Estimates of Japanese Encephalitis mortality and morbidity: A systematic review and modeling analysis

Abstract

Background: Japanese Encephalitis (JE) is known for its high case fatality ratio (CFR) and long-term neurological sequelae. Over the years, efforts in JE treatment and control might change the JE fatality risk. However, previous estimates were from 10 years ago, using data from cases in the 10 years before this. Estimating JE disease severity is challenging because data come from countries with different JE surveillance systems, diagnostic methods, and study designs. Without precise and timely JE disease severity estimates, there is continued uncertainty about the JE disease burden and the effect of JE vaccination.

Methodology: We performed a systematic review to collate age-stratified JE fatality and morbidity data. We used a stepwise model selection with BIC as the selection criteria to identify JE CFR drivers. We used stacked regression, to predict country-specific JE CFR from 1961 to 2030. JE morbidity estimates were grouped from similar study designs to estimate the proportion of JE survivors with long-term neurological sequelae.

Principal findings: We included 82 and 50 peer-reviewed journal articles published as of March 06 2021 for JE fatality and morbidity with 22 articles in both analyses. Results suggested overall JE CFR estimates of 26% (95% CI 22, 30) in 1961-1979, 20% (95% CI 17, 24) in 1980-1999, 14% (95% CI 11, 17) in 2000-2018, and 14% (95% CI 11, 17) in 2019-2030. Holding other variables constant, we found that JE fatality risk decreased over time (OR: 0.965; 95% CI: 0.947-0.983). Younger JE cases had a slightly higher JE fatality risk (OR: 1.012; 95% CI: 1.003-1.021). The odds of JE fatality in countries with JE vaccination is 0.802 (90% CI: 0.653-0.994; 95% CI: 0.62-1.033) times lower than the odds in countries without JE vaccination. Ten percentage increase in the percentage of rural population to the total population was associated with 15.35% (95% CI: 7.71, 22.57) decrease in JE fatality odds. Ten percentage increase in population growth rate is associated with 3.71% (90% CI: 0.23, 7.18; 95% CI: -0.4, 8.15) increase in JE fatality odds. Adjusting for the effect of year, rural population percent, age of JE cases, and population growth rate, we estimated that there was a higher odds of JE fatality in India compared to China. (OR: 5.46, 95% CI: 3.61-8.31). Using the prediction model we found that, in 2000-2018, Brunei, Pakistan, and Timor-Leste were predicted to have the highest JE CFR of 20%. Bangladesh, Guam, Pakistan, Philippines, and Vietnam had projected JE CFR over 20% for after 2018, whereas the projected JE CFRs were below 10% in China, Indonesia, Cambodia, Myanmar, Malaysia, and Thailand. For disability, we estimated that 36% (min-max 0-85) JE patients recovered fully at hospital discharge. One year after hospital discharge, 46% (min-max 0%-97%) JE survivors were estimated to live normally but 49% (min-max 3% - 86%)till had neurological sequelae.

Conclusion: JE CFR estimates were lower than 20% after 2000. Our study provides an updated estimation of CFR and proportion of JE cases with long-term neurological sequelae that could help to refine cost-benefit assessment for JE control and elimination programs.

Fig 1. Flowchart describing the systematic review procedure searching for Japanese encephalitis (JE) case-fatality ratio (CFR) records using the PubMed database.

Fig 2. Distribution of Japanese encephalitis (JE) diagnostic methods used by collated JE case-fatality ratio (CFR) records with clear case definition by geographical locations (Panel A) and time (Panel B).

DTC is the abbreviation of diagnostic testing category. The colors represent each method, with dark blue for cases confirmed by virus isolation, antigen or pathogen detection (DTC1), purple for cases confirmed by detection of neutralization antibody in cerebrospinal fluid (CSF) or serum (DTC2), and yellow for cases consistent with WHO JE case definition: JE Immunoglobulin M (IgM) antibody in CSF or serum as confirmed by MAC-ELISA on patients with acute encephalitis syndrome (DTC3). Only the diagnostic methods for laboratory confirmed JE cases collected from studies in our analysis were plotted.

Fig 3. The Japanese encephalitis (JE) case-fatality ratio (CFR) records and the predicted JE CFRs for each JE endemic country with more than 10 JE CFR records over time using the best model (model 6).

In all plotted JE endemic countries, the solid line and the lighter ribbon represent the mean predicted JE CFR with its 95% confidence interval. Darker ribbon shows the region of 1^st quartile and 3^rd quartile of predicted JE CFR. Dots represent the JE CFR records with color dependent on the value of log₁₀ (the number of reported JE cases).

Fig 4. Spatial and temporal distribution of Japanese encephalitis (JE) National case-fatality ratio (CFR) estimates in JE (endemic countries) from 1961–2030.

Countries without estimates were filled with grey (values for these estimates are given in Table 4). The underlying map was generated using open source data from https://www.naturalearthdata.com/.

Fig 5. Flowchart describing the systematic review procedure searching for Japanese encephalitis (JE) neurological sequelae records using PubMed database.

Fig 6. Japanese encephalitis (JE) disease outcomes by age and measurement time.

Disease outcomes are stratified by measured at hospital discharge and at least one year after hospital discharge and four subgroups: JE cases before 2000, cases after 2000, adults (JE patients older than 18 years old), and children (JE patients 18 years old and younger). Note that JE death measured at hospital discharge occur at the acute stage of JE infection, while JE death measured at least one year after hospital discharge only contains death occurred during follow up.

Fig 7. Range of Japanese encephalitis (JE) neurological deficits severity level by outcome measurement time and assessment tools.

We define dependent as JE survivors who need assistance to perform daily activities and independent as JE patients who can live independently. JE patients with complete recovery show no symptoms of any neurological sequelae. Death measured at least 6 months after hospital discharge excludes death occurred during the acute stage of JE infection. Abbreviations: GPP (Good/Partial/Poor), Liverpool Outcome Score (LOS), Modified Rankin Scale (mRS), SMM (Severe/Moderate/Minor), Glasgow Coma Scale (GCS).