Jean David Pommier, MD, Chris Gorman, PhD, Yoann Crabol, MD, Kevin Bleakley, PhD, Heng Sothy, MD, Ky Santy, MD, Huong Thi Thu Tran, MD, Lam Van Nguyen, MD, Em Bunnakea, MD, Chaw Su Hlaing, MD, Aye Mya Min Aye, MD, Julien Cappelle, DVM, Magali Herrant, PhD, Patrice Piola, MD, Bruno Rosset, Veronique Chevalier, DVM, Arnaud Tarantola, MD, Mey Channa, MD, Jerome Honnorat, MD, Anne Laure Pinto, MSc, Sayaphet Rattanavong, MD, Manivanh Vongsouvath, MD, Mayfong Mayxay, MD, Sommanikhone Phangmanixay, MD, Khounthavy Phongsavath, MD, Ommar Swe Tin, MD, Latt Latt Kyaw, MD, Htay Htay Tin, MD, Kyaw Linn, MD, Thi Mai Hung Tran, MPH, Philippe Pérot, PhD, Nguyen Thi Thu Thuy, PhD, Nguyen Hien, MD, Phuc Huu Phan, MD, Philippe Buchy, MD, Philippe Dussart, PharmD, Denis Laurent, PharmD, Marc Eloit, DVM, Audrey Dubot-Pérès, PhD, Olivier Lortholary, MD, Xavier de Lamballerie, MD, Paul N Newton, FRCP, Marc Lecuit, Prof, Philippe Buchy, Em Bunnakea, Julien Cappelle, Mey Channa, Veronique Chevalier, Yoann Crabol, Xavier de Lamballerie, Audrey Dubot-Pérès, Philippe Dussart, Marc Eloit, Chris Gorman, Magali Herrant, Nguyen Hien, Chaw Su Hlaing, Jérôme Honnorat, Tran Thi Mai Hung, Tran Thi Thu Huong, Latt Latt Kyaw, Nguyen Van Lam, Denis Laurent, Marc Lecuit, Kyaw Linn, Olivier Lortholary, Mayfong Mayxay, Aye Mya Min Aye, Paul Newton, Philippe Perot, Sommanikhone Phangmanixay, Khounthavy Phongsavath, Phan Huu Phuc, Anne-Laurie Pinto, Patrice Piola, Jean-David Pommier, Sayaphet Rattanavong, Ky Santy, Heng Sothy, Arnaud Tarantola, Nguyen Thi Thu Thuy, Htay Htay Tin, Ommar Swe Tin, Manivanh Vongsouvath, Pham Nhat An, Dang Duc Anh, Pascal Bonnet, Kimrong Bun, Danoy Chommanam, Viengmon Davong, Patrice Debré, Jean-François Delfraissy, Christian Devaux, Anousone Douangnouvong, Veasna Duong, Benoit Durand, Chanreaksmey Eng, Catherine Ferrant, Didier Fontenille, Lukas Hafner, Le Thanh Hai, Do Thu Huong, Marc Jouan, May July, Magali Lago, Jean-Paul Moatti, Bernadette Murgue, Khin Yi Oo, MengHeng Oum, Khansoudaphone Phakhounthong, Anh Tuan Pham, Do Quyen, Malee Seephonelee, Maud Seguy, Bountoy Sibounheunang, Kanarith Sim, Luong Minh Tan, Cho Thair, Win Thein, Phung Bich Thuy, Hervé Tissot-Dupont, and Malavanh Vongsouvath
Summary: Background: Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients’ conditions. Methods: In this multicentre, observational, prospective study of childhood encephalitis, four referral hospitals in Cambodia, Vietnam, Laos, and Myanmar recruited children (aged 28 days to 16 years) who presented with altered mental status lasting more than 24 h and two of the following minor criteria: fever (within the 72 h before or after presentation), one or more generalised or partial seizures (excluding febrile seizures), a new-onset focal neurological deficit, cerebrospinal fluid (CSF) white blood cell count of 5 per mL or higher, or brain imaging (CT or MRI) suggestive of lesions of encephalitis. Comprehensive diagnostic procedures were harmonised across all centres, with first-line testing was done on samples taken at inclusion and results delivered within 24 h of inclusion for main treatable causes of disease and second-line testing was done thereafter for mostly non-treatable causes. An independent expert medical panel reviewed the charts and attribution of causes of all the included children. Using multivariate analyses, we assessed risk factors associated with unfavourable outcomes (ie, severe neurological sequelae and death) at discharge using data from baseline and day 2 after inclusion. This study is registered with ClinicalTrials.gov, NCT04089436, and is now complete. Findings: Between July 28, 2014, and Dec 31, 2017, 664 children with encephalitis were enrolled. Median age was 4·3 years (1·8–8·8), 295 (44%) children were female, and 369 (56%) were male. A confirmed or probable cause of encephalitis was identified in 425 (64%) patients: 216 (33%) of 664 cases were due to Japanese encephalitis virus, 27 (4%) were due to dengue virus, 26 (4%) were due to influenza virus, 24 (4%) were due to herpes simplex virus 1, 18 (3%) were due to Mycobacterium tuberculosis, 17 (3%) were due to Streptococcus pneumoniae, 17 (3%) were due to enterovirus A71, 74 (9%) were due to other pathogens, and six (1%) were due to autoimmune encephalitis. Diagnosis was made within 24 h of admission to hospital for 83 (13%) of 664 children. 119 (18%) children had treatable conditions and 276 (42%) had conditions that could have been preventable by vaccination. At time of discharge, 153 (23%) of 664 children had severe neurological sequelae and 83 (13%) had died. In multivariate analyses, risk factors for unfavourable outcome were diagnosis of M tuberculosis infection upon admission (odds ratio 3·23 [95% CI 1·04–10·03]), coma on day 2 (2·90 [1·78–4·72]), supplementary oxygen requirement (1·89 [1·25–2·86]), and more than 1 week duration between symptom onset and admission to hospital (3·03 [1·68–5·48]). At 1 year after inclusion, of 432 children who were discharged alive from hospital with follow-up data, 24 (5%) had died, 129 (30%) had neurological sequelae, and 279 (65%) had completely recovered. Interpretation: In southeast Asia, most causes of childhood encephalitis are either preventable or treatable, with Japanese encephalitis virus being the most common cause. We provide crucial information that could guide public health policy to improve diagnostic, vaccination, and early therapeutic guidelines on childhood encephalitis in the Greater Mekong region. Funding: Institut Pasteur, Institut Pasteur International Network, Fondation Merieux, Aviesan Sud, INSERM, Wellcome Trust, Institut de Recherche pour le Développement (IRD), and Fondation Total.