Elsevier

The Lancet

Volume 361, Issue 9360, 8 March 2003, Pages 821-826
The Lancet

Articles
Interferon alfa-2a in Japanese encephalitis: a randomised double-blind placebo-controlled trial

https://doi.org/10.1016/S0140-6736(03)12709-2Get rights and content

Summary

Background

Japanese encephalitis virus (JEV), although confined to Asia, causes about 35 000–50 000 cases and 10 000 deaths every year, and is the most important cause of encephalitis worldwide. There is no known antiviral treatment for any flavivirus. Results from in-vitro studies and work in animals have shown inteferon alfa has antiviral activity on Japanese encephalitis and other flaviviruses; therefore, we aimed to assess the efficacy of inteferon alfa-2a in Japanese encephalitis.

Methods

We did a randomised double-blind placebo-controlled trial of interferon alfa-2a (10 million units/m2, daily for 7 days) in 112 Vietnamese children with suspected Japanese encephalitis, 87 of whom had serologically confirmed infections. Our primary endpoints were hospital death or severe sequelae at discharge. Analysis was by intention to treat.

Findings

Overall, 21 children (19%) died, and 17 (15%) had severe sequelae. Outcome at discharge and 3 months did not differ between the two treatment groups; 20 children in the interferon group had a poor outcome (death or severe sequelae), compared with 18 in the placebo group (p=0·85, difference 0·1%, 95% CI −17·5 to 17·6%), there were no long-term side effects of interferon.

Interpretation

The doses of interferon alfa-2a given in this regimen did not improve the outcome of patients with Japanese encephalitis.

Published online February 11,2003 http://image.thelancet.com/extras/02art9329web.pdf

Introduction

Encephalitis caused by arthropod-borne viruses (arboviruses) is recognised as an increasingly important problem.1 For example during 2002, West Nile virus, a member of the genus Flavivirus family Flaviviridae, caused its largest ever encephalitis outbreak with more than 3800 cases and 225 deaths, in North America.2 However the most important member of this serogroup wordwide is the closely related flavivirus, Japanese encephalitis virus (JEV) which causes about 35 000–50 000 cases and 10 000 deaths per year.3 JEV is a small single-stranded positive-sense RNA virus transmitted between birds, pigs, and other vertebrate hosts by mosquitoes, mainly Culex tritaeniorhynchus. JEV occurs in southeast Asia, China, the pacific rim, and Asian subcontinent, but its geographical range is expanding, with recent outbreaks in Nepal and northern Australia.4 In rural Asian countries most people are infected during childhood, but few infections in human beings result in symptoms. If disease does occur, patients usually present with severe meningoencephalitis, which is often associated with seizures.5 A smaller proportion present with aseptic meningitis, or a poliomyelitis-like acute flaccid paralysis.6 Roughly 30% of patients with Japanese encephalitis die, and half of survivors have severe neurological sequelae, which imposes a large socioeconomic burden in the poor rural settings where Japanese encephalitis occurs.

In addition to JEV and West Nile virus, other flaviviruses that cause encephalitis include: St Louis encephalitis virus, which is endemic in the Americas; Murray Valley encephalitis virus, present in Australasia; and tick-borne encephalitis virus that occurs across Europe and the former Soviet Union.7 There is no known effective antiviral treatment for these or any of the other diseases caused by flaviviruses, such as dengue and yellow fever. Indeed, until now, none has been assessed in a controlled trial. For many years, corticosteroids have been used for Japanese encephalitis, but a randomised placebo-controlled trial of dexamethasone in 40 patients showed no benefit of this treatment.8

Interferon alfa is a glycoprotein cytokine that is produced naturally in response to viral infections, including Japanese encaphalitis.9 Interferons are not directly antiviral, but induce production of effector proteins in cells, which inhibit various stages of viral replication, assembly, or release.10 Recombinant interferon alfa has become the standard treatment for chronic hepatitis B and C. In tissue culture, recombinant interferon is effective against JEV and other arboviruses, including West Nile virus.11, 12 This treatment has been given to 14 Thai patients with Japanese encephalitis, and although there has been a suggestion of benefit,13, 14 there have been no randomised double-blind trials of interferon alfa in any viral encephalitis. We aimed to assess the efficacy of interferon alfa-2a for Japanese encaphalitis.

Section snippets

Patients

Patients were recruited from the paediatric intensive-care unit at the Centre for Tropical Diseases, an infectious diseases referral centre for southern Vietnam in Ho Chi Minh city. The study protocol was approved by the hospital's scientific and ethical committee, and informed consent was obtained from the accompanying relative.

Between October, 1996 and October, 1999, we recruited children aged between 1 and 15 years who had clinically diagnosed viral encephalitis. On the basis of results from

Results

Between Oct 1, 1996, and Oct 15, 1999, 117 patients met the entry criteria. 61 (52%) were randomly allocated to receive interferon and 56 (48%) to receive placebo (figure 1). Five patients (two in the interferon group) were transferred to other hospitals when other diagnoses became apparent, and thus data from these patients could not be included in analyses. Three of these patients had tuberculous meningitis, one had a cerebral haematoma, and one had cerebral effusion revealed by CT. Thus, 59

Discussion

Our results show that intramuscular interferon alfa-2a did not improve the outcome of children with Japanese encephalitis, either at discharge or at 3 months' follow-up. Although the overall death rate (19%) was lower than that generally reported for Japanese encephalitis,4 both mortality and morbidity were similar to those expected on the basis of our previous work.5 Patients given interferon were significantly more likely to develop leucopenia and have raised transaminases, but they were no

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