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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

Anti-JEV neutralizing antibody in commercially available IVIG.Mean and standard deviation of reciprocal 50% plaque reduction neutralization titres (PRNT50) in vero cells using P3 wild type strain of JEV are shown for a: Serum control from JEV vaccinated individual, b: Vigam (USA), c: Bharat (India) batch 1, d: Hualan (China) batch 1, e: Bharat (India) batch 2, f: Hualan (China) batch 2, g: Sichuan (China), h: Reliance (India).
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pone.0122608.g002: Anti-JEV neutralizing antibody in commercially available IVIG.Mean and standard deviation of reciprocal 50% plaque reduction neutralization titres (PRNT50) in vero cells using P3 wild type strain of JEV are shown for a: Serum control from JEV vaccinated individual, b: Vigam (USA), c: Bharat (India) batch 1, d: Hualan (China) batch 1, e: Bharat (India) batch 2, f: Hualan (China) batch 2, g: Sichuan (China), h: Reliance (India).

Mentions: All IVIG preparations produced in JEV endemic regions had anti-JEV PRNT50 titres, ranging from 1:320 to 1:640 (Fig 2). Control IVIG from a non-JEV endemic area (Vigam, USA) showed minimal PRNT50 titres of 1:10; lower than serum from a JEV vaccinated individual who had a titre of 1:40. ImmunoRel IVIG produced by Reliance Biopharmaceutical (India) had the highest anti-JEV PRNT50 titre, and was chosen for treatment in this study. This ImmunoRel IVIG showed low PRNT50 titres ≤1:20 against DENV, WNV and Powassan viruses.


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)

Anti-JEV neutralizing antibody in commercially available IVIG.Mean and standard deviation of reciprocal 50% plaque reduction neutralization titres (PRNT50) in vero cells using P3 wild type strain of JEV are shown for a: Serum control from JEV vaccinated individual, b: Vigam (USA), c: Bharat (India) batch 1, d: Hualan (China) batch 1, e: Bharat (India) batch 2, f: Hualan (China) batch 2, g: Sichuan (China), h: Reliance (India).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0122608.g002: Anti-JEV neutralizing antibody in commercially available IVIG.Mean and standard deviation of reciprocal 50% plaque reduction neutralization titres (PRNT50) in vero cells using P3 wild type strain of JEV are shown for a: Serum control from JEV vaccinated individual, b: Vigam (USA), c: Bharat (India) batch 1, d: Hualan (China) batch 1, e: Bharat (India) batch 2, f: Hualan (China) batch 2, g: Sichuan (China), h: Reliance (India).
Mentions: All IVIG preparations produced in JEV endemic regions had anti-JEV PRNT50 titres, ranging from 1:320 to 1:640 (Fig 2). Control IVIG from a non-JEV endemic area (Vigam, USA) showed minimal PRNT50 titres of 1:10; lower than serum from a JEV vaccinated individual who had a titre of 1:40. ImmunoRel IVIG produced by Reliance Biopharmaceutical (India) had the highest anti-JEV PRNT50 titre, and was chosen for treatment in this study. This ImmunoRel IVIG showed low PRNT50 titres ≤1:20 against DENV, WNV and Powassan viruses.

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