Geographical distribution of primary & secondary dengue cases in India – 2017: A cross-sectional multicentric study

In recent decades, the global incidence of dengue has reached 390 million dengue infections per year, resulting in about 500,000 hospital admissions annually^1,2. There is a 30-fold increase in dengue burden over past two decades^3,4. Severe dengue infection has resulted in 372 disability-adjusted life years (DALYs) per million population^4,5. Southeast Asia including India accounts for 75 per cent of the current global burden of dengue^5,6,7. Dengue is endemic in India with cases being reported from all over the country with increased seasonal activity during the post-monsoon period. According to National Vector Borne Disease Control Programme (NVBDCP), Government of India, there was 188,401 confirmed dengue cases including 325 deaths in 2017⁸. The NVBDCP data only represent the sentinel surveillance laboratories in the government sector. All four serotypes of dengue virus have been reported from India^9,10,11.

Dengue virus infection does not confer immunity against heterologous dengue virus serotype infection, and as a result, re-infections are common^12,13. Majority of dengue virus infections are asymptomatic⁷. It has been proposed that antibody-dependent enhancement due to the pre-existing sub- or non-neutralizing anti-dengue antibody is the main pathogenesis in severe dengue^7,14,15. Secondary dengue has been believed to be associated with the dengue haemorrhagic fever and dengue shock syndrome or severe dengue with organ involvement^7,16,17,18.

The NVBDCP surveillance uses only dengue NS1 antigen ELISA assay and IgM capture ELISA assay as confirmed diagnosis of dengue virus infection. There is no mechanism to differentiate between primary and secondary dengue cases. As severe dengue is often associated with secondary dengue¹⁹ and the currently available dengue vaccine can only be used in a population with high level of secondary dengue exposure²⁰, it is important to differentiate primary and secondary dengue cases to understand the transmission dynamics and epidemiology of dengue in India. In this context, this study was conducted as a multicentre cross-sectional study to understand the geographical distribution of primary and secondary dengue cases in India.

Go to:

Material & Methods

The study was conducted at Department of Health Research / Indian Council of Medical Research (DHR)/(ICMR) viral research and diagnostic laboratories (VRDLs) and selected ICMR Institutes. ICMR VRDL at Manipal Centre for Virus Research, Kasturba Medical College, Manipal, coordinated the study. A total of 16 VRDLs were involved in the study (Box).

Box

Viral research and diagnostic laboratories (VRDLs) involved in the study

A cross-sectional study design was used. All laboratory-confirmed dengue cases with date of onset of illness less than or equal to seven days were included from all participating centres as part of the dengue surveillance from September to October 2017. Consecutive sampling was done due to the short period of study.

Laboratory assays: Dengue NS1 antigen ELISA (Panbio Dengue early ELISA, Lot No. 01P40B010, Standard Diagnostics, Inc., Gyeonggi-do, Republic of Korea) and anti-dengue IgM capture ELISA (ICMR-National Institute of Virology, Pune) were used to diagnose dengue as per the NVBDCP guidelines⁸. Further, the confirmed dengue cases were tested with anti-dengue IgG capture ELISA (Panbio Dengue IgG capture ELISA, Lot No. 01P10C001, Standard Diagnostics, Inc, Gyeonggi-do, Republic of Korea) for identifying the secondary dengue case.

A primary dengue case was defined as a laboratory-confirmed dengue infection with Dengue NS1 antigen ELISA and/or IgM capture ELISA positive and IgG capture ELISA negative. A secondary dengue case was defined as a laboratory-confirmed dengue infection with Dengue NS1 antigen ELISA and or IgM capture ELISA positive along with positive IgG capture ELISA.

This study was of surveillance in nature and was done with anonymized samples received by participating DHR/ICMR VRDLs and ICMR Institutes as part of routine virological surveillance and/or diagnosis. The ethical approval was taken from the respective institutions for the same.

Go to:

Results & Discussion

A total of 1372 serologically confirmed dengue cases were enrolled from all the centres during the study period. The median age of confirmed dengue cases was 24 yr (interquartile range (IQR) 16-34), and male to female ratio was 1.6:1 (Table).

Table

Demographic characteristics of primary and secondary dengue cases (n=1372)

Open in a separate window

IQR, interquartile range

Of the 1372 dengue cases, 897 (65%) were classified as primary dengue and 475 (35%) as secondary dengue. However, the proportion varied widely geographically, with Theni, Tamil Nadu; Tirupati, Andhra Pradesh and Udupi-Manipal, Karnataka reporting more than 65 per cent secondary dengue cases while Srinagar, Jammu and Kashmir reporting as low as 10 per cent secondary dengue cases (Table). The median age of primary dengue cases was 25 yr (IQR 17-35), and male to female ratio was 1.6:1. The median age of secondary dengue cases was 23 yr (IQR 13.5-34), and male to female ratio was 1.7:1 (Table). Secondary dengue was around 50 per cent among the children belonging to the age group 6-10 yr while it ranged between 20 and 43 per cent among other age groups (Table). There was no significant difference in the distribution of primary and secondary dengue concerning gender (Table). Only Theni site had a higher proportion of children among the confirmed dengue cases with respect to other centres.

A wide geographical variation was observed in the distribution of primary and secondary dengue cases in India. The study sites in the States of Andhra Pradesh, Karnataka and Tamil Nadu showed that two-thirds of the dengue cases were secondary while in other States, it was predominantly primary dengue. Analysis of age group did not reveal any significant pattern except that secondary dengue accounted for nearly half of dengue cases among 6-10 yr of age. However, most of the cases were from Theni, Tamil Nadu where secondary cases predominated. While confirmed dengue infection showed a male preponderance, there was no significant gender difference between the proportion of primary and secondary dengue cases.

Laboratory confirmation of secondary dengue infection case is challenging. While several methods are available, we used a well-established anti-dengue IgG capture ELISA^21,22 for identifying the secondary dengue cases among the confirmed dengue cases.

Since the first report of virologically confirmed dengue outbreak in India in 1963-1964 in Calcutta (now Kolkata)²³, dengue infections have become endemic and periodic outbreaks or epidemics have been reported from almost all parts of India^6,24 with co-circulation of multiple serotypes of dengue virus⁹. This has led to an increase in population pool with successive exposure to different serotypes of dengue leading to secondary dengue infection. This was evidenced by the current findings that several States from South India where dengue disease burden is high, had a significant proportion of clinical dengue infections presenting as secondary dengue cases.

Dengue was initially an urban disease which earlier affected the metropolitan cities of India, namely Calcutta (presently Kolkata), Delhi, Bangalore (presently Bengaluru) and Madras (presently Chennai)²⁵. Currently, the disease has spread to much-wider geographic locations as peri-urban, rural areas are being urbanized as part of the country's evolution. This is essentially due to the rapid urbanization of peri-urban and rural areas as part of the developmental activities which enables the expansion of vector breeding sites as well as wider exposure to the disease. Hence, the difference in the distribution of primary and secondary dengue in the country was seen.

Most reports on dengue infection published from India have not distinguished primary and secondary dengue. However, there are a few reports from the north as well as south India, reporting the varying proportions of primary and secondary dengue cases among laboratory-confirmed dengue^26,27,28 as has been observed by us.

Understanding the distribution of primary and secondary dengue is important on several counts. First, to identify geographical regions for strengthening clinical management of dengue cases to reduce mortality. Second, to identify the geographical areas with predominant secondary dengue cases for vaccine introduction as currently available dengue vaccine is recommended only in a population with predominant secondary dengue distribution²⁹. Third, to identify areas with limited spread or recent introduction to implement disease prevention and control strategies.

Our study had certain limitations also. First, the study period was brief and entirely from tertiary care centres leading to a bias in the inclusion of larger proportion of severe cases which might have influenced the proportion of secondary dengue cases. Second, only a single acute serum sample was used, and lack of convalescent serum would have affected case classification.

In conclusion, the distribution of primary and secondary dengue infection was widely varied geographically. Incorporating the primary and secondary dengue differentiation protocols as part of the existing national dengue surveillance programme could provide more representative dengue epidemiology in India.

Go to:

Acknowledgment

Authors acknowledge the support of Dr V.M. Katoch, former Secretary, Department of Health Research (DHR), Ministry of Health and Family Welfare, Government of India and Director General (DG), Indian Council of Medical Research (ICMR), Dr Soumya Swaminathan, former Joint Secretary DHR, Dr Sanjay Mehandale, Additional DG, ICMR, and Shri V.K. Gauba, former Joint Secretary DHR for their encouragement and support.

Go to:

Footnotes

Financial support & sponsorship: The study was funded by the DHR/ICMR Virus Research and Diagnostic Laboratories (VRDL) and ICMR Institutes.

Conflicts of Interest: None.

Go to:

References

1. Abe MAH, Marques SM, Costa PS. Dengue in children: From notification to death. Rev Paul Pediatr. 2012;30:263–71. [Google Scholar]
2. Horstick O, Tozan Y, Wilder-Smith A. Reviewing dengue: Still a neglected tropical disease? PLoS Negl Trop Dis. 2015;9:e0003632. [PMC free article] [PubMed] [Google Scholar]
3. South-East Asia Regional Office. Dengue. 2018. [accessed on May 5, 2018]. Available from: http://www.searo.who.int/entity/vector_borne_tropical_diseases/data/data_factsheet/en/
4. Cucunawangsih H, Lugito NPH. Trends of dengue disease epidemiology. Virology (Auckl) 2017;8 1178122X17695836. [PMC free article] [PubMed] [Google Scholar]
5. Shepard DS, Undurraga EA, Halasa YA. Economic and disease burden of dengue in Southeast Asia. PLoS Negl Trop Dis. 2013;7:e2055. [PMC free article] [PubMed] [Google Scholar]
6. Mutheneni SR, Morse AP, Caminade C, Upadhyayula SM. Dengue burden in India: Recent trends and importance of climatic parameters. Emerg Microbes Infect. 2017;6:e70. [PMC free article] [PubMed] [Google Scholar]
7. World Health Organization. Dengue guidelines for diagnosis, treatment, prevention and control. Geneva, Switzerland: World Health Organization; 2009. [accessed on May 5, 2018]. Available from: http://www.who.int/tdr/publications/documents/dengue-diagnosis.pdf. [Google Scholar]
8. National Vector Borne Disease Control Programme. [accessed on November 12, 2018]. Available from: http://www.nvbdcp.gov.in/index4.php?lang=1&level=0&linkid=431&lid=3715.
9. Shrivastava S, Tiraki D, Diwan A, Lalwani SK, Modak M, Mishra AC, et al. Co-circulation of all the four dengue virus serotypes and detection of a novel clade of DENV-4 (genotype I) virus in Pune, India during 2016 season. PLoS One. 2018;13:e0192672. [PMC free article] [PubMed] [Google Scholar]
10. Vaddadi K, Gandikota C, Jain PK, Prasad VSV, Venkataramana M. Co-circulation and co-infections of all dengue virus serotypes in Hyderabad, India 2014. Epidemiol Infect. 2017;145:2563–74. [PubMed] [Google Scholar]
11. Mishra B, Turuk J, Sahu SJ, Khajuria A, Kumar S, Dey A, et al. Co-circulation of all four dengue virus serotypes: First report from Odisha. Indian J Med Microbiol. 2017;35:293–5. [PubMed] [Google Scholar]
12. Waggoner JJ, Balmaseda A, Gresh L, Sahoo MK, Montoya M, Wang C, et al. Homotypic dengue virus reinfections in Nicaraguan children. J Infect Dis. 2016;214:986–93. [PMC free article] [PubMed] [Google Scholar]
13. Soo KM, Khalid B, Ching SM, Chee HY. Meta-analysis of dengue severity during infection by different dengue virus serotypes in primary and secondary infections. PLoS One. 2016;11:e0154760. [PMC free article] [PubMed] [Google Scholar]
14. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, et al. Antibody-dependent enhancement of severe dengue disease in humans. Science. 2017;358:929–32. [PMC free article] [PubMed] [Google Scholar]
15. Flipse J, Diosa-Toro MA, Hoornweg TE, van de Pol DP, Urcuqui-Inchima S, Smit JM, et al. Antibody-dependent enhancement of dengue virus infection in primary human macrophages; balancing higher fusion against antiviral responses. Sci Rep. 2016;6:29201. [PMC free article] [PubMed] [Google Scholar]
16. Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis: An integrated view. Clin Microbiol Rev. 2009;22:564–81. [PMC free article] [PubMed] [Google Scholar]
17. Rajapakse S. Dengue shock. J Emerg Trauma Shock. 2011;4:120–7. [PMC free article] [PubMed] [Google Scholar]
18. Singhi S, Kissoon N, Bansal A. Dengue and dengue hemorrhagic fever: Management issues in an intensive care unit. J Pediatr (Rio J) 2007;83:S22–35. [PubMed] [Google Scholar]
19. Aguiar M, Stollenwerk N, Halstead SB. The impact of the newly licensed dengue vaccine in endemic countries. PLoS Negl Trop Dis. 2016;10:e0005179. [PMC free article] [PubMed] [Google Scholar]
20. Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, et al. Cross-reacting antibodies enhance dengue virus infection in humans. Science. 2010;328:745–8. [PMC free article] [PubMed] [Google Scholar]
21. Sang CT, Hoon LS, Cuzzubbo A, Devine P. Clinical evaluation of a rapid immunochromatographic test for the diagnosis of dengue virus infection. Clin Diagn Lab Immunol. 1998;5:407–9. [PMC free article] [PubMed] [Google Scholar]
22. Laboratory Guidance and Diagnostic Testing, Dengue, CDC. [accessed on May 5, 2018]. Available from: https://www.cdc.gov/dengue/clinicallab/laboratory.html.
23. Gupta E, Ballani N. Current perspectives on the spread of dengue in India. Infect Drug Resist. 2014;7:337–42. [PMC free article] [PubMed] [Google Scholar]
24. Cecilia D. Current status of dengue and chikungunya in India. WHO South East Asia J Public Health. 2014;3:22–6. [PubMed] [Google Scholar]
25. Ganeshkumar P, Murhekar MV, Poornima V, Saravanakumar V, Sukumaran K, Anandaselvasankar A, et al. Dengue infection in India: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2018;12(7):e0006618. [PMC free article] [PubMed] [Google Scholar]
26. Changal KH, Raina AH, Raina A, Raina M, Bashir R, Latief M, et al. Differentiating secondary from primary dengue using IgG to IgM ratio in early dengue: An observational hospital based clinico-serological study from North India. BMC Infect Dis. 2016;16:715. [PMC free article] [PubMed] [Google Scholar]
27. Ajay Gopal K, Kalaivani V, Anandan H. Prevalence of dengue fever and comparative analysis of IgM and IgG antibodies in dengue fever in Thoothukudi- Southern Coastal city, Tamil Nadu. Ann Int Med Dent Res. 2016;2:4–7. [Google Scholar]
28. Mathew A, Rothman AL. Understanding the contribution of cellular immunity to dengue disease pathogenesis. Immunol Rev. 2008;225:300–13. [PubMed] [Google Scholar]
29. Imai N, Ferguson NM. Targeting vaccinations for the licensed dengue vaccine: Considerations for serosurvey design. PLoS One. 2018;13(6):e0199450. [PMC free article] [PubMed] [Google Scholar]

Articles from The Indian Journal of Medical Research are provided here courtesy of Wolters Kluwer -- Medknow Publications