Medical Perspectives | Infectious Diseases

September 29, 2020



Dr. Michael Miranda, M.D.

Japanese encephalitis (JE) is one of the most common vaccine-preventable causes of viral encephalitis in human beings and is existent worldwide, mainly in South-east Asia. It is caused by JE virus (JEV), a mosquito-borne flavivirus and belongs to the family Flaviviridae.

The JEV is transmitted to vertebrates through mosquitoes which were first suspected in 1930s. The virus was isolated from Culex tritaeniorynchus in 1938, which is the main vector of JE in Southern Asia, Eastern Asia, and Southeastern Asia. The natural cycle of JE virus involves water birds and Culex mosquitoes while pigs are considered to be the most important amplifying host, providing a link to humans through their proximity to housing.JE is primarily a disease of children however all age groups are affected.

There are 5 genotypes of JEV (1 to 5) which are differentiated based on structure of E protein sequences. In the Philippines genotype 3 (G3) is most common. JEV in the Philippines was first documented in 1943 when JEV was found in Philippine Horses. Since then, JEV has been considered as a cause of viral encephalitis in humans in the Philippines and the country is thought to be endemic for the disease.

Although JE is reportable to the World Health Organization (WHO) by its Member States, reporting is highly variable and incomplete.The epidemiology of JE in the Philippines is not well defined. As part of the Philippine Integrated Disease Surveillance and Response, surveillance for acute encephalitis syndrome (AES), as a proxy for JE, was established in 2008. The surveillance consisted of listings of AES, or suspected JE cases without laboratory confirmation. A more detailed surveillance with laboratory confirmation for JE was done in 2012 in four hospitals: Northern Mindanao Medical Center, PhilippineChildren’s Medical Center, San Lazaro Hospital and Western Visayas Medical Center. In 2013 a fifth hospital, Bicol Medical Center was added. The above hospitals were chosen based on criterias such as ; geographical location that could represent the major regions of the country, capability to routinely perform lumbar puncture and ability to transport the specimens to the appointed national laboratory for testing.

Based on the review done by Lopez et al, JEV is an important cause of encephalitis and febrile illness in all the three major island groups of the country namely Luzon, Visayas and Mindanao. Existing epidimioogical data from the Philippines indicate that JE is endemic with a year round transmission with peak season from July to September. The majority of the cases were seen in children younger than 15 years old since adults are considered immune to the disease. Males were more often affected than females. A recent study  by the Department of Health, epidemiology Bureau recorded a decrease of 61% confirmed JE cases from January 1- August 12, 2017 compared to the same period in 2016 (85 cases vs. 218 cases) respectively.

The incubation period of JEV ranges from 6-16 days after the bite of mosquito. Infection is mostly asymptomatic, and 1 in 300 cases present with symptoms like fever, muscle pain, headache, vomiting. The initial symptoms of children usually startwith gastrointestinal symptoms: nausea, vomiting, and abdominal pain. Serious symptoms include confusion, paralysis, abnormal posturing, seizures and coma. Most of patients present with generalized convulsions followed by  a reduced level of consciousness. In older patients, abnormal behaviour may be the only presenting feature, hence a common misdiagnosis of mental illness.

The course of disease undergoes four stages namely; prodromal stage, acute stage, late stage and sequelae stage. The prodromal stage is characterized by asudden onset of high fever with headache, malaise, anorexia, nausea, and vomiting. Acute stage includes altered mental statuswhich could range from mild clouding to stupors, semi-coma, or coma, generalized seizures with neck stiffness and weakness of extremities.

Fatal cases could progress quickly and result to instant death while uncomplicated cases usually improve and progress into the late stage which is characterized by defervescence accompanied with improved neurologic sequelae. Complete recovery ensues for mild cases once they enter the sequelae phase however severe cases would result to permanent neurologic deficits.

Fatality rate of JE is 20-30% which could be accounted to acute cerebral edema or severe respiratory distress resulting from pulmonary edema. Among the survivors, 30-50% develop permanent behavioral and neurological sequelae which could range from altered sensorium, extrapyramidal syndrome, epileptic seizures, and severe mental retardation in children. Approximately 1% of human JEV infections result in JE. JE has a fatality rate of 30% to 50% and 30% to 60% of the survivors suffer from long term neurological manifestations such asconvulsions, tremors, paralysis and ataxia.

Diagnosis of JE Patients with JE present with symptoms of acute encephalitic syndrome which are also shared by other Flaviviruses hence, laboratory confirmation is essential for the accurate diagnosis of JE. Diagnosis can be difficult because of the very low viremia and fastelimination of transient viremia by neutralizing antibodies. In 2009 the Philippines DOH designated the Research Institute for Tropical Medicine (RITM) as the national JE laboratory. Specimens from suspected cases will be referred to RITM for testing. The specimens were assayed for JE-specific IgM.

There is no treatment for JE, and only supportive care is provided to patient therefore prevention of JE is considered as an important intervention in JE. There are two strategies in order to prevent the transmission of virus namely: vector control and immunization in endemic areas.

Vector control can be done by thermal fogging and regular use of bed nets in endemic areas. Effective measures could also be done to prevent larval development such as water management and proper irrigation practices. However controlling density of rural areas could be difficult, hence vector control alone cannot prevent JE .

To control JE there should be an implementation of large scale vaccination in endemic areas like the Philippines. There are four broad classes of vaccines that are currently in use namely: Inactivated mouse-brain derived, live attenuated vaccine, live recombinant vaccine and inactivated Vero cell-derived vaccine. The only vaccine available and approved by FDA in the Philippines is the Japanese encephalitis live attenuated recombinant, chimeric vaccine (JE-CV).

The vaccine is recommended in the following schedule and dose: Children 9 months up to  17 years old, as a single primary dose the followed by a booster dose at 12-24 months after the primary dose. For immunocompetent adults, as single primary dose with no booster dose needed.

In a randomized controlled phase 3 immunogenicity study, seroconversion after  a single JE-CV vaccination was 99.1% and induced a rapid immune response with 93.6%  of the participants developing protective neutralizing antibodies to JEV as early as 14 days post-vaccination, underlining the potent immunogenicity of this live attenuated flaviviral vaccine.

In a randomized, double-blind, five year phase II study in healthy adults, live attenuated JE-CV provides 84% of sero-protection 5 years after injection with just a single dose.In a modelling data analysis, one dose of the JE-CV confers to most adults a high level of protection for at least 7 years.

The vaccine is safe with an acceptable safety profile and tolerability.The most common adverse reactions of the JE-CV were injection site reaction (12.4%), fatigue (22.8%), headache (26%), myalgia (16.6%), respiratory and gastrointestinal. JE-CV is recommended for individuals aged 9 months and older, to be given subcutaneously as a single dose. The vaccine is recommended for travellers going to endemic areas with JE such as Bangladesh, Bhutan, Brunei, Burma, Cambodia, China, India, Indonesia, Japan, Korea, Laos, Malaysia, Nepal, Papua New Guniea, Singapore, Taiwan, Thailand, Timor Leste, Vietnam.For those who wish to be protected, vaccine can be given at any time if without any contraindications.

 

REFERENCES:

Lopez AL, Aldaba, JG, Roque VG Jr., Tandoc AO III, Sy, AK, Espino F, et. Al. (2015) Epidemiology of Japanese Encephalitis in the Philippines: A systematic Review. PLoSNegl Trop Dis 9(3):e0003630.doi;10.371/journal   

Malhotra S, Sharma S, Kumar P, Hans C (2015) Japanese Encephalitis and its Epidemiology. J her 3: 243 doi: 10.4172/2332-0877.1000243

Philippine Society for Microbiology and Infectious Disease

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