Japanese Encephalitis and Associated Environmental Risk Factors in Eastern Uttar Pradesh: A time series analysis from 2001 to 2016.

India and other Southeast Asian countries are severely affected by Japanese encephalitis (JE), one of the deadliest vector-borne disease threat to human health. Several epidemiological observations suggest climate variables play a role in providing a favorable environment for mosquito development and virus transmission. In this study, generalized additive models were used to determine the association of JE admissions and mortality with climate variables in Gorakhpur district, India, from 2001-2016. The model predicted that every 1 unit increase in mean (Tmean;°C), and minimum (Tmin;°C) temperature, rainfall (RF; mm) and relative humidity (RH; %) would on average increase the JE admissions by 22.23 %, 17.83 %, 0.66 %, and 5.22 % respectively and JE mortality by 13.27 %, 11.77 %, 0.94 %, and 3.27 % respectively Conversely, every unit decrease in solar radiation (Srad; MJ/m2/day) and wind speed (WS; Kmph) caused an increase in JE admission by 17% and 11.42% and in JE mortality by 9.37% and 4.88% respectively suggesting a protective effect at higher levels. The seasonal analysis shows that temperature was significantly associated with JE in pre-monsoon and post-monsoon while RF, RH, Srad, and WS are associated with the monsoon. Effect modification due to age and gender showed an equal risk for both genders and increased risk for adults above 15 years of age, however, males and age groups under 15 years outnumbered females and adults. Sensitivity analysis results to explore lag effects in climate variables showed that climate variables show the strongest association at lag 1 to 1.5 months with significant lag effect up tp lag 0-60 days. The exposure-response curve for climate variables showed a more or less linear relationship, with an increase in JE admissions and mortality after a certain threshold and decrease were reported at extreme levels of exposure. The study concludes that climate variables could influence the JE vector development and multiplication and parasite maturation and transmission in the Gorakhpur region whose indirect impact was noted for JE admission and mortality. In response to the changing climate, public health interventions, public awareness, and early warning systems would play an unprecedented role to compensate for future risk.

Analysis of the Full Economic Cost for Japanese Encephalitis Under Different Risk Scenarios for Business Travelers to Asia.

OBJECTIVE: Methods for assessing the costs and benefits of administering vaccines to international business/occupational travelers, assignees, and expatriates have neglected the impact of health and treatment on work productivity. The research objective is to evaluate the benefit to cost ratio of the Japanese encephalitis (JE) vaccine for international business/occupational travelers to Asia and other endemic areas incorporating a health and productivity approach. METHODS: Costs and benefits were estimated using actuarial methods with data obtained from secondary sources describing prevalence of infection risk and health outcomes, and business traveler demographic and travel characteristics. Results assumed 2018 salaries and prices, with employee time valued according to total compensation. RESULTS: Risks contracting JE vary widely on the basis of length of trip, season, and destination. The productivity benefits of vaccinating a traveler outweigh the vaccination costs for those staying 30 days or longer in endemic areas during one or more transmission seasons ($2009 vs $750 per traveler), and for business travelers to endemic areas during the transmission season with outdoor activities for the average 2-week/15.4-day international business trip ($502 to $815 vs $500). Vaccination costs outweigh the productivity benefits for short-term travelers who remain in urban areas or travel outside of the transmission season ($10 vs $500). CONCLUSION: JE Vaccination for business travelers in the active transmission season has a net benefit under certain conditions that are not commonly considered risky, such as average-length trips to peri-urban areas, in situations where contracting disease would result in significant business disruption, or when multiple trips are anticipated over several years.

Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis.

OBJECTIVE: The incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear. METHODS: We investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored. RESULTS: In our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live-attenuated Japanese encephalitis vaccine (LA-JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA-JEV similar to the AChR-α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG-like phenotype in mice. INTERPRETATION: Our results describe the immunological profile of CMG. Immunization with LA-JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA-JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386-400.

Mapping the potential distributions of etiological agent, vectors, and reservoirs of Japanese Encephalitis in Asia and Australia.

Japanese encephalitis virus (JEV) is a substantial cause of viral encephalitis, morbidity, and mortality in South-East Asia and the Western Pacific. World Health Organization recognized Japanese Encephalitis (JE) as a public health priority in demands to initiate active vaccination programs. Recently, the geographic distribution of JEV has apparently expanded into other areas in the Pacific islands and northern Australia; however, major gaps exist in knowledge in regard to its current distribution. Here, we mapped the potential distribution of mosquito vectors of JEV (Culex tritaeniorhynchus, Cx. pseudovishnui, Cx. vishnui, Cx. fuscocephala, Cx. gelidus), and reservoirs (Egretta garzetta, E. intermedia, Nycticorax nycticorax) based on ecological niche modeling approach. Ecological niche models predicted all species to occur across Central, South and South East Asia; however, Cx. tritaeniorhynchus, E. garzetta, E. intermedia, and N. nycticorax had broader potential distributions extending west to parts of the Arabian Peninsula. All predictions were robust and significantly better than random (P < 0.001). We also tested the JEV prediction based on 4335 additional independent human case records collected by the Chinese Information System for Disease Control and Prevention (CISDCP); 4075 cases were successfully predicted by the model (P < 0.001). Finally, we tested the ecological niche similarity among JEV, vector, and reservoir species and could not reject any of the null hypotheses of niche similarity in all combination pairs.

IP-10 Promotes Blood-Brain Barrier Damage by Inducing Tumor Necrosis Factor Alpha Production in Japanese Encephalitis.

Japanese encephalitis is a neuropathological disorder caused by Japanese encephalitis virus (JEV), which is characterized by severe pathological neuroinflammation and damage to the blood-brain barrier (BBB). Inflammatory cytokines/chemokines can regulate the expression of tight junction (TJ) proteins and are believed to be a leading cause of BBB disruption, but the specific mechanisms remain unclear. IP-10 is the most abundant chemokine produced in the early stage of JEV infection, but its role in BBB disruption is unknown. The administration of IP-10-neutralizing antibody ameliorated the decrease in TJ proteins and restored BBB integrity in JEV-infected mice. In vitro study showed IP-10 and JEV treatment did not directly alter the permeability of the monolayers of endothelial cells. However, IP-10 treatment promoted tumor necrosis factor alpha (TNF-α) production and IP-10-neutralizing antibody significantly reduced the production of TNF-α. Thus, TNF-α could be a downstream cytokine of IP-10, which decreased TJ proteins and damaged BBB integrity. Further study indicated that JEV infection can stimulate upregulation of the IP-10 receptor CXCR3 on astrocytes, resulting in TNF-α production through the JNK-c-Jun signaling pathway. Consequently, TNF-α affected the expression and cellular distribution of TJs in brain microvascular endothelial cells and led to BBB damage during JEV infection. Regarding regulation of the BBB, the IP-10/TNF-α cytokine axis could be considered a potential target for the development of novel therapeutics in BBB-related neurological diseases.

Neurological Manifestations of Dengue Infection.

Dengue counts among the most commonly encountered arboviral diseases, representing the fastest spreading tropical illness in the world. It is prevalent in 128 countries, and each year >2.5 billion people are at risk of dengue virus infection worldwide. Neurological signs of dengue infection are increasingly reported. In this review, the main neurological complications of dengue virus infection, such as central nervous system (CNS), peripheral nervous system, and ophthalmic complications were discussed according to clinical features, treatment and possible pathogenesis. In addition, neurological complications in children were assessed due to their atypical clinical features. Finally, dengue infection and Japanese encephalitis were compared for pathogenesis and main clinical manifestations.

Identifying sources, pathways and risk drivers in ecosystems of Japanese Encephalitis in an epidemic-prone north Indian district.

Japanese Encephalitis (JE) has caused repeated outbreaks in endemic pockets of India. This study was conducted in Kushinagar, a highly endemic district, to understand the human-animal-ecosystem interactions, and the drivers that influence disease transmission. Utilizing the ecosystems approach, a cross-sectional, descriptive study, employing mixed methods design was employed. Four villages (two with pig-rearing and two without) were randomly selected from a high, a medium and a low burden (based on case counts) block of Kushinagar. Children, pigs and vectors were sampled from these villages. A qualitative arm was incorporated to explain the findings from the quantitative surveys. All human serum samples were screened for JE-specific IgM using MAC ELISA and negative samples for JE RNA by rRT-PCR in peripheral blood mononuclear cells. In pigs, IgG ELISA and rRT-PCR for viral RNA were used. Of the 242 children tested, 24 tested positive by either rRT-PCR or MAC ELISA; in pigs, 38 out of the 51 pigs were positive. Of the known vectors, Culex vishnui was most commonly isolated across all biotopes. Analysis of 15 blood meals revealed human blood in 10 samples. Univariable analysis showed that gender, religion, lack of indoor residual spraying of insecticides in the past year, indoor vector density (all species), and not being vaccinated against JE in children were significantly associated with JE positivity. In multivariate analysis, only male gender remained as a significant risk factor. Based on previous estimates of symptomatic: asymptomatic cases of JE, we estimate that there should have been 618 cases from Kushinagar, although only 139 were reported. Vaccination of children and vector control measures emerged as major control activities; they had very poor coverage in the studied villages. In addition, lack of awareness about the cause of JE, lack of faith in the conventional medical healthcare system and multiple referral levels causing delay in diagnosis and treatment emerged as factors likely to result in adverse clinical outcomes.

Neuropathogenesis of Japanese encephalitis in a primate model.

BACKGROUND: Japanese encephalitis (JE) is a major cause of mortality and morbidity for which there is no treatment. In addition to direct viral cytopathology, the inflammatory response is postulated to contribute to the pathogenesis. Our goal was to determine the contribution of bystander effects and inflammatory mediators to neuronal cell death. METHODOLOGY/PRINCIPAL FINDINGS: Material from a macaque model was used to characterize the inflammatory response and cytopathic effects of JE virus (JEV). Intranasal JEV infection induced a non-suppurative encephalitis, dominated by perivascular, infiltrates of mostly T cells, alongside endothelial cell activation, vascular damage and blood brain barrier (BBB) leakage; in the adjacent parenchyma there was macrophage infiltration, astrocyte and microglia activation. JEV antigen was mostly in neurons, but there was no correlation between intensity of viral infection and degree of inflammatory response. Apoptotic cell death occurred in both infected and non-infected neurons. Interferon-α, which is a microglial activator, was also expressed by both. Tumour Necrosis Factor-α, inducible nitric oxide synthase and nitrotyrosine were expressed by microglial cells, astrocytes and macrophages. The same cells expressed matrix metalloproteinase (MMP)-2 whilst MMP-9 was expressed by neurons. CONCLUSIONS/SIGNIFICANCE: The results are consistent with JEV inducing neuronal apoptotic death and release of cytokines that initiate microglial activation and release of pro-inflammatory and apoptotic mediators with subsequent apoptotic death of both infected and uninfected neurons. Activation of astrocytes, microglial and endothelial cells likely contributes to inflammatory cell recruitment and BBB breakdown. It appears that neuronal apoptotic death and activation of microglial cells and astrocytes play a crucial role in the pathogenesis of JE.

Using network analysis to explore if professional opinions on Japanese encephalitis risk factors in Nepal reflect a socio-ecological system perspective.

Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia and a significant public health problem in Nepal. Its epidemiology is influenced by factors affecting its amplifying hosts (pigs), vectors (mosquitoes), and dead-end hosts (including people). While most control efforts target reduced susceptibility to infection either by vaccination of people or pigs or by reduced exposure to mosquitoes; the economic reality of Nepal makes it challenging to implement standard JE control measures. An ecohealth approach has been nominated as a way to assist in finding and prioritizing locally relevant strategies for JE control that may be viable, feasible, and acceptable. We sought to understand if Nepalese experts responsible for JE management conceived of its epidemiology in terms of a socio-ecological system to determine if they would consider ecohealth approaches. Network analysis suggested that they did not conceive JE risk as a product of a socio-ecological system. Traditional proximal risk factors of pigs, mosquitoes, and vaccination predominated experts' conception of JE risk. People seeking to encourage an ecohealth approach or social change models to JE management in Nepal may benefit from adopting social marketing concepts to encourage and empower local experts to examine JE from a socio-ecological perspective.

Time series analysis of Japanese encephalitis and weather in Linyi City, China.

OBJECTIVES: To examine the relationship between meteorological factors and epidemiological pattern of Japanese encephalitis in Linyi City during 1956-2004. METHODS: Autoregressive integrated moving average (ARIMA) models were used to evaluate the relationship between monthly JE incidence and weather factors. Logarithmic transformation was applied to the JE incidence series to assure the normality and homogeneity of variance of the residuals. The effect of mass vaccination on JE incidence was also evaluated using a transfer function in the time series analysis. RESULTS: The analysis suggested that monthly average temperature [ß = 0.0574, 95% confidence interval (CI) = (0.0172, 0.0976)] and relative humidity [ß = 0.0082, 95% CI = (0.0004, 0.0158)] were positively associated with the logarithmic incidence of Japanese encephalitis after adjusting for mass vaccination in this area. CONCLUSIONS: Weather variables might be treated as possible predictors of Japanese encephalitis incidence for regions with similar geographic, weather, and socio-economic conditions to Linyi, China.

Encephalitis temporally associated with live attenuated Japanese encephalitis vaccine: four case reports.

BACKGROUND: Japanese encephalitis (JE) vaccination is the most effective measure for preventing JE disease. The live attenuated JE vaccine, which has shown good efficacy and safety, has been widely used in China. CASE PRESENTATIONS: We report four laboratory-confirmed JE cases detected in JE-endemic areas during the JE virus (JEV) transmission season, who all received a first dose of live attenuated JE vaccine within 2 weeks prior to the onset of illness. All cases presented with acute encephalitis and rapidly reduced consciousness. All cerebrospinal fluid (CSF) samples from the patients were positive for JEV-specific immunoglobulin M (IgM) antibodies, but viral isolation and polymerase chain reaction (PCR) detection of JEV were both negative. CONCLUSIONS: It is difficult to identify a causal link between the disease and the vaccination, as the source of positive CSF JEV IgM antibodies might be natural JEV infection or possibly due to a traumatic lumbar puncture. Our observations highlight the need for public health officers and doctors to consider reasonable vaccination policies during the JE season. In addition, continued surveillance as well as thorough investigation of any events that occur after JE vaccination is necessary.

Dogs as sentinels for human infection with Japanese encephalitis virus.

Because serosurveys of Japanese encephalitis virus (JEV) among wild animals and pigs may not accurately reflect risk for humans in urban/residential areas, we examined seroprevalence among dogs and cats. We found that JEV-infected mosquitoes have spread throughout Japan and that dogs, but not cats, might be good sentinels for monitoring JEV infection in urban/residential areas.

The relationship between mosquito abundance and rice field density in the Republic of Korea.

BACKGROUND: Japanese encephalitis virus (JEV), the causative agent of Japanese encephalitis (JE), is endemic to the Republic of Korea (ROK) where unvaccinated United States (U.S.) military Service members, civilians and family members are stationed. The primary vector of the JEV in the ROK is Culex tritaeniorhynchus. The ecological relationship between Culex spp. and rice fields has been studied extensively; rice fields have been shown to increase the prevalence of Cx. tritaeniorhynchus. This research was conducted to determine if the quantification of rice field land cover surrounding U.S. military installations in the ROK should be used as a parameter in a larger risk model that predicts the abundance of Cx. tritaeniorhynchus populations. Mosquito data from the U.S. Forces Korea (USFK) mosquito surveillance program were used in this project. The average number of female Cx. tritaeniorhynchus collected per trap night for the months of August and September, 2002-2008, was calculated. Rice fields were manually digitized inside 1.5 km buffer zones surrounding U.S. military installations on high-resolution satellite images, and the proportion of rice fields was calculated for each buffer zone. RESULTS: Mosquito data collected from seventeen sample sites were analyzed for an association with the proportion of rice field land cover. Results demonstrated that the linear relationship between the proportion of rice fields and mosquito abundance was statistically significant (R2 = 0.62, r = .79, F = 22.72, p < 0.001). CONCLUSIONS: The analysis presented shows a statistically significant linear relationship between the two parameters, proportion of rice field land cover and log10 of the average number of Cx. tritaeniorhynchus collected per trap night. The findings confirm that agricultural land cover should be included in future studies to develop JE risk prediction models for non-indigenous personnel living at military installations in the ROK.

Clinical and etiological profile of acute febrile encephalopathy in eastern Nepal.

OBJECTIVE: To investigate the clinical and etiological profile of acute febrile encephalopathy in children presenting to a tertiary care referral center of Eastern Nepal. METHODS: 107 children (aged 1 month to 14 yrs) presenting to the emergency with fever (> 38 C) of less than 2 weeks duration with altered sensorium with/or without seizure were prospectively investigated for etiological cause. The investigations included blood and CSF counts, blood and CSF cultures, peripheral smear and serology for malarial parasite, and serology for Japanese encephalitis (JE) virus. Other investigations included EEG and CT or MRI wherever indicated. RESULTS: The most common presenting complaints apart from fever and altered sensorium were headache and vomiting. Convulsions, neck rigidity, hypertonia, brisk deep tendon reflexes, extensor plantar response and focal neurological deficits were seen in 50%, 57%, 22.4%, 28%, 39.3% and 9.3% of the subjects, respectively. The diagnoses based on clinical presentation and laboratory findings were pyogenic meningitis in 45 (42%), non JE viral encephalitis in 26 (25%), JE in 19 (18%), cerebral malaria in 8 (7%), herpes encephalitis and tubercular meningitis in 4 (4%) each, and typhoid encephalopathy in 1 case. CONCLUSION: Pyogenic meningitis and viral encephalitis including JE are the most common causes of acute presentation with fever and encephalopathy. Preventive strategies must be directed keeping these causes in mind.

Influence of the distribution of host species on adult abundance of Japanese encephalitis vectors Culex vishnui subgroup and Culex gelidus in a rice-cultivating village in northern Vietnam.

A field study was conducted in a village in northern Vietnam to investigate how host distribution influences Japanese encephalitis (JE) vector abundance. Indoor and outdoor collections were conducted from 50 compounds. We collected three JE vector species--Culex tritaeniorhynchus and Culex vishnui that comprised the Culex vishnui group, and Culex gelidus. Spatial autocorrelation was not observed in the mosquito assemblies at any scale larger than the house compounds. Multivariate analyses revealed that the Cx. gelidus density correlated positively with both the host proximity to the breeding sites and cattle density; however, the Cx. vishnui subgroup density correlated positively only with cattle density. These results showed that the number of cattle in a compound influenced the JE vector abundance in that compound, and the abundance of Cx. gelidus, not of the Cx. vishnui subgroup, was affected by the host proximity to the breeding sites in the village.

Unravelling the neuropathogenesis of Japanese encephalitis.

Japanese encephalitis is a devastating disease that causes a frequently fatal encephalitis and is a major health problem throughout much of Asia. Mortality rates can be as high as 30%, with one-third of survivors suffering severe neurological sequelae. Viral cytopathology is important, but the contribution of blood-brain barrier breakdown, the inflammatory response and bystander cell death are unknown. Studies that address the mechanisms producing neuronal dysfunction and damage are required, including the examination of autopsy tissues. A better understanding of these mechanisms may lead to therapeutic strategies to reduce brain injury and neurological sequelae.

Clinico-laboratory profile and outcome of Japanese encephalitis in Nepali children.

BACKGROUND: Japanese encephalitis (JE) is associated with high mortality and neurological sequelae. The unpredictable course and lack of specific treatment pose major challenges in management. The tropical climate and paddy ecosystem in Nepal provide a suitable setting. AIMS: To determine the aetiology of febrile encephalopathy and describe the clinico-laboratory profile and outcome of JE in Nepali children. METHODS: A hospital-based prospective and observational study was conducted over a 1-year period (2000-2001). Children aged from >1 month to 14 years with fever >38 degrees C for <2 weeks and altered sensorium were recruited. JE was confirmed by anti-JE IgM in cerebrospinal fluid and/or serum. RESULTS: Of 117 consecutively enrolled patients, 58 had JE. Ten patients had concomitant infections, four with malaria and six with bacterial meningitis, and were excluded from analysis. Clinical findings were as follows: boys, 69%; age 4-14 years, 71%; presentation during summer and autumn, 83%; fever >3 days, 69%; altered sensorium <2 days, 50%; Glasgow coma score 8-12, 63%; seizures, 58%. Four (8.3%) died. At discharge, neurological sequelae were detected in 24 (50%) and hemiparesis was the most common form. Longer duration of vomiting, altered sensorium and focal neurological deficit on admission were independently associated with sequelae at discharge. Sequelae persisted in nine (18.8%) at 6 weeks follow-up. Long duration of altered sensorium (beta co-efficient 0.35, odds ratio 1.4, p=0.042) and presence of focal neurological deficit on admission (beta co-efficient 1.6, odds ratio 5.2, p=0.049) were independent predictors of sequelae at 6 weeks. CONCLUSION: JE was the commonest cause of febrile encephalopathy. Neurological sequelae were common but resolved in two-thirds of cases.

Transmission cycles, host range, evolution and emergence of arboviral disease.

Many pandemics have been attributed to the ability of some RNA viruses to change their host range to include humans. Here, we review the mechanisms of disease emergence that are related to the host-range specificity of selected mosquito-borne alphaviruses and flaviviruses. We discuss viruses of medical importance, including Venezuelan equine and Japanese encephalitis viruses, dengue viruses and West Nile viruses.

Japanese encephalitis virus (JEV) is an important cause of encephalitis among children in Cuddalore district, Tamil Nadu, India.

BACKGROUND: Japanese encephalitis (JE) is endemic in Cuddalore district, Tamil Nadu (TN), Southern India. The reports of JE cases from the local hospitals did not reflect the actual disease burden. It is likely that these cases were attending the nearby referral hospitals, for want of better treatment facilities. OBJECTIVES: Between July 2002 and February 2003, a pilot study was undertaken to examine whether JE was a component of paediatric acute encephalitis syndrome (AES) reported to two major referral hospitals adjacent to Cuddalore, and to map the distribution of the JE cases. STUDY DESIGN: A total of 58 hospitalized children [0-15 years] with AES were investigated. Other than the routine laboratory investigations, either CSF or sera or both [depending on the availability] collected from these children were analyzed at Center for Research in Medical Entomology, Madurai (TN) for JEV-antigen, antibody detection, virus isolation and virus genome detection by indirect immunofluorescence, MAC enzyme linked immunosorbent assay (ELISA), insect bioassay and by reverse transcriptase polymerase chain reaction (RT-PCR), respectively. RESULTS: JE was established in 17 (29%) of 58 AES cases; half of the AES cases [31/58, 53%] and 59% [10/17] of JE cases were confined to JE-endemic areas in Cuddalore district. The JE confirmation scored by different assays varied according to the clinical phase of the illness. The attack rate was high among the children aged 3-8 years. The monthly distribution of acute encephalitic syndrome cases followed the distribution of JE cases [coinciding with the rainy season in this region] suggesting encephalitis of JE origin. CONCLUSION: In JE-endemic areas, the actual JE burden can be estimated by the collection of JE case reports from the local hospitals and from the referral hospitals. Building of diagnostic facilities in hospitals for JE is necessary to achieve this goal.