Journal of Infection (2014) xx, 1e3
www.elsevierhealth.com/journals/jinf
LETTER TO THE EDITOR Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India
Sir, Seasonal outbreaks of acute encephalitis syndrome (AES) with considerable mortality and disability are frequently reported in Gorakhpur division of Uttar Pradesh, India. Japanese encephalitis (JE) has been a major and consistent cause of these outbreaks in the Gorakhpur division.1,2 AES surveillance was established in the area with the objectives of estimating the burden, assessing the effect of JE vaccination and guiding future strategies for control.3 Most AES cases are admitted in the BRD Medical College, Gorakhpur, the only tertiary care hospital in the public sector in the division and are reported to the state program officer for onward transmission to National Vector Borne Disease Control Programme.3 The laboratory of the National Institute of Virology (NIV) at the Baba Raghav Das Medical College, Gorakhpur is the regional laboratory for AES surveillance where cerebro-spinal fluid (CSF) and/or sera samples from AES cases are tested for IgM antibodies against JE using the ELISA kit developed by NIV, Pune. The kit has specificity of 85% (96% with CSF and 77% with serum) and sensitivity of 71% (75% with CSF and 71% with serum).4 As per the surveillance guidelines, positive samples are classified as JE confirmed cases and negative samples as JE negative AES. We obtained the line-list of AES cases from the NIV laboratory at Gorakhpur for 2008e2012 which contained information about demographic details, place of residence, JE vaccination details and results of JE serology. The linelist was up to date with laboratory results. We analysed the data to describe the epidemiology of AES in terms of time [incidence and 95% confidence interval (CI) for 2008e2012], place (incidence and 95% CI for different districts), and person (incidence and 95% CI by age and gender). The 2011 census population and 2001e2011 decadal growth rates for the 4 districts in Gorakhpur division was used to estimate the population for different years. During 2008e2012, a total of 10,175 cases of AES were reported from Gorakhpur division. A total of 4335 CSF and 7539 sera samples were collected from these patients. IgM
antibodies against JE virus was detected in 852 (8.4%, 95% CI: 7.8e8.9) patients while the remaining 9323 (91.6%, 95% CI: 91.1e92.2) were negative for JE. One hundred and seventy cases of JE [case fatality ratio (CFR): 20%; 95% CI: 17.4e22.7] and 1733 JE negative AES cases [CFR: 18.6%; 95% CI: 17.8e19.4] died. The average annual incidence of JE and JE negative AES in the 4 districts of Gorakhpur division ranged from 1.1 to 1.4 per 100,000 and 10.1e16.1 per 100,000 respectively (Table 1). The incidence of JE in the division has showed a decline since 2010, from 1.9 per 100,000 during 2010 to 0.5 per 100,000 in 2012 whereas the incidence of JE negative AES remained relatively stable over the past five years (Fig. 1(A) and (B)). This pattern was observed in all the four districts. The incidence of JE as well as JE negative AES peaked during August to October months with 80% cases of JE and 65% JE negative AES cases occurring during these months. The average annual incidences of JE and JE negative AES was highest among under-five children (3.4 per 100,000 and 53.5 per 100,000 respectively). Thereafter the incidences declined with age, reaching to 0.6 and 3.4 per 100,000 for JE and JE negative AES respectively among individuals aged 15 years or more (Table 1). The incidence of JE and JE negative AES was higher in males compared to females. Sixteen of the 852 JE cases gave history of JE vaccination. The information about JE vaccination however was available only for 2008 and 2011. The information about the time (month and year) of vaccination as well as number of doses received was not available in the line-list. An earlier review of AES surveillance in Kushinagar indicated poor quality of the surveillance data.5 While it is necessary to improve the quality of AES surveillance three conclusions could be drawn based on our analysis which could help better understand the epidemiology of AES in the area. First, the incidence of JE has showed a decline since 2010 in all the districts of Gorakhpur division. In Gorakhpur, mass JE vaccination was conducted during 2010 and subsequently the vaccine was introduced in the routine immunization programme in 2011. Although the evaluated coverage for 2010 mass JE vaccination campaign as well as coverage of JE vaccine administered under routine immunization is not available, the administrative coverage was high, ranging between 99 and 100% in different districts (Govt of Uttar Pradesh, unpublished data). The decline in JE incidence since 2010 could possibly be on account of JE vaccination programme. Further
0163-4453/$36 ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2014.03.013 Please cite this article in press as: Ranjan P, et al., Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.03.013
2
Letter to the Editor Table 1 Average annual incidence (per 100,000 population) of JE and JE negative AES cases by age group and gender, Gorakhpur division, 2008e12. Average population, 2008e2012 Age group 0e4 5e9 10e14 >Z15 Gender Male Female Districts Deoria Gorakhpur Kushinagar Mahrajganj Total
Number of JE cases
Average annual incidence of JE (95% CI)
Number of JE negative AES cases
1,525,525 1,512,025 1,768,529 8,694,142
257 232 122 241
3.4 3.1 1.4 0.6
(3.0e3.8) (2.8e3.5) (1.1e1.4) (0.5e0.6)
4082 2632 1128 1481
53.5 34.8 12.8 03.4
6,883,017 6,617,204
501 351
1.5 (1.4e1.5) 1.1 (1.0e1.1)
5384 3939
15.6 (15.2e16.0) 11.9 (11.6e12.3)
3,055,256 4,358,903 3,479,949 2,606,114 13,500,221
161 299 251 141 852
1.1 1.4 1.4 1.1 1.3
1786 3424 2796 1317 9323
Figure 1
(0.9e1.3) (1.3e1.6) (1.4e1.7) (0.9e1.3) (1.2e1.3)
Average annual incidence of JE negative AES (95% CI)
11. 7 15.7 16.1 10.1 13.8
(51.9e55.1) (33.5e36.1) (12.1e13.4) (03.2e03.6)
(11.2e12.2) (15.2e16.2) (15.5e16.6) (09.6e10.6) (13.5e14.0)
Annual incidence of (A) JE and (B) JE negative AES in the Gorakhpur division 2008e12.
studies are however needed to estimate the coverage of JE vaccine in Gorakhpur as the administrative coverage is generally over-estimated. Second, JE negative AES accounted for nearly 90% of AES cases. With negative aetiology for JE in the majority of AES cases, control measures aimed at reducing mosquito density would have minimal impact on the morbidity due to AES. Third, the relatively stable incidence of JE negative AES in the area and the declining incidence of JE suggest differing modes of transmission of JE and JE negative AES. The epidemiological pattern of JE negative AES in terms of declining incidence by age, strong seasonality with high incidence during rainy season and occurrence of disease over a large geographical area, suggests a possibility of faeco-oral transmission by contaminated drinking water. Relatively stable incidence of non-JE AES in any given age group over previous five years also indicates continued transmission of infection without any effect of control measures. Although enteroviruses such as EV71, EV76, EV89, Coxsackievirus B3,
B5, B6, echovirus 11, 13, 14, 32 have been detected in a small proportion of JE negative AES cases in the area,2,6e9 understanding the aetiology and modes of transmission of JE negative AES remains the immediate priority for AES control in Gorakhpur.
Financial support The study was conducted using intramural funds of National Institute of Epidemiology, Chennai and National Institute of Virology, Pune, Department of Health Research, Govt of India.
Acknowledgement Authors are thankful for the support from Encephalitis and Enteric virus groups of National Institute of Virology Pune and staff of BRD Medical College, Gorakhpur. Thanks are
Please cite this article in press as: Ranjan P, et al., Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.03.013
Letter to the Editor due to Dr Sanjay Mehendale, Director of National Institute of Epidemiology and Dr Devendra Mourya, Director of National Institute of Virology for their critical comments on the manuscript.
References 1. Fulmali PV, Sapkal GN, Athawale S, Gore MM, Mishra AC, Bondre VP. Introduction of Japanese encephalitis virus genotype I, India. Emerg Infect Dis 2011;17:319e21. 2. Sapkal GN, Bondre VP, Fulmali PV, Patil P, Gopalkrishna V, Dadhania V. Enteroviruses in patients with acute encephalitis, Uttar Pradesh, India. Emerg Infect Dis 2009;15: 295e8. 3. Directorate of National Vector Borne Diseases Control Programme. Guidelines for surveillance of acute encephalitis syndrome (with special reference to Japanese encephalitis) [cited 2013 Aug 15] http://www.nvbdcp.gov.in/Doc/AES% 20guidelines.pdf. 4. WHO Regional Office for Southeast Asia. Fourth bi-regional meeting on the control of Japanese encephalitis. Report of the meeting Bangkok, Thailand [cited 2013 Aug 15] Available at:, http://www.wpro.who.int/immunization/documents/ docs/JEBiregionalMeetingJune2009final.pdf; 7e8 June 2009. 5. Kakkar M, Rogawski ET, Abbas SS, Chaturvedi S, Dhole TN, Hossain SS, et al. Acute encephalitis syndrome surveillance, Kushinagar district, Uttar Pradesh, India, 2011e2012. Emerg Infect Dis; 2013:19. 6. Bhatt GC, Bondre VP, Sapkal GN, Sharma T, Kumar S, Gore MM, et al. Changing clinico-laboratory profile of encephalitis patients in the eastern Uttar Pradesh region of India. Trop Doct 2012;42:106e8.
3 7. Kumar A, Shukla D, Kumar R, Idris MZ, Misra UK, Dhole TN. An epidemic of encephalitis associated with human enterovirus B in Uttar Pradesh, India, 2008. J Clin Virol 2011;51:142e5. 8. Kumar A, Shukla D, Srivastava S, Idris MZ, Dhole TN. High frequency of enterovirus serotype circulation in a densely populated area of India. J Infect Dev Ctries 2013;7:475e83. 9. Kumar A, Shukla D, Kumar R, Idris MZ, Misra UK, Dhole TN. Molecular epidemiological study of enteroviruses associated with encephalitis in children from India. J Clin Microbiol 2012;50: 3509e12.
Prashant Ranjan National Institute of Epidemiology, Indian Council of Medical Research, Chennai, India Milind Gore National Institute of Virology, Indian Council of Medical Research, Field Unit, Gorakhpur, India Sriram Selvaraju National Institute of Epidemiology, Indian Council of Medical Research, Chennai, India Komal P. Kushwaha D.K. Srivastava Baba Raghav Das Medical College, Gorakhpur, India Manoj Murhekar* National Institute of Epidemiology, Indian Council of Medical Research, Chennai, India E-mail address: [email protected] Accepted 16 March 2014
* Corresponding author. National Institute of Epidemiology, R127, Tamil Nadu Housing Board, Ayapakkam, Ambattur, Chennai, India. Please cite this article in press as: Ranjan P, et al., Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.03.013
www.elsevierhealth.com/journals/jinf
LETTER TO THE EDITOR Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India
Sir, Seasonal outbreaks of acute encephalitis syndrome (AES) with considerable mortality and disability are frequently reported in Gorakhpur division of Uttar Pradesh, India. Japanese encephalitis (JE) has been a major and consistent cause of these outbreaks in the Gorakhpur division.1,2 AES surveillance was established in the area with the objectives of estimating the burden, assessing the effect of JE vaccination and guiding future strategies for control.3 Most AES cases are admitted in the BRD Medical College, Gorakhpur, the only tertiary care hospital in the public sector in the division and are reported to the state program officer for onward transmission to National Vector Borne Disease Control Programme.3 The laboratory of the National Institute of Virology (NIV) at the Baba Raghav Das Medical College, Gorakhpur is the regional laboratory for AES surveillance where cerebro-spinal fluid (CSF) and/or sera samples from AES cases are tested for IgM antibodies against JE using the ELISA kit developed by NIV, Pune. The kit has specificity of 85% (96% with CSF and 77% with serum) and sensitivity of 71% (75% with CSF and 71% with serum).4 As per the surveillance guidelines, positive samples are classified as JE confirmed cases and negative samples as JE negative AES. We obtained the line-list of AES cases from the NIV laboratory at Gorakhpur for 2008e2012 which contained information about demographic details, place of residence, JE vaccination details and results of JE serology. The linelist was up to date with laboratory results. We analysed the data to describe the epidemiology of AES in terms of time [incidence and 95% confidence interval (CI) for 2008e2012], place (incidence and 95% CI for different districts), and person (incidence and 95% CI by age and gender). The 2011 census population and 2001e2011 decadal growth rates for the 4 districts in Gorakhpur division was used to estimate the population for different years. During 2008e2012, a total of 10,175 cases of AES were reported from Gorakhpur division. A total of 4335 CSF and 7539 sera samples were collected from these patients. IgM
antibodies against JE virus was detected in 852 (8.4%, 95% CI: 7.8e8.9) patients while the remaining 9323 (91.6%, 95% CI: 91.1e92.2) were negative for JE. One hundred and seventy cases of JE [case fatality ratio (CFR): 20%; 95% CI: 17.4e22.7] and 1733 JE negative AES cases [CFR: 18.6%; 95% CI: 17.8e19.4] died. The average annual incidence of JE and JE negative AES in the 4 districts of Gorakhpur division ranged from 1.1 to 1.4 per 100,000 and 10.1e16.1 per 100,000 respectively (Table 1). The incidence of JE in the division has showed a decline since 2010, from 1.9 per 100,000 during 2010 to 0.5 per 100,000 in 2012 whereas the incidence of JE negative AES remained relatively stable over the past five years (Fig. 1(A) and (B)). This pattern was observed in all the four districts. The incidence of JE as well as JE negative AES peaked during August to October months with 80% cases of JE and 65% JE negative AES cases occurring during these months. The average annual incidences of JE and JE negative AES was highest among under-five children (3.4 per 100,000 and 53.5 per 100,000 respectively). Thereafter the incidences declined with age, reaching to 0.6 and 3.4 per 100,000 for JE and JE negative AES respectively among individuals aged 15 years or more (Table 1). The incidence of JE and JE negative AES was higher in males compared to females. Sixteen of the 852 JE cases gave history of JE vaccination. The information about JE vaccination however was available only for 2008 and 2011. The information about the time (month and year) of vaccination as well as number of doses received was not available in the line-list. An earlier review of AES surveillance in Kushinagar indicated poor quality of the surveillance data.5 While it is necessary to improve the quality of AES surveillance three conclusions could be drawn based on our analysis which could help better understand the epidemiology of AES in the area. First, the incidence of JE has showed a decline since 2010 in all the districts of Gorakhpur division. In Gorakhpur, mass JE vaccination was conducted during 2010 and subsequently the vaccine was introduced in the routine immunization programme in 2011. Although the evaluated coverage for 2010 mass JE vaccination campaign as well as coverage of JE vaccine administered under routine immunization is not available, the administrative coverage was high, ranging between 99 and 100% in different districts (Govt of Uttar Pradesh, unpublished data). The decline in JE incidence since 2010 could possibly be on account of JE vaccination programme. Further
0163-4453/$36 ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jinf.2014.03.013 Please cite this article in press as: Ranjan P, et al., Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.03.013
2
Letter to the Editor Table 1 Average annual incidence (per 100,000 population) of JE and JE negative AES cases by age group and gender, Gorakhpur division, 2008e12. Average population, 2008e2012 Age group 0e4 5e9 10e14 >Z15 Gender Male Female Districts Deoria Gorakhpur Kushinagar Mahrajganj Total
Number of JE cases
Average annual incidence of JE (95% CI)
Number of JE negative AES cases
1,525,525 1,512,025 1,768,529 8,694,142
257 232 122 241
3.4 3.1 1.4 0.6
(3.0e3.8) (2.8e3.5) (1.1e1.4) (0.5e0.6)
4082 2632 1128 1481
53.5 34.8 12.8 03.4
6,883,017 6,617,204
501 351
1.5 (1.4e1.5) 1.1 (1.0e1.1)
5384 3939
15.6 (15.2e16.0) 11.9 (11.6e12.3)
3,055,256 4,358,903 3,479,949 2,606,114 13,500,221
161 299 251 141 852
1.1 1.4 1.4 1.1 1.3
1786 3424 2796 1317 9323
Figure 1
(0.9e1.3) (1.3e1.6) (1.4e1.7) (0.9e1.3) (1.2e1.3)
Average annual incidence of JE negative AES (95% CI)
11. 7 15.7 16.1 10.1 13.8
(51.9e55.1) (33.5e36.1) (12.1e13.4) (03.2e03.6)
(11.2e12.2) (15.2e16.2) (15.5e16.6) (09.6e10.6) (13.5e14.0)
Annual incidence of (A) JE and (B) JE negative AES in the Gorakhpur division 2008e12.
studies are however needed to estimate the coverage of JE vaccine in Gorakhpur as the administrative coverage is generally over-estimated. Second, JE negative AES accounted for nearly 90% of AES cases. With negative aetiology for JE in the majority of AES cases, control measures aimed at reducing mosquito density would have minimal impact on the morbidity due to AES. Third, the relatively stable incidence of JE negative AES in the area and the declining incidence of JE suggest differing modes of transmission of JE and JE negative AES. The epidemiological pattern of JE negative AES in terms of declining incidence by age, strong seasonality with high incidence during rainy season and occurrence of disease over a large geographical area, suggests a possibility of faeco-oral transmission by contaminated drinking water. Relatively stable incidence of non-JE AES in any given age group over previous five years also indicates continued transmission of infection without any effect of control measures. Although enteroviruses such as EV71, EV76, EV89, Coxsackievirus B3,
B5, B6, echovirus 11, 13, 14, 32 have been detected in a small proportion of JE negative AES cases in the area,2,6e9 understanding the aetiology and modes of transmission of JE negative AES remains the immediate priority for AES control in Gorakhpur.
Financial support The study was conducted using intramural funds of National Institute of Epidemiology, Chennai and National Institute of Virology, Pune, Department of Health Research, Govt of India.
Acknowledgement Authors are thankful for the support from Encephalitis and Enteric virus groups of National Institute of Virology Pune and staff of BRD Medical College, Gorakhpur. Thanks are
Please cite this article in press as: Ranjan P, et al., Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.03.013
Letter to the Editor due to Dr Sanjay Mehendale, Director of National Institute of Epidemiology and Dr Devendra Mourya, Director of National Institute of Virology for their critical comments on the manuscript.
References 1. Fulmali PV, Sapkal GN, Athawale S, Gore MM, Mishra AC, Bondre VP. Introduction of Japanese encephalitis virus genotype I, India. Emerg Infect Dis 2011;17:319e21. 2. Sapkal GN, Bondre VP, Fulmali PV, Patil P, Gopalkrishna V, Dadhania V. Enteroviruses in patients with acute encephalitis, Uttar Pradesh, India. Emerg Infect Dis 2009;15: 295e8. 3. Directorate of National Vector Borne Diseases Control Programme. Guidelines for surveillance of acute encephalitis syndrome (with special reference to Japanese encephalitis) [cited 2013 Aug 15] http://www.nvbdcp.gov.in/Doc/AES% 20guidelines.pdf. 4. WHO Regional Office for Southeast Asia. Fourth bi-regional meeting on the control of Japanese encephalitis. Report of the meeting Bangkok, Thailand [cited 2013 Aug 15] Available at:, http://www.wpro.who.int/immunization/documents/ docs/JEBiregionalMeetingJune2009final.pdf; 7e8 June 2009. 5. Kakkar M, Rogawski ET, Abbas SS, Chaturvedi S, Dhole TN, Hossain SS, et al. Acute encephalitis syndrome surveillance, Kushinagar district, Uttar Pradesh, India, 2011e2012. Emerg Infect Dis; 2013:19. 6. Bhatt GC, Bondre VP, Sapkal GN, Sharma T, Kumar S, Gore MM, et al. Changing clinico-laboratory profile of encephalitis patients in the eastern Uttar Pradesh region of India. Trop Doct 2012;42:106e8.
3 7. Kumar A, Shukla D, Kumar R, Idris MZ, Misra UK, Dhole TN. An epidemic of encephalitis associated with human enterovirus B in Uttar Pradesh, India, 2008. J Clin Virol 2011;51:142e5. 8. Kumar A, Shukla D, Srivastava S, Idris MZ, Dhole TN. High frequency of enterovirus serotype circulation in a densely populated area of India. J Infect Dev Ctries 2013;7:475e83. 9. Kumar A, Shukla D, Kumar R, Idris MZ, Misra UK, Dhole TN. Molecular epidemiological study of enteroviruses associated with encephalitis in children from India. J Clin Microbiol 2012;50: 3509e12.
Prashant Ranjan National Institute of Epidemiology, Indian Council of Medical Research, Chennai, India Milind Gore National Institute of Virology, Indian Council of Medical Research, Field Unit, Gorakhpur, India Sriram Selvaraju National Institute of Epidemiology, Indian Council of Medical Research, Chennai, India Komal P. Kushwaha D.K. Srivastava Baba Raghav Das Medical College, Gorakhpur, India Manoj Murhekar* National Institute of Epidemiology, Indian Council of Medical Research, Chennai, India E-mail address: [email protected] Accepted 16 March 2014
* Corresponding author. National Institute of Epidemiology, R127, Tamil Nadu Housing Board, Ayapakkam, Ambattur, Chennai, India. Please cite this article in press as: Ranjan P, et al., Changes in acute encephalitis syndrome incidence after introduction of Japanese encephalitis vaccine in a region of India, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.03.013
