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A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal.

Rayamajhi A, Nightingale S, Bhatta NK, Singh R, Kneen R, Ledger E, Bista KP, Lewthwaite P, Mahaseth C, Turtle L, Robinson JS, Galbraith SE, Wnek M, Johnson BW, Faragher B, Griffiths MJ, Solomon T - PLoS ONE (2015)

Bottom Line: There is no known antiviral treatment for any flavivirus.IVIG's anti-inflammatory properties may also be beneficial.IL-4 and IL-6 were higher in the IVIG group.

View Article: PubMed Central - PubMed

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.

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.

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.

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Related in: MedlinePlus

Flow diagram of study participants’ recruitment and follow-up.All children enrolled, fitting the trial criteria, who were alive at discharge were attempted to be followed-up (n = 21). Twenty-one families were successfully contacted. Among these families, two children had died.
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pone.0122608.g001: Flow diagram of study participants’ recruitment and follow-up.All children enrolled, fitting the trial criteria, who were alive at discharge were attempted to be followed-up (n = 21). Twenty-one families were successfully contacted. Among these families, two children had died.

Mentions: Between May and September 2009, 22 (96%) children of 23 screened met the entry criteria; 12 in Kanti Children’s Hospital in Kathmandu and 10 in BPKIHS in Dharan. One child was not enrolled in the trial as he was moribund and met criteria for exclusion. Eleven (50%) received IVIG and 11 (50%) placebo (Fig 1). Twenty-two patients were randomized and there were no breaches of randomization protocol. None of the children were reported to have been vaccinated against JE. Seven (64%) patients in the IVIG group and 6 (55%) in the placebo group were classified as acute JEV infections by JEV/DENV IgM ELISA testing. The initial JE diagnostic classification for all patients in Nepal was confirmed by the testing at the CDC, USA. Seven out of 10 (70%) were positive for JEV in BPKIHS and 6 of 12 (50%) in Kanti Children’s Hospital. One child (placebo group) had evidence of a previous flavivirus infection. One patient with an undetermined status after local testing was found to be JEV negative by confirmatory testing at CDC; otherwise there was complete concordance between the test results in Nepal and those at CDC. All CSF tested were negative for JEV RNA by real time RT-PCR.


A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal.

Rayamajhi A, Nightingale S, Bhatta NK, Singh R, Kneen R, Ledger E, Bista KP, Lewthwaite P, Mahaseth C, Turtle L, Robinson JS, Galbraith SE, Wnek M, Johnson BW, Faragher B, Griffiths MJ, Solomon T - PLoS ONE (2015)

Flow diagram of study participants’ recruitment and follow-up.All children enrolled, fitting the trial criteria, who were alive at discharge were attempted to be followed-up (n = 21). Twenty-one families were successfully contacted. Among these families, two children had died.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401695&req=5

pone.0122608.g001: Flow diagram of study participants’ recruitment and follow-up.All children enrolled, fitting the trial criteria, who were alive at discharge were attempted to be followed-up (n = 21). Twenty-one families were successfully contacted. Among these families, two children had died.
Mentions: Between May and September 2009, 22 (96%) children of 23 screened met the entry criteria; 12 in Kanti Children’s Hospital in Kathmandu and 10 in BPKIHS in Dharan. One child was not enrolled in the trial as he was moribund and met criteria for exclusion. Eleven (50%) received IVIG and 11 (50%) placebo (Fig 1). Twenty-two patients were randomized and there were no breaches of randomization protocol. None of the children were reported to have been vaccinated against JE. Seven (64%) patients in the IVIG group and 6 (55%) in the placebo group were classified as acute JEV infections by JEV/DENV IgM ELISA testing. The initial JE diagnostic classification for all patients in Nepal was confirmed by the testing at the CDC, USA. Seven out of 10 (70%) were positive for JEV in BPKIHS and 6 of 12 (50%) in Kanti Children’s Hospital. One child (placebo group) had evidence of a previous flavivirus infection. One patient with an undetermined status after local testing was found to be JEV negative by confirmatory testing at CDC; otherwise there was complete concordance between the test results in Nepal and those at CDC. All CSF tested were negative for JEV RNA by real time RT-PCR.

Bottom Line: There is no known antiviral treatment for any flavivirus.IVIG's anti-inflammatory properties may also be beneficial.IL-4 and IL-6 were higher in the IVIG group.

View Article: PubMed Central - PubMed

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.

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.

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.

Show MeSH
Related in: MedlinePlus