Background
Dengue has become hyperendemic in many parts of India [
1,
2]. The disease is being reported from an increasing number of states, and the number of cases reported to the National Vector Borne Disease Control Program (NVBDCP) has been increasing over recent years. In 2010, the incidence of reported dengue was 2.3 cases per 100,000 individuals, increasing to 11.7 per 100,000 in 2017 [
3]. In 2016, for the first time, more than 100,000 cases were reported (total: 129,166 with 245 deaths). However, reported cases represent only the tip of the iceberg, and the true disease burden is likely significantly higher [
4]. Mild cases are particularly susceptible to under-reporting [
5]. Notably, a global cartographic modeling study by Bhatt et al. provided comprehensive global dengue burden estimates, and projected > 32 million cases in India in 2010 [
6]. A complementary study by Stanaway and colleagues from the Institute for Health Metrics and Evaluation, using verbal autopsy, vital registration and surveillance data estimated 18.6 million cases in 2013 [
7]. A local estimate focusing on the city of Chennai (population of 4.7 million) used seroprevalence data to estimate 89,700 new infections and 138,100 secondary infections every year [
8]. This distinction is important because dengue has four serotypes; and second infections are more commonly severe [
2].
In the absence of incidence data including cases which were not recognized as dengue and those who did not access healthcare, seroprevalence data provide an alternative indicator of transmission intensity. [
9] Seroprevalence describes historical infection and, when derived with standardized diagnostics, is a relatively unbiased indicator of viral exposure when compared with surveillance data. Age-stratified surveys provide data from which one can derive force of infection (FOI) estimates and therefore understand the infection rate [
10,
11]. Understanding endemicity is important for a wide range of public health decision-making and, given that the world’s first dengue vaccine’s efficacy is associated with baseline serostatus, population level seroprevalence is an important predictor of population-level vaccine impact [
12].
In India, as elsewhere, few studies have documented the seroprevalence of dengue in healthy subjects. In the earliest, Padbidri et al. measured exposure to various arboviruses, including dengue serotype-2, in the Andaman and Nicobar Islands. This 1988–89 study found 25.4% of subjects with neutralizing antibodies against dengue type-2 [
13]. More recently, Oruganti et al. examined the presence of antibodies in healthy individuals attending routine health check-ups in Hyderabad, Andhra Pradesh by indirect IgG ELISA [
14]. They found 89.5% of subjects aged 19 to 70 years of age were seropositive for dengue: 100% of those 40 years of age or older had seroconverted. In another community-based study Rodriguez et al. estimated seroprevalence in 5–40 year old healthy subjects in 2011 in Chennai [
8] They demonstrated that 93% of subjects in this age group had been exposed to dengue at least once in their lifetime, a level of exposure which was consistent with long-term endemic circulation.
We previously published results of a community-based multi-centric, cross-sectional study (DNG10) on dengue seroprevalence in Indian children aged 5–10 years (CTRI/2011/12/002243 and NCT01477671) [
15]. The study was conducted at 8 sites in 6 distinct urban and rural areas in 2011–12. Overall seroprevalence was 59.6% and increased with age. We also described monotypic serological profiles demonstrating that all four dengue serotypes circulate in India.
No previous analysis has assessed dengue FOI and its variability across multiple Indian sites. Here, we conducted a secondary analysis to estimate dengue FOI in healthy children in different geographic regions of India. In combination with census data, this enabled estimation of the number of primary dengue infections occurring annually. We also predicted seroprevalence in children aged 1–10 years of age and the ages at which 50 and 70% of children have experienced at least 1 dengue infection, to inform vaccination policy.
Discussion
We conducted a secondary analysis of dengue seroprevalence data from pediatric populations in India. We found that among dengue-naïve children, 11.9% experience their first dengue infection every year. This means that 50% of children at these sites are infected by dengue at least once by the age of 5.8 years, and 70% of them are infected by the age of 10.1 years, although there was significant variation in FOI between sites. Our study was not the first to report estimates of dengue FOI in Indian populations. Imai et al. used data from 1988 to 89 to estimate FOI of 0.2% (95% CI: 0.1–0.7%) in the Andaman and Nicobar Islands [
11,
13]. Rodriguez et al. estimated that the dengue FOI in Chennai from 2004 to 2011 was 23% (95% CI: 16–30%) [
8]. The Andaman and Nicobar Islands are a unique geography; that study detected antibodies against only one of the four serotypes of dengue (dengue serotype- 2), and was conducted at a time when dengue endemicity was probably much lower than today. Rodriguez et al. sampled probabilistically from Chennai and found high FOI in pediatric populations. We identified similar FOI from Mumbai, a city with similar ecological conditions: both are coastal with similar ranges of temperature and high levels of unplanned infrastructure, construction sites and slum housing.
We assumed these sites experienced constant FOI for the 5 years prior to sample collection, representing the time period when study subjects were infected. A different approach would consider FOI to be time-varying, in which constant FOI is assumed only for a certain period [
9]. Our assumption is broadly consistent with other studies that have found age-constant models adequately describe age-related seroprevalence data over a 6–9 year time horizon [
8,
10]. The goodness-of-fit of our constant model provided some evidence that our assumption of constant FOI is valid for four of our six sites, but to more completely explore age-varying FOI, data from a larger age range of subjects would be needed. Further, a visual inspection of Fig.
1 suggests some deviation between the modelled values and the observed data especially at more extreme ages. This may be due to cyclical dengue outbreaks in the respective geographies. For example, there were documented outbreaks in Mumbai in 2003, and in Wardha and Hyderabad in 2004 [
20‐
22]. Children were disproportionately affected in Mumbai and Wardha which might provide an explanation for outliers in our observations i.e. higher seroprevalence in older children at these sites.
Similar dengue FOI has been estimated from seroprevalence data from dengue hyperendemic Southeast Asian countries. Prayitno et al. estimated the FOI in 1–18 year old Indonesian children in 2014 to be 14.0% [
23]. Imai et al. estimated FOI in Thailand using data from 2000 to 01 in school children to be 15.7% [
11]. Using 2008–09 data in children under 12 from Colombo, Sri Lanka, Tam et al. estimated the FOI to be 14.1% [
10]. Consequently, and because reported dengue incidence rates in India are so low, we calculated the resulting number of primary dengue infections, estimating > 17 million primary infections in India, annually. Other researchers have estimated between 30 and 50% of primary infections are symptomatic [
24] which would equate to ~ 5 – ~ 8.5 million cases annually in children aged < 11. When considering cases in other age groups, and following secondary or subsequent infections; these case numbers are broadly within the same range as those reported in Bhatt et al., that India suffers ~ 35 million symptomatic episodes per year, and provide additional evidence of a very significant level of under-reporting of dengue in India [
6]. More detailed estimates of symptomatic episodes are limited by our lack of secondary infection history data; and more complex mathematical modeling was beyond the scope of our study.
This is the first study to estimate FOI in India using data from multiple geographies; urban and rural, and from multiple states. Our results point towards a high dengue FOI in children in India, which logically equates to a significant number of secondary infections and burden of symptomatic disease in this age group. With improved surveillance, we may begin to see incidence rates of dengue in India comparable to those seen in other hyperendemic countries. Longitudinal cohort studies, ideally incorporating fever surveillance and serological surveys, to more accurately describe the incidence of dengue and changing infection patterns with age, are needed [
25].
Our study has several limitations. The original seroprevalence samples were collected in 2011–12 and the FOI we have derived corresponds to cumulative exposure experienced by study subjects in the years of their life before this time. Numbers of reported cases of dengue in India have increased significantly from 2011. [
3] This can be attributed to several factors including population movement and increased exposure to the virus; improved dengue surveillance, increasing awareness among healthcare practitioners, availability of confirmatory diagnostics and improvement in access to healthcare resulting in increased reporting [
4,
26]. As demonstrated by Rodriguez et al.in Chennai, it is also very likely that FOI has increased in India over recent decades [
8]. Despite their geographical spread, study sites were not sampled to be representative of the whole of India and our extrapolation to the national level is a strong assumption which should be validated with more recent data from other sites. DNG10 also used convenience sampling for enrollment of subjects, a method which does not guarantee representativeness. We used IgG ELISA to ascertain infection history, an assay with known cross-reactivity to antibodies against other flaviviruses. However, dengue infection was confirmed by the plaque reduction neutralization test (PRNT) and > 97% of IgG positive samples were also positive by PRNT. Further, Japanese encephalitis (JE) seropositivity measured at the study sites using IgG ELISA, was 13.6% overall and with a similar trend at the site level as dengue seroprevalence (data not shown). Its confounding influence is therefore likely to be minimal. Because IgG ELISA is unable to distinguish primary from secondary infections we measured only the rate of primary seroconversion, and are unable to quantify the burden of secondary and subsequent dengue infections.
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