Japanese encephalitis virus: changing the clinical landscape of encephalitis in Australia

The Japanese encephalitis virus (JEV) has been a long‐standing public health concern in Asia, where it is the most common cause of viral encephalitis in many countries. This mosquito‐borne flavivirus is transmitted to humans from reservoirs in pigs and waterbirds. Subsequent acute encephalitis occurs in less than 1% of people infected, but when it does, it often results in death or significant neurological disability. The effectiveness of population‐wide immunisation programs in reducing the disease burden of Japanese encephalitis is well established.1,2

A major outbreak of JEV in mainland Australia was declared a Communicable Disease Incident of National Significance in March 2022.3 Human cases were spread across New South Wales, Victoria, South Australia, Queensland and the Northern Territory, with many piggeries testing positive. This has raised concerns regarding virus persistence in mainland Australia and the potential consequences of large‐scale infection in an immunologically naïve population. JEV is known to overwinter in temperate regions and cause seasonal summer–autumn outbreaks, so there is potential that JEV might become an ongoing seasonal challenge in temperate Australia. Establishing effective diagnostic pathways and developing targeted prevention strategies are key priorities to minimise the impact of this new threat.

Not just a disease of children

In endemic regions where most people are first exposed to JEV at a young age, Japanese encephalitis is largely a disease of childhood. In the Australian context, older people are unlikely to have immunity and are thus at higher risk of symptomatic disease than children. This is in keeping with other temperate regions worldwide where year‐round transmission does not occur and population immunity is lower. Most of the 2022 Australian outbreak cases occurred in older adults.3,4,5 Up to one‐third of patients with Japanese encephalitis die of the acute illness, and a further one‐third have long term neurological disability. Excellent neurological support in intensive care may mitigate these risks through seizure control and the minimisation of raised intracranial pressure, but there is an absence of evidence for any disease‐specific treatments.6,7 Seven of the 42 patients diagnosed with confirmed or probable Japanese encephalitis during the recent Australian outbreak died, with the burden of long term adverse outcomes yet to be determined.3

Clinical and neuroimaging findings

Japanese encephalitis often presents in a similar manner to other viral encephalitides, with an initial prodrome of fever and headache being common. This is often followed by one or more of altered behaviour, altered consciousness, and seizures. More specific features include parkinsonian‐like symptoms, especially a classical mask‐like facies. Risk factors such as immunisation status, geographical location, and exposure to mosquitoes should be considered when planning investigations.

Cerebrospinal fluid (CSF) sampling and neuroimaging are standard practice in the assessment of patients with suspected encephalitis.8 Japanese encephalitis is best assessed using magnetic resonance imaging (MRI). MRI findings in Japanese encephalitis are similar to those found with other endemic flaviviruses, such as Murray Valley encephalitis virus (MVEV). The most consistent finding is the presence of bilateral thalamic T2 bright lesions. These may be present with or without haemorrhage. The lesions can also be seen in the substantia nigra, brainstem and cerebellum, cerebral cortex, and the white matter. Bilateral temporal lobe lesions, particularly in the body and tail of the hippocampi, with sparing of the anterior temporal lobes, have been reported.9 The involvement of the posterior temporal lobes distinguishes Japanese encephalitis from herpes simplex virus (HSV) infection.10

Changes in the diagnostic paradigm

Current consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand were published in 2015, before the recent JEV outbreak. Due to the long‐standing presence of the closely related viruses MVEV and Kunjin virus, this guideline recommends pan‐flavivirus serology be completed on serum as a first line investigation in Australia.8

Serology has long been the mainstay of diagnosis for Japanese encephalitis, particularly the detection of JEV IgM in serum and CSF.2,5,11 It is accepted that the detection of JEV IgM in CSF confirms JEV as the cause of encephalitis, and sensitivity is greater than 95% by day 10 of illness.2,5,12 However, a recent study in Laos demonstrated a small proportion of patients had positive CSF JEV IgM results and had an alternative pathogen detected by direct methods (ie, on polymerase chain reaction [PCR] or culture),13 highlighting the limitations of serology in this endemic setting. The presence of serum IgM has the greatest sensitivity in early illness, being greater than 75% after day 4 of illness;5,12 however, serum IgM may also be present due to recent asymptomatic infection or immunisation. Where possible, serology should be completed at presentation and repeated at day 10 of illness, as IgG seroconversion or a four‐fold increase in IgG antibody titre is also indicative of acute infection.2,5,11,12

Nucleic acid detection using reverse transcription PCR (RT‐PCR) is a highly specific diagnostic method, but sensitivity is poor on blood and CSF samples in the setting of low viral loads.2,5,14 When CSF PCR is positive, this is usually early in the course of illness.2 Prolonged shedding in urine has been described in one case study,15 and it is theorised that the prompt addition of lysis buffer to urine might prevent RNA degradation in this sample type.16 One study has demonstrated the potential for detection via PCR on throat swab17 and, given the low invasiveness of this sample method and the potential for increasing diagnostic yield before seroconversion, this may be considered. Viral culture is available in select laboratories with appropriate biosecurity ratings, but is time‐ and resource‐intensive, with limited data regarding sensitivity.

The selection of first line investigations for encephalitis should be individualised based on clinical presentation, risk factors (including travel), and MRI findings. With regard to JEV, timing of investigations is also an important consideration, as there is typically a brief period of low level viraemia in the first five to seven days of illness, and seropositivity increases after day 4 of illness, as is illustrated in the Manual for the laboratory diagnosis of Japanese encephalitis virus infection of the World Health Organization.2 Given the new increased prevalence of JEV as a cause for encephalitis, JEV IgM and IgG on CSF and serum should now be considered a first line investigation for most cases of encephalitis in Australian patients, with the possibility of adding RT‐PCR‐based investigations depending on clinical features and timing of illness. A proposed diagnostic algorithm is included in the Box.

Vaccination: current recommendations and future directions

Thus far, most human cases in Australia have been acquired in areas clustering around the Murray River and its tributaries, where a number of affected piggeries are also located. State‐based recommendations, supported by the guidelines of the Australian Technical Advisory Group on Immunisation released in March 2022, were expanded following the initial release of the NSW serosurvey results, which indicate that 9% of residents in select high risk regional areas have been exposed to JEV.4,18,19,20

There are currently two vaccines widely available in Australia, Imojev (Sanofi Pasteur) and JEspect (CSL Seqirus). Imojev is a chimeric live attenuated vaccine that has the benefit of requiring only a single dose and is thus the preferred immunisation unless contraindicated. For people requiring an alternative vaccine, such as pregnant women, immunocompromised patients, and children under nine months of age, JEspect is available as an inactivated vaccine requiring two doses administered 28 days apart.4,19,20

In response to the emerging situation, many state and territory governments have introduced free immunisation programs. The first phase focused on immunising people with high risk occupational exposures, such as farmers within piggeries, veterinarians, and some laboratory workers.4,19,21 At the time of writing, a second phase is being rolled out including residents of high risk geographical areas. Recommendations are likely to change rapidly as public health networks communicate with the health care and livestock industries to identify further areas of concern. For current recommendations, refer to state and territory guidelines.

Further challenges ahead in the approach to encephalitis diagnosis

JEV is only one challenge in a rapidly changing clinical space; although the 2015 guidelines provide a framework for the diagnostic evaluation of patients with encephalitis, they require updating to reflect a number of developments since their publication.8 The emergence of coronavirus disease 2019 (COVID‐19), with which associated encephalopathy is frequent but encephalitis rare, creates another differential diagnosis that is not included in the 2015 guidelines. Our understanding of autoimmune encephalitis, including the identification of additional autoantibodies and clinical syndromes, has also expanded greatly since 2015.

Additional advances in molecular diagnostics create cost‐effective options for multiplex testing which do not require large specimen sizes; however, interpretation can be complex. For example, the CSF BioFire meningitis/encephalitis (ME; bioMérieux) panel can assess for 14 pathogens by PCR on just 200μL (four drops) of CSF, but several issues are now recognised. The detection of the human herpesvirus 6 (HHV6) in non‐immunocompromised individuals, for example, is problematic given its potential for human chromosomal integration, which is generally inherited and asymptomatic. Further, sensitivity of the BioFire ME for some pathogens, particularly the HSV1, is likely lower than that of a dedicated PCR.22 Our ability to detect new and novel pathogens will be an area of development throughout coming years. Promising emerging diagnostic methods include metagenomic next generation sequencing23 and VirScan (CDI Laboratories) virome‐wide antibody detection.24

Acute encephalitis is an important sentinel syndrome for emerging infectious diseases, and new outbreaks are likely in the years to come. Maintaining and optimising surveillance platforms is important but challenging, as notification systems are more streamlined when monitoring for diseases than syndromes. For example, some pathogens (eg, influenza virus) typically cause an infection‐associated encephalopathy, where neither viral genetic material nor pathogen‐specific antibodies are recovered from the CSF, making population‐wide surveillance challenging. As enhanced diagnostic methods become available, they may facilitate surveillance as well as providing insight into identifying novel pathogens, understanding pathogenesis and predicting outcome. Finally, pathogen‐specific treatment for encephalitis remains limited in many cases, including JEV, and is an area requiring greater attention to improve outcomes.