title: A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal.
abstract: BACKGROUND
  Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial.
  
  
  RESULTS
  We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group.
  
  
  CONCLUSIONS
  A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01856205.
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; National Academy of Medical Sciences, Kathmandu, Nepal; Kanti Children's Hospital, Kathmandu, Nepal.
authors.forename: Ajit
authors.initials: A
authors.lastname: Rayamajhi
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Nightingale
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Nisha Keshary
authors.initials: NK
authors.lastname: Bhatta
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Rupa
authors.initials: R
authors.lastname: Singh
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom, and 8: Alder Hey Children’s National Health Service Foundation Trust, Liverpool, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kneen
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ledger
authors.affiliation: Kanti Children's Hospital, Kathmandu, Nepal.
authors.forename: Krishna Prasad
authors.initials: KP
authors.lastname: Bista
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Penny
authors.initials: P
authors.lastname: Lewthwaite
authors.affiliation: National Academy of Medical Sciences, Kathmandu, Nepal; Kanti Children's Hospital, Kathmandu, Nepal.
authors.forename: Chandeshwar
authors.initials: C
authors.lastname: Mahaseth
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Lance
authors.initials: L
authors.lastname: Turtle
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Arbovirus Diseases Branch Diagnostic & Reference Laboratory, Fort Collins, Colorado, United States of America.
authors.forename: Jaimie Sue
authors.initials: JS
authors.lastname: Robinson
authors.affiliation: Institute for Health and Wellbeing, Leeds Metropolitan University, Leeds, United Kingdom.
authors.forename: Sareen Elizabeth
authors.initials: SE
authors.lastname: Galbraith
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wnek
authors.affiliation: Centers for Disease Control and Prevention, Division of Vector-Borne Diseases, Arbovirus Diseases Branch Diagnostic & Reference Laboratory, Fort Collins, Colorado, United States of America.
authors.forename: Barbara Wilmot
authors.initials: BW
authors.lastname: Johnson
authors.affiliation: Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Faragher
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; Alder Hey Children's National Health Service Foundation Trust, Liverpool, United Kingdom.
authors.forename: Michael John
authors.initials: MJ
authors.lastname: Griffiths
authors.affiliation: Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom; The Walton Centre National Health Service Foundation Trust, Liverpool, United Kingdom; National Consortium for Zoonosis Research, Liverpool, United Kingdom; National Institute for Health Research-Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Solomon
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000627:therapeutic use; D004311:Double-Blind Method; D004664:Encephalitis Virus, Japanese / Q000276:immunology; D004672:Encephalitis, Japanese / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007223:Infant; D015847:Interleukin-4 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009390:Nepal; D015990:Placebo Effect; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D057134:Antibodies, Neutralizing; D016756:Immunoglobulins, Intravenous; D015850:Interleukin-6; D015847:Interleukin-4; D003907:Dexamethasone