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Review
Impediments of reporting dengue cases in India
Sushmita Das a,∗ , Asim Sarfraz a , Nitesh Jaiswal a , Pradeep Das b
a
b
Department of Microbiology, All-India Institute of Medical Sciences (AIIMS), Patna, India
Virology Unit, Rajendra Memorial Research Institute of Medical Sciences (ICMR), Patna, India
a r t i c l e
i n f o
Article history:
Received 19 March 2016
Received in revised form 2 January 2017
Accepted 4 February 2017
Keywords:
Dengue
Under-reporting
Surveillance
Vaccine
a b s t r a c t
Dengue has emerged as one of the most important mosquito-borne, fatal flaviviral disease, apparently
expanding as a global health problem. An estimated 3.6 billion people are at risk for dengue, with 50
million infections per year occurring across 100 countries globally. The annual number of dengue fever
cases in India is many times higher than it is officially reported. This under reporting would play a
major role in the government’s decision-making. Underestimating of the disease in India encumbers
its people from taking preventive measures, discourages efforts to ensnare the sources of the disease
and deliberates efforts for vaccine research. In this article, we highlight the probable impediments of
under reporting leading to its impact on national and global public health and also offer key remedies to
effectively address the issues across the clinics to the community level.
© 2017 The Authors. Published by Elsevier Limited. This is an open access article under the CC
BY-NC-ND license ( />
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Fallacies in WHO case definition? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Problems in laboratory diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Diagnostic facility network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Surveillance network . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Introduction
Dengue is a self-limited, flu-like systemic arboviral disease
transmitted between humans by Aedes mosquitoes. An estimated
3.6 billion people are at risk for dengue [1], with 50 million infections per year occurring across 100 countries globally [2]. Global
increase in urbanisation has facilitated endemicity of dengue, especially in Asia and parts of South America [3]. India experiences cyclic
epidemics of dengue over the years and the infection imposes for
the leading cause of hospitalisation and death among children in
the country [4]. Concurrent infection in some patients with multiple serotypes of dengue resulted from co-circulation of several
serotypes of the virus in India [5]. Unplanned urban development,
∗ Corresponding author. Fax: +91 612 2634379.
E-mail address: (S. Das).
poor water storage, sub-standard sanitary conditions, increasing international travels and rising role in global economy could
account for growing public health problem of dengue in India. A
recent review has reported that India alone contributes to 34%
(about 33 million infections) of the total global threat of dengue
leading to hyper-endemicity, prevailing mostly in urban areas [6].
Notably, India reported an annual average of 20,474 dengue cases
and 132 deaths by the disease in 2006–2012 [7]. Indian Health Ministry reported more than 138 Indian people killed by the dengue
virus during the first 10 months of 2013, with more than 55,000
cases recorded across the country. According to the National Vector Borne Disease Control Programme [NVBDCP] data, the worst
affected areas in India in 2015 were Delhi, Punjab, Haryana, Gujrat,
Karnataka and Kerala with a range of about 4000–15,000 cases
and 9–60 deaths [7]. However, the wide spread problem of under
reporting of dengue cases from India has come into focus very
/>1876-0341/© 2017 The Authors. Published by Elsevier Limited. This is an open access article under the CC BY-NC-ND license ( />
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recently and the real burden of dengue in the country is heavily
ignored [5,8]. Interestingly, a recent study reports that an average of six million people a year in India had a symptomatic illness
between 2006 and 2012 with dengue [5]. Shepard et al. retrospectively collected data from 10 medical colleges across five regions
of the country. The study reports annual average of 5,778,406 clinically diagnosed dengue cases during 2006–12; which is about 282
times greater than what is reported by the Indian Ministry of Health
[5]. The NVBDCP data shows increase of case reporting in 2015 compared to the previous year in several states; viz. Arunachal Pradesh,
Haryana, Punjab, Uttar Pradesh etc. [7].
Fallacies in WHO case definition?
Dengue patients present with myriad of symptom profile; the
commonest being non-specific fever, similar to other viral infections. Quite a significant number of people in India get infected
with dengue virus every year, especially during epidemics posing a
serious threat to the health system with regard to their preparedness in controlling this menace. Therefore, it is imperative to define
and categorise dengue symptoms for early diagnosis and helping
clinicians to recognise a case for reporting. The WHO case definition is the important tool for public health surveillance studies
for early intervention and hence can significantly reduce morbidity
and mortality. However, some researchers have reported of fallacies in the WHO case definition [9,10]. In India, this definition
holds great significance as health resources are very limited especially in remote areas and clinicians rely deeply on clinical diagnosis
aided by some basic laboratory tests. Notably, the WHO definition
is not straight forward and relies on tests that reflected the situation in south east Asia in the 1960s [9]. With the advent of time, the
application of this case definition required performance of different and repeated clinical tests (haematocrit, platelets, radiographs,
serum albumin or protein, microscopic analysis of urine). This poses
critical challenges for highly populated countries like India, with
limited resources of trained health professionals, referral laboratories, accessibility to radiological support, and facilities to detect
DHF by haematocrit and plasma leakage signs. Therefore, it was
suggested that when the WHO case detection criteria are strictly
followed, many severe cases, including those that involve shock and
fatality, may be overlooked [11]. However, this may impact numbers for DHF, but not of DF. This is also evident from studies that 18%
of severe dengue did not fulfil all four criteria considered necessary
for the diagnosis of DHF by WHO, whereas over-inflation of the DHF
figures was found when WHO provisional classification scheme
was used [12]. The newer version of WHO case definition will
permit for more sensitive management of the severe disease and
allowing comparison of data across all regions [13,14]. Clinicians
in the Pan American Health Organization (PAHO), Caribbean Epidemiology Center (CAREC) and World Health Organization (WHO)
have also developed alternative classifications to guide proper clinical management [15]. Considering the limited laboratory facilities
catering to the vast population and geographical extent in India,
the WHO/PAHO/CAREC modified classification (discussed in the
next section) [15] can be effectively implemented in India to aid
correct identification of cases, effective surveillance and disease
management.
However, it is also noteworthy to mention that the WHO case
definition helps in classification of the disease and its management
strategies rather than directly impacting the reporting process.
Majority of the dengue burden is due to DF; however, DHF only
accounts for 5–20% of the total cases. Proper clinical judgement,
extensive training and awareness of the disease among clinicians,
along with prompt laboratory detection is more important in the
reporting process rather than the WHO case definition which is
mainly focussed for the management of the types. However, passive surveillance using case definitions would lack specificity due
to similarity of dengue fever with several other fever [discussed
below].
Problems in laboratory diagnosis
Diagnosis by the clinician is the most important aspect that
accounts for case reporting in India. The problem compounds
as the clinical symptoms of dengue disease vary case by case.
According to the WHO/PAHO guidelines, one clinical manoeuvre
(tourniquet test) and two laboratory studies (platelet counts and
hematocrit) should be performed for the diagnosis of dengue haemorrhagic fever in general laboratory settings [15]. In endemic areas,
physicians do not conclusively diagnose dengue based on specific
laboratory criteria, but instead use the dengue classical triad of
symptoms of fever, rash and headache, a positive tourniquet test
and the dengue classical triad observed in the complete blood
count [Thrombocytopenia (platelet = 65,000), atypical lymphocytosis (atypical lymphocyte = 8%) and haemoconcentration (Hct = 47%)
[16]. However, the problems with tourniquet test had also contributed to the under reporting. A positive Tourniquet test (TT)
reflects haemorrhagic tendency and capillary fragility. In several
observational outbreak studies, the sensitivity of the TT in DHF
varied from as low as 0% [17] to 57% [18]. Notably, studies of
Phuong et al. and Lucas et al. reported variable results for positive TT between DHF (47% and 27% positive, respectively) and DF
(39% and 26% positive, respectively) [12,19]. Moreover, percent
positive TT was also noted in dengue-like febrile illnesses, e.g. 21%
[18], 12% [19] and 5% [12]. Interestingly, previous reports suggest
that no haemorrhagic tendencies have been observed in 32–46%
of DHF cases in India [20,21]. Therefore, inclusion of positive TT
could underestimate dengue occurrences in India. A modified TT
with an elastic cuff was suggested [22], which can be easily adapted
by the Indian clinicians for better reporting of DHF. Either TT positive or negative, the clinician should be well trained to suspect
dengue and report bother DF and DHF. However, only depending
on clinical diagnosis would not suffice the needs of holistic reporting. Viruses can evolve by gaining random mutations to subvert the
host immune system and remain undetectable. Dengue virus is also
not an exception; mostly when the infections are asymptomatic or
apparent presenting as fevers of unknown origin.
Inclusion of increased haematocrit and decreasing platelet
count in diagnostic criteria can also lead to misdiagnosis especially where laboratory diagnosis of dengue is difficult to conduct.
The diagnosis of dengue haemorrhagic fever in the Indian population with the rise of haematocrit does not help much due to
the high prevalence of anaemia [23]. Variable results for thrombocytopenia in DHF had been repeatedly reported; ranging from
8.6% in Indonesia [24], 48% in Sri Lanka [19], 54% in Bangladesh
[25], 70% in India [26] and 78% in Cuba [27] outbreak studies.
These great ranges of variability can result in false reporting of
dengue cases due to non-specific haemorrhagic conditions. Of note,
several studies suggest that dengue cases can also be misdiagnosed as other tropical diseases [28–31], as concurrent infection
of dengue with other infections is possible. Studies from India also
confirm this fact [32]. A study of 118 cases, who fulfilled the clinical
WHO criteria for DF/DHF, were evaluated for serological evidence
of dengue, hantavirus, chikungunya, Rickettsia typhi, Rickettsia
tsutsugamushi, rubella virus, influenza A virus, and Leptospira.
Results suggested that only 49% were serologically tested positive
for dengue infection, while the rest were dengue-negative [28].
Therefore, differential diagnosis of dengue fever from other forms
of fever in Influenza, acute viral exanthems (Measles, Rubella), Leptospirosis, several forms of purpura or viral haemorrhagic diseases,
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septicemia and acute meningococcemia, has been widely proposed
in the WHO/PAHO guidelines [15]. On the other hand, dengue
IgM antibodies also cross-react with other flaviviruses [Japanese
encephalitis, St. Louis encephalitis and yellow fever] occurring in
the same endemic zone [33,34], which is very common in India.
Differentiation of dengue infection from other infectious diseases
may require management with specific anti-microbial therapy [35].
These complicated conditions need to be defined more elaborately
to aid the correct differential diagnosis, timely management and
reporting of cases.
The use of good dengue diagnostic tools is critical for laboratory
confirmation of DHF/DSS, counting the number of case fatalities,
establishing which strains are involved, and to calculate the total
incidence following epidemics. According to the Pan American
Health Organization (PAHO) guidelines, 80% of all dengue cases
have detectable IgM antibody by day five of illness, and 93–99%
of cases have detectable IgM by day six to ten of illness, which may
then remain detectable for over 90 days [15]. However, the abundant use of spurious, non-validated serological tests with variable
sensitivity and specificity [36,37], leads to lack of adherence to test
algorithms, increase the load of under diagnosed cases and under
reporting [5]. Recently developed molecular tools for dengue diagnosis like Nucleic acid sequence based amplification assay (NASBA)
can also be utilised, provided that the cost can be provided by the
Indian government as these tests are expensive. Studies suggest
that antigen detection through virus isolation and RT-PCR were
the most sensitive tests during the early period of illness whereas
beyond third day, IgM antibody detection was found to be the most
sensitive method of dengue diagnosis [38].
Differences in laboratory diagnostic methods for confirmation
of dengue add up to the problem of under reporting in India. Therefore, stringent quality control regulations are needed to be followed
by the government for enabling these tests to be evaluated by the
WHO-approved laboratories under the global network of dengue
laboratories programme. Instead of using variable diagnostic rules,
we should strictly follow the CDC testing algorithm for diagnosis
and reporting of dengue cases in India at specialised referral laboratories. Taken together, a combination of different tests should be
introduced following the CDC algorithm for testing and reporting
dengue cases in India [39] and the suggested algorithm should be
as follows: (a) a positive real-time PCR result is a definite proof of
current infection and it also confirms the infecting serotype, (b) IgM
antibody capture ELISA [MAC ELISA], (c) IgG ELISA can be used for
the detection of a past dengue infection, (d) NS1 ELISA can detect
acute dengue infections and (e) Plaque Reduction and Neutralization Test (PRNT) must be used when specific serological diagnostic
is required.
3
for the presence of anti-dengue antibodies. A district level sentinel
laboratory with clinicians can better monitor any outbreak to cater
to the high population load. This can be a more practical approach
in improving reporting in India. Notably, to scale up the efforts,
there are now 350 Sentinel Surveillance hospitals across India with
laboratory support for dengue diagnostics linked to a network of 14
Apex Referral laboratories that have advanced diagnostic facilities
for back up support. In recent years, several new rapid diagnostic
techniques have been developed for dengue diagnosis. The rapid
test kits used in India are manufactured by different manufacturers’, viz. Panbio, Standard Diagnostics, J. Mitra, Reckon diagnostics
etc. and have variable sensitivities and specificities [40]. As per this
study, only the Panbio IgM capture RDT was found to be reliable to
be used for dengue outbreaks. However, an ‘ideal’ dengue test, as
advocated by WHO expert group, is yet to be reported for case management, outbreak investigations and surveillance purposes [41].
Several commercial kits are available in India for serological testing with wide variable sensitivity and specificity. The widely used
serological tests in India, dengue IgM or IgG, are not a direct diagnosis of the presence of the virus, but rather the measurement of
host response. The most suitable option would be to use Panbio
IgM ELISA kits and in-house MAC ELISA testing simultaneously for
testing of dengue. An in-house reference laboratory can also be setup to monitor the tests of the sentinel sites and also validate the
surveillance data.
However, in India, antibodies to all epitopes display varying
degrees of cross-reactivity across the dengue serotypes and other
flaviviruses residing in the same location [33,34], increasing the
limitations for these serological testing. Furthermore, nonspecific
results are also observed in patients due to previous exposure to
malaria, leptospirosis etc. febrile diseases. Therefore, it is important
to find out the vector potential and prevalence of hemeagglutination inhibiting antibodies against flaviviruses through regular
periodic serosurveys to gauge the risk of the infection in an area.
However, lack of quality control and quality assurance of laboratory
investigations, erroneous specimen collection and transportation
leads to inconsistent data across clinics, aggravating the problem
further. Undoubtedly, human errors can occur when the workload
is high during phases of epidemics in poor quality laboratories in
community healthcare centres or district-level PHCs.
The diagnosis of dengue infection is generally confirmed by
a variety of commercial or in-house serological protocols. The
need to survey the accuracy of dengue serological diagnostics,
through QA/QC process, is very important for reporting in a country. Therefore, an organised external quality assurance set-up of
dengue serological practice in diagnostic laboratories is required
to evaluate the scope of improvement for detection sensitivity of
anti-dengue virus IgM antibodies against the commercial antibody
capture ELISA tests.
Diagnostic facility network
Evidently the National Vector Borne Disease Control Programme
(NVBDCP) captures only 0.35% of the clinically diagnosed dengue
cases in India [5]. This is important to mention that NVBDCP only
reports the laboratory confirmed dengue cases. It is plausible that
significant under reporting of highly endemic dengue can occur
owing to this decision of laboratory-based surveillance with about
1 billion population. Therefore, an alternate option can be developing a robust specialised laboratory network in India to predict,
detect, investigate, monitor and evaluate dengue outbreaks and
timely management of cases. Only a fixed percent of suspected
cases can help to extrapolate the estimated case load of the country.
Another option could be to design a state-wise surveillance
model with random selection of about 15–20 sentinel villages from
each district. Human sera can be randomly collected monthly from
inhabitants and subjected to serological and/or molecular detection
Surveillance network
According to the WHO, “Surveillance is the corner stone of public
health security” [42]. Quality and timely information are essential
for its prevention and control of dengue. However, infrastructure limitations impede effective surveillance in many developing
countries, including India. Access to timely and reliable epidemiologic and entomologic information is necessary for decision making
process and facilitate the dealings between the participating stakeholders. The new International Health Regulations (IHR, 2005)
requires detection of elevated disease and death rates, instant
implementation of control measures, and reporting any event to
WHO representing public health emergency of international concern [43].
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In most developing countries, human, laboratory, and infrastructure limitations impede effective surveillance. Unfortunately,
these countries do not meet core surveillance and response capacities for dengue [44]. The lack of several operative components
and control programmes is the most important shortcoming in
dengue control in India. The sensitivity of NS1 by ELISA is higher
(60–75%) compared with NS1 RDT (38–71%) [45]. This has been
noted that non-government corporate hospitals in India merely
diagnose dengue by Rapid tests (RDTs) which has been questioned and not approved by the NVBDCP. Thus, over 80% of dengue
patients, reporting at private hospital remained under reported to
the national surveillance system [8].
Recently, the routine dengue surveillance systems in six countries (Brazil, Bolivia, Cambodia, Indonesia, Maldives and Thailand)
were evaluated [46]. All routine reporting systems were found to
be useful for trend monitoring and national planning. Interestingly, use of alert signals or additional surveillance components to
increase timeliness or sensitivity (e.g. as sentinel sites or syndromic
surveillance components) had great capacity for early outbreak
detection. Recently, a web-based, geographically enabled, dengue
integral surveillance system (Dengue-GIS) was developed for the
nation-wide collection, integration, analysis and reporting of georeferenced epidemiologic, entomologic, and control interventions
data in Mexico [47]. This GIS-based model system for dengue
surveillance helps to integrate the interoperable platform for gathering basic information for problem appraisal and devise future
planning for controlling the disease. This type of web-based, electronic data management and data sharing platform can be adapted
by India for preventing under reporting of cases by effective surveillance of dengue in the country. Moreover, situation awareness can
be achieved by the novel approach of “syndromic surveillance” that
uses pre-diagnostic data, non-specific presentations and statistical
algorithms to detect epidemics earlier than the traditional surveillance systems leading to wider public health benefits [48]. Increase
in case reporting in dengue can be anticipated by traditional
surveillance programme followed by a broad deliberative process
of syndromic surveillance and publication of statistical projections.
Moreover, the Indian system can also follow the PAHO/WHO ‘Integrated Management Strategy for Dengue prevention and control
(IMS-Dengue)’ [15] that consists of successive application of laboratory participation in support of the epidemiological study of dengue
outbreaks. The widely approved IMS-Dengue strategy is designed
to integrate key components for dengue prevention and control,
viz. social communication, epidemiological surveillance, laboratory
diagnosis, environment management, clinical case management,
and Integrated Vector Management, at the national, sub-regional
and regional levels [15].
Conclusion
Under reporting of cases also seems to be politically manipulated to forge effectiveness of control programmes [49]. With this
type of practices and lack of wide-spread effective sentinel surveillance, the problem cannot be fully evaluated and controlled. For
addressing these problems, the Indian government should strictly
follow the recommendations of dengue surveillance experts. The
recommendations are: (i) reporting of dengue cases to the government should be made mandatory in all dengue endemic countries;
(ii) electronic reporting systems should be developed and used
at all areas; (iii) the government dengue surveillance data should
include age-stratified data of incidence, hospitalisation rates and
deaths; (iv) additional system sensitivity checking studies should
be performed; (v) diagnostic laboratories should share expertise
and data; (vi) dengue antigen tests should be used in patients with
fever for four days or less, whereas antibody tests should be used
after day 4 to diagnose dengue; and (vii) the national surveillance
systems should aim for early detection and prediction of dengue
outbreaks [50]. Part of the purpose of a surveillance system is to
indicate how the situation in one year compares with that in other
years. Therefore, this goal requires consistency and stability in the
system. In recommending improvements to inform vaccine introduction, it is also important to find if a crosswalk could be developed
between historical data, which would be needed for comparison,
and possible new data could be achieved.
In recommending a series of improvements to the surveillance
system, we would also suggest mandatory reporting that exists
in many endemic countries. However, enforcement is particularly
challenging for ambulatory cases and in the private sector. Dengue
is typically an urban disease in India. Of interest, the annual dengue
epidemic coincides with the beginning of India’s busiest tourist
season. The dengue vaccine development programme is underway
and the unique pathogen–host interaction complicates the process.
Moreover, adequate reliable country-specific disease surveillance
data is the major requirement for assessing the situation prior to
introduction of vaccine to a community and monitoring for its effectiveness and safety after introduction. Whatever the true dengue
burden in India, there is consensus on the fact that the numbers
are rising. The severe problem of under reporting of dengue cases
will lead to severe problems in introduction of a vaccine in India.
Quality dengue surveillance data are very important for estimating
dengue disease burden and to measure the impact of preventive
intervention [51,52]. Exact national dengue burden is important
to inform the decision makers of vaccine price and could also
enable proper negotiations between stakeholders when considering the incorporation of the dengue vaccine into the National
Immunization Program. Therefore, assessing the true burden of
dengue cases in India should be a priority of the government. The
government should choose some type of systematic sampling of
health facilities with statistically designed weighting factors to
adjust for under reporting. A cross-sectional study was conducted
in India among persons visiting a tertiary care hospital and systematic sampling procedure of health facilities was adopted [53].
The study findings suggest that future campaigns should involve
health education through active involvement of health workers
and community representatives, with the use of mass media and
health education programmes for community awareness. Thus,
understanding people’s perception and their practices could help
in identifying target areas and in formulating strategies to combat dengue outbreaks. The NVBDCP also plans to raise awareness
of the disease and vector through media channels including TV,
radio, and cinema. Communities are working together to identify
spots that encourage unabated reproduction of the vector Aedes.
Periodicity in dengue occurrence is dependent on vector biology.
During non-transmission season, the virus may be maintained in
nature by vector mosquitoes through transovarial transmission or
in some ‘hidden reservoirs’ [54]. Therefore, it is also equally important to run an effective entomological surveillance and search for
all possible reservoirs in India.
Funding
The authors did not receive any funding for this work.
Conflict of interest
The authors declare no conflict of interest.
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