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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205.

We evaluated performance of three commercial Japanese encephalitis virus (JEV) IgM antibody capture enzyme-linked immunosorbent assay (MAC ELISA) kits with a panel of serological specimens collected during a surveillance project of acute encephalitis syndrome in India and acute meningitis and encephalitis syndrome in Bangladesh. The serum and cerebral spinal fluid specimens had been referred to the Centers for Disease Control and Prevention (CDC) for confirmatory testing. The CDC results and specimen classifications were considered the reference standard. All three commercial kits had high specificity (95-99.5%), but low sensitivities, ranging from 17-57%, with both serum and cerebrospinal fluid samples. Specific factors contributing to low sensitivity compared with the CDC ELISA could not be determined through further analysis of the limits and dilution end points of IgM detection.

Infection with Japanese encephalitis virus (JEV) is a major public health problem in Asia. Detection of JEV-specific IgM in serum and cerebrospinal fluid (CSF) by the IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) is currently the most widely used diagnostic method to detect JEV infection. Because of the possible presence of IgM cross-reactivity with other flaviviruses in serum and the high ratio of inapparent-to-apparent JEV infections, a positive result in serum only suggests a recent infection and not necessarily an encephalitic illness caused by JEV. Consequently, detection of JEV-specific IgM in CSF assumes great diagnostic relevance. We evaluated two commercial JEV MAC-ELISA kits using 60 CSF samples obtained from patients with acute encephalitis syndrome. The Panbio and XCyton kits had sensitivities of 65-80% and 95% and specificities of 90% and 97.5%, respectively. Performance information on these commercial JEV MAC-ELISA kits for CSF should assist in laboratory-based JE surveillance programs.