{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:42:39Z","timestamp":1792424559487,"version":"4.5.0"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T00:00:00Z","timestamp":1574985600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T00:00:00Z","timestamp":1574985600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Infect Dis"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Influenza is the most frequent cause of acute upper respiratory tract infections during winter season. Although rare, neurological manifestations are known to occur during influenza infection and approximatively three-quarters of cases are in children. In this study, we aimed to characterize the burden and clinical spectrum of influenza-associated encephalopathy and encephalitis in children admitted at a tertiary pediatric hospital in Italy over two influenza seasons (2017\u20132019).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed clinical, laboratory, instrumental data and outcome of patients discharged with ICD9-CM 487.0 code.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fifteen children (13.1% of those discharged with a diagnosis of influenza infection in the study period), had influenza-associated central nervous system (CNS) manifestations. Eight patients (53.3%) were diagnosed as influenza encephalitis, 7 (46.7%) as influenza encephalopathy. Median age was 27\u2009months. In children under 2\u2009years of age (40% of all cases) altered consciousness was the most frequent neurological manifestation while respiratory symptoms were present at admission in all cases. Younger children also required intensive care support more frequently. Five subjects (33.3%) presented comorbidity. None of the patients had received seasonal influenza vaccination. The median time from onset of respiratory signs to onset of neurological manifestations was 24\u2009h. Cerebrospinal fluid (CSF) analysis was normal in most patients and polymerase chain reaction for influenza virus RNA on CSF, when performed, was negative in all samples. Neuroradiological investigations, performed in 5 children, reported cortical and subcortical white matter signal alterations. Oseltamivir was administered only in 2 cases. Fourteen patients recovered without sequelae, and only a 2-year-old girl had minimal impairment in fine motor skills at discharge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>All children presenting acute neurological features during influenza season should be evaluated for influenza-associated CNS complications even if the respiratory involvement is mild. Absence of underlying diseases or other risk factors are not protective factors against CNS influenza-associated complications. The lack of CSF pleocytosis does not exclude CNS involvement. Children under 2\u2009years of age are at higher risk of requiring intensive care support.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12879-019-4636-5","type":"journal-article","created":{"date-parts":[[2019,11,29]],"date-time":"2019-11-29T11:02:48Z","timestamp":1575025368000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Characteristics and outcome of influenza-associated encephalopathy\/encephalitis among children in a tertiary pediatric hospital in Italy, 2017\u20132019"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9784-3543","authenticated-orcid":false,"given":"Maria Vincenza","family":"Mastrolia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rubino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Resti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Trapani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Galli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,29]]},"reference":[{"key":"4636_CR1","first-page":"305","volume":"23","author":"GF Wang","year":"2010","unstructured":"Wang GF. Li W, Li K. Acute encephalopathy and encephalitis caused by influenza virus infection: Curr Opin Neurol. 2010;23:305\u201311.","journal-title":"Acute encephalopathy and encephalitis caused by influenza virus infection: Curr Opin Neurol"},{"key":"4636_CR2","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1097\/INF.0000000000001650","volume":"36","author":"PN Britton","year":"2017","unstructured":"Britton PN, Dale RC, Blyth CC, Macartney K, Crawford NW, Marshall H, et al. Influenza-associated Encephalitis\/Encephalopathy Identified by the Australian Childhood Encephalitis Study 2013\u20132015. Pediatr Infect Dis J. 2017;36:1021\u20136.","journal-title":"Pediatr Infect Dis J"},{"key":"4636_CR3","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.jns.2015.04.051","volume":"354","author":"N Ishii","year":"2015","unstructured":"Ishii N, Mochizuki H, Moriguchi-Goto S, Shintaku M, Asada Y, Taniguchi A, et al. An autopsy case of elderly-onset acute necrotizing encephalopathy secondary to influenza. J Neurol Sci. 2015;354:129\u201330.","journal-title":"J Neurol Sci"},{"key":"4636_CR4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/j.1600-0404.2007.00809.x","volume":"115","author":"M Mizuguchi","year":"2007","unstructured":"Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M. Acute encephalopathy associated with influenza and other viral infections. Acta Neurol Scand. 2007;115:45\u201356.","journal-title":"Acta Neurol Scand"},{"key":"4636_CR5","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1093\/pch\/pxy085","volume":"24","author":"A Albaker","year":"2019","unstructured":"Albaker A, Soder C, Top KA. Acute encephalopathy associated with influenza infection: case report and review of the literature. Paediatr Child Health. 2019;24:122\u20134.","journal-title":"Paediatr Child Health"},{"key":"4636_CR6","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s00381-017-3554-3","volume":"34","author":"MS Paksu","year":"2018","unstructured":"Paksu MS, Aslan K, Kendirli T, Akyildiz BN, Yener N, Yildizdas RD, et al. Neuroinfluenza: evaluation of seasonal influenza associated severe neurological complications in children (a multicenter study). Childs Nerv Syst. 2018;34:335\u201347.","journal-title":"Childs Nerv Syst"},{"key":"4636_CR7","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1093\/cid\/cit922","volume":"58","author":"A Goenka","year":"2014","unstructured":"Goenka A, Michael BD, Ledger E, Hart IJ, Absoud M, Chow G, et al. Neurological manifestations of influenza infection in children and adults: results of a National British Surveillance Study. Clin Infect Dis. 2014;58:775\u201384.","journal-title":"Clin Infect Dis"},{"key":"4636_CR8","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1093\/cid\/cix412","volume":"65","author":"PN Britton","year":"2017","unstructured":"Britton PN, Blyth CC, Macartney K, Dale RC, Li-Kim-Moy J, Khandaker G, et al. The Spectrum and burden of influenza-associated neurological disease in children: combined encephalitis and influenza sentinel site surveillance from Australia, 2013-2015. Clin Infect Dis Off Publ Infect Dis Soc Am. 2017;65:653\u201360.","journal-title":"Clin Infect Dis Off Publ Infect Dis Soc Am"},{"key":"4636_CR9","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/S0140-6736(98)12449-2","volume":"352","author":"S Fujimoto","year":"1998","unstructured":"Fujimoto S, Kobayashi M, Uemura O, Iwasa M, Ando T, Katoh T, et al. PCR on cerebrospinal fluid to show influenza-associated acute encephalopathy or encephalitis. Lancet Lond Engl. 1998;352:873\u20135.","journal-title":"Lancet Lond Engl"},{"key":"4636_CR10","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1093\/cid\/cix1126","volume":"66","author":"H Okuno","year":"2018","unstructured":"Okuno H, Yahata Y, Tanaka-Taya K, Arai S, Satoh H, Morino S, et al. Characteristics and outcomes of influenza-associated encephalopathy cases among children and adults in Japan, 2010\u20132015. Clin Infect Dis. 2018;66:1831\u20137.","journal-title":"Clin Infect Dis"},{"key":"4636_CR11","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.ejpn.2018.09.009","volume":"23","author":"E Macdonald-Laurs","year":"2019","unstructured":"Macdonald-Laurs E, Koirala A, Britton PN, Rawlinson W, Hiew CC, Mcrae J, et al. CSF neopterin, a useful biomarker in children presenting with influenza associated encephalopathy? Eur J Paediatr Neurol. 2019;23:204\u201313.","journal-title":"Eur J Paediatr Neurol"},{"key":"4636_CR12","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1097\/INF.0b013e318162a13b","volume":"27","author":"T Nagao","year":"2008","unstructured":"Nagao T, Morishima T, Kimura H, Yokota S, Yamashita N, Ichiyama T, et al. Prognostic Factors in Influenza-associated Encephalopathy. Pediatr Infect Dis J. 2008;27:384\u20139.","journal-title":"Pediatr Infect Dis J"},{"key":"4636_CR13","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.braindev.2006.12.005","volume":"29","author":"Y Fukumoto","year":"2007","unstructured":"Fukumoto Y, Okumura A, Hayakawa F, Suzuki M, Kato T, Watanabe K, et al. Serum levels of cytokines and EEG findings in children with influenza associated with mild neurological complications. Brain Dev. 2007;29:425\u201330.","journal-title":"Brain Dev"},{"key":"4636_CR14","volume-title":"Donnerstag F, et al","author":"M Dadak","year":"2019","unstructured":"Dadak M, Pul R, Lanfermann H, Hartmann H, Hehr U. Donnerstag F, et al. Clin Neuroradiol: Varying Patterns of CNS Imaging in Influenza A Encephalopathy in Childhood; 2019."},{"key":"4636_CR15","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1055\/s-0042-111686","volume":"228","author":"A Welk","year":"2016","unstructured":"Welk A, Schmeh I, Knuf M, Groendahl B, Goebel J, Staatz G, et al. Acute encephalopathy in children associated with influenza a: a retrospective case series. Klin P\u00e4diatr. 2016;228:280\u20131.","journal-title":"Klin P\u00e4diatr"},{"key":"4636_CR16","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/j.1348-0421.2008.00100.x","volume":"53","author":"T Wada","year":"2009","unstructured":"Wada T, Morishima T, Okumura A, Tashiro M, Hosoya M, Shiomi M, et al. Differences in clinical manifestations of influenza-associated encephalopathy by age. Microbiol Immunol. 2009;53:83\u20138.","journal-title":"Microbiol Immunol"},{"key":"4636_CR17","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1016\/S0140-6736(11)61051-9","volume":"378","author":"H Nair","year":"2011","unstructured":"Nair H, Brooks WA, Katz M, Roca A, Berkley JA, Madhi SA, et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet Lond Engl. 2011;378:1917\u201330.","journal-title":"Lancet Lond Engl"},{"key":"4636_CR18","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1177\/2051013613519217","volume":"2","author":"F Havers","year":"2014","unstructured":"Havers F, Fry A, Peacock G, Finelli L. Influenza vaccination and treatment in children with neurologic disorders. Ther Adv Vaccines. 2014;2:95\u2013105.","journal-title":"Ther Adv Vaccines"},{"key":"4636_CR19","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/j.braindev.2018.05.019","volume":"40","author":"L-W Chen","year":"2018","unstructured":"Chen L-W, Teng C-K, Tsai Y-S, Wang J-N, Tu Y-F, Shen C-F, et al. Influenza-associated neurological complications during 2014-2017 in Taiwan. Brain Dev. 2018;40:799\u2013806.","journal-title":"Brain Dev"},{"key":"4636_CR20","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1111\/j.1442-200X.2003.01813.x","volume":"45","author":"S Ono","year":"2003","unstructured":"Ono S, Kudo M, Aoki K, Ezaki F, Misumi J. Effect of mass immunization against influenza encephalopathy on mortality rates in children. Pediatr Int Off J Jpn Pediatr Soc. 2003;45:680\u20137.","journal-title":"Pediatr Int Off J Jpn Pediatr Soc"},{"key":"4636_CR21","first-page":"bcr2014206930","volume":"2014","author":"P McSwiney","year":"2014","unstructured":"McSwiney P, Purnama J, Kornberg A, Danchin M. A severe neurological complication of influenza in a previously well child. Case Rep. 2014;2014:bcr2014206930.","journal-title":"Case Rep"},{"key":"4636_CR22","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.pediatrneurol.2014.04.026","volume":"51","author":"AN Wilking","year":"2014","unstructured":"Wilking AN, Elliott E, Garcia MN, Murray KO, Munoz FM. Central nervous system manifestations in pediatric patients with influenza a H1N1 infection during the 2009 pandemic. Pediatr Neurol. 2014;51:370\u20136.","journal-title":"Pediatr Neurol"},{"key":"4636_CR23","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1086\/341407","volume":"35","author":"T Morishima","year":"2002","unstructured":"Morishima T, Togashi T, Yokota S, Okuno Y, Miyazaki C, Tashiro M, et al. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis Off Publ Infect Dis Soc Am. 2002;35:512\u20137.","journal-title":"Clin Infect Dis Off Publ Infect Dis Soc Am"},{"key":"4636_CR24","unstructured":"InfluNet-Vir: Italian virological surveillance of Influenza, season 2017\u201318, https:\/\/www.epicentro.iss.it\/influenza\/FluNews17-18#vir n.d."},{"key":"4636_CR25","unstructured":"InfluNet-Vir: Italian virological surveillance of Influenza, season 2018\u201319, https:\/\/www.epicentro.iss.it\/influenza\/FluNews#vir n.d."},{"key":"4636_CR26","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1136\/adc.2005.092890","volume":"91","author":"R Surtees","year":"2006","unstructured":"Surtees R, DeSousa C. Influenza virus associated encephalopathy. Arch Dis Child. 2006;91:455\u20136.","journal-title":"Arch Dis Child"},{"key":"4636_CR27","doi-asserted-by":"publisher","first-page":"NP49","DOI":"10.1177\/0883073813499610","volume":"29","author":"S Shah","year":"2014","unstructured":"Shah S, Keil A, Gara K, Nagarajan L. Neurologic complications of influenza. J Child Neurol. 2014;29:NP49\u201353.","journal-title":"J Child Neurol"},{"key":"4636_CR28","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1007\/s12028-010-9436-0","volume":"13","author":"PT Akins","year":"2010","unstructured":"Akins PT, Belko J, Uyeki TM, Axelrod Y, Lee KK, Silverthorn J. H1N1 encephalitis with malignant edema and review of neurologic complications from influenza. Neurocrit Care. 2010;13:396\u2013406.","journal-title":"Neurocrit Care"},{"key":"4636_CR29","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s00401-002-0605-x","volume":"105","author":"Y Nakai","year":"2003","unstructured":"Nakai Y, Itoh M, Mizuguchi M, Ozawa H, Okazaki E, Kobayashi Y, et al. Apoptosis and microglial activation in influenza encephalopathy. Acta Neuropathol (Berl). 2003;105:233\u20139.","journal-title":"Acta Neuropathol (Berl)"},{"key":"4636_CR30","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1046\/j.1442-200x.2000.01203.x","volume":"42","author":"M Takahashi","year":"2000","unstructured":"Takahashi M, Yamada T, Nakashita Y, Saikusa H, Deguchi M, Kida H, et al. Influenza virus-induced encephalopathy: clinicopathologic study of an autopsied case. Pediatr Int Off J Jpn Pediatr Soc. 2000;42:204\u201314.","journal-title":"Pediatr Int Off J Jpn Pediatr Soc"},{"key":"4636_CR31","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.jiac.2016.10.007","volume":"23","author":"S Morichi","year":"2017","unstructured":"Morichi S, Morishita N, Takeshita M, Ishida Y, Oana S, Yamanaka G, et al. Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) levels in the cerebrospinal fluid of children with influenza-associated encephalopathy. J Infect Chemother. 2017;23:80\u20134.","journal-title":"J Infect Chemother"},{"key":"4636_CR32","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.jns.2015.01.017","volume":"349","author":"G Sun","year":"2015","unstructured":"Sun G, Ota C, Kitaoka S, Chiba Y, Takayanagi M, Kitamura T, et al. Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy. J Neurol Sci. 2015;349:190\u20135.","journal-title":"J Neurol Sci"},{"key":"4636_CR33","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1086\/589747","volume":"47","author":"AR Tunkel","year":"2008","unstructured":"Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis Off Publ Infect Dis Soc Am. 2008;47:303\u201327.","journal-title":"Clin Infect Dis Off Publ Infect Dis Soc Am"}],"container-title":["BMC Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12879-019-4636-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12879-019-4636-5\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12879-019-4636-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T19:09:29Z","timestamp":1606504169000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcinfectdis.biomedcentral.com\/articles\/10.1186\/s12879-019-4636-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,29]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["4636"],"URL":"https:\/\/doi.org\/10.1186\/s12879-019-4636-5","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.2.14416\/v3","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.14416\/v4","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.14416\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.14416\/v2","asserted-by":"object"}]},"ISSN":["1471-2334"],"issn-type":[{"value":"1471-2334","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,29]]},"assertion":[{"value":"9 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The project has been approved by the Ethics Committee of the university hospital \u201cAzienda Ospedaliero-Universitaria Meyer\u201d of Florence on March 2017 (Hospital Institution Review board Cod 87). Data were obtained from an electronic database using ICD-9-CM. A specific informed consent was not considered necessary because this was a descriptive epidemiological study performed on administrative data, which are routinely collected from any hospitalized patient after obtaining his\/her consent. Furthermore, no human experimentation was foreseen by the study and patient information was anonymized and de-identified prior to analysis.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1012"}}