Chapter 26 - Japanese encephalitis virus infection

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Abstract

Japanese encephalitis is the most important epidemic encephalitis in the world, responsible for a higher burden of disability than any other arthropod-borne virus. Twenty-four countries, home to over 2.5 billion people, within Asia and the Western Pacific rim are endemic for Japanese encephalitis. In these countries the burden of disease is mostly on children. The adult population is typically immune following childhood exposure. Although only a minority of people exposed to the virus develop disease, Japanese encephalitis is estimated to be responsible for nearly 70 000 cases and 20 000 deaths annually. Patients develop a febrile illness followed by headache, vomiting, impaired consciousness, and often seizures. A wide range of neurologic abnormalities are observed. Typically 20–30% of patients die, and 30–50% of survivors have severe neuropsychiatric sequelae. There are no proven effective therapies and treatment is supportive; however, Japanese encephalitis can be prevented by vaccination.

Introduction

Japanese encephalitis (JE) is numerically one of the most important causes of viral encephalitis worldwide, with an estimated 67 900 cases and 20 400 deaths annually (Campbell et al., 2011). Twenty-four countries are reported to be endemic for JE virus (JEV) within Asia and the Western Pacific rim, with outbreaks also reported outside these regions, such as in Northern Australia (Campbell et al., 2011). Although, only a minority of those infected with the virus develop JE, the impact of the disease is devastating. Typically 20–30% of patients with JE die, and 30–50% of survivors have severe and often persistent neurologic, cognitive, and/or behavioral problems (Solomon et al., 2002).

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Historic perspective

Epidemics of encephalitis were described in Japan from the 1870 s onwards. The term type B encephalitis was used originally to distinguish these summer epidemics from von Economo's encephalitis lethargica (sleeping sickness, and then known as type A encephalitis), but the “B” has since been dropped. In 1933 a filterable agent was transmitted from the brain of a fatal case of JE to cause encephalitis in monkeys; the prototype Nakayama strain of JEV was isolated from the brain of a fatal case in

Epidemiology

Molecular virologic studies have traced flaviviruses back to a common viral ancestor that evolved some 10 000–20 000 years ago (Gould et al., 1997). Although flaviviruses are genetically closely related, they are found in geographically different parts of the globe. JEV is transmitted by Culex mosquitoes. Being transmitted by mosquitoes, it is thus an arthropod-borne virus, or arbovirus; arthropods means insects or ticks. Examples of other mosquito-borne neurotropic flaviviruses include Murray

Virology

Akin to all flaviviruses, JEV has a small (50 nm) lipoprotein envelope surrounding a nucleocapsid comprising core protein and positive-sense single-stranded RNA This RNA strand is 11 kb in length in JEV (McMinn, 1997). The virion's outer surface is comprised of a lipid membrane, derived from the host cell, in which are embedded the viral envelope (E) and pre-membrane (prM) proteins. During viral release from the cell, prM is cleaved to its mature membrane (M) protein form which yields the mature,

Clinical features

Only about 1 in 25 to 1 in 1000 humans infected with JEV develop clinical features of infection (Halstead and Grosz, 1962, Huang, 1982, Vaughn and Hoke, 1992). These may range from a mild flu-like illness to a fatal meningoencephalomyelitis.

Outcome

The global burden of disability secondary to JE is estimated at 709 000 disability-adjusted life years (DALY). In comparison, malaria has an estimated global burden of 46 000 000 DALY (Mathers et al., 2007, Campbell et al., 2011). This makes JE responsible for a higher burden of disability than any other arthropod-borne virus. About 30% of patients admitted to hospital with JE die, and around half of the survivors have severe neurologic sequelae. About 30% of survivors have frank motor

Investigations

A neutrophil predominance is frequently seen in peripheral blood, and hyponatremia may occasionally occur as a consequence of inappropriate antidiuretic hormone secretion. The CSF opening pressure is increased in about 50% of patients. High pressures (> 25 cm CSF) are associated with a poor outcome. Typically there is a moderate CSF pleocytosis – median 53 (range 10–100) cells/mm3, with predominant lymphocytes, mildly increased protein – median 62 (range 13–168) mg/dL, and a normal glucose ratio.

Diagnosis

There is no routine laboratory parameter that is specific for JE diagnosis. A definitive diagnosis is made by finding anti-JEV-specific immunoglobulin M (IgM) in the CSF of a patient in the context of acute encephalitis syndrome (Burke et al., 1985b). JEV is rarely isolated from clinical specimens. By the time encephalitis has developed, the viraemia is typically over (Sapkal et al., 2007). Virus is occasionally grown from CSF; such cases are more likely to be fatal (Burke et al., 1985a, Leake

Pathogenesis

The pathogenesis of JE remains incompletely understood. Aspects of viral replication, CNS invasion, and the nature of the immune response are still being uncovered. Viral factors such as route of entry, titer, and genetic variation within the virus no doubt play an important role, but host factors such as pre-existing immunity, general health, age, and variations in the host immune responses are also likely to be critical determinants of clinical outcome.

Treatment

Treatment for JE is supportive. Supportive measures can have a significant impact on outcome (Solomon et al., 2000, Tiroumourougane et al., 2003, Rayamajhi et al., 2011). Appropriate fluid provision and management of shock are important, with patients who are unconscious at risk of dehydration. However, fluid should be given carefully, with aspiration pneumonia a potentially fatal complication in patients who are unconscious or suffering dysphagia. Complications such as raised intracranial

Vaccines

Vaccines against JE have been available for immunization for many decades. The earliest JE vaccines used formalin inactivated JEV propagated in mouse brain or via cell culture. A live attenuated vaccine based on the SA14-14-2 strain of JEV became available in the 1980s. More recently, a formalin inactivated vaccine based on the SA14-14-2 strain was been developed. The World Health Organization (WHO) provides recommendations on production and quality control of vaccines to guide national

Future directions

Since outbreaks of encephalitis were described in Japan nearly 150 years ago, JE has become a major cause of illness and death across Asia. Unlike smallpox and polio, for which humans are the only host and elimination by vaccination is feasible, the enzootic nature of JEV means that there is no possibility of global eradication. The area endemic for JEV has grown steadily since its first recognition; the effects of global climate change make it unlikely that this spread will halt any time soon.

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