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ABSTRACT |
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Since 1978, Nepal has experienced epidemics and post-monsoon, seasonal increases of encephalitis cases in the Terai, the flat southern plains that borders India and includes nearly 12.5 million people. Based on aggregated, clinical reports collected from hospitals during the period of 1978 to 2003, nearly 26,700 suspected JE cases with 5,400 deaths have been identified.2
In most Asian countries, it is difficult to measure the disease burden from JE because of varying or unstated case definitions, limited availability of laboratory diagnostic testing especially in rural areas, and problems with ascertaining disease outcome.3 The Department of Health Services of Nepal’s Ministry of Health and Population recognized these as critical issues when developing JE surveillance and, in May 2004, instituted new JE surveillance guidelines. It entailed enhanced case-based surveillance using a standardized definition for Acute Encephalitis Syndrome (AES), an increase in surveillance sites, and an increased access to laboratory facilities performing JE testing.
We report here the results of the first 2 years of hospital-based JE surveillance in Nepal. Using these data, the age-specific incidence, mortality, and case fatality ratio for JE cases detected at government hospitals located throughout Nepal are calculated. The implication of these findings for developing a national immunization strategy to reduce JE morbidity and mortality is given.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Nepal has previously immunized children against JE. In 1999, 224,000 doses of SA 14-14-2 JE vaccine were given to children 1 to 15 years old in 3 districts (i.e., Bardiya, Banke, and Kailali) of the 4 hyperendemic western districts.4,5 In 2000 to 2001, 378,112 persons 6 months through 10 years of age residing in 3 of the 4 hyperendemic districts (Kailali, Banke, and Dang) and in 2 adjacent districts (Kanchanpur and Rupandehi) received a complete regimen of 3 doses of a cell culture inactivated vaccine grown in hamster kidney cells.4 Despite these attempts to control JE, this disease remains highly endemic in Nepal.
Disease surveillance. This Nepal model for JE surveillance is based on experience implementing syndromic encephalitis surveillance and from integrating many JE surveillance activities with the infrastructure developed for Acute Flaccid Paralysis (AFP) surveillance. From AFP surveillance, for example, data management was integrated into the computer database used for monitoring AFP and specimens were transported by the same reverse cold chain used to ship stool specimens for poliovirus detection. Technical assistance and quality control of laboratory procedures were provided by the WHO technical staff in Nepal.
Sixty-four referral hospitals located throughout Nepal were enrolled in laboratory-based JE surveillance. AES cases were defined as any patient presenting with acute onset of fever and a deterioration in mental status (e.g., confusion, disorientation, coma, or inability to talk) and/or new onset of seizures excluding simple febrile seizures.6 Using a structured reporting form, information on age, gender, district of residence, and whether the patient had been immunized against JE were recorded. Clinic data including date of disease onset and symptoms (e.g., fever, neck rigidity, convulsions) as well as outcome at discharge (i.e., cured, referred, death, unknown) were recorded. Five ml of serum or 2 mL of cerebrospinal fluid (CSF) were obtained from each patient. The serum and CSF samples were labeled with the patient identification number and stored at 2° to 8°C until transported in cold boxes with ice packs to a diagnostic laboratory. Specimen transportation took no more than 4 hrs by plane or road. Laboratory results were entered into a computer database by a data entry clerk and rechecked independently by a second clerk.
Because this was a national surveillance activity, written informed consent was not required by the Ministry of Health and Population.
Diagnosis. Upon arrival at the referral laboratory, serum and CSF samples were again stored at 2° to 8°C or, if batch testing was not planned for the next week, they were kept at –70°C. Laboratory confirmation was made from a single serum or CSF sample by detection of anti-JE immunoglobulin M (IgM) antibody titers using an IgM antibody capture enzyme-linked immunoassay.7,8 Serum and CSF specimens were tested at the National Public Health Laboratory (NPHL) of the Department of Health Services in Kathmandu or the B. P. Koirala Institute of Health Sciences (BPKIHS) in Dharan. Test reagents were provided to NPHL and BPKIHS by the Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok, Thailand.
Analysis. The annualized, age-specific incidence and mortality rate was the number of JE IgM-positive cases or deaths during the 2 years divided by 2 and then divided by the age-specific population multiplied by 100,000. Population estimates were taken from the 2001 national census, the last census in Nepal. Age categories were infants (< 1 year), toddlers (1–4 years old), children (5–14 years old), adolescents (15–19 years old), adults (20–34 years old), and older adults (35 years and older). The case fatality ratio (CFR) was defined as the percentage of JE IgM-positive deaths among total number of JE IgM-positive cases. Since mortality data were not available for each patient, the denominator only included persons from whom we received these data.
To visualize the geographic distribution of laboratory identified JE cases, we plotted one dot for each case by district of residence on a map of Nepal. Each dot was randomly assigned within the case’s district of residence.
To estimate the potential effectiveness of the proposed immunization strategy, we identified the number of JE IgM-positive cases and deaths that would have been prevented had the population been immunized against JE according to the suggested strategy at the start of surveillance in May 2004. We assumed that the vaccine had 98.5% effectiveness, the estimate of vaccine efficacy for persons aged one to 15 years old, 12 to 15 months after immunization.9 The expected number of cases or deaths if persons would have been immunized against JE was calculated as observed cases or deaths during the 2 years of surveillance multiplied by 1 minus 0.985.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Japanese encephalitis cases were found in 43 of 75 districts, but 92% (N = 951) of JE cases occurred in the 24 southern Terai districts (Figure 1
). The remaining cases (N = 84) occurred sporadically throughout other areas of Nepal (population = 12.5 million) including a cluster of cases (N = 54) around Kathmandu, the capital.
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). Although there were fewer cases the first year (N = 371), the seasonal pattern was essentially the same as the second year.
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Because the government has designated the Terai districts as endemic for JE4 and the majority of cases occur in the Terai, we have limited the remainder of the analysis to this region. With a population of about 12.4 million, the annualized incidence rate for the Terai was 3.8 JE cases per 100,000 per year. The annualized incidence was higher for males at 4.3 cases per 100,000 (537/2/6,296,635) than females at 3.4 cases per 100,000 (414/2/6,085,654) per year.
Of the 24 districts, 4 districts in western Terai (i.e., Kailali, Bardiya, Banke, and Dang) accounted for the majority of cases (N = 616, 65%) and deaths (N = 66, 88%). The incidence and mortality rate per 100,000 persons and the CFR for the 4 western Terai districts was 16.7%, 1.8%, and 14.7%, respectively (Table 1). The same values were 1.6%, 0.04%, and 6.3%, respectively, for the other 20 Terai districts.
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For the 4 western Terai districts, infants had the lowest annualized mortality rates (0.0 deaths per 100,000) and CFR (0.0%), although the number of cases (N = 4) was also low. The highest mortality rate (3.2 per 100,000) and CFR (25.0%) was for persons 35 years and older. For the other endemic districts, the mortality rate never exceeded 0.1 deaths per 100,000; the CFR was highest for persons 15 to 19 years old (10.0%) and for persons 35 years and older (10.0%). There were no deaths reported among children less than 5 years old.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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Contrary to previous reports emphasizing JE in pediatric populations, we found JE in Nepal to also produce morbidity and mortality in adults. Noteworthy was the high mortality in adults over 35 years old in the 4 western Terai districts. We suggest that persons from the hills and mountains may have migrated to this area for work and may have been non-immune to JE. To the best of our knowledge, this has not been investigated. This observation also implies a limitation to studies and vaccine trials that only consider children.14–17
We observed that about one-third of AES cases were JE IgM-positive. A study of JE in Bali using similar diagnostic procedures detected 30% more JE infections when testing an acute and convalescent CSF sample from patients.18 Even if our case load was increased by 30%, there would still be a significant number of cases that were JE negative, suggesting that agents other than JE may be responsible for some AES cases.
Before examining the implication of these results, we comment on some of the limitations of their data. Firstly, we were unable to obtain diagnostic specimens for all cases. Those patients without specimens were similar to those with specimens in terms of age (mean 22 vs. 18 years), gender (46% vs. 43% female), and residence (52% vs. 44% from 4 western Terai districts). However, we did observe that patients without specimens had a higher CFR than patients with specimens. This may suggest that patients without samples were admitted with severe, life-threatening disease that precluded obtaining a sample. If these cases were JE, we have underestimated the number of JE cases and deaths. Secondly, if our diagnostic test was unreliable, our test results may not be the true rates. Confirmatory and blinded samples from Nepal, using AFRIMS results as the standard, found sensitivity of 99% among 677 JE positive samples and a specificity of 76% among 101 JE negative samples. The high sensitivity and moderate specificity imply that these results are worth reporting. Thirdly, our diagnosis was based on a single serum or CSF sample. A positive result on serum specimen can provide at most a diagnosis of probable JE. Only a positive result on CSF specimen is considered diagnostic for JE as a cause of AES. However, the WHO has suggested that a single serum sample from an acutely encephalitic patient is adequate for surveillance efforts.6 Finally, it has been proposed that samples taken during the first week after disease onset may be falsely negative because this may be too early in the natural history of disease to detect anti-JE IgM antibodies. About 67% of our specimens were collected during this period, and we may have false negatives.
Implications for an immunization strategy. Based on studies conducted in Nepal, the Government of Nepal has approved the use of the SA 14-14-2, a live-attenuated JE vaccine. All 3 studies suggest that this vaccine may be efficacious and safe.2,5,9 After the administration of 224,000 vaccine doses in the year 1999, a case-control study conducted in the western Terai suggested 99% (95% Confidence Interval [CI]: 95%–100%) protection for children when vaccine was administered only days to weeks before the seasonal increase in JE cases.2 A second study found 98.5% protection (CI: 90.1%–99.2%) 12 to 15 months after immunization9 and a third study conducted 5 years after the immunization program found 96.2% protection (CI: 73.1%– 99.9%).5 No significant adverse events after immunization were reported in children or adults.
Given the geographic distribution of JE cases, our surveillance data suggests an immunization campaign targeting the 24 southern districts with further prioritization to the 4 western Terai districts where JE morbidity and mortality is at its highest for all ages. It appears that a campaign immunizing all persons greater than 1 year old with SA 14-14-2 JE vaccine would be appropriate for these districts. Such a campaign in these 4 districts would have reduced JE cases by 63% and deaths by 87% if started prior to May 2004 (Table 2). For the remaining 20 districts, a program immunizing all persons greater than 1 year would be ideal, but the large population (< 10 million) for financial and logistical reasons precludes such an activity at this time. Still, a campaign limited to 1-year-olds through 14-year-olds in the 20 districts with SA 14-14-2 would have prevented an additional 21% of cases and 5% of deaths, nationally. Given the seasonality of disease, this campaign should be completed by April, providing 1 month before the seasonal increase in disease to ensure that all recipients have sufficient time to develop a vaccine induced immune response.
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This immunization strategy may have limitations. First, the effectiveness of SA 14-14-2 was 98.5% (95% CI: 90.1%–99.2%) at 12 to 15 months after immunization and the second study was 96.2% (CI: 73.1%– 99.9%) at 5 years. At the lower confidence interval of effectiveness, up to 10% of immunized persons may not be protected after 12 to 15 months and 27% after 5 years. Second, this strategy does not protect against JE occurring outside the Terai or within the Terai among cases 15 years old or older residing in the 20 non-western districts. To protect these persons, an immunization campaign would need to cover an additional 17 million individuals. Finally, efficacy has not been tested in children less than 8 months of age, and there is a risk that maternal antibodies may interfere with development of immunity. For infants, environmental controls including bed nets and appropriate clothing to protect against mosquito bites should be investigated.
To the best of our knowledge, this is the most extensive laboratory-based, JE surveillance activity in the Southeast Asia region of the WHO and demonstrates how other immunization preventable diseases could be integrated into AFP surveillance. Nepal’s JE surveillance system provides critical data for documenting the disease burden and rationale for an immunization strategy. As JE immunization strategies are implemented, surveillance will continue to define changes in disease epidemiology and immunization policy.
Received June 6, 2007. Accepted for publication January 29, 2008.
Acknowledgments: The authors thank the Surveillance Medical Officers of the WHO in Nepal for their efforts to develop JE surveillance during difficult times. We also thank Mahendra Bahadur Bista, the Director General and Director of the Epidemiology and Disease Control Division, Shyam Raj Upreti, Chief of the National Immunization Program, and Mr. Shyam P Khanal, Medical Technologist, National Public Health Laboratory of Nepal for their cooperation.
Disclaimer: The opinions and assertions contained herein are not to be construed as official or as reflecting the views of the U.S. government or the U.S. Department of Defense.
Financial support: Financial support was provided by the United States Agency for International Development.
* Address correspondence to Thomas F. Wierzba, US NAMRU2, 4540 Phnom Penh Place, Dulles, VA 20189. E-mail: wierzba{at}namru2.org.kh 
Authors’ addresses: Thomas F. Wierzba, U.S. Naval Medical Research Unit No. 2, 4540 Phnom Penh Place, Dulles, VA 20189, Tel: 855-23-884228 (Phnom Penh), Fax: 855-23-883-561, E-mail: wierzba{at}namru2.org.kh. Prakash Ghimire and Tika R. Sedai, Program for Immunization Preventable Diseases, World Health Organization, P.O. Box 108, UN House, Pulchowk, Lalitpur, Kathmandu, Nepal; Sarala Malla, National Public Health Laboratory, Department of Health Services, Ministry of Health and Population, Teku, Kathmandu, Nepal. Manas Kumar Banerjee, Epidemiology and Disease Control Division, Department of Health Services, Ministry of Health and Population, Teku, Kathmandu, Nepal. Sanjaya Shrestha and Robert V. Gibbons, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences (USAMC-AFRIMS) APO AP 96546, USA. Basudha Khanal, B. P. Koirala Institute of Health Sciences, Ghopa, Dharan, Nepal.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES |
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