ( 25 ). 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 ( 32 ). This peak coincides with the peak in hospitalized cases observed in the present study in Okinawa (Fig. 3 ). 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, possibly due to waning maternal antibodies and greater exposure to older siblings. (Fig. 4 , Table 1 ). Although hospitalizations decreased after 12 months, a considerable number of cases still required admission up to 24 months, 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 ( 33 , 34 ). 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. 5 ). During the pandemic, the proportion of cases in infants under 6 months increased significantly, while that in the 6–12 month group declined (Fig. 5 ). This shift suggests that, due to limited social interaction, the relative contribution of household transmission to RSV infection increased, particularly among younger infants. Regarding respiratory support, approximately two-thirds of the moderate RSV group required oxygen therapy. In contrast, 94.0% of the severe group received high-flow nasal cannula, and 41.0% were intubated for mechanical ventilation, confirming that the severity classification corresponds with the clinical respiratory management burden (Table 2 ). Overall, 99.8% of patients recovered without any complications, and there were no fatalities (Table 2 ). Only three patients— all from the severe group— experienced complications: two required prolonged mechanical ventilation, and one developed RSV encephalopathy, resulting in 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 high-risk infants ( 12 , 13 ). In recent years, nirsevimab has been approved in several countries ( 14 , 15 , 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 ( 15 ). 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 ( 16 ). Taken together, nirsevimab and maternal vaccination are expected to become the primary approaches for preventing severe RSV infection in infants. This multi-center epidemiological study covering the entire Okinawa prefecture offers a valuable foundation for understanding the regional burden and characteristics of moderate-to-severe RSV infections. Limitations include the absence of data on preventive measures such as palivizumab, nirsevimab, and maternal RSV vaccination. However, detailed information on seasonality, age distribution, household composition, childcare facility uses, and underlying diseases is expected to provide important insights for optimizing preventive strategies and serve as an essential basis for evaluating and enhancing the implementation of RSV preventive measures. Conclusions This four-year multicenter study provides the first comprehensive epidemiological overview of moderate-to-severe RSV infections among children in subtropical Okinawa, Japan. Approximately 60% of hospitalizations occurred in infants under 12 months, with the highest incidence observed in those aged 0–2 months. Younger age and the presence of siblings were associated with greater severity. The observed summer seasonality contrasts with the winter peaks observed in mainland Japan, aligning more closely with patterns in subtropical and tropical regions. A marked decline and temporal shift in RSV activity during the COVID-19 pandemic highlight the impact of public health measures on viral transmission. These findings provide crucial baseline data to guide the development of RSV prevention strategies adapted to regional epidemiological patterns. Abbreviations RSV respiratory syncytial virus ALRTIs acute lower respiratory tract infections HRGs high-risk groups MSAs medical service areas ONMC Okinawa Nanbu Medical Center & Children’s Medical Center ICU intensive care unit NOIs non-pharmaceutical interventions Declarations Ethics approval and consent to participate This study was approved by the Clinical Research Review Committee of Okinawa Chubu Hospital, Okinawa, Japan (Approval No. 2020-68). Patient data were anonymized prior to analysis. Consent for publication This study does not include any personal data; therefore, this category is not applicable. All authors have approved the publication. Availability of data and materials The data analyzed in this study were extracted from patient medical records maintained at each participating institution and were anonymized to prevent personal identification. In accordance with institutional policies and ethical regulations, the dataset cannot be made publicly available. Competing interest The authors declare that they have no competing interests. Funding No funding was received for this study. Authors’ contributions KF-A supervised the overall study, collected data at Chubu Hospital, selected and analyzed the data, and drafted the manuscript. KA collected and verified data at Yaeyama Hospital. HF collected and verified the data at Miyako Hospital. YC collected and verified the data at ONMC. KM collected and verified the data at Yaeyama Hospital and Chubu Hospital. TM collected and verified the data at the NICU of Chubu Hospital. SK collected and verified the data at Chubu Hospital. TY provided guidance on the overall study and data analysis and was responsible for the manuscript's overall writing. References Collins PL, Karron RA. Respiratory syncytial virus and metapneumovirus. In: Knipe DM, Howley PM, editors. Fields Virology. 3. 7 ed. Philadelphia: Wolters Kluwer; 2022. p. 267–318. Shi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. 2017;390(10098):946–58. Okada K, Mizuno M, Moriuchi H, Kusuda S, Morioka I, Mori M, et al. The Working Group for Revision of "Guidelines for the Use of Palivizumab in Japan": A Committee Report. Pediatr Int. 2020;62(11):1223–9. Stein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354(9178):541–5. Jackson DJ. Early-life viral infections and the development of asthma: a target for asthma prevention? Curr Opin Allergy Clin Immunol. 2014;14(2):131–6. Obando-Pacheco P, Justicia-Grande AJ, Rivero-Calle I, Rodriguez-Tenreiro C, Sly P, Ramilo O, et al. Respiratory Syncytial Virus Seasonality: A Global Overview. J Infect Dis. 2018;217(9):1356–64. Staadegaard L, Caini S, Wangchuk S, Thapa B, de Almeida WAF, de Carvalho FC, et al. Defining the seasonality of respiratory syncytial virus around the world: National and subnational surveillance data from 12 countries. Influenza Other Respir Viruses. 2021;15(6):732–41. Jung SM, Lee H, Yang Y, Nishiura H. Quantifying the causal impact of funding bedside antigen testing on the incidence of respiratory syncytial virus infection in Japan: a difference-in-differences study. Ann Transl Med. 2020;8(21):1441. Kanou K, Arima Y, Kinoshita H, Ito H, Okuno H, Saito N, et al. Respiratory Syncytial Virus Surveillance System in Japan: Assessment of Recent Trends, 2008–2015. Jpn J Infect Dis. 2018;71(3):250–5. Japan Meteorological Agency. Search past weather data [Web Page]. Japan Meteorological Agency; [Japan Meteorological Agency]. Available from: https://www.data.jma.go.jp/stats/etrn/ . Japan Institute for Health Security. Surveillance [Web Page]. Tokyo, Japan: Japan Institute for Health Security; [Available from: https://id-info.jihs.go.jp/en/surveillance/index.html . Palivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. Pediatrics. 1998;102(3):531–7. Robbie GJ, Zhao L, Mondick J, Losonsky G, Roskos LK. Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother. 2012;56(9):4927–36. Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med. 2022;386(9):837–46. Noto S, Kieffer A, Soudani S, Arashiro T, Tadera C, Eymere S, et al. Cost-Effectiveness and Public Health Impact of Universal Prophylaxis with Nirsevimab Against Respiratory Syncytial Virus (RSV) Infections in all Infants in Japan. Infect Dis Ther. 2025;14(4):847–65. Kampmann B, Madhi SA, Munjal I, Simoes EAF, Pahud BA, Llapur C, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023;388(16):1451–64. Okinawa Prefecture Government. Basic Resident Register Population by Age [Web Page]. Okinawa Prefecture: Okinawa Prefecture Government; [Basic Resident Register Population by Age]. Available from: https://honyaku.j-server.com/LUCOKNWP/ns/tl.cgi/https://www.pref.okinawa.jp/kensei/shinko/1016703/1016705/1016773/1022611/1016805.html?SLANG=ja &TLANG=en&XMODE=0&XCHARSET=utf-8&XJSID=0. Sekine I, Uojima H, Koyama H, Kamio T, Sato M, Yamamoto T, et al. Impact of non-pharmaceutical interventions for the COVID-19 pandemic on emergency department patient trends in Japan: a retrospective analysis. Acute Med Surg. 2020;7(1):e603. Kishimoto K, Bun S, Shin JH, Takada D, Morishita T, Kunisawa S, et al. Early impact of school closure and social distancing for COVID-19 on the number of inpatients with childhood non-COVID-19 acute infections in Japan. Eur J Pediatr. 2021;180(9):2871–8. Havdal LB, Boas H, Bekkevold T, Bakken Kran AM, Rojahn AE, Stordal K, et al. Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age. Front Pediatr. 2022;10:1004739. Sommer C, Resch B, Simoes EA. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol J. 2011;5:144–54. Aikphaibul P, Theerawit T, Sophonphan J, Wacharachaisurapol N, Jitrungruengnij N, Puthanakit T. Risk factors of severe hospitalized respiratory syncytial virus infection in tertiary care center in Thailand. Influenza Other Respir Viruses. 2021;15(1):64–71. Hall CB, Simoes EA, Anderson LJ. Clinical and epidemiologic features of respiratory syncytial virus. Curr Top Microbiol Immunol. 2013;372:39–57. Shi T, Vennard S, Mahdy S, Nair H, investigators R. Risk Factors for Poor Outcome or Death in Young Children With Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection: A Systematic Review and Meta-Analysis. J Infect Dis. 2022;226(Suppl 1):S10-S6. Okinawa Prefectural Government. Trends in RS Virus Infections (As of Week 38, 2021) (Japanese) Okinses Japan: Okinawa Prefectural Government; 2021 [cited 2025. PDF; Okinawa Prefecture Press Releases Page]. Available from: https://www.pref.okinawa.lg.jp/_res/projects/default_project/_page_/001/018/064/rsvirus_shiryou1_20210930.pdf . Yoshioka S, Phyu WW, Wagatsuma K, Nagai T, Sano Y, Taniguchi K, et al. Molecular Epidemiology of Respiratory Syncytial Virus during 2019–2022 and Surviving Genotypes after the COVID-19 Pandemic in Japan. Viruses. 2023;15(12). Shinzato A, Hibiya K, Nishiyama N, Ikemiyagi N, Arakaki W, Kami W, et al. Unseasonal respiratory syncytial virus epidemics during the COVID-19 pandemic: Relationship between climatic factors and epidemic strain switching. Int J Infect Dis. 2025;154:107833. Wagatsuma K, Koolhof IS, Shobugawa Y, Saito R. Shifts in the epidemic season of human respiratory syncytial virus associated with inbound overseas travelers and meteorological conditions in Japan, 2014–2017: An ecological study. PLoS One. 2021;16(3):e0248932. Iha Y, Kinjo T, Parrott G, Higa F, Mori H, Fujita J. Comparative epidemiology of influenza A and B viral infection in a subtropical region: a 7-year surveillance in Okinawa, Japan. BMC Infect Dis. 2016;16(1):650. Tsai HP, Kuo PH, Liu CC, Wang JR. Respiratory viral infections among pediatric inpatients and outpatients in Taiwan from 1997 to 1999. J Clin Microbiol. 2001;39(1):111–8. Hsu HT, Huang FL, Ting PJ, Chang CC, Chen PY. The epidemiological features of pediatric viral respiratory infection during the COVID-19 pandemic in Taiwan. J Microbiol Immunol Infect. 2022;55(6 Pt 1):1101–7. Sitthikarnkha P, Uppala R, Niamsanit S, Sutra S, Thepsuthammarat K, Techasatian L, et al. Burden of Respiratory Syncytial Virus Related Acute Lower Respiratory Tract Infection in Hospitalized Thai Children: A 6-Year National Data Analysis. Children (Basel). 2022;9(12). Leija-Martinez JJ, Esparza-Miranda LA, Rivera-Alfaro G, Noyola DE. Impact of Nonpharmaceutical Interventions during the COVID-19 Pandemic on the Prevalence of Respiratory Syncytial Virus in Hospitalized Children with Lower Respiratory Tract Infections: A Systematic Review and Meta-Analysis. Viruses. 2024;16(3). Uwak I, Johnson N, Mustapha T, Rahman M, Tonpay T, Regan AK, et al. Quantifying changes in respiratory syncytial virus-associated hospitalizations among children in Texas during COVID-19 pandemic using records from 2006 to 2021. Front Pediatr. 2023;11:1124316. Agency EM. Beyfortus (niservimab) [Web Page]. European Medicines Agency; 2022 [updated 24/06/2025. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/beyfortus . Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files RSVTables.xlsx Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Tropical Medicine and Health → Version 1 posted Editorial decision: Revision requested 24 Aug, 2025 Reviews received at journal 24 Aug, 2025 Reviews received at journal 17 Aug, 2025 Reviews received at journal 17 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers invited by journal 15 Aug, 2025 Editor assigned by journal 14 Aug, 2025 Submission checks completed at journal 14 Aug, 2025 First submitted to journal 07 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7316076","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":501605312,"identity":"2a6ab699-8976-4277-91fd-116261065466","order_by":0,"name":"Kahoru Fukuoka-Araki","email":"","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":false,"prefix":"","firstName":"Kahoru","middleName":"","lastName":"Fukuoka-Araki","suffix":""},{"id":501605313,"identity":"3bc64977-a37c-4ac2-acf4-a79ca9271da6","order_by":1,"name":"Kotaro Araki","email":"","orcid":"","institution":"Yaeyama Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kotaro","middleName":"","lastName":"Araki","suffix":""},{"id":501605314,"identity":"bfc1bf98-bf85-4794-9921-3ee72eebe49e","order_by":2,"name":"Hiromi Fukuoka","email":"","orcid":"","institution":"Okinawa Miyako Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiromi","middleName":"","lastName":"Fukuoka","suffix":""},{"id":501605315,"identity":"d02f6776-2de9-4eba-a5df-7066badd55ff","order_by":3,"name":"Yoshiaki Cho","email":"","orcid":"","institution":"Okinawa Prefectural Nanbu Medical Center \u0026 Children's Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yoshiaki","middleName":"","lastName":"Cho","suffix":""},{"id":501605316,"identity":"3110c0a6-ada1-49e2-a903-581710de27b9","order_by":4,"name":"Kei Matayoshi","email":"","orcid":"","institution":"Okinawa Chubu Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Matayoshi","suffix":""},{"id":501605317,"identity":"26557424-41e6-4bf3-af6b-ebaa94c6f0ce","order_by":5,"name":"Tomoko Makiya","email":"","orcid":"","institution":"Okinawa Chubu Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Makiya","suffix":""},{"id":501605318,"identity":"d0372688-9ab5-4ecc-afab-567de78ce2d3","order_by":6,"name":"Saori Kinjo","email":"","orcid":"","institution":"Okinawa Chubu Hospital","correspondingAuthor":false,"prefix":"","firstName":"Saori","middleName":"","lastName":"Kinjo","suffix":""},{"id":501605319,"identity":"1ff9204f-badb-4d10-ac44-1f4ef559cf43","order_by":7,"name":"Tetsu Yamashiro","email":"data:image/png;base64,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","orcid":"","institution":"University of the Ryukyus","correspondingAuthor":true,"prefix":"","firstName":"Tetsu","middleName":"","lastName":"Yamashiro","suffix":""}],"badges":[],"createdAt":"2025-08-07 07:53:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7316076/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7316076/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s41182-025-00824-3","type":"published","date":"2025-11-11T15:57:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89976623,"identity":"8806c1ca-9629-4c46-b77b-ea723aa8abda","added_by":"auto","created_at":"2025-08-27 06:04:50","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":35417,"visible":true,"origin":"","legend":"\u003cp\u003eMap of Okinawa Prefecture showing the Okinawa main island along with the Miyako and Yaeyama Islands. The Okinawa main island lies approximately 1,600 km southwest of Tokyo, while the Miyako and Ishigaki Islands are located about 300 km and 400 km from the main island, respectively. The locations of the four participating hospitals (ONMC, Chubu, Miyako, and Yaeyama) are indicated.\u003c/p\u003e","description":"","filename":"Fig.1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/4e5c8008b768c21c65277015.jpeg"},{"id":89973161,"identity":"6fb80d8e-7c9e-424f-b36d-28894a1c836d","added_by":"auto","created_at":"2025-08-27 05:48:50","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44535,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of case enrollment and selection. A total of 1,561 records of children under 5 years of age with moderate-to-severe RSV infection were initially identified. After excluding 20 cases due to not meeting the case definition or duplication, 1,541 cases were included in the final analysis: 548 from ONMC, 522 from Chubu Hospital, 169 from Miyako Hospital, and 302 from Yaeyama Hospital.\u003c/p\u003e","description":"","filename":"Fig.2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/2b9e4504b68adb9a56b2c8f0.jpeg"},{"id":89973170,"identity":"39840af2-078f-440f-a403-7fd960f910ce","added_by":"auto","created_at":"2025-08-27 05:48:51","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":52320,"visible":true,"origin":"","legend":"\u003cp\u003eSeasonal distribution of moderate-to-severe RSV infections in children under 5 years of age across four hospitals in Okinawa Prefecture from April 2017 to March 2020. Consistent summer peaks (June–August) were observed from 2017 to 2019 across all regions, including the main island and the Miyako and Yaeyama Islands. In 2020, coinciding with the onset of the COVID-19 pandemic, the peak incidence declined, shifted to winter, and became broader in distribution.\u003c/p\u003e","description":"","filename":"Fig.3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/cbd8679d380810775c7eb7f8.jpeg"},{"id":89973166,"identity":"0c246282-3658-45bc-960d-8ed3f9050efb","added_by":"auto","created_at":"2025-08-27 05:48:50","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":36750,"visible":true,"origin":"","legend":"\u003cp\u003eAge distribution of moderate-to-severe RSV infections in children under 24 months. Among 1,373 cases, the 0–2-month group accounted for the largest proportion (26%), followed by a secondary peak in the 9–11-month group. Cases declined progressively after 12 months of age, with no notable regional differences observed. *, statistically significant difference (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.05)\u003c/p\u003e","description":"","filename":"Fig.4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/d9006681a1d4996e846ecf34.jpeg"},{"id":89973177,"identity":"21c7ae49-d31a-48ab-a513-959696a64ce3","added_by":"auto","created_at":"2025-08-27 05:48:51","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":30184,"visible":true,"origin":"","legend":"\u003cp\u003eAge distribution of moderate-to-severe RSV infections in children under 5 years before (2017–2020) and during (2020–2021) the COVID-19 pandemic. Cases decreased by 62% during the pandemic (1,369 vs. 172). Infants under 6 months accounted for the largest proportion in both periods, increasing significantly during the pandemic, while the proportion of 6–11-month-olds declined. No significant change was seen in children ≥12 months.\u003c/p\u003e","description":"","filename":"Fig.5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/33acc4c388e384f033027595.jpeg"},{"id":96105969,"identity":"9711ebc2-ea0d-4820-a672-ca29b837f832","added_by":"auto","created_at":"2025-11-17 16:12:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":656646,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/6cf01656-cb48-438d-8309-f0ccbc56808f.pdf"},{"id":89973184,"identity":"e82c4b8c-c8b1-458a-b425-95cc9db6506f","added_by":"auto","created_at":"2025-08-27 05:48:51","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11300961,"visible":true,"origin":"","legend":"","description":"","filename":"RSVTables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7316076/v1/c6cc23a9304597f09ddddedc.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Epidemiology of Moderate-to-Severe Respiratory Syncytial Virus Infections in Children in Subtropical Okinawa, Japan: A Four-Year Retrospective Study","fulltext":[{"header":"Background","content":"\u003cp\u003eRespiratory syncytial virus (RSV), a member of the genus Orthopneumovirus in the family Pneumoviridae, is an enveloped, non-segmented, negative-sense RNA virus and a leading cause of acute lower respiratory tract infections (ALRTIs) in infants and young children worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Globally, RSV is responsible for approximately 33\u0026nbsp;million ALRTIs episodes annually, leading to more than 3\u0026nbsp;million hospitalization and an estimated 118,200 deaths among children under five years of age, with the majority occurring in low- and middle-income countries (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). High-risk groups (HRGs) for moderate-to-severe RSV infection include preterm infants, children with chronic lung disease or congenital heart disease, immunocompromised individuals, and those with genetic conditions such as Down syndrome (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Severe RSV infection in early infancy has also been associated with long-term respiratory sequelae, including recurrent wheezing and increased risk of asthma in childhood (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe prevalence and seasonality of RSV infection are strongly influenced by climatic factors. In temperate regions, RSV epidemics typically peak during the winter months, from September to January in the northern hemisphere, coinciding with cold and dry conditions (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In contrast, tropical and subtropical regions, characterized by high humidity and rainfall, often experience year-round RSV activity with less distinct seasonal peaks (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn Japan, RSV is a major cause of pediatric hospitalization due to acute respiratory infections. The annual incidence is estimated at 1,761 per 100,000 children, with 19\u0026ndash;36 deaths reported each year (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The country\u0026rsquo;s pronounced climatic gradient between northern and southern regions (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) results in substantial variation in RSV epidemic timing nationwide. Consequently, continuous monitoring of regional RSV activity and issuing timely, region-specific public health alerts are considered critical for effective disease control. In Japan, RSV surveillance is carried out through sentinel pediatric sites across the country, which report weekly case and demographic data to health authorities. The Japan Institute for Health Security (JHIS) collects and analyzes this data (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e), although clinical severity and outcomes are not included.\u003c/p\u003e\u003cp\u003eUntil recently, palivizumab was the only approved preventive option for infants, but its use was limited to HRGs and required monthly injections during the RSV season (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In recent years, nirsevimab\u0026mdash;a long-acting monoclonal antibody that offers season-long protection with a single dose for all infants (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u0026mdash;and maternal RSV vaccination have emerged as promising preventive strategies (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). To support the successful implementation of these measures, detailed data on seasonality, age groups, household structure, childcare attendance, and underlying diseases are essential for identifying high-risk populations and tailoring prevention strategies to regional needs.\u003c/p\u003e\u003cp\u003eOkinawa Prefecture is separated from mainland Japan and consists of the main Okinawa Island as well as the Miyako and Yaeyama islands. It has a subtropical to tropical climate. Due to its geographical isolation, most residents receive medical care within the prefecture, and inter-prefectural patient transfer is uncommon, making Okinawa an ideal setting for comprehensive regional epidemiological studies. This study represents the first report to analyze detailed demographic and clinical characteristics, including annual incidence, hospitalization outcomes, oxygen therapy use, preterm birth status, and underlying conditions, of moderate-to-severe RSV cases requiring hospitalization in Okinawa Prefecture over a four-year period beginning in April 2017. Notably, the study period overlapped with the global COVID-19 pandemic, allowing us to examine the potential impact of nationwide infection control measures on the age distribution and severity profile of moderate-to-severe RSV cases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy setting and population\u003c/p\u003e\u003cp\u003eOkinawa Prefecture, located approximately 1,600 km southwest of Tokyo, comprises the Okinawa main island and multiple remote islands, including the Miyako and Yaeyama island groups situated about 300 km and 400 km further southwest, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The region has a subtropical to tropical oceanic climate, with an average maximum temperature of 29.1\u0026deg;C in July and an average minimum of 17.3\u0026deg;C in January, and total annual precipitation of 2,161 mm over the five-year period beginning in 2020 (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The prefecture has a total population of approximately 1.5\u0026nbsp;million, including approximately 76,800 children under 5 years of age. Population distribution is concentrated on the main island of Okinawa and its surrounding islands, which account for 92.4% of the residents, while the Miyako and Yaeyama Islands comprise 3.81% and 3.75%, respectively (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). For healthcare administration, Okinawa Prefecture is divided into five medical service areas (MSAs) based on clusters of municipalities. On the main island, three MSAs\u0026mdash;Northern, Central, and Southern\u0026mdash;cover 9\u0026ndash;16 adjacent municipalities each. The Miyako and Yaeyama MSAs correspond to the Miyako and Yaeyama Islands, respectively.\u003c/p\u003e\u003cp\u003eStudy design and participating hospitals\u003c/p\u003e\u003cp\u003eThis is a retrospective, chart-based epidemiological study conducted over a four-year period from April 2017 to March 2021 at four regional core hospitals in Okinawa Prefecture: Okinawa Nanbu Medical Center \u0026amp; Children\u0026rsquo;s Medical Center (ONMC), Chubu Hospital, Miyako Hospital, and Yaeyama Hospital. ONMC (444 beds), located near Naha City, serves the Southern MSA, which accounts for approximately 54.5% of the main island population. Chubu Hospital (559 beds), located in Uruma City, serves the Central MSA, covering approximately 38.0% of the main island population. Miyako Hospital (276 beds) and Yaeyama Hospital (302 beds) are the sole core hospitals serving the Miyako and Yaeyama MSAs, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePatient enrollment and case classification\u003c/p\u003e\u003cp\u003eChildren under 5 years of age hospitalized for laboratory-confirmed RSV infection were eligible for inclusion. Patients admitted exclusively to a general pediatric ward were classified as moderate cases, whereas those requiring intensive care unit (ICU) management were classified as severe cases.\u003c/p\u003e\u003cp\u003eData collection\u003c/p\u003e\u003cp\u003eClinical and demographic data were extracted from medical records, including age, sex, presence of siblings, nursery school attendance, preterm birth (gestational age\u0026thinsp;\u0026lt;\u0026thinsp;37 weeks), underlying diseases, ICU admission, type of respiratory support, and discharge outcomes. Respiratory support modalities were recorded cumulatively, as individual patients could receive multiple interventions during hospitalization.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003cp\u003e This study was approved by the Clinical Research Review Committee of Okinawa Chubu Hospital, Okinawa, Japan (Approval No. 2020-68). Patient data were anonymized prior to analysis.\u003c/p\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were summarized as medians with interquartile ranges (IQRs) and compared using the Mann\u0026ndash;Whitney U test. Categorical variables were expressed as counts and percentages and analyzed using the chi-square test or Fisher\u0026rsquo;s exact test as appropriate. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical interface for R. A two-sided p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatients\u003c/p\u003e\n\u003cp\u003eA total of 1,561 records of children under 5 years of age with moderate-to- severe RSV infection were initially enrolled. After excluding 20 cases due to failure to meet the case definition or duplication, 1,541 cases were included in the final analyses. Of the 1,541 cases,\u0026nbsp;548 were reported from ONMC, 522 from Chubu Hosp., 169 from Miyako Hosp., and 302 from Yaeyama Hosp.\u0026nbsp;(Fig. 2).\u0026nbsp;The 1,541 children hospitalized with RSV infection were classified into two groups: those with severe cases requiring ICU care and those with moderate cases not requiring ICU admission.\u0026nbsp;A comparative analysis was conducted between the two groups regarding demographic characteristics, sibling status, nursery school attendance, and the presence and type of underlying diseases\u0026nbsp;(Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe median age was significantly lower in the severe group than in the moderate group. The proportion of children with siblings was significantly higher in the severe group. In contrast, the rate of nursery school attendance was significantly lower in the severe group. No significant differences were observed between the two groups in terms of female ratio or the proportion of preterm births (Table 1).\u003c/p\u003e\n\u003cp\u003eUnderlying diseases were present in 14.8% of all cases, with 14.5% in the moderate group and 18.8% in the severe group. The higher occurrence in severe cases was not statistically significant. When analyzing individual diseases, cardiovascular disease was found in 3.4% of severe cases (4/117) and 1.6% of moderate cases (23/1,424), with no significant difference. No other disease categories showed significant variation by severity. However, the proportion of patients with two or more underlying diseases was significantly greater in the severe group than in the moderate group (6.0% [7/117] vs. 2.6% [37/1,424], p \u0026lt; 0.05) （Table 1）.\u003c/p\u003e\n\u003cp\u003eSeasonal and regional distribution of moderate-to-severe RSV infections\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFigure 3 illustrates the seasonal distribution of moderate-to-severe RSV infection cases across four hospitals in Okinawa Prefecture from April 2017 to March 2021.\u0026nbsp;During this four-year surveillance period, seasonal peaks consistently occurred in the summer months, June to August, from 2017 through 2019.\u0026nbsp;In contrast, RSV activity was minimal between December and February throughout the study period.\u0026nbsp;This seasonal pattern was observed uniformly across the regions of Okinawa Prefectures\u0026nbsp;(Fig. 3). The peak incidence of RSV infections gradually increased from 2017 to 2019.\u0026nbsp;However, in 2020, coinciding with the onset of the COVID-19 pandemic, the peak incidence markedly decreased and shifted from summer to winter.\u0026nbsp;Additionally, the peak became broader in distribution, with the timing of peak months varying across the four hospitals: ONMC observed its peak from September to November, Chubu around December, and Yaeyama in February. In contrast, Miyako did not exhibit a distinct seasonal peak during this period\u0026nbsp;(Fig. 3).\u003c/p\u003e\n\u003cp\u003eAge distribution of moderate-to-severe RSV infections in children under 24 months\u003c/p\u003e\n\u003cp\u003eAmong the 1,541 patients with moderate-to-severe RSV infection, 89.0% (n = 1,373) were under 24 months of age. The age distribution in three-month intervals is shown in Figure 4. The largest subgroup was the 0–2-month age group, accounting for 26% (n = 360) of cases. The number of cases dropped sharply in the 3–5-month group, increased again in the 6–11-month groups with a secondary peak at 9–11 months, and then declined steadily through 21–23 months. These patterns were consistent across all regions, with no notable regional differences observed (Figure 4).\u003c/p\u003e\n\u003cp\u003eComparison of age-specific proportions of moderate-to-severe RSV cases before and during COVID-19\u003c/p\u003e\n\u003cp\u003eThe age-stratified distribution of children under 5 with moderate-to-severe RSV infection was analyzed for the periods before and during the pandemic. From April 2017 to March 2020, 1,369 cases were reported (approximately 456 annually), whereas only 172 cases occurred during April 2020–March 2021, representing a statistically significant 62% decrease from the pre-pandemic average. In both periods, infants aged \u0026lt;6 months accounted for the largest proportion of cases; this proportion increased significantly in the pandemic period, while the proportion of infants aged 6 to \u0026lt;12 months decreased significantly. There were no significant differences between periods for children aged ≥12 months (Figure 5).\u003c/p\u003e\n\u003cp\u003eRespiratory support and clinical outcomes in patients with moderate-to- severe RSV Infection\u003c/p\u003e\n\u003cp\u003eOf the 1,541 patients with moderate-to-severe RSV infection, 1,039 (67.4%) required some form of respiratory support. Normal flow oxygen support via facial mask or nasal cannula was the most frequently used modality, administered to 998 patients (64.8%), including 898 moderate cases (63.1%) and 100 severe cases (85.5%). High-flow nasal cannula was used in 314 patients (20.3%), comprising 204 moderate cases (14.3%) and 110 severe cases (94.0%). Mechanical ventilation was provided to 51 patients (3.3%), including 3 moderate cases (0.2%) and 48 severe cases (41.0%). Respiratory support was not required in 502 patients (32.6%), consisting of 501 moderate cases (35.2%) and 1 severe case (0.9%).\u0026nbsp;Overall, 1,538 patients (99.8%) recovered without complications. Complications occurred in three patients, all in the severe group. Of these, two required long-term mechanical ventilation, and one developed RSV encephalopathy with subsequent developmental delay. None of the three patients with complications had underlying diseases. No deaths were reported (Table 2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOkinawa Prefecture, located in the East China Sea between mainland Japan and Taiwan, comprises more than 150 islands, 38 of which are inhabited. It is the only prefecture in Japan characterized by a subtropical to tropical climate. This retrospective epidemiological study was conducted using medical records from four prefectural hospitals in Okinawa: ONMC, Chubu Hospital, Miyako Hospital, and Yaeyama Hospital. The first two are located in the main island of Okinawa and serve over 90% of its population, while the latter two are situated on Miyako and Yaeyama Islands, respectively, functioning as the primary referral centers in their respective regions.\u003c/p\u003e\u003cp\u003eThis is the first study to examine 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 non-pharmaceutical interventions (NPIs), including physical distancing, mask use, and school closures, in Japan (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). These circumstances offered a unique opportunity to examine how such measures affected the epidemiology of moderate-to-severe RSV infections in Okinawa, focusing on changes in the timing of peak incidence and the age distribution of patients.\u003c/p\u003e\u003cp\u003eIn our analysis, the severe group had a median age of 3 months, significantly younger than the moderate group \u0026mdash; and previous reports indicate that being under 3 months of age increases the need for respiratory support (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In the severe group, 88.3% had siblings, suggesting that transmission from older children may contribute to severity. Previous studies have also identified having siblings as a risk factor for severe RSV infection (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhile nursery school attendance has been identified as a risk factor for severe RSV infection in previous studies (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), a higher attendance rate was observed among moderate cases in the present study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This discrepancy may be explained by the younger age distribution of the severe group, as many of these children had not yet reached the typical age for nursery enrollment. Earlier studies have reported that chronic lung disease, congenital heart disease, and immunodeficiency are risk factors for severe RSV infection (\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). In our study, however, the prevalence of each individual underlying diseases did not differ significantly between the moderate and severe groups. In contrast, the proportion of patients with two or more underlying diseases was significantly higher in the severe group compared to the moderate group (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe epidemiological pattern of RSV infection in Okinawa differs substantially from that observed in mainland Japan (\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). According to the nationwide sentinel surveillance, RSV epidemics in mainland Japan exhibited a sharp annual peak from October to November during the 2012\u0026ndash;2015 seasons. In contrast, Okinawa demonstrated broader or bimodal peaks, generally occurring between June and August, approximately six months earlier than in mainland Japan (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Between the 2016 and 2019 seasons, the peak timing of RSV epidemics in mainland Japan shifted earlier, from November to around September (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). 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 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). During the four-year study period from April 2017 to March 2021, analysis of medical records from four participating hospitals revealed that the number of moderate-to-severe RSV cases peaked between June and August (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This timing coincided with the peak of overall RSV infections\u0026mdash;regardless of severity\u0026mdash;reported in Okinawa Prefecture through the nationwide sentinel hospital-based surveillance (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In 2020, following the implementation of NPIs against COVID-19, the typical seasonal peak of RSV infections disappeared nationwide, while in Okinawa, the peak was delayed by about six months, occurring between September and December (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTaiwan 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 (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In Taiwan, RSV showed no clear seasonality between 1997 and 1999 (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), but from 2015 to 2020, a broad summer peak\u0026mdash;especially from July to September\u0026mdash;was observed, followed by a winter decline (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). This pattern closely resembles that of Okinawa, where RSV also peaks in summer (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). 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 (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). This peak coincides with the peak in hospitalized cases observed in the present study in Okinawa (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). 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.\u003c/p\u003e\u003cp\u003eMost hospitalizations for moderate-to-severe RSV infection in this study occurred in infants under 12 months, with a clear peak in the 0\u0026ndash;2 month age group\u0026mdash;consistent with findings from Europe and other regions (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u0026mdash;and a secondary peak at 9\u0026ndash;11 months, possibly due to waning maternal antibodies and greater exposure to older siblings. (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Although hospitalizations decreased after 12 months, a considerable number of cases still required admission up to 24 months, 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.\u003c/p\u003e\u003cp\u003eIn 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 (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). 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.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). During the pandemic, the proportion of cases in infants under 6 months increased significantly, while that in the 6\u0026ndash;12 month group declined (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). This shift suggests that, due to limited social interaction, the relative contribution of household transmission to RSV infection increased, particularly among younger infants.\u003c/p\u003e\u003cp\u003eRegarding respiratory support, approximately two-thirds of the moderate RSV group required oxygen therapy. In contrast, 94.0% of the severe group received high-flow nasal cannula, and 41.0% were intubated for mechanical ventilation, confirming that the severity classification corresponds with the clinical respiratory management burden (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Overall, 99.8% of patients recovered without any complications, and there were no fatalities (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Only three patients\u0026mdash; all from the severe group\u0026mdash; experienced complications: two required prolonged mechanical ventilation, and one developed RSV encephalopathy, resulting in developmental delays. The occurrence of these severe outcomes in patients without underlying diseases highlights the potential severity of RSV infection.\u003c/p\u003e\u003cp\u003ePalivizumab has long been the standard method for preventing severe RSV infection; however, it requires monthly injections and is limited to high-risk infants (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In recent years, nirsevimab has been approved in several countries (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). 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 (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). 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 (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Taken together, nirsevimab and maternal vaccination are expected to become the primary approaches for preventing severe RSV infection in infants.\u003c/p\u003e\u003cp\u003e This multi-center epidemiological study covering the entire Okinawa prefecture offers a valuable foundation for understanding the regional burden and characteristics of moderate-to-severe RSV infections. Limitations include the absence of data on preventive measures such as palivizumab, nirsevimab, and maternal RSV vaccination. However, detailed information on seasonality, age distribution, household composition, childcare facility uses, and underlying diseases is expected to provide important insights for optimizing preventive strategies and serve as an essential basis for evaluating and enhancing the implementation of RSV preventive measures.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis four-year multicenter study provides the first comprehensive epidemiological overview of moderate-to-severe RSV infections among children in subtropical Okinawa, Japan. Approximately 60% of hospitalizations occurred in infants under 12 months, with the highest incidence observed in those aged 0\u0026ndash;2 months. Younger age and the presence of siblings were associated with greater severity. The observed summer seasonality contrasts with the winter peaks observed in mainland Japan, aligning more closely with patterns in subtropical and tropical regions. A marked decline and temporal shift in RSV activity during the COVID-19 pandemic highlight the impact of public health measures on viral transmission. These findings provide crucial baseline data to guide the development of RSV prevention strategies adapted to regional epidemiological patterns.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRSV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erespiratory syncytial virus\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eALRTIs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eacute lower respiratory tract infections\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHRGs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehigh-risk groups\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMSAs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emedical service areas\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eONMC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOkinawa Nanbu Medical Center \u0026amp; Children\u0026rsquo;s Medical Center\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eintensive care unit\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNOIs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003enon-pharmaceutical interventions\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Clinical Research Review Committee of Okinawa Chubu Hospital, Okinawa, Japan (Approval No. 2020-68). Patient data were anonymized prior to analysis.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eThis study does not include any personal data; therefore, this category is not applicable. All authors have approved the publication.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe data analyzed in this study were extracted from patient medical records maintained at each participating institution and were anonymized to prevent personal identification. In accordance with institutional policies and ethical regulations, the dataset cannot be made publicly available.\u003c/p\u003e\n\u003cp\u003eCompeting interest\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003cp\u003eAuthors’ contributions\u003c/p\u003e\n\u003cp\u003eKF-A supervised the overall study, collected data at Chubu Hospital, selected and analyzed the data, and drafted the manuscript. KA collected and verified data at Yaeyama Hospital. HF collected and verified the data at Miyako Hospital. YC collected and verified the data at ONMC. KM collected and verified the data at Yaeyama Hospital and Chubu Hospital. TM collected and verified the data at the NICU of Chubu Hospital. SK collected and verified the data at Chubu Hospital. TY provided guidance on the overall study and data analysis and was responsible for the manuscript's overall writing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCollins PL, Karron RA. Respiratory syncytial virus and metapneumovirus. In: Knipe DM, Howley PM, editors. Fields Virology. 3. 7 ed. Philadelphia: Wolters Kluwer; 2022. p. 267\u0026ndash;318.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShi T, McAllister DA, O'Brien KL, Simoes EAF, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet. 2017;390(10098):946\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOkada K, Mizuno M, Moriuchi H, Kusuda S, Morioka I, Mori M, et al. The Working Group for Revision of \"Guidelines for the Use of Palivizumab in Japan\": A Committee Report. Pediatr Int. 2020;62(11):1223\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStein RT, Sherrill D, Morgan WJ, Holberg CJ, Halonen M, Taussig LM, et al. Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years. Lancet. 1999;354(9178):541\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJackson DJ. Early-life viral infections and the development of asthma: a target for asthma prevention? Curr Opin Allergy Clin Immunol. 2014;14(2):131\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eObando-Pacheco P, Justicia-Grande AJ, Rivero-Calle I, Rodriguez-Tenreiro C, Sly P, Ramilo O, et al. Respiratory Syncytial Virus Seasonality: A Global Overview. J Infect Dis. 2018;217(9):1356\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStaadegaard L, Caini S, Wangchuk S, Thapa B, de Almeida WAF, de Carvalho FC, et al. Defining the seasonality of respiratory syncytial virus around the world: National and subnational surveillance data from 12 countries. Influenza Other Respir Viruses. 2021;15(6):732\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJung SM, Lee H, Yang Y, Nishiura H. Quantifying the causal impact of funding bedside antigen testing on the incidence of respiratory syncytial virus infection in Japan: a difference-in-differences study. Ann Transl Med. 2020;8(21):1441.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKanou K, Arima Y, Kinoshita H, Ito H, Okuno H, Saito N, et al. Respiratory Syncytial Virus Surveillance System in Japan: Assessment of Recent Trends, 2008\u0026ndash;2015. Jpn J Infect Dis. 2018;71(3):250\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJapan Meteorological Agency. Search past weather data [Web Page]. Japan Meteorological Agency; [Japan Meteorological Agency]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.data.jma.go.jp/stats/etrn/\u003c/span\u003e\u003cspan address=\"https://www.data.jma.go.jp/stats/etrn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJapan Institute for Health Security. Surveillance [Web Page]. Tokyo, Japan: Japan Institute for Health Security; [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://id-info.jihs.go.jp/en/surveillance/index.html\u003c/span\u003e\u003cspan address=\"https://id-info.jihs.go.jp/en/surveillance/index.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePalivizumab, a Humanized Respiratory Syncytial Virus Monoclonal Antibody, Reduces Hospitalization From Respiratory Syncytial Virus Infection in High-risk Infants. Pediatrics. 1998;102(3):531\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRobbie GJ, Zhao L, Mondick J, Losonsky G, Roskos LK. Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother. 2012;56(9):4927\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, et al. Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants. N Engl J Med. 2022;386(9):837\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNoto S, Kieffer A, Soudani S, Arashiro T, Tadera C, Eymere S, et al. Cost-Effectiveness and Public Health Impact of Universal Prophylaxis with Nirsevimab Against Respiratory Syncytial Virus (RSV) Infections in all Infants in Japan. Infect Dis Ther. 2025;14(4):847\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKampmann B, Madhi SA, Munjal I, Simoes EAF, Pahud BA, Llapur C, et al. Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants. N Engl J Med. 2023;388(16):1451\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOkinawa Prefecture Government. Basic Resident Register Population by Age [Web Page]. Okinawa Prefecture: Okinawa Prefecture Government; [Basic Resident Register Population by Age]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://honyaku.j-server.com/LUCOKNWP/ns/tl.cgi/https://www.pref.okinawa.jp/kensei/shinko/1016703/1016705/1016773/1022611/1016805.html?SLANG=ja\u003c/span\u003e\u003cspan address=\"https://honyaku.j-server.com/LUCOKNWP/ns/tl.cgi/https://www.pref.okinawa.jp/kensei/shinko/1016703/1016705/1016773/1022611/1016805.html?SLANG=ja\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u0026amp;TLANG=en\u0026amp;XMODE=0\u0026amp;XCHARSET=utf-8\u0026amp;XJSID=0.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSekine I, Uojima H, Koyama H, Kamio T, Sato M, Yamamoto T, et al. Impact of non-pharmaceutical interventions for the COVID-19 pandemic on emergency department patient trends in Japan: a retrospective analysis. Acute Med Surg. 2020;7(1):e603.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKishimoto K, Bun S, Shin JH, Takada D, Morishita T, Kunisawa S, et al. Early impact of school closure and social distancing for COVID-19 on the number of inpatients with childhood non-COVID-19 acute infections in Japan. Eur J Pediatr. 2021;180(9):2871\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHavdal LB, Boas H, Bekkevold T, Bakken Kran AM, Rojahn AE, Stordal K, et al. Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age. Front Pediatr. 2022;10:1004739.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSommer C, Resch B, Simoes EA. Risk factors for severe respiratory syncytial virus lower respiratory tract infection. Open Microbiol J. 2011;5:144\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAikphaibul P, Theerawit T, Sophonphan J, Wacharachaisurapol N, Jitrungruengnij N, Puthanakit T. Risk factors of severe hospitalized respiratory syncytial virus infection in tertiary care center in Thailand. Influenza Other Respir Viruses. 2021;15(1):64\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHall CB, Simoes EA, Anderson LJ. Clinical and epidemiologic features of respiratory syncytial virus. Curr Top Microbiol Immunol. 2013;372:39\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShi T, Vennard S, Mahdy S, Nair H, investigators R. Risk Factors for Poor Outcome or Death in Young Children With Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection: A Systematic Review and Meta-Analysis. J Infect Dis. 2022;226(Suppl 1):S10-S6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOkinawa Prefectural Government. Trends in RS Virus Infections (As of Week 38, 2021) (Japanese) Okinses Japan: Okinawa Prefectural Government; 2021 [cited 2025. PDF; Okinawa Prefecture Press Releases Page]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.pref.okinawa.lg.jp/_res/projects/default_project/_page_/001/018/064/rsvirus_shiryou1_20210930.pdf\u003c/span\u003e\u003cspan address=\"https://www.pref.okinawa.lg.jp/_res/projects/default_project/_page_/001/018/064/rsvirus_shiryou1_20210930.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoshioka S, Phyu WW, Wagatsuma K, Nagai T, Sano Y, Taniguchi K, et al. Molecular Epidemiology of Respiratory Syncytial Virus during 2019\u0026ndash;2022 and Surviving Genotypes after the COVID-19 Pandemic in Japan. Viruses. 2023;15(12).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShinzato A, Hibiya K, Nishiyama N, Ikemiyagi N, Arakaki W, Kami W, et al. Unseasonal respiratory syncytial virus epidemics during the COVID-19 pandemic: Relationship between climatic factors and epidemic strain switching. Int J Infect Dis. 2025;154:107833.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWagatsuma K, Koolhof IS, Shobugawa Y, Saito R. Shifts in the epidemic season of human respiratory syncytial virus associated with inbound overseas travelers and meteorological conditions in Japan, 2014\u0026ndash;2017: An ecological study. PLoS One. 2021;16(3):e0248932.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIha Y, Kinjo T, Parrott G, Higa F, Mori H, Fujita J. Comparative epidemiology of influenza A and B viral infection in a subtropical region: a 7-year surveillance in Okinawa, Japan. BMC Infect Dis. 2016;16(1):650.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsai HP, Kuo PH, Liu CC, Wang JR. Respiratory viral infections among pediatric inpatients and outpatients in Taiwan from 1997 to 1999. J Clin Microbiol. 2001;39(1):111\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHsu HT, Huang FL, Ting PJ, Chang CC, Chen PY. The epidemiological features of pediatric viral respiratory infection during the COVID-19 pandemic in Taiwan. J Microbiol Immunol Infect. 2022;55(6 Pt 1):1101\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSitthikarnkha P, Uppala R, Niamsanit S, Sutra S, Thepsuthammarat K, Techasatian L, et al. Burden of Respiratory Syncytial Virus Related Acute Lower Respiratory Tract Infection in Hospitalized Thai Children: A 6-Year National Data Analysis. Children (Basel). 2022;9(12).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeija-Martinez JJ, Esparza-Miranda LA, Rivera-Alfaro G, Noyola DE. Impact of Nonpharmaceutical Interventions during the COVID-19 Pandemic on the Prevalence of Respiratory Syncytial Virus in Hospitalized Children with Lower Respiratory Tract Infections: A Systematic Review and Meta-Analysis. Viruses. 2024;16(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUwak I, Johnson N, Mustapha T, Rahman M, Tonpay T, Regan AK, et al. Quantifying changes in respiratory syncytial virus-associated hospitalizations among children in Texas during COVID-19 pandemic using records from 2006 to 2021. Front Pediatr. 2023;11:1124316.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAgency EM. Beyfortus (niservimab) [Web Page]. European Medicines Agency; 2022 [updated 24/06/2025. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ema.europa.eu/en/medicines/human/EPAR/beyfortus\u003c/span\u003e\u003cspan address=\"https://www.ema.europa.eu/en/medicines/human/EPAR/beyfortus\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"tropical-medicine-and-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tmah","sideBox":"Learn more about [Tropical Medicine and Health](https://tropmedhealth.biomedcentral.com/)","snPcode":"41182","submissionUrl":"https://submission.springernature.com/new-submission/41182/3","title":"Tropical Medicine and Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Respiratory syncytial virus, COVID-19, Respiratory infection, Pediatric infectious disease, Okinawa islands, Subtropical region","lastPublishedDoi":"10.21203/rs.3.rs-7316076/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7316076/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e\u003cp\u003eRespiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections (ALRTIs) in infants and young children worldwide. While its epidemiology is well-characterized in temperate climates, data from subtropical regions such as Okinawa, Japan, remain limited. This study aimed to describe the clinical and demographic characteristics, risk factors, and seasonality of moderate-to-severe RSV infections in children under five years across Okinawa.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eThis retrospective, multicenter study analyzed pediatric cases of laboratory-confirmed RSV infection requiring hospitalization between April 2017 and March 2021. Data were collected from four core hospitals across Okinawa Prefecture. Patients were categorized as having moderate or severe disease based on ICU admission status. Demographic variables, underlying medical conditions, household and childcare characteristics, and seasonal trends were assessed.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003eA total of 1,541 hospitalized RSV cases were included, of which 117 (7.6%) were classified as severe. Approximately 60% of cases were in infants under 12 months, with the highest burden in the 0\u0026ndash;2 month age group. The severe group had a significantly lower median age and higher proportion of children with siblings. Nursery school attendance was more common in the moderate group, likely reflecting the younger age of severe cases. While the prevalence of individual comorbidities did not differ between groups, having multiple underlying conditions was significantly associated with disease severity. RSV activity peaked during summer (June\u0026ndash;August) in 2017\u0026ndash;2019 but shifted to winter in 2020\u0026ndash;2021, coinciding with the COVID-19 pandemic and a 62% reduction in cases.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e\u003cp\u003eThis study offers the first region-wide assessment of moderate-to-severe pediatric RSV infections in a subtropical setting in Japan. Despite not including data on the use of palivizumab, nirsevimab, or maternal vaccination, the findings provide essential baseline data to guide the implementation of new preventive strategies tailored to local epidemiology.\u003c/p\u003e","manuscriptTitle":"Epidemiology of Moderate-to-Severe Respiratory Syncytial Virus Infections in Children in Subtropical Okinawa, Japan: A Four-Year Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 05:48:45","doi":"10.21203/rs.3.rs-7316076/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-08-25T02:42:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-25T02:35:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-18T00:25:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-17T14:40:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153825096791278809512260659168160046244","date":"2025-08-15T22:01:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18847652153766266389593683658736328669","date":"2025-08-15T21:10:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"159109068495896290671860645390275936355","date":"2025-08-15T17:54:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-15T14:13:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-15T01:28:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-15T01:28:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Tropical Medicine and Health","date":"2025-08-07T07:45:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"tropical-medicine-and-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"tmah","sideBox":"Learn more about [Tropical Medicine and Health](https://tropmedhealth.biomedcentral.com/)","snPcode":"41182","submissionUrl":"https://submission.springernature.com/new-submission/41182/3","title":"Tropical Medicine and Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7885e05c-3b8c-46be-8d29-3ef575f3a395","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T16:11:24+00:00","versionOfRecord":{"articleIdentity":"rs-7316076","link":"https://doi.org/10.1186/s41182-025-00824-3","journal":{"identity":"tropical-medicine-and-health","isVorOnly":false,"title":"Tropical Medicine and Health"},"publishedOn":"2025-11-11 15:57:35","publishedOnDateReadable":"November 11th, 2025"},"versionCreatedAt":"2025-08-27 05:48:45","video":"","vorDoi":"10.1186/s41182-025-00824-3","vorDoiUrl":"https://doi.org/10.1186/s41182-025-00824-3","workflowStages":[]},"version":"v1","identity":"rs-7316076","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7316076","identity":"rs-7316076","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}