To reform the control strategies and take timely intervention to prevent future epidemics, an epidemiological study on the proportion of both asymptomatic and symptomatic dengue infections in selected population was conducted
jo ur nal home p age: www.elsev ier .com/ locate /ac ta t ropica
n epidemiological study of dengue in Delhi, India
umar Vikrama, B.N Nagpala,∗, Veena Pandeb, Aruna Srivastavaa, Rekha Saxenaa,nup Anvikara, Aparup Dasa, Himmat Singha, Anushritaa, Sanjeev K. Guptaa, N.R. Tuli c,livier Telled, N.K. Yadavc, Neena Valechaa, Richard Pauld
National Institute of Malaria Research (ICMR), Delhi, IndiaKumaun University, Nainital, IndiaMunicipal Corporation of Delhi, IndiaInstitut Pasteur, Paris, France
r t i c l e i n f o
rticle history:eceived 5 June 2015eceived in revised form9 September 2015ccepted 27 September 2015vailable online 1 October 2015
Delhi, the capital of India, is an important metropolitan hub for major financial and socioculturalexchanges, offering challenging threats to current public health infrastructure. In recent past, an upsurgeof dengue cases in Delhi posed a significant menace to the existing dengue control policies. To reformthe control strategies and take timely intervention to prevent future epidemics, an epidemiological studyon the proportion of both asymptomatic and symptomatic dengue infections in selected population wasconducted. The aim of the study was to investigate and assess the epidemiology of dengue infection andto estimate the proportion of asymptomatic and symptomatic dengue infections in Delhi. In this study,around 50 confirmed dengue cases, a total of 2125 individuals as household and neighbourhood contacts,with or without dengue febrile illness, were finger pricked and serologically detected as dengue positiveor negative using SD Duo Bioline Rapid Diagnostic Test (SD Inc, Korea) with NS1, IgM & IgG combo test,which detected dengue virus antigen and antibodies to dengue virus in human blood. Out of 2125 individ-uals, 768 (36.1%) individuals showed positive dengue test with past (25.5%), primary (1.88%) or secondary(8.8%) dengue infections. Higher percentage of IgG was found in age groups 15–24 years and 25–50 years(36% each). Infants (<1 year) presented higher incidence of new infections (22% of NS1 + IgM positives) ascompared to adults. Further analysis revealed that out of the 226 newly infected cases (including NS1 andIgM positives), 142 (63%) were asymptomatic and 84 (37%) were symptomatic, as per WHO guidelines.Our findings also suggest that out of the total population screened, 10.6% dengue infection was eitherprimary or secondary. On the basis of these results, it may be hypothesized that there are large number of
asymptomatic dengue infections in the community as compared to reported symptomatic cases in Delhi.For the effective control of dengue transmission in such community like Delhi where dengue epidemicshave frequently been encountered, it is essential to ascertain the proportion of asymptomatic dengueinfections which may act as a reservoir for dengue transmission, as well as threat for developing denguehaemorrhagic fever (DHF).
Dengue infection is one of the most common arbo-viral diseasesorldwide. It is prevalent in most of the tropical and sub-tropical
ountries and is caused by four serotypes (DEN-1, DEN-2, DEN-3nd DEN-4) in humans. All four serotypes can cause a spectrumf illness ranging from inapparent or mild febrile dengue fever to
∗ Corresponding author at: GIS, Taxonomy and OVBD Division, National Institutef Malaria Research, New Delhi – 110 077.
severe and fatal haemorrhagic disease (Gubler, 1998; Whitehornand Farrar, 2010; Innis, 1995). It is transmitted mainly by Aedesaegypti mosquito and also by Aedes albopictus (Whitehorn andFarrar, 2010). Dengue fever represents high disease burden inendemic countries (Gubler and Meltzer, 1999; Beatty et al., 2011;Donald et al., 2013). An estimated 3.6 billion people live in high riskareas worldwide. It is also presumed that over 230 million bear theload of infection and approximately 2 million suffer with dengue
fever and its severe forms with 21,000 deaths as reported (Beattyet al., 2008).
The incidence of dengue fever (DF) and dengue hemor-rhagic fever (DHF) has increased dramatically over the last four
ecades and approximately 50% of world’s population is at risk ofengue virus infection (DENV) (Bennett et al., 2003; World Healthrganization, 1997,2004). High proximity of densely populatedreas provides ample opportunities for the transmission of dis-ases. Asia’s contribution is 70% (approx 67 million) toward thepparent infections in the comprehensive global disease burden.ndia contributes 34% to the global infection which amounts tobout 33 million infections (Chakravarti et al., 2012; Wichmannt al., 2011; Kakkar, 2012). The prolific increase in incidence ratever last decade has been connected to societal changes such asopulation growth and increasing urbanization. Human populationlikely including infected hosts) and domestic & international trav-lers are constantly introducing new vectors and pathogens intoovel geographical areas.
DENV infection is endemic in many parts of India, and epidemicsre more frequent. Out of last six years, 2013 witnessed the worstengue outbreak in India with 75,808 dengue cases and 193 deathss reported by National Vector Borne Disease Control ProgrammeNVBDCP). Since 1967, Delhi has experienced several outbreaks ofENV infection (Broor et al., 1997; Dar et al., 1999) with the last
eported 5574 cases by Municiple Corporation of Delhi (MCD) in013. The DENV infection often shows no clinical manifestationsr mild illness in humans and is referred to as asymptomatic ornapparent DENV infection (Simmons et al., 2012; World Healthrganization, 2009; Endy et al., 2011).
Currently, we know very little about the epidemiology ofubclinical infections such as frequency, factors determining theymptomatic/asymptomatic outcome of infection, infectivity toosquitoes, duration of infection from symptomatic episode. The
ole of individuals with asymptomatic infection in spreading theirus needs to be addressed. Such epidemiological informations crucial to predict local dengue epidemiology as asymptomaticENV infection represents dengue disease burden that goes unde-
ected (Halstead et al., 1969; Deller et al., 1967). Bhatt et al.stimated 96 million apparent DENV infections and 217–392 mil-ion inapparent infections worldwide in 2010 (Bhatt et al., 2013).hus the estimation of disease burden has been identified as one ofmportant factors essential before the introduction of newly devel-ped vaccines in a population (Mahoney and Maynard, 1999). Theata on disease burden provides the rationale for effective deci-ion making to properly allocate resources, both with respect tohe needed regions for a specific disease and region with relativeurden of various diseases.
The present study has included household and neighbourhoodontacts of an index case to enable us to determine the proportionf asymptomatic and symptomatic infections in the community.hese findings of the study would assist in formulation of policyor appropriate control of disease in Delhi.
. Materials & methods
.1. Study sites
The National Capital Territory of Delhi covers an area of484 km2 (573 sq mi), of which 783 km2 (302 sq mi) is designatedural and 700 km2 (270 sq mi) urban, therefore, making it theargest city in terms of area in the country (Mohan, 2002). Accordingo the 2011 Census of India, the population of Delhi is 16,753,235Census of India, 2011). The corresponding population density was1,297 persons per km2, with a sex ratio of 866 women per 1000en, and a literacy rate of 86.34% (Economic Survey of Delhi
005–2006). In Delhi, due to migration of 6.87 lakhs (approx) peo-le from 2001 to 2011, the population has increased and this hasade Delhi as one of the fastest growing cities in the world (Eco-
omic Survey of Delhi, 2012–13).
ca 153 (2016) 21–27
The study was conducted in collaboration with Pasteur Insti-tut, Paris, France and Municipal Corporation of Delhi (MCD). MCDassisted in selection of 18 localities (suburbs) and their categoriza-tion as Low, Medium and High income group on the basis of socioeconomic status, family annual income and housing pattern definedby Delhi Development Authority (DDA). Six localties each from LowIncome Group (LIG) i.e. Mangolpuri, Budha Vihar, Prem Nagar, Hast-sal Village, Najafgarh (Jai Vihar), Sangam Vihar; Medium IncomeGroup (MIG) i.e. Bapanagar, Madhu Vihar, Palam Colony, KotalaMubarkPur, Raghubir Nagar, Rani Garden and High Income Group(HIG) i.e. Paschim Vihar, Rajouri Garden, RK Puram, Kirti Nagar,Vasant Kunj, Mukherjee Nagar were selected, as shown in the map(Fig. 1).
2.2. Study design
A community based descriptive study was conducted in theidentified localities during the period June– December, 2013. Forthe diagnosis of dengue cases, MCD had identified 37 sentinelhospitals in Delhi to facilitate management of such cases. Fifty con-firmed cases of dengue reported by these sentinel hospitals, fromthe identified 18 localities, covering maximum zones of Delhi, wereinvestigated. For the purpose of the study, index case is definedas any serologically positive dengue case reported by MCD. Afterthe identification of index cases, all household and neighbourhoodcontacts of a dengue case were screened for asymptomatic DENVinfection. Household contacts i.e. the index case and co-habitingfamily members and neighborhood contacts i.e. those residentsliving in close vicinity (within 200 m radius of the index case)were included in the study (Mammen et al., 2008). SymptomaticDENV infection was defined as fever with at least two symp-toms of dengue (myalgia, headache, retro-ocular pain, arthralgiaand rash) as per WHO guidelines (World Health Organization,2009). Asymptomatic DENV infection—no clinical signs or symp-toms of disease as mentioned above in symptomatic infection(World Health Organization, 2009).
The aim and procedure of the study was briefly described toall the participants and their legal guardians prior to taking theirconsent for the enrollment in this study. Upon enrollment, finger-prick blood samples were obtained from all consenting individualsand serologically tested. Each individual was also administered aquestionnaire including presence or absence of any dengue likesymptoms. All serologically positive symptomic dengue infectionswere reffered to respective sentinel hospitals for further man-agement while individuals with asymptomatic infections wereprovided appropriate counselling.
2.3. Serological test
The rapid detection of DENV infection was performed by com-mercially available kits provided by Pasteur Institut, Paris, France.Total 2125 individuals (household and neighborhood individuals)with or without dengue febrile illness, were finger pricked andserologically diagnosed as dengue positive or negative by usingSD BIOLINE Dengue Duo combo device (Standard Diagnostic Inc.,Korea). The kit provides two windows, one detection of NS1 anti-gen and other for dengue specific IgM and IgG antibodies. All tests inthis study were carried out in accordance with the manufacturer’sinstructions and results were examined and interpreted accord-ingly; the blood sample of individuals containing IgM or/and NS1were considered as primary/acute dengue infection, i.e. they wereinfected by DENV for the first time. The tests indicating IgG + IgM/
NS1 were considered as secondary infection, i.e. such patient wasalready infected by dengue in past. If the individual was detectedpositive for IgG but negative for other tests (IgM and NS1), wereconsidered as past infection or secondary DENV infection with
K. Vikram et al. / Acta Tropica 153 (2016) 21–27 23
18 loc
sddsdmsa1a
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Fig. 1. Map of Delhi showing
ymptoms. The presence color line (control) in each result win-ow indicates a negative result. NS1 antigen is found from the firstay and up to 9 days after onset of fever in sample of primary orecondary dengue infected patients. Usually IgM does not becomeetectable until 5–10 days after the onset of illness in cases of pri-ary dengue infection and until 4–5 days after onset of illness in
econdary infections. In primary infections, IgG appear the 14th daynd persist for life. Secondary infections show that IgG rise with in–2 days after the onset of symptoms and induce IgM responsefter 20 days of infection (as per SD Bioline Dengue Kit manual).
Limitation of the study: Those individuals in which only IgGas found positive but without any symptoms of DENV infectionere considered as past infections, while those having symptoms
f DENV infection were considered as secondary infections.
.4. Entomological surveys
A house-to house entomological survey was carried out in ordero detect A. aegypti breeding in all containers in domestic anderidomestic areas of all selected localities by standard (WHO)ntomological techniques. The larvae were collected from eachocality, by using dipping and pipetting methods and emergence
as done in laboratory. The emerged adult mosquitoes were iden-ified by using the standard keys of Barraud (1934). The House indexHI), Breteau index (BI), Container index (CI) and Pupal index (PI)ere also calculated from these localities.
.5. Statistical analysis
The data was entered in Excel 2007 and SPSS software package
version 20) was used for statistical analysis. Group comparison forrevalence of IgG and IgM and other clinical symptoms was donesing ANOVA.Odds ratio was calculated to ascertain the odds ofetting asymptomatic patients in three income groups.
alities included in the study.
3. Results
A total of 2125 individuals as household and neighbourhoodcontacts consisted of 932 males and 1193 females from 18 localitiesagainst the 50 index cases of Delhi were tested and analyzed withthe NS1–IgM–IgG RDT kit. The data was further grouped into threeincome groups i.e. High, Medium and Low. In LIG 711 individulascomprised of 314 males and 397 females, in MIG 870 individualscomprised of 374 males and 496 females, in HIG 544 individu-las comprised of 244 males and 300 females were serologicallytested for dengue infection. Out of total 2125 individulas tested, 768individuals—comprising 59% (451/768) females and 41% (317/768)males—were found positive for either IgG, IgM or NS1 test. Wenoted that sero-prevalence of the DENV infection was equal to36.14% of all tested individuals (768/2125). Out of the these, 542(25.5% of all individuals tested) cases were past infections as theywere only IgG positive without any symptoms, 40 primary infec-tions (1.88%) and 186 (8.8%) secondary dengue infections. Total 226individuals(29.4%) were found positive for either primary or sec-ondary dengue infection. It is to note that 63% of the primary andsecondary infections were asymptomatic(Table 1).
The study showed that individuals people in the age group of15–24 and 25–50 had maximum (36% each) past or secondary infec-tions. Individuals aged >50 years and young children aged 9–14years had 35% past or secondary infections. Infants <1 year oldshowed least (17%) past or secondary infections. On the contrary,primary infection was found highest (22%) in the age group <1year old. The proportion of primary cases generally declined withincrease in age (Fig. 2).
Out of 711 individuals tested from LIG, 212 were past infectionand 103 were primary/secondary out of which 72 were asymp-tomatic infections. For MIG, 232 were past infections and 81 were
either primary or secondary out of which 45 were asymptomatic.While for HIG, 98 were past infections, 42 were either primary orsecondary out of which 25 were asymptomatic. Odds of gettingasymptomatic DENV infections in three income groups was esti-
24 K. Vikram et al. / Acta Tropica 153 (2016) 21–27
Table 1Number and percentage of test positives to IgG, IgM and NS1 tests.
Test positives No. of individuals % of total Sympt. (S) Asympt. (AS) Category of infection Asymptomatic (per category) %
ated. The odds of getting asymptomatic infections in LIG was 1.85imes greater than MIG (OR = 1.85, 95% CI- 1.01–3.41). The odds ofetting asymptomatic infections in HIG was 1.7 times greater thanIG (OR = 1.17, 95% CI- 0.55–2.50). While comparing High Income
roup to Low income it was found that odds of getting asymp-omatic infections in LIG was 0.63 times greater than HIG (OR = 0.63,5% CI- 0.30–1.33).
Further analysis of the spread over gender and various ageroups was performed and it was found that both symptomatic andsymptomatic patients were found maximum in females belongingo the age group of 25–50 years (Fig. 3).
For 50 index cases, 155 individuals were included in house-old study and 1970 individuals were included in neighborhoodtudy. Out of 155 individuals in household study, 95 (61.3%) wereound test positive either for IgG, IgM or NS1 and of these 75 weregG positive indicating past infections and rest 20 were primaryr secondary infections. Of the total positive cases, 13 were asymp-omatic (65%) & 7 (35%) were symptomatic. In neighborhood study,ut of 1970 individuals, 673 (34%) were tested positive either forgG, IgM or NS1 and out of which 467 were IgG positive. In other
ords, out of 1970 individuals tested, 23.7% had past infectionsnd rest 206 (10.5%) were either primary or secondary infectionsith 129 asymptomatic (63%) & 77 (37%) symptomatic infections.
he difference of asymptomatic and symptomatic infections inoth household and neighbourhood contacts was not significantX2 = 0.04 (1), p < .05 = 0.83).
Data collected for 18 localities was pooled for 3 income groups
nd 6 localities each were binned as per income groups. Betweenhe groups ANOVA was conducted to study the difference in preva-ence of clinical symptoms. A significant difference for myalgiap = 0.04) and insignificant difference in rashes, severe headache,
nd NS1 positive per age group.
retro-orbital pain (p > .05) inferred that rashes, severe headacheand retro-orbital pain were commonly observed in all three incomegroups. Although the independent between groups ANOVA yieldeda significant difference in prevelance of IgM F (2,2122) = 18.163,p = .000 as well as IgG F (2,2122) = 22.447, p = .000 inferring thatprevelance of primary/ past or secondary dengue infections variedamong these income groups
All localities were found positive for A. aegypti mosquitoes irre-spective of their income group but breeding was higher in lowincome group. In HIG, the observed annual HI, BI, CI and PI were3.22, 7.41, 3.44 and 0.91 respectively. In MIG, the observed annualHI, BI, CI and PI were 4.33, 8.45, 4.14 and 1.21 respectively. Simi-larly, in LIG, annual HI, BI, CI and PI were calculated as 4.54, 9.45,5.08 and 1.51.
4. Discussion
In present study, we have demonstrated that IgG was positive in34.2% of all tested individuals (either past or secondary infections).This is less than the percentage detected in Kolkata, where 73.51%of tested individuals from 2005 to 2007 were IgG positive (Hati,2009). In Rio de Janeiro (Honorio et al., 2009) similar percentage ofpast antibodies were found in the population (between 67 and 85%of positives IgG). This shows that population of Delhi has been lessexposed to dengue virus than some of other high endemic cities.We can observe that with the increasing age of the individuals,
the positivity for IgG increased accept in age group >50 indicatingthe past exposure of dengue infection. On the other hand the newinfection was observed more in young children and declined withthe advancement of age.
K. Vikram et al. / Acta Tropica 153 (2016) 21–27 25
Fig. 3. Proportion of symptomatic and asymptomatic cases over various age groups in males and females.
Fig. 4. Mean lowest temperature recorded during day in Rio (Brasil), Bangkok (Thaïland), Kolkata and Delhi (India).
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The lesser proportion of past infections can be linked to climaticactors. Urban areas like Kolkata, Bangkok or Rio de Janeiro haveelatively high temperatures during inter epidemic season (Fig. 4),hile Delhi experiences very low temperatures (under 15 ◦C) dur-
ng winter i.e. interepidemic season (November– February). Thisold temperature impacts vector abundance and its ability to trans-it virus during interepidemic period. Considering the extreme
emperature during summer (when temperature is above 45 ◦C),he temporal window for dengue virus to spread is observed to beonsiderably less in comparison to other cities where round theear transmission is observed (along with strong peaks as seenfter monsoon period). This confirms that Delhi reports more casesith an efficient surveillance system as compared with other indian
ities (Mumbai, Chennai, Kolkata) which are officialy less affectedut have a favourable climatic environment for round the yearransmission. On the contrary, population of Delhi poses lessermmunity to the virus. Hence future consequences can be bigger
han what was observed as temperature continues to rise duringinter seasons opening new avenues to the DENV.
Another important outcome of our study is to reveal the largehare of asymptomatic infections compared with symptomatic
infections. These results infer similar rate of asymptomatic DENVinfections as reported in previous studies carried out in Thailand,Singapore (ratio of asymptomatic/symptomatic infections between2:1 and 10:1) (Burke et al., 1988; Wilder-Smith et al., 2009) and alsowith the findings of other countries that large proportion of denguecases being asymptomatic which might lead to silent transmissionof the disease (Chen et al., 1996; Teixeira et al., 2002). Thus, onthe basis of these surveys it’s reasonable to say that the ratio ofasymptomatic/symptomatic DENV infection varies extensively. Inour study the type of infecting DENV was not determined since onlyserologic testing was performed.
In dengue, the asymptomatic cases are more frequent thanthe symptomatic cases although their role as potential reser-voir is not known but their relative number varies according tothe geographical areas, the epidemiological context and individ-ual immunological attributes as exemplified by different surveys(Balmaseda et al., 2006; Halstead, 2006). In contrast, another
prospective study was conducted in Kamphaeng Phet, North-ern Thailand, between 1998 and 2000 and the incidence ofasymptomatic DENV infection was reported nearly equal to thesymptomatic infections (Endy et al., 2002).
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To assess the eventual role of asymptomatic DENV infectionsn the transmission of this disease, the quantification of viremiaevel in such cases is important and remains to be evaluated. Iningapore, Health authorities suggested that “it is likely, althought’s not proven that viremia is lower and shorter in duration insymptomatic persons than in symptomatic persons” (Wilder-mith et al., 2009). In another study which was performed inambodia during 2006 and 2007, authors stated that “the levelf viremia in asymptomatic DENV infections was not significantlyower than in all dengue confirmed cases (p = 0.145)” (Duong et al.,011). On the basis of this study we can hypothesize that viremia
evel of some asymptomatic DENV infections match the lowest levelf viremia of symptomatic cases. Keeping this thing in mind, it isogically possible that such asymptomatic DENV infections can acts source of new foci for disease transmission, if competent Aedesosquito colonies are existing in the areas with high asymptomaticENV infections. This finding illustrates the complexity of DENV
ransmission in a population and the potential of asymptomaticENV infections to existing burden. Our results also showed that
he rate of secondary infection (8.7%) is 4.5 folds higher than thatf primary infection (1.8%) which indicates that these cases aret higher risk of getting dengue haemorrhagic fever (DHF)/denguehock syndrome (DSS) (Vaughn et al., 2000).
Annually, approximately 70,000 people migrate to Delhi fromther states for personal economic progress. The rapid urbaniza-ion and development in Delhi provides ample opportunities for theoor, semiskilled and unskilled rural population resulting in theiremand in secondary and tertiary economic sector. Such popula-ion is pulled in cities like Delhi and are forced to reside in extremelynhygienic, unauthorized & slums designated areas. High volumef human migration leads to unplanned urbanization in these areasacking adequate facilities & infrastructure for water supply and
aste management (Economic Survey of Delhi, 2012–13).In recent years, the risk of dengue in Delhi has increased due
o poor water management leading to improper water storageractices in such areas. A. aegypti, readily exploits such watertorage containers as larval habitats leading to proliferation ofedes-breeding sites (Vikram et al., 2015a,b). Such factors playn important role in increasing the incidence of dengue feverMillennium Ecosystem Assessment Report, 2005). The inter-
ittent supply of water, increasing numbers of water storageontainers and improper solid waste management are the majoroncerns for dengue and vector control programmes in city of Delhihich would need social mobilization at large for community par-
icipation for effective control of dengue.
. Conclusion
The main aim of this study was to identify the proportion ofsymptomatic DENV infection in localities of Delhi. On the basis ofur data, we estimated the proportion to be 63% among individualsf all 18 localities of Delhi. The risk of acquiring DENV infection isignificantly higher in residents of low income group as comparedo medium income groups and high income groups of Delhi. Ourndings suggests that 10.6% of the total population screened con-
ered DENV infection either primary or secondary. On the basis ofhese results, we can hypothesize the unestimated dengue infectionhouldered by 1.6 million people residing in Delhi.
This study facilitated collection of clinical information and rapidetection of DENV infection in Delhi metropolitan area. The resultsf this study can be helpful in planning and implementing ade-
uate preventative measures against DENV infection in the city ofelhi. There is a need for further study to demonstrate the rolef asymptomatic dengue infection in transmission of DENV in theommunity.
ca 153 (2016) 21–27
Ethics
The study protocol and consent forms were approved by theScientific Advisory Committee and Ethics Review Committee of theNational Institute of Malaria Research, New Delhi, India.
Acknowlegment
Authors are thankful to Paster Institut, Paris, France for the fund-ing support ANR. We are also thankful to MCD for helping us inselection of study sites in Delhi. We thank the entire field stafffor their careful performance in serological testing and data col-lection. We would like to thank Ms Shruti Bahadur for giving hercritical overview to the manuscript. Acknowledgement is also dueto Mr. Mrityunjay Prasad and Mr. Rakesh Jacob for data manage-ment. Institute Publication Committee is acknowledged for givingconsent for publication of manuscript vide Approval No. 027/2015.
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