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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

Difference in neutralizing antibody titres to JEV in children with acute encephalitis syndrome treated with IVIG or placebo.Median and inter-quartile range of the difference in JEV PRNT50 titres pre and post treatment is presented. Patients are grouped according to treatment. Difference in tires was assessed via Wilcoxon-Mann-Whitney test. Note: Two patients who received IVIG were not included in this analysis because of insufficient sample to undertake PRNT measurements.
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pone.0122608.g003: Difference in neutralizing antibody titres to JEV in children with acute encephalitis syndrome treated with IVIG or placebo.Median and inter-quartile range of the difference in JEV PRNT50 titres pre and post treatment is presented. Patients are grouped according to treatment. Difference in tires was assessed via Wilcoxon-Mann-Whitney test. Note: Two patients who received IVIG were not included in this analysis because of insufficient sample to undertake PRNT measurements.

Mentions: The difference in neutralizing antibody titres pre and post treatment were analysed by treatment group (IVIG or placebo) Neutralizing antibody titres increased significantly among participants who received IVIG compared to placebo (p = 0.038: Fig 3). Separating results by anti-JEV IgM antibody status, titres showed a greater increase among those who received IVIG compared to placebo in both anti-JEV antibody status groups. The median increase in neutralizing antibody titre was greater (16 fold) in anti-JEV IgM positive compared to negative patients (median increase in titre post treatment was 1920 versus 120 for IgM positive and negative patients respectively; S4 Table and S1 Fig). However, the increase in neutralizing antibody titres following IVIG treatment was only significant among anti-JEV IgM negative patients (p = 0.048 and p = 0.24 respectively). Patient anti-JEV IgM status prior to treatment was not a significant source of variation in change in neutralizing antibody titre as assessed by 2 way ANOVA (p = 0.29; S5 Table).


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)

Difference in neutralizing antibody titres to JEV in children with acute encephalitis syndrome treated with IVIG or placebo.Median and inter-quartile range of the difference in JEV PRNT50 titres pre and post treatment is presented. Patients are grouped according to treatment. Difference in tires was assessed via Wilcoxon-Mann-Whitney test. Note: Two patients who received IVIG were not included in this analysis because of insufficient sample to undertake PRNT measurements.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0122608.g003: Difference in neutralizing antibody titres to JEV in children with acute encephalitis syndrome treated with IVIG or placebo.Median and inter-quartile range of the difference in JEV PRNT50 titres pre and post treatment is presented. Patients are grouped according to treatment. Difference in tires was assessed via Wilcoxon-Mann-Whitney test. Note: Two patients who received IVIG were not included in this analysis because of insufficient sample to undertake PRNT measurements.
Mentions: The difference in neutralizing antibody titres pre and post treatment were analysed by treatment group (IVIG or placebo) Neutralizing antibody titres increased significantly among participants who received IVIG compared to placebo (p = 0.038: Fig 3). Separating results by anti-JEV IgM antibody status, titres showed a greater increase among those who received IVIG compared to placebo in both anti-JEV antibody status groups. The median increase in neutralizing antibody titre was greater (16 fold) in anti-JEV IgM positive compared to negative patients (median increase in titre post treatment was 1920 versus 120 for IgM positive and negative patients respectively; S4 Table and S1 Fig). However, the increase in neutralizing antibody titres following IVIG treatment was only significant among anti-JEV IgM negative patients (p = 0.048 and p = 0.24 respectively). Patient anti-JEV IgM status prior to treatment was not a significant source of variation in change in neutralizing antibody titre as assessed by 2 way ANOVA (p = 0.29; S5 Table).

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