{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:39:22Z","timestamp":1790419162944,"version":"4.1.0"},"reference-count":27,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T00:00:00Z","timestamp":1618012800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Grant-in-Aid for Emerging and Reemerging Infectious Diseases from the Ministry of Health, Labor and Welfare, Japan","award":["10110400"],"award-info":[{"award-number":["10110400"]}]},{"name":"JSPS KAKENHI","award":["18K10036"],"award-info":[{"award-number":["18K10036"]}]},{"name":"JSPS KAKENHI","award":["20K08210"],"award-info":[{"award-number":["20K08210"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>We aimed to detect influenza variants with reduced susceptibility to baloxavir marboxil (baloxavir) and oseltamivir and identify differences in the clinical course between children with and without these variants after antiviral treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>During the 2019\u20132020 influenza season, we enrolled children with confirmed influenza A (20 treated with baloxavir and 16 with oseltamivir). We analyzed patients\u2019 sequential viral RNA loads and infectious virus titers, the drug susceptibilities of clinical isolates, and amino acid substitutions in the viral polymerase acidic protein subunits or neuraminidase. We assessed patients\u2019 clinical information using questionnaires.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>All viral RNA loads and virus titers were significantly decreased after treatment, but we detected baloxavir-resistant and oseltamivir-resistant variants in 5 of 20 and 3 of 16 patients, respectively. The duration of fever was similar between patients with and without the variants, but infectious viral shedding lasted 3 days longer in patients with baloxavir-resistant variants. In addition, the duration to improvement of clinical symptoms was longer in these patients (75.0 vs 29.5 hours; P = .106).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>After antiviral treatment, the emergence of baloxavir-resistant variants may affect the patients\u2019 clinical course, but oseltamivir-resistant variants had no clinical impact.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiab196","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T11:08:39Z","timestamp":1617707319000},"source":"Crossref","is-referenced-by-count":10,"title":["Detection of Variants With Reduced Baloxavir Marboxil and Oseltamivir Susceptibility in Children With Influenza A During the 2019\u20132020 Influenza Season"],"prefix":"10.1093","author":[{"given":"Masatoki","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Fukushima Medical University, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emi","family":"Takashita","sequence":"additional","affiliation":[{"name":"Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Katayose","sequence":"additional","affiliation":[{"name":"Nanohana Kids Clinic, Soma, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Nemoto","sequence":"additional","affiliation":[{"name":"Nemoto Kids Clinic, Shirakawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuko","family":"Sakai","sequence":"additional","affiliation":[{"name":"Jin Kids Clinic, Koriyama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichiro","family":"Fujisaki","sequence":"additional","affiliation":[{"name":"Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fukushima Medical University, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuaki","family":"Hosoya","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Fukushima Medical University, Fukushima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,10]]},"reference":[{"key":"2021070809093936400_CIT0001","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1056\/NEJM200001273420401","article-title":"The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children","volume":"342","author":"Neuzil","year":"2000","journal-title":"N Engl J Med"},{"key":"2021070809093936400_CIT0002","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1016\/j.vaccine.2010.12.049","article-title":"The effectiveness of trivalent inactivated influenza vaccine in children over six consecutive influenza seasons","volume":"29","author":"Katayose","year":"2011","journal-title":"Vaccine"},{"key":"2021070809093936400_CIT0003","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1016\/j.vaccine.2019.05.090","article-title":"Effectiveness of inactivated influenza vaccine in children by vaccine dose, 2013-18","volume":"37","author":"Shinjoh","year":"2019","journal-title":"Vaccine"},{"key":"2021070809093936400_CIT0004","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/irv.12534","article-title":"Five years of monitoring for the emergence of oseltamivir resistance in patients with influenza A infections in the Influenza Resistance Information Study","volume":"12","author":"Lina","year":"2018","journal-title":"Influenza Other Respir Viruses"},{"key":"2021070809093936400_CIT0005","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.1128\/AAC.01755-09","article-title":"Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection","volume":"54","author":"Sugaya","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"key":"2021070809093936400_CIT0006","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1111\/ped.12658","article-title":"Clinical findings in 10 children with H275Y influenza A(H1N1)pdm09 virus infection","volume":"57","author":"Kakuya","year":"2015","journal-title":"Pediatr Int"},{"key":"2021070809093936400_CIT0007","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.antiviral.2018.10.008","article-title":"In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit","volume":"160","author":"Noshi","year":"2018","journal-title":"Antiviral Res"},{"key":"2021070809093936400_CIT0008","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1056\/NEJMoa1716197","article-title":"Baloxavir marboxil for uncomplicated influenza in adults and adolescents","volume":"379","author":"Hayden","year":"2018","journal-title":"N Engl J Med"},{"key":"2021070809093936400_CIT0009","first-page":"346","article-title":"Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza","volume":"221","author":"Uehara","year":"2020","journal-title":"J Infect Dis"},{"key":"2021070809093936400_CIT0010","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1093\/cid\/ciz908","article-title":"Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes","volume":"71","author":"Hirotsu","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2021070809093936400_CIT0011","doi-asserted-by":"crossref","first-page":"1800698","DOI":"10.2807\/1560-7917.ES.2019.24.3.1800698","article-title":"Detection of influenza A(H3N2) viruses exhibiting reduced susceptibility to the novel cap-dependent endonuclease inhibitor baloxavir in Japan, December 2018","volume":"24","author":"Takashita","year":"2019","journal-title":"Euro Surveill"},{"key":"2021070809093936400_CIT0012","doi-asserted-by":"crossref","first-page":"1900170","DOI":"10.2807\/1560-7917.ES.2019.24.12.1900170","article-title":"Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019","volume":"24","author":"Takashita","year":"2019","journal-title":"Euro Surveill"},{"key":"2021070809093936400_CIT0013","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/infdis\/jiaa061","article-title":"Detection of variants with reduced baloxavir marboxil susceptibility after treatment of children with influenza A during the 2018\u20132019 influenza season","volume":"222","author":"Sato","year":"2020","journal-title":"J Infect Dis"},{"key":"2021070809093936400_CIT0014","doi-asserted-by":"crossref","first-page":"104951","DOI":"10.1016\/j.antiviral.2020.104951","article-title":"Duration of fever and symptoms in children after treatment with baloxavir marboxil and oseltamivir during the 2018\u20132019 season and detection of variant influenza A viruses with polymerase acidic subunit substitutions","volume":"183","author":"Saito","year":"2020","journal-title":"Antiviral Res"},{"key":"2021070809093936400_CIT0015","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S1386-6532(03)00122-7","article-title":"Design and performance testing of quantitative real time PCR assays for influenza A and B viral load measurement","volume":"29","author":"Ward","year":"2004","journal-title":"J Clin Virol"},{"key":"2021070809093936400_CIT0016","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1128\/JCM.00785-10","article-title":"Analytical performance determination and clinical validation of the novel Roche RealTime Ready Influenza A\/H1N1 Detection Set","volume":"48","author":"Wenzel","year":"2010","journal-title":"J Clin Microbiol"},{"key":"2021070809093936400_CIT0017","author":"National Institute of Infectious Diseases"},{"key":"2021070809093936400_CIT0018","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1038\/s41564-019-0433-6","article-title":"A humanized MDCK cell line for the efficient isolation and propagation of human influenza viruses","volume":"4","author":"Takada","year":"2019","journal-title":"Nat Microbiol"},{"key":"2021070809093936400_CIT0019","doi-asserted-by":"crossref","first-page":"3026","DOI":"10.3389\/fmicb.2018.03026","article-title":"Susceptibility of influenza viruses to the novel cap-dependent endonuclease inhibitor baloxavir marboxil","volume":"9","author":"Takashita","year":"2018","journal-title":"Front Microbiol"},{"key":"2021070809093936400_CIT0020","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.antiviral.2015.02.003","article-title":"Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2013\u20132014","volume":"117","author":"Takashita","year":"2015","journal-title":"Antiviral Res"},{"key":"2021070809093936400_CIT0021","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.antiviral.2018.07.001","article-title":"Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals 2016\u20132017","volume":"157","author":"Lackenby","year":"2018","journal-title":"Antiviral Res"},{"key":"2021070809093936400_CIT0022","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.3201\/eid2511.190757","article-title":"Human-to-human transmission of influenza A(H3N2) virus with reduced susceptibility to baloxavir, Japan, February 2019","volume":"25","author":"Takashita","year":"2019","journal-title":"Emerg Infect Dis"},{"key":"2021070809093936400_CIT0023","doi-asserted-by":"crossref","first-page":"8593","DOI":"10.1073\/pnas.1916825117","article-title":"Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility","volume":"117","author":"Jones","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2021070809093936400_CIT0024","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1097\/INF.0000000000002748","article-title":"Baloxavir marboxil 2% granules in Japanese children with influenza: an open-label phase 3 study","volume":"39","author":"Yokoyama","year":"2020","journal-title":"Pediatr Infect Dis J"},{"key":"2021070809093936400_CIT0025","article-title":"Influenza polymerase inhibitors: mechanisms of action and resistance [manuscript published online ahead of print 2 March 2020]","author":"Takashita","year":"2020","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2021070809093936400_CIT0026","doi-asserted-by":"crossref","first-page":"104718","DOI":"10.1016\/j.antiviral.2020.104718","article-title":"Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017\u20132018","volume":"175","author":"Takashita","year":"2020","journal-title":"Antiviral Res"},{"key":"2021070809093936400_CIT0027","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1056\/NEJMoa1915341","article-title":"Baloxavir marboxil for prophylaxis against influenza in household contacts","volume":"383","author":"Ikematsu","year":"2020","journal-title":"N Engl J Med"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiab196\/38530432\/jiab196.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiab196\/38530432\/jiab196.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T18:03:57Z","timestamp":1625767437000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/advance-article\/doi\/10.1093\/infdis\/jiab196\/6219607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,10]]},"references-count":27,"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiab196","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,10]]},"article-number":"jiab196"}}