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Influenza-associated Encephalitis/Encephalopathy Identified by the Australian Childhood Encephalitis Study 2013–2015

Britton, Philip N. FRACP*†‡; Dale, Russell C. PhD*‡; Blyth, Christopher C. PhD§¶‖; Macartney, Kristine MD*‡**; Crawford, Nigel W. PhD††‡‡; Marshall, Helen MD§§; Clark, Julia E. PhD¶¶; Elliott, Elizabeth J. MD***‖‖; Webster, Richard I. MD; Cheng, Allen C. PhD***†††; Booy, Robert PhD*†‡**; Jones, Cheryl A. PhD*†‡on behalf of the ACE study investigators and PAEDS network

The Pediatric Infectious Disease Journal: November 2017 - Volume 36 - Issue 11 - p 1021–1026
doi: 10.1097/INF.0000000000001650
Original Studies

Background: Influenza-associated encephalitis/encephalopathy (IAE) is an important cause of acute encephalitis syndrome in children. IAE includes a series of clinicoradiologic syndromes or acute encephalopathy syndromes that have been infrequently reported outside East Asia. We aimed to describe cases of IAE identified by the Australian Childhood Encephalitis study.

Methods: Children ≤ 14 years of age with suspected encephalitis were prospectively identified in 5 hospitals in Australia. Demographic, clinical, laboratory, imaging, and outcome at discharge data were reviewed by an expert panel and cases were categorized by using predetermined case definitions. We extracted cases associated with laboratory identification of influenza virus for this analysis; among these cases, specific IAE syndromes were identified where clinical and radiologic features were consistent with descriptions in the published literature.

Results: We identified 13 cases of IAE during 3 southern hemisphere influenza seasons at 5 tertiary children’s hospitals in Australia; 8 children with specific acute encephalopathy syndromes including: acute necrotizing encephalopathy, acute encephalopathy with biphasic seizures and late diffusion restriction, mild encephalopathy with reversible splenial lesion, and hemiconvulsion-hemiplegia syndrome. Use of influenza-specific antiviral therapy and prior influenza vaccination were infrequent. In contrast, death or significant neurologic morbidity occurred in 7 of the 13 children (54%).

Conclusions: The conditions comprising IAE are heterogeneous with varied clinical features, magnetic resonance imaging changes, and outcomes. Overall, outcome of IAE is poor emphasizing the need for optimized prevention, early recognition, and empiric management.

From the *Sydney Medical School, University of Sydney, NSW, Australia; Marie Bashir Institute of Infectious Diseases and Biosecurity Institute, University of Sydney, NSW, Australia; The Children’s Hospital at Westmead, NSW, Australia; §Department of Infectious Diseases, Princess Margaret Hospital, Subiaco, Western Australia, Australia; School of Medicine, University of Western Australia, Australia; Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Australia; **National Centre for Immunisation Research and Surveillance, NSW, Australia; ††Royal Children’s Hospital, Melbourne, Victoria, Australia; ‡‡Murdoch Children’s Research Institute and University of Melbourne, Victoria, Australia; §§Women’s and Children’s Hospital, Robinson Research Institute and School of Medicine, University of Adelaide, Adelaide, South Australia, Australia; ¶¶Infection Management and Prevention service, Lady Cilento Children’s Hospital, Queensland, Australia; ‖‖Australian Paediatric Surveillance Unit, NSW, Australia; ***School of Public Health and Preventive Medicine, Monash University, Victoria, Australia; and †††Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Victoria, Australia.

Accepted for publication March 17, 2017.

Helen Marshall has been an investigator on clinical trials of investigational vaccines sponsored by industry and has received grants for investigator-led research from GSK, Novartis, Pfizer, and Seqiris. Robert Booy works with several manufacturers of influenza vaccines in an advisory capacity, as a researcher on vaccines and as a presenter of academic information at conferences, and also occasionally as an advisory board member. He receives support to travel and attend conferences and meetings from, among others, BioCSL/Seqiris, GSK, Sanofi, Novartis, and Medimmune/Astra Zeneca. On occasions that he also receives an honorarium; it is paid directly to his institution. Any funding received is directed to a research account at The Children’s Hospital at Westmead and is not personally accepted. All other authors report no potential conflicts.

Address for correspondence: Philip N. Britton, FRACP, Discipline of Child and Adolescent Health, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia 2145. E-mail:

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