Disease burden of respiratory syncytial virus infection in the pediatric population in Japan

  • Koo Nagasawa
    Correspondence
    Corresponding author. Division of Infectious Diseases, Chiba Children's Hospital, 579-1, Heta-cho, Midori-ku, Chiba, 266-0007, Japan.
    Affiliations
    Division of Infectious Diseases, Chiba Children's Hospital, 579-1, Heta-cho, Midori-ku, Chiba 266-0007, Japan

    Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2, Nitona-cho, Chuo-ku, Chiba 260-8717, Japan
    Search for articles by this author
  • Naruhiko Ishiwada
    Affiliations
    Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba-shi, Chiba 260-8673, Japan
    Search for articles by this author
Open AccessPublished:December 21, 2021DOI:https://doi.org/10.1016/j.jiac.2021.11.007

      Abstract

      Introduction

      Respiratory syncytial virus (RSV) is one of the most common causes of lower respiratory tract infections in children aged <5 years and is associated with long-term respiratory morbidities such as recurrent wheezing and asthma, decreased lung function, and allergic sensitization. The objective of this review was to evaluate the epidemiology and burden of RSV infection in the pediatric population in Japan.

      Methods

      Studies indexed in PubMed and ICHUSHI databases during January 2010–December 2020 were manually reviewed. Data on proportion of RSV infections, seasonality, length of stay (LoS), mortality, medical expenses, and palivizumab use were extracted from the selected articles.

      Results

      Ninety-three articles were included (PubMed, 64; ICHUSHI, 29). The proportion of patients/samples with an RSV infection was 5.5%–66.7%, and 6.0%–29.9% in the inpatient and outpatient departments, respectively. RSV infections generally occurred during autumn/winter; however, recently the peak has shifted to summer. The LoS was variable and depended on factors such as age, infection severity, wheezing, and RSV subgroups. Mortality rates varied from <1% to 19% depending on the infection severity. The average daily hospitalization and intensive care unit cost was JPY 34,548 while intensive care unit incurred an additional cost of JPY 541,293. Palivizumab was indicated for high-risk infants and 0%–3% of patients required hospitalization despite palivizumab use.

      Conclusions

      RSV imposes a significant burden on the Japanese healthcare system, suggesting a need to create awareness among caregivers of children, pregnant women and healthcare professionals to ensure early recognition of infection and adequate treatment or prophylaxis.

      Keywords

      Abbreviations

      ALRI
      acute lower respiratory infection
      ARI
      acute respiratory infection
      BPD
      bronchopulmonary dysplasia
      CHD
      congenital heart disease
      CI
      confidence interval
      CLD
      chronic lung disease
      COVID-19
      novel coronavirus disease of 2019
      DPC
      diagnosis procedure combination
      Gavi
      Global Alliance for Vaccines and Immunization
      hMPV
      human metapneumovirus
      hs-CHD
      hemodynamically significant CHD
      ICU
      intensive care unit
      IPD
      inpatient department
      JPY
      Japanese Yen
      LRI
      lower respiratory inflammation
      LoS
      length of stay
      LRTI
      lower respiratory tract infection
      mAb
      monoclonal antibody
      NESID
      National Epidemiological Surveillance of Infectious Diseases
      NIID
      National Institute of Infectious Diseases
      OPD
      outpatient department
      OR
      odds ratio
      RR
      relative risk
      RSV
      respiratory syncytial virus
      SD
      standard deviation
      UR
      uncertainty range
      wGA
      weeks gestational age
      WHO
      World Health Organization

      Authorship statement

      Both authors have made substantial contributions to all of the following and meet the ICMJE authorship criteria: (1) conception and design of the study and the acquisition, analysis, and interpretation of data; (2) drafting the article and revising it critically for important intellectual content; and (3) final approval of the version to be submitted.

      1. Introduction

      Respiratory syncytial virus (RSV) is the most common cause of childhood acute lower respiratory infection (ALRI) necessitating hospitalization for more severe forms and is also one of the leading causes of childhood death from ALRI [
      • Nair H.
      • Nokes D.J.
      • Gessner B.D.
      • Dherani M.
      • Madhi S.A.
      • Singleton R.J.
      • et al.
      Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.
      ]. There is a single RSV serotype that is genetically divided into two subgroups—A and B, and while strains of both subgroups often co-circulate, one subgroup usually predominates [
      • Borchers A.T.
      • Chang C.
      • Gershwin M.E.
      • Gershwin L.J.
      Respiratory syncytial virus--a comprehensive review.
      ]. At least 50% of infants become infected during their first year of life and nearly 100% by their second year; however, life-long immunity is not guaranteed [
      Respiratory syncytial virus infection.
      ]. Reinfections with RSV are observed in 30%–75% of children aged <2 years who have experienced an RSV infection during their first 12 months of life and usually occur during the following season, with the rate of reinfection being dependent on the strength of the epidemic [
      • Borchers A.T.
      • Chang C.
      • Gershwin M.E.
      • Gershwin L.J.
      Respiratory syncytial virus--a comprehensive review.
      ]. In infants, around 50% of pneumonia cases and 50%–90% of bronchiolitis cases are due to RSV [
      Respiratory syncytial virus infection.
      ].
      In 2005, an estimated 33.8 (95% confidence interval [CI]: 19.3–46.2) million new episodes of RSV-associated ALRI occurred globally in children aged <5 years, accounting for 22% of ALRI episodes, with ≥3.4 (95% CI: 2.8–4.3) million episodes representing severe RSV-associated ALRI necessitating hospitalization [
      • Nair H.
      • Nokes D.J.
      • Gessner B.D.
      • Dherani M.
      • Madhi S.A.
      • Singleton R.J.
      • et al.
      Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.
      ]. Around 66,000–199,000 deaths in children aged <5 years in 2005 were attributed to RSV-associated severe ALRI [
      • Nair H.
      • Nokes D.J.
      • Gessner B.D.
      • Dherani M.
      • Madhi S.A.
      • Singleton R.J.
      • et al.
      Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.
      ]. Similarly, in 2015, globally, there were 33.1 (uncertainty range [UR]: 21.6–50.3) million episodes of RSV-ALRI, which resulted in around 3.2 (UR: 2.7–3.8) million hospitalizations, and 59,600 (UR: 48,000–74,500) in-hospital deaths in children aged <5 years [
      • Shi T.
      • McAllister D.A.
      • O'Brien K.L.
      • Simoes E.A.F.
      • Madhi S.A.
      • Gessner B.D.
      • 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.
      ]. In children aged <6 months, 1.4 (UR: 1.2–1.7) million hospitalizations and 27,300 (UR: 20,700–36,200) in-hospital deaths were attributed to RSV-ALRI [
      • Shi T.
      • McAllister D.A.
      • O'Brien K.L.
      • Simoes E.A.F.
      • Madhi S.A.
      • Gessner B.D.
      • 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.
      ]. Globally, the overall (combined hospital and community) RSV-ALRI mortality in 2015 was estimated to be 118,200 (UR: 94,600–149,400) in children aged <5 years [
      • Shi T.
      • McAllister D.A.
      • O'Brien K.L.
      • Simoes E.A.F.
      • Madhi S.A.
      • Gessner B.D.
      • 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.
      ]. RSV-ALRI during the first 3 years of life is associated with long-term respiratory morbidities such as recurrent wheezing and asthma, decreased lung function, and allergic sensitization [
      • Fauroux B.
      • Simões E.A.F.
      • Checchia P.A.
      • Paes B.
      • Figueras-Aloy J.
      • Manzoni P.
      • et al.
      The burden and long-term respiratory morbidity associated with respiratory syncytial virus infection in early childhood.
      ].
      In Japan, in accordance with the amendment of the Infectious Diseases Control Law (effective November 5, 2003), RSV infection is grouped under category V infectious diseases and monitored under the National Epidemiological Surveillance of Infectious Diseases (NESID) program's pediatric sentinel surveillance system, with the reporting requiring laboratory diagnosis [
      Respiratory syncytial virus infection.
      ]. Since October 2011, the number of pediatric sentinel sites, particularly clinics, reporting RSV infection has been increasing annually in Japan owing to the inclusion of RSV antigen detection testing in the National Health Insurance for outpatients aged <1 year [
      Respiratory syncytial virus infection.
      ].
      Preterm birth, low birth weight, hemodynamically significant congenital heart disease (hs-CHD) or chronic lung disease (CLD), congenital or acquired immunodeficiencies, and Down's syndrome are some of the well-known risk factors for RSV-associated hospitalizations [
      • Borchers A.T.
      • Chang C.
      • Gershwin M.E.
      • Gershwin L.J.
      Respiratory syncytial virus--a comprehensive review.
      ]. Management of RSV infections includes supportive treatment such as oxygen administration, infusion therapy, or respiratory management [
      Respiratory syncytial virus infection.
      ]. Palivizumab is a highly potent RSV-neutralizing monoclonal antibody (mAb) that is approved for the prophylaxis of RSV-associated hospitalizations in high-risk infants [
      • Resch B.
      Product review on the monoclonal antibody palivizumab for prevention of respiratory syncytial virus infection.
      ]. Nirsevimab is a newly developed mAb with an extended half-life to protect infants for an entire RSV season with a single intramuscular dose [
      • Griffin M.P.
      • Yuan Y.
      • Takas T.
      • Domachowske J.B.
      • Madhi S.A.
      • Manzoni P.
      • et al.
      Single-dose nirsevimab for prevention of RSV in preterm infants.
      ].
      Palivizumab is the only product licensed for prophylaxis against RSV and is available only for use in high-risk infants; however, a number of vaccines and mAbs are being developed for the general population with the aim to reduce the global healthcare impact of RSV [
      • Simões E.A.F.
      • Bont L.
      • Manzoni P.
      • Fauroux B.
      • Paes B.
      • Figueras-Aloy J.
      • et al.
      Past, present and future approaches to the prevention and treatment of respiratory syncytial virus infection in children.
      ]. The World Health Organization (WHO) has a strategic vision to develop and license high-quality, safe, and effective RSV vaccines that prevent severe disease and death in infants aged <12 months and reduce morbidity in children aged <5 years [
      • Vekemans J.
      • Moorthy V.
      • Giersing B.
      • Friede M.
      • Hombach J.
      • Arora N.
      • et al.
      Respiratory syncytial virus vaccine research and development: world Health Organization technological roadmap and preferred product characteristics.
      ]. Currently, there are approximately 40 vaccines against RSV in different stages of preclinical and clinical development that are pending approval for use in the pediatric population, pregnant women, and the elderly [].
      Upon the future approval of vaccines, their effectiveness can only be adequately assessed by comparison of epidemiological data before and after approval. However, in Japan, such data are mainly derived in single-center settings and without the availability of comprehensive information in English. The objective of this review was to evaluate the epidemiology and burden of RSV infection in the pediatric population in Japan.

      2. Methods

      A literature review was performed in PubMed with the search string (([respiratory AND syncytial AND virus] OR [RSV]) AND (Japanese OR Japan)). Another search was performed in ICHUSHI with the search string ((RS uirusu kansensho/TH or rs uirusu kansensho/AL) or (RS uirusu/TH or RSV/AL)) and (hassyo/AL or rikan/AL or itijitiryo/AL or nijitiryo/AL or (nyuuin/TH or nyuuin/AL) or (sibou/TH or sibou/AL) or (kouisho/TH or kouisho/AL) or (iryouhi/TH or iryouhi/AL) or (iryoukeizaigaku/TH or iryoukeizai/AL) or (hiyoukoukabunseki/TH or hiyoutaikouka/AL) or (seikatsunoshitsu/TH or QOL/AL)). Relevant original and review articles covering the pediatric population and published in English or Japanese from January 1, 2010 to December 31, 2020 were included. To evaluate the effect of the novel coronavirus disease of 2019 (COVID-19) on the number of RSV infections, an editorial was also included. Relevant data on the weekly incidence and seasonality of RSV available on the National Institute of Infectious Diseases (NIID) website, Japan, were also included. Case reports, non-human or in vitro studies, and review articles were excluded.
      The variables of interest were the proportion of RSV infections, seasonality and geographic distribution of RSV infection, hospitalization and length of stay (LoS), complications and sequelae, mortality, medical expenses, reinfection, and the use of palivizumab in patients with RSV. The results for each variable were summarized using descriptive statistics.

      3. Results

      A total of 528 records were identified for screening from the PubMed (n = 413) and ICHUSHI (n = 115) databases. The records were manually screened by two reviewers based on the title and abstract and duplicate articles were eliminated. After excluding 435 records, which were not relevant to the primary objective of the study, 93 articles were included for qualitative analysis (Fig. 1).
      Fig. 1
      Fig. 1Study screening and selection Search
      string used on PubMed: (([respiratory AND syncytial AND virus] OR [RSV]) AND (Japanese OR Japan))
      Search string used on ICHUSHI: ((RS uirusu kansensho/TH or rs uirusu kansensho/AL) or (RS uirusu/TH or RSV/AL)) and (hassyo/AL or rikan/AL or itijitiryo/AL or nijitiryo/AL or (nyuuin/TH or nyuuin/AL) or (sibou/TH or sibou/AL) or (kouisho/TH or kouisho/AL) or (iryouhi/TH or iryouhi/AL) or (iryoukeizaigaku/TH or iryoukeizai/AL) or (hiyoukoukabunseki/TH or hiyoutaikouka/AL) or (seikatsunoshitsu/TH or QOL/AL)).
      Filters applied: Search period: January 1, 2010 to December 31, 2020, region: Japan, language: English or Japanese.

      3.1 Proportion of RSV infections

      RSV was the most commonly detected virus (n = 23/90, 26.0%) in outpatients (median age 1.5 years) with acute respiratory infection (ARI) [
      • Metoki T.
      • Okamoto M.
      • Suzuki A.
      • Kitaoka S.
      • Miyabayashi H.
      • Rokugo Y.
      • et al.
      Concurrent community transmission of enterovirus D68 with human rhinoviruses and respiratory syncytial virus among children in Sendai, Japan.
      ]. RSV was also the most commonly detected virus in hospitalized infants and young children aged 0–24 months, of whom 44% were aged <6 months [
      • Moriyama Y.
      • Hamada H.
      • Okada M.
      • Tsuchiya N.
      • Maru H.
      • Shirato Y.
      • et al.
      Distinctive clinical features of human bocavirus in children younger than 2 years.
      ]. Of the 402 children aged 0–24 months hospitalized for lower respiratory tract infections (LRTIs), 111 (27.6%) were RSV positive and 99/111 patients had RSV as the only detected pathogen [
      • Moriyama Y.
      • Hamada H.
      • Okada M.
      • Tsuchiya N.
      • Maru H.
      • Shirato Y.
      • et al.
      Distinctive clinical features of human bocavirus in children younger than 2 years.
      ]. In studies that enrolled patients in the inpatient department (IPD), outpatient department (OPD), and both IPD and OPD, the proportion of patients/samples with an RSV infection ranged from 5.5% to 66.7% [
      • Moriyama Y.
      • Hamada H.
      • Okada M.
      • Tsuchiya N.
      • Maru H.
      • Shirato Y.
      • et al.
      Distinctive clinical features of human bocavirus in children younger than 2 years.
      ,
      • Abe N.
      • Yasudo H.
      • Fukano R.
      • Nakamura T.
      • Okada S.
      • Wakiguchi H.
      • et al.
      Multi-season analyses of causative pathogens in children hospitalized with asthma exacerbation.
      ,
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ,
      • Taniguchi A.
      • Kawada J.I.
      • Go K.
      • Fujishiro N.
      • Hosokawa Y.
      • Maki Y.
      • et al.
      Comparison of clinical characteristics of human metapneumovirus and respiratory syncytial virus infections in hospitalized young children.
      ,
      • Okada T.
      • Matsubara K.
      • Matsushima T.
      • Komiyama O.
      • Chiba N.
      • Hamano K.
      • et al.
      [Analysis of clinical features of community-acquired pneumonia caused by pediatric respiratory syncytial virus and human metapneumovirus].
      ,
      • Akiyoshi K.
      • Tamura T.
      • Haruta T.
      Virus-related lower respiratory inflammation: detection of human metapneumovirus from severe pneumonia cases with A/H1N1pdm virus.
      ,
      • Satoh K.
      • Wakejima Y.
      • Gau M.
      • Kiguchi T.
      • Matsuda N.
      • Takasawa R.
      • et al.
      Risk of coronary artery lesions in young infants with Kawasaki disease: need for a new diagnostic method.
      ,
      • Uda K.
      • Kitazawa K.
      Febrile status epilepticus due to respiratory syncytial virus infection.
      ,
      • Azuma J.
      • Yamamoto T.
      • Sakurai M.
      • Amou R.
      • Yamada C.
      • Hashimoto K.
      • et al.
      Urinary β2-microglobulin as an early marker of infantile enterovirus and human parechovirus infections.
      ,
      • Kato M.
      • Yamada Y.
      • Maruyama K.
      • Hayashi Y.
      Differential effects of corticosteroids on serum eosinophil cationic protein and cytokine production in rhinovirus- and respiratory syncytial virus-induced acute exacerbation of childhood asthma.
      ,
      • Numata M.
      • Takayanagi R.
      • Chiba Y.
      Comparison of symptoms and acute otitis media between hospitalized children with human metapneumovirus or respiratory syncytial virus infection. Shoni Kansen Meneki.
      ,
      • Hamada H.
      • Ogura J.
      • Hotta C.
      • Wakui T.
      • Ogawa T.
      • Terai M.
      Epidemiological study of respiratory viruses detected in patients under two years old who required admission because of lower respiratory disease.
      ,
      • Narita A.
      • Nishimura N.
      • Arakawa Y.
      • Suzuki M.
      • Sakamoto K.
      • Sakamoto M.
      • et al.
      Relationship between lower respiratory tract infections caused by respiratory syncytial virus and subsequent development of asthma in Japanese children.
      ,
      • Takeyama A.
      • Hashimoto K.
      • Sato M.
      • Sato T.
      • Tomita Y.
      • Maeda R.
      • et al.
      Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years.
      ,
      • Morikawa Y.
      • Miura M.
      • Furuhata M.Y.
      • Morino S.
      • Omori T.
      • Otsuka M.
      • et al.
      Nebulized hypertonic saline in infants hospitalized with moderately severe bronchiolitis due to RSV infection: a multicenter randomized controlled trial.
      ,
      • Osamura T.
      • Omae T.
      • Tagawa K.
      • Hirao T.
      • Kawabe Y.
      • Hasegawa M.
      • et al.
      Current status of pediatric inpatients with infectious disease in our hospital.
      ,
      • Okuno H.
      • Inoue T.
      • Ishikawa J.
      • Amo K.
      • Togawa M.
      • Shiomi M.
      Respiratory infection pathogens of apnea related to respiratory infection in infants.
      ,
      • Okamoto N.
      • Ikeda M.
      • Okuda M.
      • Sakamoto T.
      • Takasugi M.
      • Takahashi N.
      • et al.
      Increased eosinophilic cationic protein in nasal fluid in hospitalized wheezy infants with RSV infection.
      ,
      • Sugai K.
      • Kimura H.
      • Miyaji Y.
      • Tsukagoshi H.
      • Yoshizumi M.
      • Sasaki-Sakamoto T.
      • et al.
      MIP-1α level in nasopharyngeal aspirates at the first wheezing episode predicts recurrent wheezing.
      ], 6.0%–29.9% [
      • Mizuta K.
      • Abiko C.
      • Aoki Y.
      • Ikeda T.
      • Matsuzaki Y.
      • Itagaki T.
      • et al.
      Seasonal patterns of respiratory syncytial virus, influenza A virus, human metapneumovirus, and parainfluenza virus type 3 infections on the basis of virus isolation data between 2004 and 2011 in Yamagata, Japan.
      ,
      • Nakamura M.
      • Hirano E.
      • Kowada K.
      • Ishiguro F.
      • Mochizuki M.
      Virus surveillance of acute respiratory infections in Fukui prefecture.
      ,
      • Hara M.
      • Takao S.
      • Shimazu Y.
      • Nishimura T.
      Three-year study of viral etiology and features of febrile respiratory tract infections in Japanese pediatric outpatients.
      ,
      • Shimizu H.
      • Sekine K.
      • Hirai K.
      • Takakura H.
      • Suzuki K.
      • Tada N.
      • et al.
      Clinical and epidemiological characteristics of 395 patients with respiratory syncytial virus infection from 2008 to 2013 in one pediatric clinic.
      ], and 14.0%–61.6% [
      • Kaida A.
      • Kubo H.
      • Takakura K.
      • Sekiguchi J.
      • Yamamoto S.P.
      • Kohdera U.
      • et al.
      Associations between co-detected respiratory viruses in children with acute respiratory infections.
      ,
      • Kato M.
      • Tsukagoshi H.
      • Yoshizumi M.
      • Saitoh M.
      • Kozawa K.
      • Yamada Y.
      • et al.
      Different cytokine profile and eosinophil activation are involved in rhinovirus- and RS virus-induced acute exacerbation of childhood wheezing.
      ,
      • Miyaji Y.
      • Kobayashi M.
      • Sugai K.
      • Tsukagoshi H.
      • Niwa S.
      • Fujitsuka-Nozawa A.
      • et al.
      Severity of respiratory signs and symptoms and virus profiles in Japanese children with acute respiratory illness.
      ,
      • Fujitsuka A.
      • Tsukagoshi H.
      • Arakawa M.
      • Goto-Sugai K.
      • Ryo A.
      • Okayama Y.
      • et al.
      A molecular epidemiological study of respiratory viruses detected in Japanese children with acute wheezing illness.
      ,
      • Harada Y.
      • Kinoshita F.
      • Yoshida L.M.
      • Minh L.N.
      • Suzuki M.
      • Morimoto K.
      • et al.
      Does respiratory virus coinfection increases the clinical severity of acute respiratory infection among children infected with respiratory syncytial virus?.
      ], respectively. In two other studies, the proportion of patients with an RSV infection ranged from 7.1% to 7.4%, but it was unclear if the patients had been enrolled from the IPD or OPD [
      • Yoshida A.
      • Kiyota N.
      • Kobayashi M.
      • Nishimura K.
      • Tsutsui R.
      • Tsukagoshi H.
      • et al.
      Molecular epidemiology of the attachment glycoprotein (G) gene in respiratory syncytial virus in children with acute respiratory infection in Japan in 2009/2010.
      ,
      • Kushibuchi I.
      • Kobayashi M.
      • Kusaka T.
      • Tsukagoshi H.
      • Ryo A.
      • Yoshida A.
      • et al.
      Molecular evolution of attachment glycoprotein (G) gene in human respiratory syncytial virus detected in Japan 2008-2011.
      ]. Although the proportion varies considerably depending on the reports, the proportion tended to be higher for younger patients, inpatients, and those with respiratory tract infection (Fig. 2 and Supplementary Table 1). RSV accounted for 3.2%–4.1% of specimens in the <4-year age group, and the rate of isolation decreased with increasing age [
      • Mizuta K.
      • Abiko C.
      • Aoki Y.
      • Ikeda T.
      • Matsuzaki Y.
      • Itagaki T.
      • et al.
      Seasonal patterns of respiratory syncytial virus, influenza A virus, human metapneumovirus, and parainfluenza virus type 3 infections on the basis of virus isolation data between 2004 and 2011 in Yamagata, Japan.
      ]. RSV was detected in 82/153 (53.6%) patients (aged <2 years) with LRTI admitted to the pediatric intensive care unit (ICU) during 2007–2012 [
      • Deguchi K.
      • Hamada H.
      • Hirose S.
      • Takafumi Honda T.
      • Yasukawa K.
      • Nishijima H.
      • et al.
      Clinical features of respiratory viruses detected in patients in the pediatric intensive care unit for lower respiratory tract infection from 2012 to 2017.
      ]. The RSV subgroup was not significantly related to the clinical severity [
      • Utsunomiya T.
      • Hibino A.
      • Taniguchi K.
      • Nagai T.
      • Saito N.
      • Tanabe I.
      • et al.
      Factors contributing to symptom duration and viral reduction in outpatient children with respiratory syncytial virus infection.
      ]. In patients with suspected influenza A infection from the pandemic and lower respiratory inflammation (LRI), RSV was detected in 9/153 patients with LRI who had pneumonia and 11/153 patients with LRI who had bronchitis [
      • Akiyoshi K.
      • Tamura T.
      • Haruta T.
      Virus-related lower respiratory inflammation: detection of human metapneumovirus from severe pneumonia cases with A/H1N1pdm virus.
      ]. Among hospitalized patients with ALRI, patients who were RSV-positive were younger and less frequently had underlying diseases than those with no detectable virus [
      • Hasuwa T.
      • Kinoshita F.
      • Harada S.
      • Nakashima K.
      • Yoshihara K.
      • Toku Y.
      • et al.
      Viral etiology of acute lower respiratory tract infections in hospitalized children in Nagasaki, a regional city of Japan in 2013-2015.
      ].
      Fig. 2
      Fig. 2Proportion of RSV infections in Japan
      a. Patients aged 0–1 year
      b. Patients aged >1–2 years
      c. Patients aged >2–6 years
      d. By clinical presentation of patients For
      figures a, b, and c, studies have been categorized based on the mean or median age of patients
      aPatients were aged <24 months and hence included under 0–1 year as well as >1–2 years
      bThe mean/median age of patients was not specified; however, the majority of patients were aged <6 months
      cThe mean age of one group was 16.9 months and that of the other group was 28.5 months, and hence included under >1–2 years as well as >2–6 years
      dProportion of RSV infection is based on the number of samples tested (eg. nasopharyngeal swabs, tracheal aspirates, and throat swabs)
      eThe age of patients had not been specified in the reference. However, based on the height of the bars in the results section of the reference, it seems that the majority of patients were aged between 1 and 2 years. Hence, this study has been categorized under 1–2 years.
      fThe study setting was not defined explicitly; however, based on the description provided in these studies, these have been categorized as IPD and OPD
      gPatients with overlapping clinical presentations have been included under more than one category
      hRTI includes LRTI, acute viral infections, acute bronchiolitis, and community-acquired pneumonia
      IPD, inpatient department; LRTI, lower respiratory tract infection; OPD, outpatient department; RSV, respiratory syncytial virus; RTI, respiratory tract infection; SD, standard deviation.
      The number of sentinel sites reporting ≥1 RSV case during the RSV surveillance year showed an increasing annual trend—1638 (52%) in the year 2008/09 and 2632 (80%) in 2014/15; excluding the year 2009/10, the total number of RSV notifications increased steadily every year [
      • 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.
      ]. Among the sites continuously reporting new infections, the ratio of cases reported by outpatient clinics to hospitals increased from 1.3 in 2008/09 to 1.8 in 2014/15 [
      • 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.
      ]. The incidence of RSV infections across the age distribution of patients captured in the NESID system remained relatively stable, with patients aged <2 years being predominantly affected (seasonal variability of 75%, 68%, 72%, 75%, 74%, 74%, and 72%, from 2008/09 to 2014/15, respectively) [
      • 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.
      ]. The coverage of RSV antigen testing by the Japanese National Health Insurance to all infants aged <12 months and to outpatients for whom palivizumab was indicated from October 2011 resulted in an increase in the mean incidence of RSV infection in children aged 0–4 years from 1121 to 1953 per 100,000 individuals during the 2008/09–2011/12 and 2012/13–2016/17 periods, respectively [
      • Jung S.M.
      • 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.
      ]. In December 2014, NESID recorded ∼30,000 cases nationwide, representing the highest number of RSV cases since the start of the national RSV surveillance in 2003 [
      • Hibino A.
      • Saito R.
      • Taniguchi K.
      • Zaraket H.
      • Shobugawa Y.
      • Matsui T.
      • et al.
      Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1.
      ].
      The multiple-pathogen infection rate for RSV was 26.8% [
      • Hara M.
      • Takao S.
      • Shimazu Y.
      • Nishimura T.
      Three-year study of viral etiology and features of febrile respiratory tract infections in Japanese pediatric outpatients.
      ]; RSV was frequently detected alongside the human bocavirus [
      • Moriyama Y.
      • Hamada H.
      • Okada M.
      • Tsuchiya N.
      • Maru H.
      • Shirato Y.
      • et al.
      Distinctive clinical features of human bocavirus in children younger than 2 years.
      ,
      • Miyaji Y.
      • Kobayashi M.
      • Sugai K.
      • Tsukagoshi H.
      • Niwa S.
      • Fujitsuka-Nozawa A.
      • et al.
      Severity of respiratory signs and symptoms and virus profiles in Japanese children with acute respiratory illness.
      ], rhinovirus [12,21,25, 30,37–39), adenovirus (12,37,39), and human metapneumovirus [
      • Moriyama Y.
      • Hamada H.
      • Okada M.
      • Tsuchiya N.
      • Maru H.
      • Shirato Y.
      • et al.
      Distinctive clinical features of human bocavirus in children younger than 2 years.
      ]. In children with acute exacerbations of wheezing, RSV was also detected alongside the coxsackie virus and parainfluenza-3 virus [
      • Kato M.
      • Yamada Y.
      • Maruyama K.
      • Hayashi Y.
      Differential effects of corticosteroids on serum eosinophil cationic protein and cytokine production in rhinovirus- and respiratory syncytial virus-induced acute exacerbation of childhood asthma.
      ]. A study carried out in Chiba prefecture that had enrolled 188 pediatric inpatients with RSV bronchopulmonary infection revealed that bacterial coinfections are common in these patients with pathogenic bacteria being isolated from 43.6% of patients [
      • Hishiki H.
      • Ishiwada N.
      • Fukasawa C.
      • Abe K.
      • Hoshino T.
      • Aizawa J.
      • et al.
      Incidence of bacterial coinfection with respiratory syncytial virus bronchopulmonary infection in pediatric inpatients.
      ]. Haemophilus influenzae (43.9%), Streptococcus pneumoniae (36.6%), and Moraxella catarrhalis (29.3%) were the three most frequently isolated bacteria [
      • Hishiki H.
      • Ishiwada N.
      • Fukasawa C.
      • Abe K.
      • Hoshino T.
      • Aizawa J.
      • et al.
      Incidence of bacterial coinfection with respiratory syncytial virus bronchopulmonary infection in pediatric inpatients.
      ]. In the birth cohort study in Hokkaido on Environment and Children's Health that enrolled 1558 mother-child pairs, RSV infection was reported in 12.6% of patients aged ≤4 years with prenatal exposure to perfluoroalkyl acids [
      • Goudarzi H.
      • Miyashita C.
      • Okada E.
      • Kashino I.
      • Chen C.J.
      • Ito S.
      • et al.
      Prenatal exposure to perfluoroalkyl acids and prevalence of infectious diseases up to 4 years of age.
      ]. Among the mother-child pairs that were followed up until the age of 7 years, the prevalence of RSV infection was 16.8% in children [
      • Ait Bamai Y.
      • Goudarzi H.
      • Araki A.
      • Okada E.
      • Kashino I.
      • Miyashita C.
      • et al.
      Effect of prenatal exposure to per- and polyfluoroalkyl substances on childhood allergies and common infectious diseases in children up to age 7 years: the Hokkaido study on environment and children's health.
      ]. RSV infection rates were lower during the COVID-19 pandemic, which may be attributable to the widespread preventive measures against COVID-19, such as social distancing and lockdown measures, and the lower probability of disease spread in the community owing to children not attending childcare facilities during the pandemic [
      • Fujita J.
      Mycoplasma pneumoniae pneumonia and respiratory syncytial virus infection in Japan during the severe acute respiratory syndrome coronavirus 2 pandemic.
      ].

      3.2 Seasonality and geographic distribution of RSV infection

      In Japan, RSV infections occur mostly from autumn to winter [
      • Metoki T.
      • Okamoto M.
      • Suzuki A.
      • Kitaoka S.
      • Miyabayashi H.
      • Rokugo Y.
      • et al.
      Concurrent community transmission of enterovirus D68 with human rhinoviruses and respiratory syncytial virus among children in Sendai, Japan.
      ,
      • Mizuta K.
      • Abiko C.
      • Aoki Y.
      • Ikeda T.
      • Matsuzaki Y.
      • Itagaki T.
      • et al.
      Seasonal patterns of respiratory syncytial virus, influenza A virus, human metapneumovirus, and parainfluenza virus type 3 infections on the basis of virus isolation data between 2004 and 2011 in Yamagata, Japan.
      ,
      • Shimizu H.
      • Sekine K.
      • Hirai K.
      • Takakura H.
      • Suzuki K.
      • Tada N.
      • et al.
      Clinical and epidemiological characteristics of 395 patients with respiratory syncytial virus infection from 2008 to 2013 in one pediatric clinic.
      ,
      • Fujitsuka A.
      • Tsukagoshi H.
      • Arakawa M.
      • Goto-Sugai K.
      • Ryo A.
      • Okayama Y.
      • et al.
      A molecular epidemiological study of respiratory viruses detected in Japanese children with acute wheezing illness.
      ,
      • Okubo Y.
      • Morisaki N.
      • Michihata N.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Dose-dependent relationships between weight status and clinical outcomes among infants hospitalized with respiratory syncytial virus infections.
      ,
      • Yamashita M.
      • Nakajima S.
      • Sakaida M.
      • Kawabata N.
      Summary of the 2009 annual report according to the national epidemiological surveillance of infectious diseases in miyazaki prefecture. Annual Report of the Miyazaki Prefectural Institute for Public Health and Environment.
      ,
      • Matsuoka W.
      • Koga H.
      Assessing the severity of respiratory syncytial virus infection in hospitalized early infants: a retrospective cohort study.
      ,
      • Tamura M.
      • Tsuchida S.
      • Hatakeyama M.
      • Kimura S.
      Status of medical treatment for the patients with RS virus infection in our hospital.
      ,
      • Shikano T.
      • Takahashi Y.
      Annual change of inpatients with RS virus infection and influenza virus infection.
      ,
      • Onozuka D.
      The influence of diurnal temperature range on the incidence of respiratory syncytial virus in Japan.
      ] or September–January [
      • Taniguchi A.
      • Kawada J.I.
      • Go K.
      • Fujishiro N.
      • Hosokawa Y.
      • Maki Y.
      • et al.
      Comparison of clinical characteristics of human metapneumovirus and respiratory syncytial virus infections in hospitalized young children.
      ,
      • Akiyoshi K.
      • Tamura T.
      • Haruta T.
      Virus-related lower respiratory inflammation: detection of human metapneumovirus from severe pneumonia cases with A/H1N1pdm virus.
      ,
      • Hamada H.
      • Ogura J.
      • Hotta C.
      • Wakui T.
      • Ogawa T.
      • Terai M.
      Epidemiological study of respiratory viruses detected in patients under two years old who required admission because of lower respiratory disease.
      ,
      • Osamura T.
      • Omae T.
      • Tagawa K.
      • Hirao T.
      • Kawabe Y.
      • Hasegawa M.
      • et al.
      Current status of pediatric inpatients with infectious disease in our hospital.
      ,
      • Mizuta K.
      • Abiko C.
      • Aoki Y.
      • Ikeda T.
      • Matsuzaki Y.
      • Itagaki T.
      • et al.
      Seasonal patterns of respiratory syncytial virus, influenza A virus, human metapneumovirus, and parainfluenza virus type 3 infections on the basis of virus isolation data between 2004 and 2011 in Yamagata, Japan.
      ,
      • Nakamura M.
      • Hirano E.
      • Kowada K.
      • Ishiguro F.
      • Mochizuki M.
      Virus surveillance of acute respiratory infections in Fukui prefecture.
      ,
      • Hara M.
      • Takao S.
      • Shimazu Y.
      • Nishimura T.
      Three-year study of viral etiology and features of febrile respiratory tract infections in Japanese pediatric outpatients.
      ,
      • Kato M.
      • Tsukagoshi H.
      • Yoshizumi M.
      • Saitoh M.
      • Kozawa K.
      • Yamada Y.
      • et al.
      Different cytokine profile and eosinophil activation are involved in rhinovirus- and RS virus-induced acute exacerbation of childhood wheezing.
      ,
      • 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.
      ,
      • Matsuoka W.
      • Koga H.
      Assessing the severity of respiratory syncytial virus infection in hospitalized early infants: a retrospective cohort study.
      ,
      • Furuta T.
      • Hasegawa S.
      • Mizutani M.
      • Iwai T.
      • Ohbuchi N.
      • Kawano S.
      • et al.
      Burden of human metapneumovirus and respiratory syncytial virus infections in asthmatic children.
      ,
      • Yanagisawa T.
      • Nakamura T.
      Survey of hospitalization for respiratory syncytial virus in Nagano, Japan.
      ,
      • Matsuda K.
      • Tsuboya N.
      • Okamura S.
      • Kokumai T.
      • Mitsushima S.
      • Yoshino A.
      • et al.
      Clinical characteristics of infants and children hospitalized with human metapneumovirus respiratory infection in our hospital in recent two years.
      ,
      • Kushibuchi I.
      • Funatogawa K.
      Respiratory virus detection in children hospitalized to medical institutions in Tochigi prefecture. Annual Report of Tochigi Prefectural Institute of Public Health and Environmental Science.
      ,
      • Mihara Y.
      • Yoshino S.
      • Nakatani K.
      • Nishimura T.
      • Kan H.
      • Yamamura Y.
      • et al.
      Bordetella pertussis is a common pathogen in infants hospitalized for acute lower respiratory tract infection during the winter season.
      ] with the peak occurring in December [
      • Moriyama Y.
      • Hamada H.
      • Okada M.
      • Tsuchiya N.
      • Maru H.
      • Shirato Y.
      • et al.
      Distinctive clinical features of human bocavirus in children younger than 2 years.
      ,
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ,
      • Hara M.
      • Takao S.
      • Shimazu Y.
      • Nishimura T.
      Three-year study of viral etiology and features of febrile respiratory tract infections in Japanese pediatric outpatients.
      ,
      • Yamashita M.
      • Nakajima S.
      • Sakaida M.
      • Kawabata N.
      Summary of the 2009 annual report according to the national epidemiological surveillance of infectious diseases in miyazaki prefecture. Annual Report of the Miyazaki Prefectural Institute for Public Health and Environment.
      ,
      • Matsuoka W.
      • Koga H.
      Assessing the severity of respiratory syncytial virus infection in hospitalized early infants: a retrospective cohort study.
      ,
      • Tamura M.
      • Tsuchida S.
      • Hatakeyama M.
      • Kimura S.
      Status of medical treatment for the patients with RS virus infection in our hospital.
      ,
      • Shikano T.
      • Takahashi Y.
      Annual change of inpatients with RS virus infection and influenza virus infection.
      ,
      • Furuta T.
      • Hasegawa S.
      • Mizutani M.
      • Iwai T.
      • Ohbuchi N.
      • Kawano S.
      • et al.
      Burden of human metapneumovirus and respiratory syncytial virus infections in asthmatic children.
      ]. However, recent RSV outbreaks occurred during summer [
      • Saito M.
      The Difference of the clinical features in respiratory syncytial virus (RSV) infected infants according to the seasonal change of the RSV infection epidemic.
      ,
      • Ohtani K.
      • Inagaki H.
      Evaluation of epidemic season of RSV infection in Sagamihara.
      ,
      • Kaji K.
      RSV infection evaluated by the positive number of cases in RSV rapid antigen test.
      ,
      • Tandai K.
      • Kudo S.
      • Suzuki H.
      Research on clinical symptoms of patients with respiratory syncytial virus in 2017 season and risk factors.
      ,
      • Kinoshita D.
      Proper use of palivizumab: trends of the incidence of severe RSV infection in Kyoto and preventive measures.
      ,
      • Kurosawa Y.
      • Kuruma K.
      • Murase T.
      • Furumoto M.
      • Houkibara S.
      • Aoyama K.
      Evaluation of patients admitted to our hospital with respiratory syncytial virus infection between 2013 and 2018.
      ,
      • Saito Y.
      • Iriyama M.
      • Nishida K.
      • Sakumura N.
      • Ueno K.
      • Shimao A.
      • et al.
      RSV epidemic pattern in Toyama in 2019 season and relationship with palivizumab dosing initiation.
      ], which is evident from the 10-year seasonality data of RSV infection in Japan in the NESID database (Fig. 3). In 2016, 2017, and 2018, hospitalization with RSV infection among patients aged <24 months started to increase in August, July, and June, respectively, in 16 pediatric institutions in Kyoto [
      • Kinoshita D.
      Proper use of palivizumab: trends of the incidence of severe RSV infection in Kyoto and preventive measures.
      ]. On the other hand, Hokkaido, the northernmost part of Japan located at the boundary of a cool temperate-to-subarctic zone, did not have apparent seasonal patterns of RSV infections [
      • Shobugawa Y.
      • Takeuchi T.
      • Hibino A.
      • Hassan M.R.
      • Yagami R.
      • Kondo H.
      • et al.
      Occurrence of human respiratory syncytial virus in summer in Japan.
      ]. Japan's 47 prefectures span 11 climate zones, which affects the timing of onset of the RSV epidemic [
      • Yamagami H.
      • Kimura H.
      • Hashimoto T.
      • Kusakawa I.
      • Kusuda S.
      Detection of the onset of the epidemic period of respiratory syncytial virus infection in Japan.
      ].
      Fig. 3
      Fig. 3Seasonality of RSV infections in Japan
      RSV, respiratory syncytial virus.
      In terms of RSV subgroups, RSV-A predominated during the 2012/13 (78.9%) and 2014/15 (93.2%) seasons, while similar levels of RSV-A and RSV-B were recorded during the 2013/14 season (RSV-A, 46.4%; RSV-B, 53.6%) [
      • Hibino A.
      • Saito R.
      • Taniguchi K.
      • Zaraket H.
      • Shobugawa Y.
      • Matsui T.
      • et al.
      Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1.
      ]. During the 2012/13 season, RSV-A constituted 60%–100% of positive cases in all 14 prefectures for which specimens were available. During the subsequent season, 7/14 prefectures displayed predominance of RSV-B (61.1%–100%). In the 2014/15 season, nine prefectures showed an RSV-A predominance (81.9%–100%) [
      • Hibino A.
      • Saito R.
      • Taniguchi K.
      • Zaraket H.
      • Shobugawa Y.
      • Matsui T.
      • et al.
      Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1.
      ]. During 2012–2015, a shift from RSV-A to RSV-B and back to RSV-A was observed in Niigata, Shizuoka, and Kumamoto [
      • Hibino A.
      • Saito R.
      • Taniguchi K.
      • Zaraket H.
      • Shobugawa Y.
      • Matsui T.
      • et al.
      Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1.
      ]. A new genotype, ON1, was the most common RSV genotype circulating in Okinawa in 2014 before becoming the dominant genotype nationwide during the 2014/15 season [
      • Hibino A.
      • Saito R.
      • Taniguchi K.
      • Zaraket H.
      • Shobugawa Y.
      • Matsui T.
      • et al.
      Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1.
      ].

      3.3 Hospitalization and LoS

      RSV was the leading cause of hospitalization in infants aged <12 months [
      • Inagaki A.
      • Kitano T.
      • Nishikawa H.
      • Suzuki R.
      • Onaka M.
      • Nishiyama A.
      • et al.
      The epidemiology of admission-requiring pediatric respiratory infections in a Japanese community hospital using multiplex PCR.
      ] and the rate of RSV-related hospitalization in children ranged from 21.3% to 56.7% [
      • Shimizu H.
      • Sekine K.
      • Hirai K.
      • Takakura H.
      • Suzuki K.
      • Tada N.
      • et al.
      Clinical and epidemiological characteristics of 395 patients with respiratory syncytial virus infection from 2008 to 2013 in one pediatric clinic.
      ,
      • Chinen M.
      • Shinzato H.
      • Minei S.
      • Hirata K.
      • Kohama M.
      The management of bronchiolitis due to RS virus infection in a private pediatric office.
      ]. The age-stratified hospitalization rates were as follows: <3 months, 43.8%; 3 to <6 months, 20%; 6 months to <1 year, 26.8%; 1 to <2 years, 17.5%; 2 to <3 years, 14%; and ≥3 years, 5.3% [
      • Shimizu H.
      • Sekine K.
      • Hirai K.
      • Takakura H.
      • Suzuki K.
      • Tada N.
      • et al.
      Clinical and epidemiological characteristics of 395 patients with respiratory syncytial virus infection from 2008 to 2013 in one pediatric clinic.
      ]. Lower gestational age (28–31 weeks gestational age [wGA]) was associated with a higher rate of hospitalization (3.8%) due to RSV infection compared with higher gestational age (32–≥40 wGA, 1.6%–2.3%) [
      • Suzumura H.
      • Takahashi N.
      • Yamazaki Y.
      • Shimaoka H.
      • Takahashi T.
      • Ishii T.
      • et al.
      Infantile respiratory syncytial virus infestion-associated hospitalization rate by gestational week.
      ]. A modeling study using inpatient claims data showed that ∼12% of patients with RSV infection required emergency treatment, and ∼1% required ICU admission [
      • Sruamsiri R.
      • Kubo H.
      • Mahlich J.
      Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
      ].
      The LoS varied according to patient age [
      • Nomura S.
      • Saito S.
      • Kikuchi H.
      • Ishihara M.
      • Yamamoto M.
      • Hisakawa H.
      • et al.
      Clinical evaluation of patients admitted to our hospital with RSV infection in past 10 years.
      ,
      • Urushihara Y.
      • Senzaki H.
      • Asano Y.
      • Yamaguchi S.
      • Kurishima K.
      • Saito T.
      • et al.
      Clinical characteristics of hospitalized patients with respiratory syncytial virus infection: single center experience in 2005.
      ], severity of infection [
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ,
      • Fujita S.
      • Hirose S.
      • Hamada H.
      • Fujimori M.
      • Yasukawa K.
      • Takahashi J.
      Epidemic season of respiratory syncytial virus infection is shifting to midsummer in Chiba, Japan: a single center study for clinical characteristics of hospitalized patients in summer, compared with those in winter.
      ], body weight [
      • Okubo Y.
      • Morisaki N.
      • Michihata N.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Dose-dependent relationships between weight status and clinical outcomes among infants hospitalized with respiratory syncytial virus infections.
      ], presence or absence of wheezing at the time of admission [
      • Takeyama A.
      • Hashimoto K.
      • Sato M.
      • Sato T.
      • Tomita Y.
      • Maeda R.
      • et al.
      Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years.
      ], presence or absence of hypoxia [
      • Furuta T.
      • Hasegawa S.
      • Mizutani M.
      • Iwai T.
      • Ohbuchi N.
      • Kawano S.
      • et al.
      Burden of human metapneumovirus and respiratory syncytial virus infections in asthmatic children.
      ], season [
      • Koshiba Y.
      • Taniguchi H.
      • Itani K.
      • Kaji M.
      • Nakano K.
      • Ota K.
      Summer outbreak of respiratory syncytial virus (RSV) infection in Japan.
      ], and RSV subgroups [
      • Takeyama A.
      • Hashimoto K.
      • Sato M.
      • Kawashima R.
      • Kawasaki Y.
      • Hosoya M.
      Respiratory syncytial virus shedding by children hospitalized with lower respiratory tract infection.
      ] (Fig. 4). The median (range) LoS was 7 (4–10) days before the health insurance coverage for RSV rapid antigen detection test and was reduced to 5 (1–9) days after the coverage (Fig. 4). Median LoS was 5 days for patients with moderate RSV infection and 7.5 days for patients with severe RSV infection [
      • Fujita S.
      • Hirose S.
      • Hamada H.
      • Fujimori M.
      • Yasukawa K.
      • Takahashi J.
      Epidemic season of respiratory syncytial virus infection is shifting to midsummer in Chiba, Japan: a single center study for clinical characteristics of hospitalized patients in summer, compared with those in winter.
      ]. Mean ± standard deviation (SD) LoS was 5.38 ± 2.03 days for mild RSV infection and was 24.6 ± 7.56 days for severe RSV infection [
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ]. Underweight children aged <12 months and hospitalized with RSV infections had a significantly higher risk of requiring intensive care (adjusted odds ratio [OR]: 1.35; 95% CI, 1.18–1.82) and a longer LoS (adjusted difference, 0.12 days; 95% CI: 0.04–0.20 days) than those in the normal-weight group [
      • Okubo Y.
      • Morisaki N.
      • Michihata N.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Dose-dependent relationships between weight status and clinical outcomes among infants hospitalized with respiratory syncytial virus infections.
      ]. The median (range) LoS was 5 (3–14) days and 5 (2–11) days in patients with and without wheezing at admission, respectively [
      • Takeyama A.
      • Hashimoto K.
      • Sato M.
      • Sato T.
      • Tomita Y.
      • Maeda R.
      • et al.
      Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years.
      ]. The median (range) LoS was 6 (0–45) days in patients with RSV infection and 7 (2–45) days in patients with hypoxia after RSV infection [
      • Furuta T.
      • Hasegawa S.
      • Mizutani M.
      • Iwai T.
      • Ohbuchi N.
      • Kawano S.
      • et al.
      Burden of human metapneumovirus and respiratory syncytial virus infections in asthmatic children.
      ].
      Fig. 4
      Fig. 4Factors affecting length of stay in patients hospitalized with RSV infection The
      *Data presented as median (range) or mean ± SD.
      Early and late phase refer to the time period before and after indication expansion of the rapid antigen test (date: October 17, 2011).
      LoS, length of stay; NR, not reported; RSV, respiratory syncytial virus; SD, standard deviation.
      length of hospitalization in Japanese children with RSV infection varied depending on the age and body weight of the patients, severity of RSV infection, RSV subgroups, presence or absence of wheezing and hypoxia at the time of hospitalization, time of infection (during the RSV epidemic season versus non-epidemic season), and the phase of infection.

      3.4 Complications and sequelae

      RSV was associated with bronchiolitis [
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ,
      • Hayakawa I.
      • Kubota M.
      Electroencephalography of bronchiolitis-related apnea in infants.
      ], pneumonia including community-acquired pneumonia [
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ,
      • Okada T.
      • Morozumi M.
      • Sakata H.
      • Takayanagi R.
      • Ishiwada N.
      • Sato Y.
      • et al.
      A practical approach estimating etiologic agents using real-time PCR in pediatric inpatients with community-acquired pneumonia.
      ], acute otitis media [
      • Numata M.
      • Takayanagi R.
      • Chiba Y.
      Comparison of symptoms and acute otitis media between hospitalized children with human metapneumovirus or respiratory syncytial virus infection. Shoni Kansen Meneki.
      ,
      • Sawada S.
      • Okutani F.
      • Kobayashi T.
      Comprehensive detection of respiratory bacterial and viral pathogens in the middle ear fluid and nasopharynx of pediatric patients with acute otitis media.
      ], apnea [
      • Hayakawa I.
      • Kubota M.
      Electroencephalography of bronchiolitis-related apnea in infants.
      ], afebrile seizures [
      • Miyama S.
      • Goto T.
      Afebrile seizures associated with respiratory syncytial virus infection: a situation-related seizure disorder in early infancy.
      ], febrile status epilepticus [
      • Uda K.
      • Kitazawa K.
      Febrile status epilepticus due to respiratory syncytial virus infection.
      ], encephalopathy [
      • Kawashima H.
      • Kashiwagi Y.
      • Ioi H.
      • Morichi S.
      • Oana S.
      • Yamanaka G.
      • et al.
      Production of chemokines in respiratory syncytial virus infection with central nervous system manifestations.
      ,
      • Kawasaki Y.
      • Suyama K.
      • Go H.
      • Hosoya M.
      Clinical manifestations of respiratory syncytial virus-associated encephalopathy in Fukushima, Japan.
      ,
      • Morichi S.
      • Kawashima H.
      • Ioi H.
      • Yamanaka G.
      • Kashiwagi Y.
      • Hoshika A.
      • et al.
      Classification of acute encephalopathy in respiratory syncytial virus infection.
      ,
      • Morichi S.
      • Morishita N.
      • Ishida Y.
      • Oana S.
      • Yamanaka G.
      • Kashiwagi Y.
      • et al.
      Examination of neurological prognostic markers in patients with respiratory syncytial virus-associated encephalopathy.
      ], bronchial asthma [
      • Tanaka K.
      • Kurita K.
      • Hoshino E.
      • Ukiami M.
      • Kikuoka N.
      • Umehara H.
      • et al.
      A retrospective cohort study regarding RS virus infections and asthma development.
      ,
      • Matsuda S.
      • Kato M.
      • Koike T.
      • Kama Y.
      • Suzuki K.
      • Enseki M.
      • et al.
      Differences in virus detection and cytokine profiles between first wheeze and childhood asthma.
      ], and acute myocarditis [
      • Takeuchi S.
      • Kawada J.I.
      • Okuno Y.
      • Horiba K.
      • Suzuki T.
      • Torii Y.
      • et al.
      Identification of potential pathogenic viruses in patients with acute myocarditis using next-generation sequencing.
      ]. RSV was the most commonly detected virus in the middle ear fluid of pediatric patients with acute otitis media [
      • Sawada S.
      • Okutani F.
      • Kobayashi T.
      Comprehensive detection of respiratory bacterial and viral pathogens in the middle ear fluid and nasopharynx of pediatric patients with acute otitis media.
      ]. RSV-associated encephalopathy could be of different types including metabolic error, cytokine storm, excitotoxic, or hypoxic [
      • Morichi S.
      • Kawashima H.
      • Ioi H.
      • Yamanaka G.
      • Kashiwagi Y.
      • Hoshika A.
      • et al.
      Classification of acute encephalopathy in respiratory syncytial virus infection.
      ] and was associated with sequelae such as epilepsy, mental retardation, hypacusis [
      • Kawasaki Y.
      • Suyama K.
      • Go H.
      • Hosoya M.
      Clinical manifestations of respiratory syncytial virus-associated encephalopathy in Fukushima, Japan.
      ], hemiparesis, tetraparesis, and severe cognitive impairment [
      • Uda K.
      • Kitazawa K.
      Febrile status epilepticus due to respiratory syncytial virus infection.
      ].

      3.5 Mortality

      RSV notifications increased over time from 2008 to 2015; however, the annual number of deaths decreased from 36 cases in 2008 to 19 in 2015 [
      • 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.
      ]. The mortality rate of RSV infection was <1% [
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ]; however, in patients with severe RSV infections such as those requiring intubation, the mortality rates ranged from 12.8% to 19.0% [
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ,
      • Ito H.
      • Otabe O.
      • Kubota J.
      • Oomae T.
      • Osamura T.
      Survey of patients with severe respiratory syncytial virus in Kyoto prefecture.
      ]. Among patients aged <4 years who were hospitalized with severe RSV infection, the mortality rate was significantly higher in those requiring medical care before RSV infection (e.g., respiration, intubation or tracheotomy, nasopharyngeal airway, intravenous hyperalimentation, and stoma) vs patients not requiring medical care (9.1% [12/132] vs 0.1% [6/5595]; P < 0.001) [
      • Watabe S.
      • Korematsu S.
      • Mori T.
      • Uematsu S.
      • Funamoto H.
      • Hoshino R.
      Surveillance of severe RSV infection: relationship with underlying diseases and medical care.
      ].

      3.6 Medical expenses

      RSV hospitalizations in Japan incurred a mean ± SD total cost of Japanese Yen (JPY) 365,583 ± 628,801 and diagnosis procedure combination (DPC) cost of JPY 318,713 ± 580,438 in children aged ≤5 years [
      • Sruamsiri R.
      • Kubo H.
      • Mahlich J.
      Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
      ]. In children aged <1 year, the mean ± SD total cost and DPC cost were JPY 420,146 ± 818,589 and JPY 370,093 ± 756,592, respectively [
      • Sruamsiri R.
      • Kubo H.
      • Mahlich J.
      Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
      ]. The cost of hospitalization per day was JPY 34,548 while ICU hospitalization incurred an additional cost of JPY 541,293 per day [
      • Sruamsiri R.
      • Kubo H.
      • Mahlich J.
      Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
      ]. Oxygen therapy administered to 44.2% of patients increased the total costs by JPY 56,414 per hospitalization [
      • Sruamsiri R.
      • Kubo H.
      • Mahlich J.
      Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
      ]. The greatest drivers of cost were blood transfusion, tube feeding, dialysis, cardiac catheterization, mechanical ventilation, and echocardiography, with additional expenses of JPY 699,931; JPY 384,076; JPY 338,048; JPY 192,421; JPY 190,344; and JPY 164,651, respectively [
      • Sruamsiri R.
      • Kubo H.
      • Mahlich J.
      Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
      ]. The mean total hospitalization cost for underweight children (JPY 18,242) was the highest followed by that for overweight/obese children (JPY 17,145) and normal-weight children (JPY 16,983) [
      • Okubo Y.
      • Morisaki N.
      • Michihata N.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Dose-dependent relationships between weight status and clinical outcomes among infants hospitalized with respiratory syncytial virus infections.
      ]; however, no significant differences in total costs for hospitalization were observed among the underweight, normal-weight, and overweight/obese groups, though hospitalization of underweight children tended to be expensive [
      • Okubo Y.
      • Morisaki N.
      • Michihata N.
      • Matsui H.
      • Fushimi K.
      • Yasunaga H.
      Dose-dependent relationships between weight status and clinical outcomes among infants hospitalized with respiratory syncytial virus infections.
      ].

      3.7 Reinfection

      In eight successive seasons (2001–2009), 7.8% of children were infected more than once with any of the three genotypes of RSV-A (GA5, NA1, and NA2) and/or the six genotypes of RSV-B (BA4, BA5, and BA7–BA10) with repeated infections occurring more frequently with the RSV-A than with RSV-B strains [
      • Yamaguchi M.
      • Sano Y.
      • Dapat I.C.
      • Saito R.
      • Suzuki Y.
      • Kumaki A.
      • et al.
      High frequency of repeated infections due to emerging genotypes of human respiratory syncytial viruses among children during eight successive epidemic seasons in Japan.
      ]. Children could be infected with RSV multiple times even within a single short epidemic, with Yui et al. reporting that 19/42 (45.2%) of pediatric outpatients with symptoms of LRTI experienced multiple (two or three times) RSV infections within a single epidemic year [
      • Yui I.
      • Fujino M.
      • Sawada A.
      • Nakayama T.
      Novel clinical features of recurrent human respiratory syncytial virus infections.
      ].

      3.8 Use of palivizumab in patients with RSV infections

      In 2002, palivizumab was approved for clinical use in Japan for preterm infants who were <36 wGA and infants with bronchopulmonary dysplasia (BPD) [
      • 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.
      ]. In 2005, the indication was expanded to include infants with CHD [
      • 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.
      ]. In a study conducted in 12 hospitals across Japan during October 2007 to April 2008 that enrolled children hospitalized for RSV infection, palivizumab was administered to 24/811 (3.0%) high-risk infants who were covered by health insurance, which included CHD (n = 10), and preterm infants (n = 12) covered by health insurance [
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ]. In 2013, palivizumab indication was further expanded to cover immunocompromised children and those with Down's syndrome [
      • 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.
      ]. The prophylactic use of palivizumab in children with Down's syndrome increased from 30% before the expansion of the indication (2007–2012) to 83% after the expansion of the indication (2013–2015) [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ]. Among children with Down's syndrome but without additional high-risk factors, palivizumab use surged from 0% to 73% [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ].
      RSV infection occurred in 4.2% (16/384) of patients aged ≤24 months with Down's syndrome with palivizumab prophylaxis and 6.0% (15/248) of patients without palivizumab prophylaxis [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ]. Administration of palivizumab reduced the average hospitalization rate by 72% [
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ]. The RSV-related hospitalization rate in patients who received palivizumab ranged from 0% to 3.0% (Table 1) [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ,
      • Mori M.
      • Onodera M.
      • Morimoto A.
      • Kosaka Y.
      • Morio T.
      • Notario G.F.
      • et al.
      Palivizumab use in Japanese infants and children with immunocompromised conditions.
      ,
      • Kashiwagi T.
      • Okada Y.
      • Nomoto K.
      Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
      ,
      • Yoshihara S.
      • Kusuda S.
      • Mochizuki H.
      • Okada K.
      • Nishima S.
      • Simões E.A.F.
      • et al.
      Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
      ,
      • Mochizuki H.
      • Kusuda S.
      • Okada K.
      • Yoshihara S.
      • Furuya H.
      • Simões E.A.F.
      • et al.
      Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study.
      ]. A multivariate analysis showed that palivizumab use was associated with reduced RSV-related hospitalization (OR: 0.41; 95% CI: 0.18–0.92; P = 0.03) [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ] and that children who received palivizumab prophylaxis in infancy had a statistically significant reduction in subsequent outpatient visits due to respiratory disease (12.1 and 14.1 visits per person for palivizumab recipients and control infants, respectively; relative risk [RR]: 0.88; 95% CI: 0.83–0.94; P < 0.001) [
      • Yoshihara S.
      • Kusuda S.
      • Mochizuki H.
      • Okada K.
      • Nishima S.
      • Simões E.A.F.
      • et al.
      Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
      ]. However, there was no impact of prophylaxis on the number of hospitalizations due to respiratory disease (0.07 and 0.09 hospitalizations per person for palivizumab recipients and control infants, respectively; RR: 0.81; 95% CI: 0.51–1.29; P = 0.37) [
      • Yoshihara S.
      • Kusuda S.
      • Mochizuki H.
      • Okada K.
      • Nishima S.
      • Simões E.A.F.
      • et al.
      Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
      ]. These results have been confirmed in a 6-year follow-up study, which found that children who received palivizumab prophylaxis in infancy had a significant reduction in outpatient respiratory visits (19.0 and 23.9 visits per person for palivizumab recipients and control infants, respectively; P = 0.018), whereas there was no difference in the number of hospitalizations due to respiratory disease (0.24 and 0.34 hospitalizations per person for palivizumab recipients and control infants, respectively; P = 0.46) [
      • Mochizuki H.
      • Kusuda S.
      • Okada K.
      • Yoshihara S.
      • Furuya H.
      • Simões E.A.F.
      • et al.
      Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study.
      ]. In preterm infants (33–35 wGA), recurrent wheezing was observed in 6.4% of patients who received palivizumab and in 18.9% of patients in the control group (RR: 0.34; 95% CI: 0.19–0.60; P < 0.001) [
      • Yoshihara S.
      • Kusuda S.
      • Mochizuki H.
      • Okada K.
      • Nishima S.
      • Simões E.A.F.
      • et al.
      Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
      ].
      Table 1Use of palivizumab for RSV prophylaxis in Japan.
      First author, year of publicationStudy designPatient characteristicsTotal number of RSV infectionsNumber of patients who received palivizumabNumber of doses of palivizumab used per seasonRSV-related hospitalization in patients who received palivizumab, n (%)
      References 14 and 59 represent the number of hospitalized patients who received palivizumab while references 98–102 represent the number of patients who were hospitalized despite receiving palivizumab.
      Incidence of AEs/ADRs (%)
      Kusuda, 2011 [
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ]
      ProspectiveTrisomy 18 syndrome (n = 1), CHD (n = 10), preterm infants (n = 12), and unknown (n = 1)81124NA24 (3.0)NA
      Yanagisawa, 2018 [
      • Yanagisawa T.
      • Nakamura T.
      Survey of hospitalization for respiratory syncytial virus in Nagano, Japan.
      ]
      ProspectiveChildren treated for RSV infection4386NA6 (1.4)NA
      Kimura, 2020 [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ]
      Retrospective studyChildren aged ≤24 months with Down's syndrome at the start of the RSV epidemic season (2007–2015)NA384NAPalivizumab group: 3.0%

      Control group: 6.0% (P = 0.03)
      NA
      Mori, 2014 [
      • Mori M.
      • Onodera M.
      • Morimoto A.
      • Kosaka Y.
      • Morio T.
      • Notario G.F.
      • et al.
      Palivizumab use in Japanese infants and children with immunocompromised conditions.
      ]
      Multicenter, open-label, uncontrolled, multiple dose studyJapanese children aged ≤24 monthsThree patients experienced a total of 4 respiratory infections suspected to be RSV; however, results of RSV antigen testing for all 4 cases were negative.28Mean ± SD: 6.2 ± 1.250 (0.0)96.4/NA
      Kashiwagi, 2018 [
      • Kashiwagi T.
      • Okada Y.
      • Nomoto K.
      Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
      ]
      Prospective, multicenter, post-marketing surveillanceNewborns, infants, or young children aged ≤24 months with immunocompromised medical conditions,

      Down's syndrome, without a current hs-CHD if they had experienced persistent respiratory symptoms or regular outpatient treatment due to a respiratory tract infection in previous RSV seasons
      5 (1.7%)304 (immunocompromised, 167; Down syndrome without hs-CHD, 138; immunocompromised condition and Down syndrome without hs-CHD, 1)Mean ± SD: 5.3 ± 2.42 (0.7)32.56/8.22
      Yoshihara, 2013 [
      • Yoshihara S.
      • Kusuda S.
      • Mochizuki H.
      • Okada K.
      • Nishima S.
      • Simões E.A.F.
      • et al.
      Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
      ]
      Prospective, multicenter, observational case-control studyPreterm infants at 33–to 35-wGANA349≥3Palivizumab group: 0.07 per person

      Control group: 0.09 per person (RR: 0.81 [95% CI: 0.51–1.29]; P = 0.37)
      NA
      Mochizuki, 2017 [
      • Mochizuki H.
      • Kusuda S.
      • Okada K.
      • Yoshihara S.
      • Furuya H.
      • Simões E.A.F.
      • et al.
      Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study.
      ]
      Prospective, multicenter, observational case-control studyPreterm infants 33–35 wGANA349NAPalivizumab group: 0.24 hospitalizations per person

      Control group: 0.34 hospitalizations per person (P = 0.46)
      NA
      ADR, adverse drug reactions; AE, adverse events; CHD, congenital heart disease; CI, confidence interval; hs-CHD, hemodynamically significant congenital heart disease; NA, not available; RR, relative risk; RSV, respiratory syncytial virus; SD, standard deviation; wGA, weeks' gestation.
      a References 14 and 59 represent the number of hospitalized patients who received palivizumab while references 98–102 represent the number of patients who were hospitalized despite receiving palivizumab.
      After the approval of palivizumab for all children with Down's syndrome in 2013, the percentage of patients with Down's syndrome aged ≤24 months receiving palivizumab increased from 49.2% before approval to 82.2% after approval [
      • Okamoto K.
      • Morio T.
      • Nakamura Y.
      • Hataya H.
      • Mizuta K.
      • Mori M.
      Hospitalisations due to respiratory syncytial virus infection in children with Down syndrome before and after palivizumab recommendation in Japan.
      ]; however, the expanded indication of palivizumab for prophylaxis of RSV infection in children with Down's syndrome did not have a population-level benefit in terms of reduced hospitalization [
      • Takeuchi M.
      • Kawakami K.
      Universal palivizumab prophylaxis for children with Down syndrome in Japan: analysis with interrupted time-series.
      ]. According to a retrospective, nationwide surveillance of severe RSV infection conducted by the Japan Pediatric Society (August 2014–July 2016), underlying diseases outside of the indication of palivizumab (e.g., respiratory disease, chromosomal abnormality, malformation syndrome, and nerve and muscular disorders) were commonly observed in patients (aged <4 years) hospitalized with severe RSV infection who did not require medical care such as respirator, intubation or tracheotomy, nasopharyngeal airway, intravenous hyperalimentation, and stoma [
      • Watabe S.
      • Korematsu S.
      • Mori T.
      • Uematsu S.
      • Funamoto H.
      • Hoshino R.
      Surveillance of severe RSV infection: relationship with underlying diseases and medical care.
      ]. In a post-marketing surveillance study, palivizumab was administered for prophylaxis against RSV in children with immunocompromised conditions or Down's syndrome [
      • Kashiwagi T.
      • Okada Y.
      • Nomoto K.
      Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
      ]. The mean ± SD number of palivizumab doses during each RSV season, dose, and dose interval was 5.3 ± 2.4 doses, 14.87 ± 1.08 mg/kg and 31.4 ± 7.4 days, respectively [
      • Kashiwagi T.
      • Okada Y.
      • Nomoto K.
      Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
      ]. Overall, 85.5% (260/304) of patients completed the planned course of palivizumab prophylaxis, whereas 14.5% (44/304) discontinued administration [
      • Kashiwagi T.
      • Okada Y.
      • Nomoto K.
      Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
      ]. The incidence of adverse events, serious adverse events, adverse drug reactions, and serious adverse drug reactions was 32.6%, 17.4%, 8.2%, and 3.6%, respectively, with infections and infestations being the most common type of event in each of the categories [
      • Kashiwagi T.
      • Okada Y.
      • Nomoto K.
      Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
      ].

      4. Discussion

      RSV infections account for a majority of outpatient and inpatient cases of children with respiratory symptoms in Japan [
      • Metoki T.
      • Okamoto M.
      • Suzuki A.
      • Kitaoka S.
      • Miyabayashi H.
      • Rokugo Y.
      • et al.
      Concurrent community transmission of enterovirus D68 with human rhinoviruses and respiratory syncytial virus among children in Sendai, Japan.
      ,
      • Hayakawa I.
      • Nomura O.
      • Uda K.
      • Funakoshi Y.
      • Sakakibara H.
      • Horikoshi Y.
      Incidence and aetiology of serious viral infections in young febrile infants.
      ]. RSV notifications have increased in Japan; however, since late 2011, the interpretation of trends has been challenging owing to a suspected increase in the testing frequency and the expansion of the insurance coverage for RSV testing to include certain outpatients [
      • 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.
      ]. The wide range in the proportion of RSV infections in this study may be attributed to the age of patients and clinical presentation. RSV was reported in 66.7% of Japanese children with acute LRTI, with a median age of 5 months, whereas it was reported in 5.5% of patients hospitalized for an asthma attack, with a median age of 1.6 years [
      • Abe N.
      • Yasudo H.
      • Fukano R.
      • Nakamura T.
      • Okada S.
      • Wakiguchi H.
      • et al.
      Multi-season analyses of causative pathogens in children hospitalized with asthma exacerbation.
      ,
      • Sugai K.
      • Kimura H.
      • Miyaji Y.
      • Tsukagoshi H.
      • Yoshizumi M.
      • Sasaki-Sakamoto T.
      • et al.
      MIP-1α level in nasopharyngeal aspirates at the first wheezing episode predicts recurrent wheezing.
      ]. Although there is a certain degree of heterogeneity among the data and stratification by age group is not straightforward, generally, careful monitoring and management of RSV infection is recommended in patients aged <6 months. Overall, >80% articles included in this study reported RSV prevalence of <35%, which is in agreement with studies from China and Europe, where the prevalence of RSV infection in children was reported to be 17.0% and 33.4%, respectively [
      • Feng L.
      • Li Z.
      • Zhao S.
      • Nair H.
      • Lai S.
      • Xu W.
      • et al.
      Viral etiologies of hospitalized acute lower respiratory infection patients in China, 2009-2013.
      ,
      • Kohns Vasconcelos M.
      • Loens K.
      • Sigfrid L.
      • Iosifidis E.
      • Epalza C.
      • Donà D.
      • et al.
      Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.
      ].
      The determination of the peak season of RSV infection is important to enable prophylaxis with palivizumab. The peak of the RSV epidemic in Japan has changed from December to August–September [
      • Yamagami H.
      • Kimura H.
      • Hashimoto T.
      • Kusakawa I.
      • Kusuda S.
      Detection of the onset of the epidemic period of respiratory syncytial virus infection in Japan.
      ], which has been attributed to the higher temperature and higher relative humidity [
      • Shobugawa Y.
      • Takeuchi T.
      • Hibino A.
      • Hassan M.R.
      • Yagami R.
      • Kondo H.
      • et al.
      Occurrence of human respiratory syncytial virus in summer in Japan.
      ]. In 2020, there was no RSV epidemic in Japan except in Okinawa and Kagoshima [
      Trends by prefecture.
      ], which may be attributed to the preventive measures taken for COVID-19, which also served as prophylaxis against the spread of RSV infections [
      • Fujita J.
      Mycoplasma pneumoniae pneumonia and respiratory syncytial virus infection in Japan during the severe acute respiratory syndrome coronavirus 2 pandemic.
      ]. It is essential to carefully observe the trend of RSV infection during and after the COVID-19 pandemic. Yamagami et al. have developed a model to detect the onset of the RSV season using national surveillance data [
      • Yamagami H.
      • Kimura H.
      • Hashimoto T.
      • Kusakawa I.
      • Kusuda S.
      Detection of the onset of the epidemic period of respiratory syncytial virus infection in Japan.
      ], which may enable identification of the peak of RSV infection and planning for suitable prophylactic measures.
      RSV is one of the leading causes of hospitalization due to ALRI globally [
      • Nair H.
      • Nokes D.J.
      • Gessner B.D.
      • Dherani M.
      • Madhi S.A.
      • Singleton R.J.
      • et al.
      Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.
      ]. In Japan, many pediatric patients required hospitalizations for ≥5 days [
      • Fujita S.
      • Hirose S.
      • Hamada H.
      • Fujimori M.
      • Yasukawa K.
      • Takahashi J.
      Epidemic season of respiratory syncytial virus infection is shifting to midsummer in Chiba, Japan: a single center study for clinical characteristics of hospitalized patients in summer, compared with those in winter.
      ,
      • Ito H.
      • Otabe O.
      • Kubota J.
      • Oomae T.
      • Osamura T.
      Survey of patients with severe respiratory syncytial virus in Kyoto prefecture.
      ]. Furthermore, the hospitalization rate was higher for younger children. Young age is thought to be a risk factor for severe RSV infection because the diameter of the bronchial tube is smaller, and thoracic compliance is lower in younger children than in older patients; thus, dyspnea may develop more easily in younger patients [
      • Piedimonte G.
      • Perez M.K.
      Respiratory syncytial virus infection and bronchiolitis.
      ]. Younger patients also have higher viral loads and exhibit a prolonged period of viral shedding, thereby increasing the possibility of spreading the infection to their caretakers [
      • Utsunomiya T.
      • Hibino A.
      • Taniguchi K.
      • Nagai T.
      • Saito N.
      • Tanabe I.
      • et al.
      Factors contributing to symptom duration and viral reduction in outpatient children with respiratory syncytial virus infection.
      ]. In the current situation where the dual-income household rate is increasing, not only medical expenses but also nursing of the affected patient becomes a heavy burden to parents [
      • Nakagomi T.
      • Nakagomi O.
      • Tsutsumi H.
      • Kato K.
      Cost-effectiveness of rotavirus vaccination using direct non-medical costs and opportunity costs estimated from the internet survey data.
      ].
      In patients with RSV infection, the mortality rate varied from <1% to 19% [
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ,
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ,
      • Ito H.
      • Otabe O.
      • Kubota J.
      • Oomae T.
      • Osamura T.
      Survey of patients with severe respiratory syncytial virus in Kyoto prefecture.
      ], depending on the severity of infection. The reports with mortality rates of >10% were for severe RSV patients with mechanical ventilation or cardiopulmonary arrest, while the report with the mortality rate of <1% was for hospitalized patients with mild RSV infection [
      • Kusuda S.
      • Takahashi N.
      • Saitoh T.
      • Terai M.
      • Kaneda H.
      • Kato Y.
      • et al.
      Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
      ,
      • Ito H.
      • Osamura T.
      • Nakajima F.
      • Fujiwara D.
      • Kuwabara Y.
      • Yamamoto T.
      • et al.
      Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
      ,
      • Ito H.
      • Otabe O.
      • Kubota J.
      • Oomae T.
      • Osamura T.
      Survey of patients with severe respiratory syncytial virus in Kyoto prefecture.
      ]. Moreover, these reports were published about 10 years ago. Over the last decade, palivizumab insurance coverage has expanded, which may explain the decline in the mortality rates due to RSV infection in Japan in the recent years. Globally, the in-hospital deaths in children with RSV-ALRI aged <5 years is estimated to be 0.0%–0.1% in industrialized countries [
      • Shi T.
      • McAllister D.A.
      • O'Brien K.L.
      • Simoes E.A.F.
      • Madhi S.A.
      • Gessner B.D.
      • 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.
      ].
      According to an expert consensus, palivizumab is recommended for preterm infants (<29 wGA and ≤31 wGA and ≤9 and ≤ 6 months of age; high-risk 32–35 wGA), former preterm children aged ≤24 months with CLD/BPD, children aged ≤24 months with significant CHD; and other high-risk populations, such as children aged ≤24 months with Down's syndrome, pulmonary/neuromuscular disorders, cystic fibrosis, and those who are immunocompromised [
      • Luna M.S.
      • Manzoni P.
      • Paes B.
      • Baraldi E.
      • Cossey V.
      • Kugelman A.
      • et al.
      Expert consensus on palivizumab use for respiratory syncytial virus in developed countries.
      ]. In Japan, palivizumab is recommended for preterm infants (≤28 wGA and 29–35 wGA) and ≤12 and ≤ 6 months of age; children aged ≤24 months with CLD/BPD and treated within 6 months; children aged ≤24 months with significant CHD; children aged ≤24 months with Down's syndrome; and immunocompromised children aged ≤24 months [
      Consensus guideline for the use of palivizumab in Japan.
      ]. As palivizumab is now covered by health insurance, the number of hospitalizations in children with underlying disease appears to be decreasing; however, 3.0% of patients who received palivizumab prophylaxis in Japan required hospitalization [
      • Kimura T.
      • Takeuchi M.
      • Kawakami K.
      Utilization and efficacy of palivizumab for children with Down syndrome.
      ]. Palivizumab requires monthly administration to prevent RSV infection, but the annual number of doses is regulated by each municipality in Japan [
      • Yamagishi H.
      • Oyama K.
      • Miura M.
      • Ono H.
      • Yokoyama U.
      • Kusuda S.
      • et al.
      Consensus guidelines for the use of palivizumab in infants and young children with congenital heart disease (JSPCCS 2019).
      ]. According to a modeling study, a strategy combining a maternal vaccine candidate and palivizumab prevented 14% of RSV-associated LRTIs in outpatient clinics, 13% of RSV-associated LRTIs in emergency departments, and 25% of RSV-associated LRTI hospitalizations compared with no immunization [
      • Rainisch G.
      • Adhikari B.
      • Meltzer M.I.
      • Langley G.
      Estimating the impact of multiple immunization products on medically-attended respiratory syncytial virus (RSV) infections in infants.
      ].
      The development of a vaccine seems to be a promising strategy for the prophylaxis of RSV and the target populations for effective vaccination include neonates, young children, pregnant women, and the elderly [
      • Drysdale S.B.
      • Barr R.S.
      • Rollier C.S.
      • Green C.A.
      • Pollard A.J.
      • Sande C.J.
      Priorities for developing respiratory syncytial virus vaccines in different target populations.
      ]. Maternal immunization is an attractive strategy for the prevention of infectious diseases such as RSV for the following reasons: potential to prevent the targeted infection in both the pregnant woman and her infant, offering protection to infants before their own primary immunization series begin, and the increased accessibility to medical care during pregnancy ensuring the efficient implementation of vaccination [
      • Edwards K.M.
      Maternal immunisation in pregnancy to protect newborn infants.
      ]. The goals of a maternal program against RSV are to prevent infant death and hospitalization, prevent or reduce the severity of LRTI in infants, reduce transmission in the household and community, reduce antibiotic use for the treatment of LRTI, and potentially reduce the maternal effects of RSV on the unborn child during pregnancy [
      • Giles M.L.
      • Krishnaswamy S.
      • Wallace E.M.
      Maternal immunisation: what have been the gains? Where are the gaps? What does the future hold?.
      ].
      In a phase 3, randomized, placebo-controlled, multicountry trial that enrolled 4636 pregnant women between 28 and 36 weeks of gestation due for delivery during the start of the RSV season, the vaccine efficacy was determined to be 39.4% (95% CI: 5.3–61.2); however, the primary endpoint of RSV-associated medically significant LRTIs, up to 90 days of life was not met [
      • Madhi S.A.
      • Polack F.P.
      • Piedra P.A.
      • Munoz F.M.
      • Trenholme A.A.
      • Simões E.A.F.
      • et al.
      Respiratory syncytial virus vaccination during pregnancy and effects in infants.
      ]. The vaccine efficacy against RSV-associated LRTI with severe hypoxemia was 48.3% (95% CI: −8.2 to 75.3) and that for hospitalization for RSV-associated LRTI was 44.4% (95% CI: 19.6–61.5) [
      • Madhi S.A.
      • Polack F.P.
      • Piedra P.A.
      • Munoz F.M.
      • Trenholme A.A.
      • Simões E.A.F.
      • et al.
      Respiratory syncytial virus vaccination during pregnancy and effects in infants.
      ]. Transplacental antibody transfer ranged between 90% and 120% across assays for infants of vaccinated women; women with an interval of ≥30 days between vaccination and delivery demonstrated higher placental antibody transfer rates than those with an interval <30 days [
      • Muňoz F.M.
      • Swamy G.K.
      • Hickman S.P.
      • Agrawal S.
      • Piedra P.A.
      • Glenn G.M.
      • et al.
      Safety and immunogenicity of a respiratory syncytial virus fusion (F) protein nanoparticle vaccine in healthy third-trimester pregnant women and their infants.
      ]. The half-life of RSV-specific antibodies in infants was approximately 40 days and there was no evidence of severe RSV disease in infants of vaccinated mothers [
      • Muňoz F.M.
      • Swamy G.K.
      • Hickman S.P.
      • Agrawal S.
      • Piedra P.A.
      • Glenn G.M.
      • et al.
      Safety and immunogenicity of a respiratory syncytial virus fusion (F) protein nanoparticle vaccine in healthy third-trimester pregnant women and their infants.
      ]. Considering that the antibody transfer rate was the highest in appropriate-for-gestational-age infants, maternal vaccination strategies may be less effective in small-for-gestational-age and large-for-gestational-age infants [
      • Yildiz M.
      • Kara M.
      • Sutcu M.
      • Mese S.
      • Demircili M.E.
      • Sivrikoz T.S.
      • et al.
      Evaluation of respiratory syncytial virus IgG antibody dynamics in mother-infant pairs cohort.
      ]. A modeling study for the period 2023–2035 revealed that a maternal RSV vaccine with 60% efficacy offering 5 months of infant protection implemented across 73 low- and middle-income Global Alliance for Vaccines and Immunizations (Gavi)-supported countries could avert 10.1–12.5 million cases, 2.8–4.0 million hospitalizations, 123.7–177.7 thousand deaths, and 8.5–11.9 million disability-adjusted life-years among infants aged <6 months, suggesting that RSV maternal immunization could substantially reduce mortality and morbidity among infants [
      • Baral R.
      • Li X.
      • Willem L.
      • Antillon M.
      • Vilajeliu A.
      • Jit M.
      • et al.
      The impact of maternal RSV vaccine to protect infants in Gavi-supported countries: estimates from two models.
      ]. A modeling study in Turkey has found that vaccination of infants and/or pregnant women against RSV to be cost-effective in terms of reduced general practitioner visits, hospitalizations, and deaths [
      • Pouwels K.B.
      • Bozdemir S.E.
      • Yegenoglu S.
      • Celebi S.
      • McIntosh E.D.
      • Unal S.
      • et al.
      Potential cost-effectiveness of RSV vaccination of infants and pregnant women in Turkey: an illustration based on bursa data.
      ]. Another study in Gavi-eligible countries has also found that vaccination is more cost-effective in terms of reducing RSV-associated hospitalizations and deaths compared with therapy using mAbs [
      • Li X.
      • Willem L.
      • Antillon M.
      • Bilcke J.
      • Jit M.
      • Beutels P.
      Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries.
      ].
      Despite the benefits of maternal immunization against RSV, the awareness of RSV is poor among the general public [
      • Wilcox C.R.
      • Calvert A.
      • Metz J.
      • Kilich E.
      • MacLeod R.
      • Beadon K.
      • et al.
      Attitudes of pregnant women and healthcare professionals toward clinical trials and routine implementation of antenatal vaccination against respiratory syncytial virus: a multicenter questionnaire study.
      ,
      • Giles M.L.
      • Buttery J.
      • Davey M.A.
      • Wallace E.
      Pregnant women's knowledge and attitude to maternal vaccination including group B streptococcus and respiratory syncytial virus vaccines.
      ] but is higher among parents with preterm infants [
      • Bracht M.
      • Bacchini F.
      • Paes B.
      A survey of parental knowledge of respiratory syncytial virus and other respiratory infections in preterm infants.
      ]. A study carried out in the United Kingdom revealed that pregnant women and midwives had little or no awareness about RSV, whereas obstetricians were aware of RSV [
      • Wilcox C.R.
      • Calvert A.
      • Metz J.
      • Kilich E.
      • MacLeod R.
      • Beadon K.
      • et al.
      Attitudes of pregnant women and healthcare professionals toward clinical trials and routine implementation of antenatal vaccination against respiratory syncytial virus: a multicenter questionnaire study.
      ]. Furthermore, 29% and 75% of pregnant women would likely accept vaccination as part of a trial or if routinely recommended, respectively [
      • Wilcox C.R.
      • Calvert A.
      • Metz J.
      • Kilich E.
      • MacLeod R.
      • Beadon K.
      • et al.
      Attitudes of pregnant women and healthcare professionals toward clinical trials and routine implementation of antenatal vaccination against respiratory syncytial virus: a multicenter questionnaire study.
      ]. Similar results were reported in an Australian study in which 83% of pregnant women reported that they had never heard of RSV; however, when these women were provided information about RSV, the acceptance of a hypothetical vaccine increased [
      • Giles M.L.
      • Buttery J.
      • Davey M.A.
      • Wallace E.
      Pregnant women's knowledge and attitude to maternal vaccination including group B streptococcus and respiratory syncytial virus vaccines.
      ]. In Japan, there are currently no studies evaluating the awareness of RSV vaccines among pregnant women; however, as seen with other vaccines, pregnant women have concerns about being vaccinated and they are willing to be vaccinated upon being provided with adequate information [
      • Kitano T.
      • Onishi T.
      • Takeyama M.
      • Shima M.
      Questionnaire survey on maternal pertussis vaccination for pregnant women and mothers in Nara prefecture, Japan.
      ,
      • Yamada T.
      • Abe K.
      • Baba Y.
      • Inubashiri E.
      • Kawabata K.
      • Kubo T.
      • et al.
      Vaccination during the 2013-2014 influenza season in pregnant Japanese women.
      ].

      5. Conclusion

      RSV infections cause a large number of hospitalizations even in developed countries such as Japan resulting in increased medical expenses. Prevention with palivizumab is insufficient and early prophylaxis through vaccination and specific treatments is required. There is a need to create awareness around RSV infection in the Japanese population, as well as among obstetricians, pediatricians, and childhood disease specialists to ensure early recognition of infection and adequate treatment or prophylaxis.

      Funding

      Literature review and medical writing work was funded by Pfizer Japan .

      Declaration of competing interest

      NI has received research funding from Sanofi Pasteur.

      Acknowledgments

      Literature review and medical writing support based on authors' detailed directions were provided by Sarayu Pai, PhD, Mami Hirano, MS, and Juliane Moloney, PhD, of Cactus Life Sciences (part of Cactus Communications Pvt. Ltd., Mumbai, India).

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Nair H.
        • Nokes D.J.
        • Gessner B.D.
        • Dherani M.
        • Madhi S.A.
        • Singleton R.J.
        • et al.
        Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.
        Lancet. 2010; 375: 1545-1555https://doi.org/10.1016/S0140-6736(10)60206-1
        • Borchers A.T.
        • Chang C.
        • Gershwin M.E.
        • Gershwin L.J.
        Respiratory syncytial virus--a comprehensive review.
        Clin Rev Allergy Immunol. 2013; 45: 331-379https://doi.org/10.1007/s12016-013-8368-9
      1. Respiratory syncytial virus infection.
        (January 2014-September 2018)
        https://www.niid.go.jp/niid/en/iasren/865-iasr/8491-466te.html
        Date: 2020
        Date accessed: November 16, 2020
        • Shi T.
        • McAllister D.A.
        • O'Brien K.L.
        • Simoes E.A.F.
        • Madhi S.A.
        • Gessner B.D.
        • 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: 946-958https://doi.org/10.1016/S0140-6736(17)30938-8
        • Fauroux B.
        • Simões E.A.F.
        • Checchia P.A.
        • Paes B.
        • Figueras-Aloy J.
        • Manzoni P.
        • et al.
        The burden and long-term respiratory morbidity associated with respiratory syncytial virus infection in early childhood.
        Infect Dis Ther. 2017; 6: 173-197https://doi.org/10.1007/s40121-017-0151-4
        • Resch B.
        Product review on the monoclonal antibody palivizumab for prevention of respiratory syncytial virus infection.
        Hum Vaccin. Immunother. 2017; 13: 2138-2149https://doi.org/10.1080/21645515.2017.1337614
        • Griffin M.P.
        • Yuan Y.
        • Takas T.
        • Domachowske J.B.
        • Madhi S.A.
        • Manzoni P.
        • et al.
        Single-dose nirsevimab for prevention of RSV in preterm infants.
        N Engl J Med. 2020; 383: 415-425
        • Simões E.A.F.
        • Bont L.
        • Manzoni P.
        • Fauroux B.
        • Paes B.
        • Figueras-Aloy J.
        • et al.
        Past, present and future approaches to the prevention and treatment of respiratory syncytial virus infection in children.
        Infect Dis Ther. 2018; 7: 87-120https://doi.org/10.1007/s40121-018-0188-z
        • Vekemans J.
        • Moorthy V.
        • Giersing B.
        • Friede M.
        • Hombach J.
        • Arora N.
        • et al.
        Respiratory syncytial virus vaccine research and development: world Health Organization technological roadmap and preferred product characteristics.
        Vaccine. 2019; 37: 7394-7395https://doi.org/10.1016/j.vaccine.2017.09.092
      2. RSV vaccine and mAb snapshot.
        • Metoki T.
        • Okamoto M.
        • Suzuki A.
        • Kitaoka S.
        • Miyabayashi H.
        • Rokugo Y.
        • et al.
        Concurrent community transmission of enterovirus D68 with human rhinoviruses and respiratory syncytial virus among children in Sendai, Japan.
        Pediatr Infect Dis J. 2018; 37: 394-400
        • Moriyama Y.
        • Hamada H.
        • Okada M.
        • Tsuchiya N.
        • Maru H.
        • Shirato Y.
        • et al.
        Distinctive clinical features of human bocavirus in children younger than 2 years.
        Eur J Pediatr. 2010; 169: 1087-1092https://doi.org/10.1007/s00431-010-1183-x
        • Abe N.
        • Yasudo H.
        • Fukano R.
        • Nakamura T.
        • Okada S.
        • Wakiguchi H.
        • et al.
        Multi-season analyses of causative pathogens in children hospitalized with asthma exacerbation.
        Pediatr Allergy Immunol. 2019; 30: 724-731https://doi.org/10.1111/pai.13102
        • Kusuda S.
        • Takahashi N.
        • Saitoh T.
        • Terai M.
        • Kaneda H.
        • Kato Y.
        • et al.
        Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan.
        Pediatr Int. 2011; 53: 368-373https://doi.org/10.1111/j.1442-200X.2010.03249.x
        • Taniguchi A.
        • Kawada J.I.
        • Go K.
        • Fujishiro N.
        • Hosokawa Y.
        • Maki Y.
        • et al.
        Comparison of clinical characteristics of human metapneumovirus and respiratory syncytial virus infections in hospitalized young children.
        Jpn J Infect Dis. 2019; 72: 237-242https://doi.org/10.7883/yoken.JJID.2018.480
        • Okada T.
        • Matsubara K.
        • Matsushima T.
        • Komiyama O.
        • Chiba N.
        • Hamano K.
        • et al.
        [Analysis of clinical features of community-acquired pneumonia caused by pediatric respiratory syncytial virus and human metapneumovirus].
        Kansenshogaku Zasshi. 2010; 84 ([Japanese]): 42-47
        • Akiyoshi K.
        • Tamura T.
        • Haruta T.
        Virus-related lower respiratory inflammation: detection of human metapneumovirus from severe pneumonia cases with A/H1N1pdm virus.
        Jpn J Infect Dis. 2011; 64: 89-91
        • Satoh K.
        • Wakejima Y.
        • Gau M.
        • Kiguchi T.
        • Matsuda N.
        • Takasawa R.
        • et al.
        Risk of coronary artery lesions in young infants with Kawasaki disease: need for a new diagnostic method.
        Int. J. Rheum. Dis. 2018; 21: 746-754https://doi.org/10.1111/1756-185X.13223
        • Uda K.
        • Kitazawa K.
        Febrile status epilepticus due to respiratory syncytial virus infection.
        Pediatr Int. 2017; 59: 878-884https://doi.org/10.1111/ped.13300
        • Azuma J.
        • Yamamoto T.
        • Sakurai M.
        • Amou R.
        • Yamada C.
        • Hashimoto K.
        • et al.
        Urinary β2-microglobulin as an early marker of infantile enterovirus and human parechovirus infections.
        Medicine (Baltim). 2018; 97e12930
        • Kato M.
        • Yamada Y.
        • Maruyama K.
        • Hayashi Y.
        Differential effects of corticosteroids on serum eosinophil cationic protein and cytokine production in rhinovirus- and respiratory syncytial virus-induced acute exacerbation of childhood asthma.
        Int Arch Allergy Immunol. 2011; 155: 77-84https://doi.org/10.1159/000327434
        • Numata M.
        • Takayanagi R.
        • Chiba Y.
        Comparison of symptoms and acute otitis media between hospitalized children with human metapneumovirus or respiratory syncytial virus infection. Shoni Kansen Meneki.
        J. Pediatr. Infect. Dis. Immunol. 2018; 30 ([Japanese]): 212-222
        • Hamada H.
        • Ogura J.
        • Hotta C.
        • Wakui T.
        • Ogawa T.
        • Terai M.
        Epidemiological study of respiratory viruses detected in patients under two years old who required admission because of lower respiratory disease.
        Kansenshogaku Zasshi. 2014; 88 ([Japanese]): 423-429
        • Narita A.
        • Nishimura N.
        • Arakawa Y.
        • Suzuki M.
        • Sakamoto K.
        • Sakamoto M.
        • et al.
        Relationship between lower respiratory tract infections caused by respiratory syncytial virus and subsequent development of asthma in Japanese children.
        Jpn J Infect Dis. 2011; 64: 433-435
        • Takeyama A.
        • Hashimoto K.
        • Sato M.
        • Sato T.
        • Tomita Y.
        • Maeda R.
        • et al.
        Clinical and epidemiologic factors related to subsequent wheezing after virus-induced lower respiratory tract infections in hospitalized pediatric patients younger than 3 years.
        Eur J Pediatr. 2014; 173: 959-966https://doi.org/10.1007/s00431-014-2277-7
        • Morikawa Y.
        • Miura M.
        • Furuhata M.Y.
        • Morino S.
        • Omori T.
        • Otsuka M.
        • et al.
        Nebulized hypertonic saline in infants hospitalized with moderately severe bronchiolitis due to RSV infection: a multicenter randomized controlled trial.
        Pediatr Pulmonol. 2018; 53: 358-365https://doi.org/10.1002/ppul.23945
        • Osamura T.
        • Omae T.
        • Tagawa K.
        • Hirao T.
        • Kawabe Y.
        • Hasegawa M.
        • et al.
        Current status of pediatric inpatients with infectious disease in our hospital.
        Medical Journal of Kyoto Second Red Cross Hospital. 2011; 32 ([Japanese]): 70-87
        • Okuno H.
        • Inoue T.
        • Ishikawa J.
        • Amo K.
        • Togawa M.
        • Shiomi M.
        Respiratory infection pathogens of apnea related to respiratory infection in infants.
        Shoni Kansen Meneki. 2012; 24 (–9 [Japanese]): 285
        • Okamoto N.
        • Ikeda M.
        • Okuda M.
        • Sakamoto T.
        • Takasugi M.
        • Takahashi N.
        • et al.
        Increased eosinophilic cationic protein in nasal fluid in hospitalized wheezy infants with RSV infection.
        Allergol Int. 2011; 60: 467-472https://doi.org/10.2332/allergolint.10-OA-0263
        • Sugai K.
        • Kimura H.
        • Miyaji Y.
        • Tsukagoshi H.
        • Yoshizumi M.
        • Sasaki-Sakamoto T.
        • et al.
        MIP-1α level in nasopharyngeal aspirates at the first wheezing episode predicts recurrent wheezing.
        J Allergy Clin Immunol. 2016; 137: 774-781https://doi.org/10.1016/j.jaci.2015.08.032
        • Mizuta K.
        • Abiko C.
        • Aoki Y.
        • Ikeda T.
        • Matsuzaki Y.
        • Itagaki T.
        • et al.
        Seasonal patterns of respiratory syncytial virus, influenza A virus, human metapneumovirus, and parainfluenza virus type 3 infections on the basis of virus isolation data between 2004 and 2011 in Yamagata, Japan.
        Jpn J Infect Dis. 2013; 66: 140-145https://doi.org/10.7883/yoken.66.140
        • Nakamura M.
        • Hirano E.
        • Kowada K.
        • Ishiguro F.
        • Mochizuki M.
        Virus surveillance of acute respiratory infections in Fukui prefecture.
        2010. Annual Report of Fukui Prefectural Institute of Public Health. 9. 2010: 93-96 ([Japanese])
        • Hara M.
        • Takao S.
        • Shimazu Y.
        • Nishimura T.
        Three-year study of viral etiology and features of febrile respiratory tract infections in Japanese pediatric outpatients.
        Pediatr Infect Dis J. 2014; 33: 687-692
        • Shimizu H.
        • Sekine K.
        • Hirai K.
        • Takakura H.
        • Suzuki K.
        • Tada N.
        • et al.
        Clinical and epidemiological characteristics of 395 patients with respiratory syncytial virus infection from 2008 to 2013 in one pediatric clinic.
        Shoni Kansen Meneki. 2015; 27 ([Japanese]): 119-125
        • Kaida A.
        • Kubo H.
        • Takakura K.
        • Sekiguchi J.
        • Yamamoto S.P.
        • Kohdera U.
        • et al.
        Associations between co-detected respiratory viruses in children with acute respiratory infections.
        Jpn J Infect Dis. 2014; 67: 469-475https://doi.org/10.7883/yoken.67.469
        • Kato M.
        • Tsukagoshi H.
        • Yoshizumi M.
        • Saitoh M.
        • Kozawa K.
        • Yamada Y.
        • et al.
        Different cytokine profile and eosinophil activation are involved in rhinovirus- and RS virus-induced acute exacerbation of childhood wheezing.
        Pediatr Allergy Immunol. 2011; 22: e87-94https://doi.org/10.1111/j.1399-3038.2010.01026.x
        • Miyaji Y.
        • Kobayashi M.
        • Sugai K.
        • Tsukagoshi H.
        • Niwa S.
        • Fujitsuka-Nozawa A.
        • et al.
        Severity of respiratory signs and symptoms and virus profiles in Japanese children with acute respiratory illness.
        Microbiol Immunol. 2013; 57: 811-821https://doi.org/10.1111/1348-0421.12102
        • Fujitsuka A.
        • Tsukagoshi H.
        • Arakawa M.
        • Goto-Sugai K.
        • Ryo A.
        • Okayama Y.
        • et al.
        A molecular epidemiological study of respiratory viruses detected in Japanese children with acute wheezing illness.
        BMC Infect Dis. 2011; 11: 168https://doi.org/10.1186/1471-2334-11-168
        • Harada Y.
        • Kinoshita F.
        • Yoshida L.M.
        • Minh L.N.
        • Suzuki M.
        • Morimoto K.
        • et al.
        Does respiratory virus coinfection increases the clinical severity of acute respiratory infection among children infected with respiratory syncytial virus?.
        Pediatr Infect Dis J. 2013; 32: 441-445
        • Yoshida A.
        • Kiyota N.
        • Kobayashi M.
        • Nishimura K.
        • Tsutsui R.
        • Tsukagoshi H.
        • et al.
        Molecular epidemiology of the attachment glycoprotein (G) gene in respiratory syncytial virus in children with acute respiratory infection in Japan in 2009/2010.
        J Med Microbiol. 2012; 61: 820-829
        • Kushibuchi I.
        • Kobayashi M.
        • Kusaka T.
        • Tsukagoshi H.
        • Ryo A.
        • Yoshida A.
        • et al.
        Molecular evolution of attachment glycoprotein (G) gene in human respiratory syncytial virus detected in Japan 2008-2011.
        Infect Genet Evol. 2013; 18: 168-173https://doi.org/10.1016/j.meegid.2013.05.010
        • Deguchi K.
        • Hamada H.
        • Hirose S.
        • Takafumi Honda T.
        • Yasukawa K.
        • Nishijima H.
        • et al.
        Clinical features of respiratory viruses detected in patients in the pediatric intensive care unit for lower respiratory tract infection from 2012 to 2017.
        J. Tokyo Women's Med. Univ. 2020; 90 ([Japanese]): 14-20
        • Utsunomiya T.
        • Hibino A.
        • Taniguchi K.
        • Nagai T.
        • Saito N.
        • Tanabe I.
        • et al.
        Factors contributing to symptom duration and viral reduction in outpatient children with respiratory syncytial virus infection.
        Pediatr Infect Dis J. 2020; 39: 678-683
        • Hasuwa T.
        • Kinoshita F.
        • Harada S.
        • Nakashima K.
        • Yoshihara K.
        • Toku Y.
        • et al.
        Viral etiology of acute lower respiratory tract infections in hospitalized children in Nagasaki, a regional city of Japan in 2013-2015.
        Pediatr Infect Dis J. 2020; 39: 687-693
        • 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: 250-255https://doi.org/10.7883/yoken.JJID.2017.261
        • Jung S.M.
        • 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: 1441
        • Hibino A.
        • Saito R.
        • Taniguchi K.
        • Zaraket H.
        • Shobugawa Y.
        • Matsui T.
        • et al.
        Molecular epidemiology of human respiratory syncytial virus among children in Japan during three seasons and hospitalization risk of genotype ON1.
        PLoS One. 2018; 13e0192085https://doi.org/10.1371/journal.pone.0192085
        • Hishiki H.
        • Ishiwada N.
        • Fukasawa C.
        • Abe K.
        • Hoshino T.
        • Aizawa J.
        • et al.
        Incidence of bacterial coinfection with respiratory syncytial virus bronchopulmonary infection in pediatric inpatients.
        J Infect Chemother. 2011; 17: 87-90https://doi.org/10.1007/s10156-010-0097-x
        • Goudarzi H.
        • Miyashita C.
        • Okada E.
        • Kashino I.
        • Chen C.J.
        • Ito S.
        • et al.
        Prenatal exposure to perfluoroalkyl acids and prevalence of infectious diseases up to 4 years of age.
        Environ Int. 2017; 104: 132-138https://doi.org/10.1016/j.envint.2017.01.024
        • Ait Bamai Y.
        • Goudarzi H.
        • Araki A.
        • Okada E.
        • Kashino I.
        • Miyashita C.
        • et al.
        Effect of prenatal exposure to per- and polyfluoroalkyl substances on childhood allergies and common infectious diseases in children up to age 7 years: the Hokkaido study on environment and children's health.
        Environ Int. 2020; 143: 105979https://doi.org/10.1016/j.envint.2020.105979
        • Fujita J.
        Mycoplasma pneumoniae pneumonia and respiratory syncytial virus infection in Japan during the severe acute respiratory syndrome coronavirus 2 pandemic.
        Respir. Investig. 2021; 59: 5-7https://doi.org/10.1016/j.resinv.2020.11.002
        • Okubo Y.
        • Morisaki N.
        • Michihata N.
        • Matsui H.
        • Fushimi K.
        • Yasunaga H.
        Dose-dependent relationships between weight status and clinical outcomes among infants hospitalized with respiratory syncytial virus infections.
        Pediatr Pulmonol. 2018; 53: 461-466https://doi.org/10.1002/ppul.23949
        • Yamashita M.
        • Nakajima S.
        • Sakaida M.
        • Kawabata N.
        Summary of the 2009 annual report according to the national epidemiological surveillance of infectious diseases in miyazaki prefecture. Annual Report of the Miyazaki Prefectural Institute for Public Health and Environment.
        . 2010; 21 ([Japanese]): 41-50
        • Matsuoka W.
        • Koga H.
        Assessing the severity of respiratory syncytial virus infection in hospitalized early infants: a retrospective cohort study.
        Shonika Rinsho. 2015; 68 ([Japanese]): 52-58
        • Tamura M.
        • Tsuchida S.
        • Hatakeyama M.
        • Kimura S.
        Status of medical treatment for the patients with RS virus infection in our hospital.
        Med. J. Jpn. Red Cross Akita Cent. 2018; 6 ([Japanese]): 18-23
        • Shikano T.
        • Takahashi Y.
        Annual change of inpatients with RS virus infection and influenza virus infection.
        Shonika Rinsho. 2011; 64 ([Japanese]): 2007-2010
        • Onozuka D.
        The influence of diurnal temperature range on the incidence of respiratory syncytial virus in Japan.
        Epidemiol Infect. 2015; 143: 813-820
        • Furuta T.
        • Hasegawa S.
        • Mizutani M.
        • Iwai T.
        • Ohbuchi N.
        • Kawano S.
        • et al.
        Burden of human metapneumovirus and respiratory syncytial virus infections in asthmatic children.
        Pediatr Infect Dis J. 2018; 37: 1107-1111
        • Yanagisawa T.
        • Nakamura T.
        Survey of hospitalization for respiratory syncytial virus in Nagano, Japan.
        Pediatr Int. 2018; 60: 835-838https://doi.org/10.1111/ped.13638
        • Matsuda K.
        • Tsuboya N.
        • Okamura S.
        • Kokumai T.
        • Mitsushima S.
        • Yoshino A.
        • et al.
        Clinical characteristics of infants and children hospitalized with human metapneumovirus respiratory infection in our hospital in recent two years.
        Mie Pediatr. Assoc. Rep. 2015; 97 ([Japanese]): 27-29
        • Kushibuchi I.
        • Funatogawa K.
        Respiratory virus detection in children hospitalized to medical institutions in Tochigi prefecture. Annual Report of Tochigi Prefectural Institute of Public Health and Environmental Science.
        . 2014; 18 ([Japanese]): 59-61
        • Mihara Y.
        • Yoshino S.
        • Nakatani K.
        • Nishimura T.
        • Kan H.
        • Yamamura Y.
        • et al.
        Bordetella pertussis is a common pathogen in infants hospitalized for acute lower respiratory tract infection during the winter season.
        J Infect Chemother. 2021; 27: 497-502https://doi.org/10.1016/j.jiac.2020.11.002
        • Saito M.
        The Difference of the clinical features in respiratory syncytial virus (RSV) infected infants according to the seasonal change of the RSV infection epidemic.
        Kansenshogaku Zasshi [The Journal of the Japanese Association for Infectious Diseases. 2020; 94 ([Japanese]): 181-185
        • Ohtani K.
        • Inagaki H.
        Evaluation of epidemic season of RSV infection in Sagamihara.
        Shoni Kansen Meneki [The Journal of Pediatric Infectious Disease and Immunology. 2020; 32 ([Japanese]): 83-93
        • Kaji K.
        RSV infection evaluated by the positive number of cases in RSV rapid antigen test.
        Osaka Kyukyu. 2018; 98 ([Japanese]): 23-27
        • Tandai K.
        • Kudo S.
        • Suzuki H.
        Research on clinical symptoms of patients with respiratory syncytial virus in 2017 season and risk factors.
        Med. J. Morioka Red Cross Hosp. 2019; 28 ([Japanese]): 44-48
        • Kinoshita D.
        Proper use of palivizumab: trends of the incidence of severe RSV infection in Kyoto and preventive measures.
        J Jpn Pharm Assoc. 2019; 58 ([Japanese]): 101-104
        • Kurosawa Y.
        • Kuruma K.
        • Murase T.
        • Furumoto M.
        • Houkibara S.
        • Aoyama K.
        Evaluation of patients admitted to our hospital with respiratory syncytial virus infection between 2013 and 2018.
        Yamanashi Igaku. 2019; 46 ([Japanese]): 11-16
        • Saito Y.
        • Iriyama M.
        • Nishida K.
        • Sakumura N.
        • Ueno K.
        • Shimao A.
        • et al.
        RSV epidemic pattern in Toyama in 2019 season and relationship with palivizumab dosing initiation.
        The Med. J. Toyama Prefect. Cent. Hosp. 2020; 43 ([Japanese]): 54-56
        • Shobugawa Y.
        • Takeuchi T.
        • Hibino A.
        • Hassan M.R.
        • Yagami R.
        • Kondo H.
        • et al.
        Occurrence of human respiratory syncytial virus in summer in Japan.
        Epidemiol Infect. 2017; 145: 272-284https://doi.org/10.1017/S095026881600220X
        • Yamagami H.
        • Kimura H.
        • Hashimoto T.
        • Kusakawa I.
        • Kusuda S.
        Detection of the onset of the epidemic period of respiratory syncytial virus infection in Japan.
        Front. Publ. Health. 2019; 7: 39https://doi.org/10.3389/fpubh.2019.00039
        • Inagaki A.
        • Kitano T.
        • Nishikawa H.
        • Suzuki R.
        • Onaka M.
        • Nishiyama A.
        • et al.
        The epidemiology of admission-requiring pediatric respiratory infections in a Japanese community hospital using multiplex PCR.
        Jpn J Infect Dis. 2021; 74: 23-28https://doi.org/10.7883/yoken.JJID.2020.154
        • Chinen M.
        • Shinzato H.
        • Minei S.
        • Hirata K.
        • Kohama M.
        The management of bronchiolitis due to RS virus infection in a private pediatric office.
        Shonika Rinsho. 2012; 65 (Japanese]): 2661-2667
        • Suzumura H.
        • Takahashi N.
        • Yamazaki Y.
        • Shimaoka H.
        • Takahashi T.
        • Ishii T.
        • et al.
        Infantile respiratory syncytial virus infestion-associated hospitalization rate by gestational week.
        Shonika Rinsho. 2011; 64 ([Japanese]): 2021-2026
        • Sruamsiri R.
        • Kubo H.
        • Mahlich J.
        Hospitalization costs and length of stay of Japanese children with respiratory syncytial virus: a structural equation modeling approach.
        Medicine (Baltim). 2018; 97e11491
        • Nomura S.
        • Saito S.
        • Kikuchi H.
        • Ishihara M.
        • Yamamoto M.
        • Hisakawa H.
        • et al.
        Clinical evaluation of patients admitted to our hospital with RSV infection in past 10 years.
        Kochi Prefect. Pediat. Assoc. Rep. 2019; 31 ([Japanese]): 41-46
        • Urushihara Y.
        • Senzaki H.
        • Asano Y.
        • Yamaguchi S.
        • Kurishima K.
        • Saito T.
        • et al.
        Clinical characteristics of hospitalized patients with respiratory syncytial virus infection: single center experience in 2005.
        J. Jpn. Soc. Emerg. Pediatr. 2011; 10 ([Japanese]): 5-8
        • Ito H.
        • Osamura T.
        • Nakajima F.
        • Fujiwara D.
        • Kuwabara Y.
        • Yamamoto T.
        • et al.
        Survey of severe respiratory syncytial virus infection in Kyoto Prefecture from 2003 to 2007.
        Pediatr Int. 2010; 52: 273-278https://doi.org/10.1111/j.1442-200X.2009.02962.x
        • Fujita S.
        • Hirose S.
        • Hamada H.
        • Fujimori M.
        • Yasukawa K.
        • Takahashi J.
        Epidemic season of respiratory syncytial virus infection is shifting to midsummer in Chiba, Japan: a single center study for clinical characteristics of hospitalized patients in summer, compared with those in winter.
        J. Jpn. Soc. Emerg. Pediatr. 2019; 18 ([Japanese]): 16-21
        • Koshiba Y.
        • Taniguchi H.
        • Itani K.
        • Kaji M.
        • Nakano K.
        • Ota K.
        Summer outbreak of respiratory syncytial virus (RSV) infection in Japan.
        Shoni Hoken Kenkyu. 2015; 74 ([Japanese]): 422-426
        • Takeyama A.
        • Hashimoto K.
        • Sato M.
        • Kawashima R.
        • Kawasaki Y.
        • Hosoya M.
        Respiratory syncytial virus shedding by children hospitalized with lower respiratory tract infection.
        J Med Virol. 2016; 88: 938-946https://doi.org/10.1002/jmv.24434
        • Hayakawa I.
        • Kubota M.
        Electroencephalography of bronchiolitis-related apnea in infants.
        Pediatr Int. 2020; 62: 998-1000https://doi.org/10.1111/ped.14225
        • Okada T.
        • Morozumi M.
        • Sakata H.
        • Takayanagi R.
        • Ishiwada N.
        • Sato Y.
        • et al.
        A practical approach estimating etiologic agents using real-time PCR in pediatric inpatients with community-acquired pneumonia.
        J Infect Chemother. 2012; 18: 832-840https://doi.org/10.1007/s10156-012-0422-7
        • Sawada S.
        • Okutani F.
        • Kobayashi T.
        Comprehensive detection of respiratory bacterial and viral pathogens in the middle ear fluid and nasopharynx of pediatric patients with acute otitis media.
        Pediatr Infect Dis J. 2019; 38: 1199-1203
        • Miyama S.
        • Goto T.
        Afebrile seizures associated with respiratory syncytial virus infection: a situation-related seizure disorder in early infancy.
        Pediatr Int. 2011; 53: 113-115https://doi.org/10.1111/j.1442-200X.2010.03188.x
        • Kawashima H.
        • Kashiwagi Y.
        • Ioi H.
        • Morichi S.
        • Oana S.
        • Yamanaka G.
        • et al.
        Production of chemokines in respiratory syncytial virus infection with central nervous system manifestations.
        J Infect Chemother. 2012; 18: 827-831https://doi.org/10.1007/s10156-012-0418-3
        • Kawasaki Y.
        • Suyama K.
        • Go H.
        • Hosoya M.
        Clinical manifestations of respiratory syncytial virus-associated encephalopathy in Fukushima, Japan.
        Pediatr Int. 2019; 61: 802-806https://doi.org/10.1111/ped.13928
        • Morichi S.
        • Kawashima H.
        • Ioi H.
        • Yamanaka G.
        • Kashiwagi Y.
        • Hoshika A.
        • et al.
        Classification of acute encephalopathy in respiratory syncytial virus infection.
        J Infect Chemother. 2011; 17: 776-781https://doi.org/10.1007/s10156-011-0259-5
        • Morichi S.
        • Morishita N.
        • Ishida Y.
        • Oana S.
        • Yamanaka G.
        • Kashiwagi Y.
        • et al.
        Examination of neurological prognostic markers in patients with respiratory syncytial virus-associated encephalopathy.
        Int J Neurosci. 2017; 127: 44-50https://doi.org/10.3109/00207454.2016.1138951
        • Tanaka K.
        • Kurita K.
        • Hoshino E.
        • Ukiami M.
        • Kikuoka N.
        • Umehara H.
        • et al.
        A retrospective cohort study regarding RS virus infections and asthma development.
        Shonika Rinsho. 2016; 69 ([Japanese]): 1685-1691
        • Matsuda S.
        • Kato M.
        • Koike T.
        • Kama Y.
        • Suzuki K.
        • Enseki M.
        • et al.
        Differences in virus detection and cytokine profiles between first wheeze and childhood asthma.
        Tokai J Exp Clin Med. 2020; 45: 10-17
        • Takeuchi S.
        • Kawada J.I.
        • Okuno Y.
        • Horiba K.
        • Suzuki T.
        • Torii Y.
        • et al.
        Identification of potential pathogenic viruses in patients with acute myocarditis using next-generation sequencing.
        J Med Virol. 2018; 90: 1814-1821https://doi.org/10.1002/jmv.25263
        • Ito H.
        • Otabe O.
        • Kubota J.
        • Oomae T.
        • Osamura T.
        Survey of patients with severe respiratory syncytial virus in Kyoto prefecture.
        J. Jpn. Soc. Emerg. Pediatr. 2012; 11 ([Japanese]): 354-358
        • Watabe S.
        • Korematsu S.
        • Mori T.
        • Uematsu S.
        • Funamoto H.
        • Hoshino R.
        Surveillance of severe RSV infection: relationship with underlying diseases and medical care.
        J. Japan Pediat. Soc. 2020; 124 ([Japanese]): 927-936
        • Yamaguchi M.
        • Sano Y.
        • Dapat I.C.
        • Saito R.
        • Suzuki Y.
        • Kumaki A.
        • et al.
        High frequency of repeated infections due to emerging genotypes of human respiratory syncytial viruses among children during eight successive epidemic seasons in Japan.
        J Clin Microbiol. 2011; 49: 1034-1040
        • Yui I.
        • Fujino M.
        • Sawada A.
        • Nakayama T.
        Novel clinical features of recurrent human respiratory syncytial virus infections.
        J Med Virol. 2014; 86: 1629-1638https://doi.org/10.1002/jmv.23809
        • 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: 1223-1229https://doi.org/10.1111/ped.14410
        • Kimura T.
        • Takeuchi M.
        • Kawakami K.
        Utilization and efficacy of palivizumab for children with Down syndrome.
        Pediatr Int. 2020; 62: 677-682https://doi.org/10.1111/ped.14157
        • Mori M.
        • Onodera M.
        • Morimoto A.
        • Kosaka Y.
        • Morio T.
        • Notario G.F.
        • et al.
        Palivizumab use in Japanese infants and children with immunocompromised conditions.
        Pediatr Infect Dis J. 2014; 33: 1183-1185
        • Kashiwagi T.
        • Okada Y.
        • Nomoto K.
        Palivizumab prophylaxis against respiratory syncytial virus infection in children with immunocompromised conditions or Down syndrome: a multicenter, post-marketing surveillance in Japan.
        Paediatr. Drug. 2018; 20: 97-104https://doi.org/10.1007/s40272-017-0264-y
        • Yoshihara S.
        • Kusuda S.
        • Mochizuki H.
        • Okada K.
        • Nishima S.
        • Simões E.A.F.
        • et al.
        Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants.
        Pediatrics. 2013; 132: 811-818https://doi.org/10.1542/peds.2013-0982
        • Mochizuki H.
        • Kusuda S.
        • Okada K.
        • Yoshihara S.
        • Furuya H.
        • Simões E.A.F.
        • et al.
        Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study.
        Am J Respir Crit Care Med. 2017; 196: 29-38https://doi.org/10.1164/rccm.201609-1812OC
        • Okamoto K.
        • Morio T.
        • Nakamura Y.
        • Hataya H.
        • Mizuta K.
        • Mori M.
        Hospitalisations due to respiratory syncytial virus infection in children with Down syndrome before and after palivizumab recommendation in Japan.
        Acta Paediatr. 2021; 110: 1299-1306https://doi.org/10.1111/apa.15641
        • Takeuchi M.
        • Kawakami K.
        Universal palivizumab prophylaxis for children with Down syndrome in Japan: analysis with interrupted time-series.
        Hum Vaccin. Immunother. 2021; 17: 1235-1238https://doi.org/10.1080/21645515.2020.1809265
        • Hayakawa I.
        • Nomura O.
        • Uda K.
        • Funakoshi Y.
        • Sakakibara H.
        • Horikoshi Y.
        Incidence and aetiology of serious viral infections in young febrile infants.
        J Paediatr Child Health. 2020; 56: 586-589https://doi.org/10.1111/jpc.14692
        • Feng L.
        • Li Z.
        • Zhao S.
        • Nair H.
        • Lai S.
        • Xu W.
        • et al.
        Viral etiologies of hospitalized acute lower respiratory infection patients in China, 2009-2013.
        PLoS One. 2014; 9e99419
        • Kohns Vasconcelos M.
        • Loens K.
        • Sigfrid L.
        • Iosifidis E.
        • Epalza C.
        • Donà D.
        • et al.
        Aetiology of acute respiratory infection in preschool children requiring hospitalisation in Europe-results from the PED-MERMAIDS multicentre case-control study.
        BMJ Open Respir. Res. 2021; 8e000887
      3. Trends by prefecture.
        https://rsvinfo.net/news
        Date: 2021
        Date accessed: February 22, 2021
        • Piedimonte G.
        • Perez M.K.
        Respiratory syncytial virus infection and bronchiolitis.
        Pediatr Rev. 2014; 35: 519-530https://doi.org/10.1542/pir.35-12-519
        • Nakagomi T.
        • Nakagomi O.
        • Tsutsumi H.
        • Kato K.
        Cost-effectiveness of rotavirus vaccination using direct non-medical costs and opportunity costs estimated from the internet survey data.
        Rinsho to Uirusu. 2013; 41 ([Japanese]): 239-250
        • Luna M.S.
        • Manzoni P.
        • Paes B.
        • Baraldi E.
        • Cossey V.
        • Kugelman A.
        • et al.
        Expert consensus on palivizumab use for respiratory syncytial virus in developed countries.
        Paediatr Respir Rev. 2020; 33: 35-44https://doi.org/10.1016/j.prrv.2018.12.001
      4. Consensus guideline for the use of palivizumab in Japan.
        ([Japanese])
        • Yamagishi H.
        • Oyama K.
        • Miura M.
        • Ono H.
        • Yokoyama U.
        • Kusuda S.
        • et al.
        Consensus guidelines for the use of palivizumab in infants and young children with congenital heart disease (JSPCCS 2019).
        J. Ped. Cardiol. Card. Surg. 2020; 4: 45-52https://doi.org/10.24509/jpccs.0401G1
        • Rainisch G.
        • Adhikari B.
        • Meltzer M.I.
        • Langley G.
        Estimating the impact of multiple immunization products on medically-attended respiratory syncytial virus (RSV) infections in infants.
        Vaccine. 2020; 38: 251-257https://doi.org/10.1016/j.vaccine.2019.10.023
        • Drysdale S.B.
        • Barr R.S.
        • Rollier C.S.
        • Green C.A.
        • Pollard A.J.
        • Sande C.J.
        Priorities for developing respiratory syncytial virus vaccines in different target populations.
        Sci Transl Med. 2020; 12eaax2466
        • Edwards K.M.
        Maternal immunisation in pregnancy to protect newborn infants.
        Arch Dis Child. 2019; 104: 316-319https://doi.org/10.1136/archdischild-2017-313530
        • Giles M.L.
        • Krishnaswamy S.
        • Wallace E.M.
        Maternal immunisation: what have been the gains? Where are the gaps? What does the future hold?.
        F1000Res. 2018; 7 (Faculty Rev-1733): F1000https://doi.org/10.12688/f1000research.15475.1
        • Madhi S.A.
        • Polack F.P.
        • Piedra P.A.
        • Munoz F.M.
        • Trenholme A.A.
        • Simões E.A.F.
        • et al.
        Respiratory syncytial virus vaccination during pregnancy and effects in infants.
        N Engl J Med. 2020; 383: 426-439
        • Muňoz F.M.
        • Swamy G.K.
        • Hickman S.P.
        • Agrawal S.
        • Piedra P.A.
        • Glenn G.M.
        • et al.
        Safety and immunogenicity of a respiratory syncytial virus fusion (F) protein nanoparticle vaccine in healthy third-trimester pregnant women and their infants.
        J Infect Dis. 2019; 220: 1802-1815https://doi.org/10.1093/infdis/jiz390
        • Yildiz M.
        • Kara M.
        • Sutcu M.
        • Mese S.
        • Demircili M.E.
        • Sivrikoz T.S.
        • et al.
        Evaluation of respiratory syncytial virus IgG antibody dynamics in mother-infant pairs cohort.
        Eur J Clin Microbiol Infect Dis. 2020; 39: 1279-1286https://doi.org/10.1007/s10096-020-03841-8
        • Baral R.
        • Li X.
        • Willem L.
        • Antillon M.
        • Vilajeliu A.
        • Jit M.
        • et al.
        The impact of maternal RSV vaccine to protect infants in Gavi-supported countries: estimates from two models.
        Vaccine. 2020; 38: 5139-5147https://doi.org/10.1016/j.vaccine.2020.06.036
        • Pouwels K.B.
        • Bozdemir S.E.
        • Yegenoglu S.
        • Celebi S.
        • McIntosh E.D.
        • Unal S.
        • et al.
        Potential cost-effectiveness of RSV vaccination of infants and pregnant women in Turkey: an illustration based on bursa data.
        PLoS One. 2016; 11e0163567https://doi.org/10.1371/journal.pone.0163567
        • Li X.
        • Willem L.
        • Antillon M.
        • Bilcke J.
        • Jit M.
        • Beutels P.
        Health and economic burden of respiratory syncytial virus (RSV) disease and the cost-effectiveness of potential interventions against RSV among children under 5 years in 72 Gavi-eligible countries.
        BMC Med. 2020; 18: 82https://doi.org/10.1186/s12916-020-01537-6
        • Wilcox C.R.
        • Calvert A.
        • Metz J.
        • Kilich E.
        • MacLeod R.
        • Beadon K.
        • et al.
        Attitudes of pregnant women and healthcare professionals toward clinical trials and routine implementation of antenatal vaccination against respiratory syncytial virus: a multicenter questionnaire study.
        Pediatr Infect Dis J. 2019; 38: 944-951
        • Giles M.L.
        • Buttery J.
        • Davey M.A.
        • Wallace E.
        Pregnant women's knowledge and attitude to maternal vaccination including group B streptococcus and respiratory syncytial virus vaccines.
        Vaccine. 2019; 37: 6743-6749https://doi.org/10.1016/j.vaccine.2019.08.084
        • Bracht M.
        • Bacchini F.
        • Paes B.
        A survey of parental knowledge of respiratory syncytial virus and other respiratory infections in preterm infants.
        Neonatal. Netw. 2021; 40: 14-24
        • Kitano T.
        • Onishi T.
        • Takeyama M.
        • Shima M.
        Questionnaire survey on maternal pertussis vaccination for pregnant women and mothers in Nara prefecture, Japan.
        Hum Vaccin. Immunother. 2020; 16: 335-339https://doi.org/10.1080/21645515.2019.1651000
        • Yamada T.
        • Abe K.
        • Baba Y.
        • Inubashiri E.
        • Kawabata K.
        • Kubo T.
        • et al.
        Vaccination during the 2013-2014 influenza season in pregnant Japanese women.
        Eur J Clin Microbiol Infect Dis. 2015; 34: 543-548https://doi.org/10.1007/s10096-014-2259-8