(Article) CSM - February 2013: Japanese Encephalitis in India
Japanese encephalitis (JE)- epidemics have been reported in many parts of the country. The incidence has been reported to be high among pediatric group with high mortality. The incidence of JE in recent times is showing an increasing trend. It appears that JE may become one of the major public health problems in India, considering the quantum of the vulnerable pediatric population, the proportion of JEV infections among the encephalitic children and wide scattering of JE-prone areas. JE burden can be estimated satisfactorily to some extend by strengthening diagnostic facilities for JE confirmation in hospitals and by maintenance of contact with the nearby referral hospitals to collect the particulars on JE cases. Vaccination proves to be the best to protect the individual against any disease. In the case of JE, it is essential to immunize the pigs (amplifying host) also to interrupt the transmission of the disease.
Japanese encephalitis—previously known as Japanese B encephalitis to distinguish it from von Economo’s A encephalitis— is a disease caused by the mosquito- borne Japanese encephalitis virus. The Japanese encephalitis virus is a virus from the family Flaviviridae. Domestic pigs and wild birds (herons) are reservoirs of the virus; transmission to humans may cause severe symptoms. Amongst the most important vectors of this disease are the mosquitoes Culex tritaeniorhynchus and Culex vishnui. This disease is most prevalent in Southeast Asia and the Far East.
What is Japanese Encephalitis (JE)?
JE is the mosquito-borne virus which mainly affects the CNS or Central Nervous System. It can be transmitted to human beings if infected mosquito bites. Mosquitoes in turn are affected when they feed on domestic pigs that carry this virus. JE usually affects children who are below 15 years of age. Around 25 percent affected children usually die and among those who survive, 30-40 percent suffers from mental and physical impairment. In 2011, it was reported that JE had occurred in 135 districts in 17 states of India. Japanese encephalitis has an incubation period of 5 to 15 days and the vast majority of infections are asymptomatic: only 1 in 250 infections develop into encephalitis. Severe rigors mark the onset of this disease in humans. Fever, headache and malaise are other nonspecific symptoms of this disease which may last for a period of between 1 and 6 days. Signs which develop during the acute encephalitic stage include neck rigidity, cachexia, hemiparesis, convulsions and a raised body temperature between 38 and 41 degrees Celsius. Mental retardation developed from this disease usually leads to coma. Mortality of this disease varies but is generally much higher in children. Transpla- cental spread has been noted. Lifelong neurological defects such as deafness, emotional lability and hemiparesis may occur in those who have had central nervous system involvement. In known cases some effects also include nausea, headache, fever, vomiting and sometimes swelling of the testicles.
Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, with 30,000–50,000 cases reported annually. Case-fatality rates range from 0.3% to 60% and depends on the population and on age. Rare outbreaks in U.S. territories in Western Pacific have occurred. Residents of rural areas in endemic locations are at highest risk; Japanese encephalitis does not usually occur in urban areas. Countries which have had major epidemics in the past, but which have controlled the disease primarily by vaccination, include China, Korea, Japan, Taiwan and Thailand. Other countries that still have periodic epidemics include Vietnam, Cambodia, Myanmar, India, Nepal, and Malaysia. Japanese encephalitis has been reported on the Torres Strait Islands and two fatal cases were reported in mainland northern Australia in 1998. The spread of the virus in Australia is of particular concern to Australian health officials due to the unplanned introduction of Culex gelidus, a potential vector of the virus, from Asia. However, the current presence on mainland Australia is minimal.
Human, cattle and horses are dead-end hosts and disease manifests as fatal encephalitis. Swine acts as amplifying host and has very important role in epidemiology of the disease. Infection in swine is asymptomatic, except in pregnant sows, when abortion and fetal abnormalities are common sequelae. The most important vector is Culex tritaeniorhynchus, which feeds on cattle in preference to humans, it has been proposed that moving swine away from human habitation can divert the mosquito away from humans and swine. The natural host of the Japanese encephalitis virus is bird, not human, and many believe the virus will therefore never be completely eliminated. In November 2011, Japanese encephalitis virus was reported in Culex bitaeniorhynchus in the Republic of Korea.
Increased microglial activation following JEV infection has been found to influence the outcome of viral pathogenesis. Microglia are the resident immune cells of the central nervous system (CNS) and have a critical role in host defense against invading microorganisms. Activated microglia secrete cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-á), which can cause toxic effects in the brain. Additionally, other soluble factors such as neurotoxins, excitatory neurotransmitters, prostaglandin, reactive oxygen, and nitrogen species are secreted by activated microglia.
In a murine model of JE, it was found that in the hippocampus and the striatum, the number of activated microglia was more than anywhere else in the brain closely followed by that in the thalamus. In the cortex, number of activated microglia was significantly less when compared with other regions of the mouse brain. An overall induction of differential expression of pro-inflammatory cytokines and chemokines from different brain regions during a progressive JEV infection was also observed. Although the net effect of the pro-inflammatory mediators is to kill infectious organisms and infected cells as well as to stimulate the production of molecules that amplify the mounting response to damage, it is also evident that in a non-regenerating organ such as brain, a deregulated innate immune response would be deleterious. In JE the tight regulation of microglia activation appears to be disturbed, resulting in an auto toxic loop of microglia activation that possibly leads to bystander neuronal damage. In animals, key signs include infertility and abortion in pigs, neurological disease in horses and systemic signs including fever, lethargy and anorexia.
The virus appears to have originated from its ancestral virus in the mid 1500s in the Indonesia- Malaysia region and evolved there into five different genotypes and spread across Asia. The mean evolutionary rate has been estimated to be 4.35 × 10 (-4) (range: 3.4906 × 10 (-4) to 5.303 × 10 (-4)) nucleotide substitutions per site per year.
The causative agent Japanese encephalitis virus is an enveloped virus of the genus flavivirus and is closely related to the West Nile virus and St. Louis encephalitis virus. The positive sense single stranded RNA genome is packaged in the capsid which is formed by the capsid protein. The outer envelope is formed by envelope (E) protein and is the protective antigen. It aids in entry of the virus to the inside of the cell. The genome also encodes several nonstructural proteins also (NS1,NS2a,NS2b,NS3,N4a,NS4b,NS5). NS1 is produced as secretory form also. NS3 is a putative helicase, and NS5 is the viral polymerase. It has been noted that the Japanese encephalitis virus (JEV) infects the lumen of the endoplasmic reticulum (ER) and rapidly accumulates substantial amounts of viral proteins for the JEV.
Japanese Encephalitis is diagnosed by detection of antibodies in serum and CSF (cerebrospinal fluid) by IgM capture ELISA. Viral antigen can also be shown in tissues by indirect fluorescent antibody staining. Based on the envelope gene (E) there are five genotypes (I - V). The Muar strain, isolated from patient in Malaya in 1952, is the prototype strain of genotype V. Genotype IV appears to be the ancestral strain and the virus appears to have evolved in the Indonesian-Malayasian region. The first clinical reports date from 1870 but the virus appears to have evolved in the mid 1500s. Over 60 complete genomes of this virus have been sequenced as of 2010.
Infection with JEV confers lifelong immunity. All current vaccines are based on the genotype III virus. A formalin-inactivated mouse-brain derived vaccine was first produced in Japan in the 1930s and was validated for use in Taiwan in the 1960s and in Thailand in the 1980s. The widespread use of vaccine and urbanisation has led to control of the disease in Japan, Korea, Taiwan and Singapore. The high cost of the vaccine, which is grown in live mice, means that poorer countries have not been able to afford to give it as part of a routine immunisation programme. The most common adverse effects are redness and pain at the injection site. Uncommonly, an urticarial reaction can develop about four days after injection. Because the vaccine is produced from mouse brain, there is a risk of autoimmune neurological complications of around 1 per million vaccinations. However in the case of IXIARO where the vaccine is not produced in mouse brains but in vitro using cell culture there is little adverse effects compared to the Placebo, the main side effects are headache and myalgia. Neutralising antibody persists in the circulation for at least two to three years and perhaps longer. The total duration of protection is unknown, but because there is no firm evidence for protection beyond three years, boosters are ecommended every three years for people who remain at risk. Furthermore there is also no data available regarding the interchangeability of other JE vaccines and IXIARO and recommended those previously immunised with other JE vaccines receive Green Cross or JE-Vax or a primary course of IXIARO.
There is no specific treatment for Japanese encephalitis and treatment is supportive; with assistance given for feeding, breathing or seizure control as required. Raised intracranial pressure may be managed with mannitol. There is no transmission from person to person and therefore patients do not need to be isolated. A breakthrough in the field of Japanese encephalitis therapeutics is the identification of macrophage receptor involvement in the disease severity. A recent report of an Indian group demonstrates the involvement of monocyte and macrophage receptor CLEC5A in severe inflammatory response in JEV infection of brain. This transcriptomic study provides a hypothesis of neuroinflammation and a new lead in development of appropriate therapeutic against Japanese encephalitis.
First vaccine of the world was developed against Japanese Encephalitis (JE) using the Indian strain of virus. National Institute of Virology (NIV), Pune offered the strain of JE virus to Bharat Biotech. This JE virus was gathered from Kolar in Karnataka. Bharat Biotech had submitted results from final human trials to Drug Controller General of India (DCGI) so that it could have marketing clearance. The vaccine is an injectable one and offers protection rate of more than 90 percent. It can be used for age group of 1-15 years. The application has been sent for marketing approval to DCGI. Clinical data about the same would also be put forward to Indian Council of Medical Research (ICMR) for reviewing which would take place in January 2013. The scientific committee of ICMR would provide technical support to government in context of the effectiveness of this JE vaccine, after which decision to introduce this in public health programme would be taken.
Country Programme Leader of PATH (the organisation which plays a crucial role in conducting the vaccination of JE in India in 15 states as well as 118 districts since 2006), informed that apart from providing protection against Indian strains of JE, the vaccine would also be effective against Nakayama strain (the strain from Japan) as well as Biken strain (which circulates in the Asian countries). Currently, India imports the stock of JE vaccine from National Biotech Group of China. The arrival of this indigenous Indian vaccination will help in protection of the Indian population against the disease which is largely growing in the country.
S. K. Singh