Archives of Virology (2025) 170:48

https://doi.org/10.1007/s00705-025-06235-3

REVIEW

Dengue: epidemiology, diagnosis methods, treatment options, and

prevention strategies
Dimple Kothari1 · Niralee Patel1 · Ashok Kumar Bishoyi1

Received: 10 June 2024 / Accepted: 3 December 2024

© The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature 2025

Abstract
Dengue is an arboviral disease caused by dengue virus, which is mostly found in tropical regions, and the number of
human cases has increased dramatically since 2000, with 5.2 million cases reported in 2019, according to WHO reports,
70% of which were in Southeast Asia, the Western Pacific, and Asia. Dengue infection can result in a wide range of clini-
cal manifestations, ranging from fever to severe dengue shock syndrome, which can be fatal, particularly in those with
secondary dengue. This review of the aetiology of dengue fever examines the complex interactions between the virus and
the immune system and the interaction between viral and host factors and also covers outbreaks, the severity of disease
caused by different serotypes, and methods for diagnosis of dengue, such as serological tests, nucleic acid amplification
tests, and ELISA assays for detecting the NS1 antigen. Current treatment options and prevention strategies, including
vector control measures, environmental interventions, and insect repellents are also discussed. This review highlights
the challenges involved in developing a dengue vaccine, which is complicated by the need for an efficient and balanced
immune response against all genotypes of the four serotypes.

Abbreviations ELISA Enzyme-linked immunosorbent assay

RNA Ribonucleic acid HI Hemagglutination inhibition
DENV Dengue virus NT Neutralization test
DHF Dengue haemorrhagic fever CF Complement-fixation test
GOARN Global Outbreak Alert and Response PRNT Plaque reduction neutralization test
Network FDA Food and Drug Administration
SEA Southeast Asia CYD-TDV Chimeric yellow fever virus DENV tetrava-
DENV 1 Dengue virus 1 lent dengue vaccine
DENV 2 Dengue virus 2 LATVs Live-attenuated tetravalent dengue vaccine
DENV 3 Dengue virus 3 NIH National Institutes of Health
DENV 4 Dengue virus 4 ADE Antibody-dependent enhancement
PCR Polymerase chain reaction CR Complement receptor
qRT-PCR Quantitative reverse transcription PCR DEG Differentially expressed gene
SD Severe dengue
CP Convalescent patient
NK Natural killer cell
Handling Editor: Eiji Morita ACOT Acyl-CoA thioesterase
Niralee Patel
[email protected]
Introduction
Dimple Kothari
[email protected]
Dengue virus (DENV) is an arthropod-borne virus that is
Ashok Kumar Bishoyi
[email protected] spread by Aedes aegypti and Aedes albopictus mosquitoes
in subtropical and tropical regions. Aedes aegypti is a perid-
1
Department of Microbiology, Faculty of Science, Marwadi omestic species that is mostly found in urban areas, whereas
University, Rajkot, Gujarat 360003, India

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 48 Page 2 of 14 D. Kothari et al.

Fig. 1 Structure of dengue virus

Table 1 Functions of the structural and non-structural proteins of den-

Aedes albopictus, whose populations are expanding rapidly, gue virus
is a potential vector in rural areas [1]. Clinical features of Gene/ Length Function
dengue include headache, arthralgia, fever, thrombocyto- protein
penia, skin rash, leukopenia, and increased liver activity. It C 100 aa Genome encapsulation
has become a global public health threat over the past seven Pre M/M 166/75 aa Pre M/M functions as a cap-like structure
that prevents the E protein from inducing
decades [2]. About 50% of the global population is at risk
premature fusion.
of DENV infection, and over the past 50 years, the number E 493–495 E mediates viral binding and fusion.
of reported DENV infection cases has increased by 30-fold aa Domain III contains determinants of host
in both rural and urban areas across the world [3]. The risk range, tropism, and virulence.
factors for severe dengue include young age, individual NS1 46 aa NS1 inhibits complement activation and
genetic characteristics, and previous infection with a differ- is involved in viral replication.
NS2A 218 aa NS2A coordinates the switching between
ent dengue virus serotype [4]. In suburban and urban areas, RNA packaging and replication and is
mosquitoes breed in containers and thrive in warm, humid involved in antagonism of interferon
conditions [5]. production
It has been estimated that, globally, there are 390 mil- NS2B 130 aa NS2B is a cofactor for NS3 involved in
lion dengue fever cases and around 22,000 associated deaths the structural activation of the DENV
serine protease.
each year [4, 6, 7]. The World Health Organization (WHO)
NS3 618 aa NS3 is a multifunctional protein with
estimates that there were 5.52 billion cases of dengue fever chymotrypsin-like serine protease, RNA
from 2000 to 2019 [8], with 40–50% of the population living helicase, and RNA triphosphatase (RTP/
in areas where dengue fever is common. In Asia, America, NTPase) activity that is involved in poly-
protein processing and RNA replication.
and Africa, dengue is a major disease with a prevalence of
NS4A 150 aa NS4A causes membrane modifications
70%, 16%, and 14%, respectively, and DENV is considered that are essential for virus replication.
endemic in over 100 countries [5, 8]. NS4B 245–249 NS4B facilitates viral RNA replication
DENV is a spherical, positive-sense, single-stranded aa by interacting directly with NS3 and
RNA virus. Its genome is approximately 10–11 kb in length hinders interferon-induced signalling.
and has a capped structure, and DENV virions have a diam- NS5 900 aa NS5 is a bifunctional enzyme with meth-
yltransferase and RNA-dependent RNA
eter of about 50 nm [9]. The structure of dengue virus and its
polymerase activity
genome are depicted in Fig. 1. The genome encodes a single
polyprotein of 3.4 kDa, which is cleaved into three struc-
tural proteins (capsid, membrane precursor, and envelope) both the structural and non-structural proteins are listed in
and seven non-structural proteins (NS1, NS2A, NS2B, NS3, Table 1.
NS4A, NS4B, and NS5) [10]. The single open reading frame
is flanked by 5' and 3' untranslated regions ranging from 95 Virus transmission cycle
to 135 nt and 114 to 650 nt in length, respectively [11]. The
non-structural proteins, which are not incorporated into the Aedes aegypti is an efficient vector of arboviruses that is
virion, are responsible for immune evasion and replication highly anthropophilic and feeds multiple times before com-
of the viral genome [12]. The functions and composition of pleting the oogenesis process [10]. The eggs of female
mosquitoes are often deposited in tires, flower pots, or

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water-filled buckets, which can serve as breeding sites for DENV invades the host cell through endocytosis. Within
mosquitoes that facilitate the spread of the virus [13]. The the cell, the viral membrane fuses with the endosomal mem-
transmission cycle of DENV and symptoms of dengue are brane to discharge the viral genetic material into the cyto-
depicted in Fig. 2. plasm, where it is translated from viral RNA into 10 proteins.
Humans are the primary amplification host of DENV, Virus particles are assembled on the surface of the endoplas-
which is spread by female mosquitoes when they ingest the mic reticulum and mature in the Golgi network before they
blood of infected individuals. The virus replicates in the are released from the cell in their infectious form [17]. The
mid-gut of the mosquito and then spreads to secondary tis- replication cycle of dengue virus is illustrated in Fig. 3.
sue such as the salivary gland. There is an extrinsic incuba-
tion period of 8–12 days between the time of ingestion and DENV outbreaks
transmission of the virus to a new recipient [10]. During this
period, virions are released in the saliva, allowing the virus In the Eastern Mediterranean, the Americas, Southeast
to be transmitted to the human host [14]. Asia, Africa, and the Western Pacific, DENV is endemic in
100–128 countries, with a large number of fatal cases [18].
Pathophysiology of dengue WHO reported around 12 million cases of dengue illness
and dengue haemorrhagic fever (DHF) in 1998, with 3448
After an infected mosquito bites the host, there is an incuba- fatal cases, resulting in fatality rates of 0.5–3.5% in Asian
tion period of up to 2 weeks (commonly 5 to 7 days) before countries [19]. Globally, DENV infects around 400 million
the symptoms develop. The pathogenesis of dengue is influ- individuals each year, with 100 million experiencing clinical
enced by a number of viral and host factors. There are three symptoms [20]. Dengue outbreaks were reported in Indone-
phases to the illness: an initial phase of febrile illness, a crit- sia and Egypt already in 1779, and, in 2003, dengue fever
ical phase starting about 4–5 days after the onset of fever, was reported in Bangladesh, Thailand, Indonesia, India, Sri
and a spontaneous recovery phase [15]. During the fever Lanka, the Maldives, Myanmar, and Timor-Leste [10, 21].
phase, the infected individual develops a high temperature Bhutan reported its first DENV outbreak in 2004, and the
(39 to 40°C) with symptoms such as headache, vomiting, Global Outbreak Alert and Response Network (GOARN)
nausea, myalgia, and joint pain. The critical phase occurs reported an outbreak in Timor-Leste with a fatality rate of
about 42–76 hours after the onset of illness [10]. Based about 3.55% in 2005. Nepal reported its first dengue fever
on symptoms alone, DENV infections are difficult to dif- case in 2006. From 2001 to 2007, 1299 people suffered from
ferentiate from other infectious diseases such as malaria, DHF, with a fatality rate of 1.2% [10]. From 2010 to 2016,
leptospirosis, influenza, measles, typhoid, or rickettsia, or approximately 1.6 million dengue cases were reported in
coronavirus or Zika infections [16]. South and North America, 49,000 of which were severe.
The largest outbreak was in 2016, when 2.38 million cases
Fig. 2 Transmission cycle of
DENV

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Fig. 3 The replication cycle of

dengue virus

were reported. In the years 2010 to 2020, there was a large Status of dengue in India
increase in the hospitalization of children between 10 and
19 years of age due to dengue in the US territory of Puerto In India, the capital city of Delhi has seen a concerning
Rico [22]. In 2014, Japan experienced its first outbreak in 70 increase in dengue cases, but no fatalities have been reported
years [23]. At that time, Brazil recorded its highest number recently. Typically, dengue cases are reported in India dur-
of cases, around 1.5 million, which then increased to 3 mil- ing July and November. However, the financial hub Mum-
lion cases by 2019 [24]. DENV transmission has also been bai has also seen a notable increase in dengue infections,
documented in various European countries, indicating that it and other states, including Andhra Pradesh, Tamil Nadu,
is not limited to the tropics [25]. A study conducted between Telangana, Karnataka, Maharashtra, West Bengal, and
1990 and 2019 found that dengue illness had increased by Uttarakhand, are also reporting cases. The National Vector
85.47% worldwide during that period [26]. Afghanistan, Borne Disease Control Program (NVBDCP) has made pub-
Côte d'Ivoire, Tanzania, Benin, the Democratic Republic lic official data indicating that, as of August 30, 2022, India
of the Congo, Burkina Faso, Angola, and many European had recorded 30,627 dengue cases, 12 of which were fatal.
countries are among the countries into which DENV has However, in the previous year, 2021, there had been 93,245
expanded recently [18, 27, 28]. According to the European cases, 36 of which were fatal [32].
Centre for Disease Prevention and Control (ECDC), more
than 7.5 million dengue cases and over 3000 deaths have Association of serotypes with disease severity
been reported in 73 countries. The current status of dengue
is illustrated in Fig. 4. Dengue viruses that infect humans can be classified into four
The dengue burden is higher in South and Southeast serotypes: DENV-1, DENV-2, DENV-3, and DENV-4. The
Asian countries, including Bangladesh, India, Pakistan, existence of multiple serotypes plays an important role in
Nepal, Sri Lanka, and the Maldives, with 1.3 billion cases the commonly observed phenomenon that secondary DENV
worldwide [21, 27, 29, 30]. Data from 2015–2019 indi- infections often cause more-severe disease than do primary
cated a 46% increase in the number of dengue cases, from infections. This is believed to be due in part to antibody-
451,442 to 658,301. However, there was a slight decrease in dependent enhancement (ADE), in which serotype-specific
mortality during that period, with the number of fatal cases antibodies are formed during a primary infection and con-
decreasing from 1584 to 1555 [8]. Together, China, Malay- fer long-lasting immunity against the infecting serotype,
sia, Japan, Singapore, Indonesia, Korea, Myanmar, Thai- but, when the individual is infected later with a different
land, Vietnam, Laos, the Philippines, Cambodia, and other serotype, the antibodies generated are unable to neutralize
East Asian countries account for 60% of dengue cases [31]. the virus and instead combine with it to form immune com-
plexes that infect cells more efficiently than the virus alone.

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Fig. 4 Current status of dengue worldwide

During a secondary infection, experimental animals show a phenotypic variation, survival of strains, and adaptation of
higher peak of virus production than during the first infec- the host, which affects the epidemiology of the virus and
tion [33]. The envelope proteins of the four dengue virus supports its circulation in endemic regions [40]. The intro-
serotypes differ in their amino acid sequences by about 30% duction of various serotypes and their persistence over time
[34]. Furthermore, the severity of infection also depends on increases the risk of clinical re-infection with different sero-
which serotype caused the first infection. Anantapreecha and types [41].
colleagues reported that primary infection with DENV-1 is DENV-2 is constantly changing due to its high rate of
associated with more-severe secondary infections when mutation and migration, resulting in the emergence of new
compared to other serotypes [35]. In a study evaluating the strains. The concurrent circulation of various strains of the
immunogenic effects of different dengue serotypes, it was virus in a region can lead to a larger number of epidemic
found that the NS4A, NS4B, and E proteins of DENV-2 events than are caused by the other three serotypes [42–45].
and DENV-3 elicited stronger cytokine responses, includ- There are five different genotypes of DENV-2: American or
ing TNF-α and IFN-γ responses, when compared to other genotype I, which is prevalent in the Caribbean and South
serotypes [36]. On the other hand, DENV-4 was found to be Pacific; cosmopolitan or genotype II, in Taino, the Philip-
less immunogenic [37]. pines, New Guinea, and Thailand; Asian-American or geno-
DENV-2, which causes infections worldwide and is type III, in Vietnam, Jamaica, and Thailand; Asian I and II
more commonly associated with major diseases than the or genotype IV, in Indonesia, the Seychelles, Burkina Faso,
other serotypes, is circulating extensively in South America Sri Lanka, and Vietnam; and sylvatic or genotype V, in rural
[3, 38] and has been associated with an increased mortal- areas of Africa [46]. The distribution of these genotypes is
ity rate in Brazil [24]. The risk of severe disease increases shown in Fig. 5.
with the co-circulation of multiple DENV serotypes due to Widespread travel has contributed to the high genetic
the potential for infection with different serotypes [39]. Sev- diversity of all four dengue serotypes, and this has impor-
eral studies have provided information on the global spread tant implications for immunity or vaccine efficacy [47–50].
of DENV-2, highlighting the need for further research on The number of arbovirus infections can be reduced by

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Fig. 5 Genotypes of DENV-2

monitoring their ongoing spread worldwide, investigating indicate that complement overactivation contributes to DHF
the possible causes of their recurrence, and conducting epi- pathogenesis. During the acute phase of the disease, soluble
demiological surveys in endemic areas [51]. immune complexes (IC) formed by circulating DENV and
DENV-specific antibodies have been detected in patients'
Genes and enzymes involved in dengue circulation [58]. These complexes can be opsonised with
pathogenesis complement molecules and rapidly captured by comple-
ment receptors (CR1) on red blood cells (RBCs). The com-
The pathogenesis of dengue is influenced by immune plement-fixing ICs adhere to the cells until IC-bound RBCs
responses to DENV infection. Individuals with DHF often pass through the spleen and liver, where IC is removed
exhibit elevated levels of circulating cytokines and chemo- from the RBCs and deposited in these tissues [57]. While
kines, along with extensive immune activation [52, 53]. The this mechanism is crucial for viral clearance from the cir-
heightened risk of severe dengue during secondary infec- culation, DENV, in the form of an IC, potentially exploits
tion is partly explained by antibody-dependent enhance- this opportunity to infect Fc-receptor-bearing cells in the
ment (ADE) of infection and partly by the phenomenon liver, potentially disseminating the infection. However, this
of T-cell "original antigenic sin", in which memory B and hypothesis requires further investigation. It is worth noting
T cells activated by the initial serotype may show reduced that soluble IC activates complement less efficiently than
affinity for epitopes of the subsequent infecting serotype large immune complexes where anti-DENV antibodies bind
[54]. ADE occurs when antibodies from a previous infec- to dengue antigens present on DENV-infected cell surfaces
tion bind to viral particles of a different DENV serotype in [59].
the current infection, but instead of effectively neutralising Microarray technology enables the analysis of differ-
the infecting virus, these antibodies facilitate viral entry entially expressed genes (DEGs) during dengue infection,
into Fc-receptor-bearing immune cells, such as monocytes revealing virus-host interactions and identifying biomarkers
and dendritic cells, thereby increasing viral replication and for dengue and severe dengue through genome analysis of
the overall viral burden [54, 55]. Although the complement host gene expression in peripheral blood [60]. However, the
system plays a protective role in limiting viral replication, gene sets identified thus far have not demonstrated universal
its excessive activation can lead to more-severe disease applicability. It is therefore useful to examine differences
by intensifying the inflammatory response. Initial studies in gene expression signatures between four pairs of groups:
showed the occurrence of extensive complement activation (1) DF and healthy controls (CO), (2) SD and healthy CO,
and a significant decrease in the levels of plasma comple- (3) convalescent patients (CP) and DF, and (4) CP and SD.
ment proteins in DHF patients [56]. Plasma from patients MICB has been identified as a crucial gene in dengue
with severe dengue during a secondary infection with a dif- infection. This gene produces an activating ligand for natu-
ferent serotype showed elevated levels of complement ana- ral killer cells (NK) and potentially CD8 T lymphocytes.
phylatoxins (C3a and C5a) and the terminal complement Changes in MICB levels can affect the antiviral capabilities
complex (sC5b-9), suggesting a link between complement of NK cells, thereby increasing the risk of severe dengue
activation and dengue severity [57]. These observations (SD) [61]. MICB is upregulated in the DF vs. CO and SD

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vs. CO scenarios, with a 0.9-fold change, whilst in the CP can vary significantly among the DENV serotypes. For
vs. DF and CP vs. SD scenarios it is downregulated, with instance, DENV-2 has been associated with more-severe
a 0.1-fold change. Toll-like receptors (TLRs) are essential disease manifestations compared to DENV-1, partly due to
for recognising pathogens and activating inflammatory differences in how these serotypes interact with the host's
pathways during dengue infection [62]. TLR6 gene expres- immune system and the role of enzymes involved in these
sion decreases in DF vs. CO and SD vs. CO comparisons, processes [68].
with fold changes of -1.325 and − 1.422, respectively. In The upregulation of diverse lipid species plays a crucial
contrast, TLR7 gene expression increases by 1.3-fold in role in the life cycle of DENV serotype 2 (DENV2). Nota-
both cases. TLR7, which recognises single-stranded RNA bly, host phospholipids and sphingolipids become more
viruses, modulates host immune responses by detecting abundant during infection, some of which facilitate viral
viral uridine-containing single-strand RNAs. Among the replication, while other are involved in the host response to
immune-response-associated genes, enhanced expression of infection [69]. These molecules originate from fatty acyl-
TNFSF13B has been observed, with a 1.27- and 1.39-fold CoAs, which are fatty acids that have undergone esterifi-
change in DF vs. CO and SD vs. CO comparisons, respec- cation to coenzyme A (CoA). The acyl-CoA thioesterases
tively. Conversely, TNFRSF10B, C, and 14 showed reduced (ACOTs) are a family of hydrolases that regulate the intra-
expression. TNFSF13B is linked to B cell activation and cellular equilibrium between fatty acyl-CoAs and free fatty
is involved in the immune response to live attenuated tet- acids (FFAs). These enzymes catalyse the hydrolysis of fatty
ravalent dengue vaccine candidates [63]. Furthermore, acyl-CoA to release FFA and coenzyme A [70]. siRNA-
TNFRSF17, which is critical for regulating humoral immu- mediated loss-of-function studies have shown that simulta-
nity and promoting B cell survival, showed upregulation, neous knockdown of type I ACOTs 1 and 2 significantly
with 3.8- and 2.8-fold changes in SD vs. CO and DF vs. CO enhanced the release of infectious DENV2 particles. Con-
comparisons [37]. A group of genes encoding nuclear fac- versely, isolated knockdown of ACOT2 markedly reduced
tors 1A, 1B, and 1C display downregulation in SD vs. CO DENV2 protein translation, genome replication, and the
and DF vs. CO comparisons. release of infectious virus. Similarly, the loss of the function
of ACOT7, a mitochondrial type II ACOT, has been shown
Enzyme specificity and its role in differences to suppress DENV2 replication [70].
between dengue serotypes By identifying the specific types of enzymes involved
and their mechanisms of action, new insights can be gained
Enzymes play a multifaceted role in the context of dengue that might lead to innovative therapeutic approaches as well
serotypes, influencing both viral replication and the host as a better understanding of dengue pathogenesis.
immune response. Each of the four DENV serotypes has
a unique enzymatic profile that influences its pathogenic- Diagnosis
ity and the immune response it elicits [64]. One of the key
viral enzymes is the NS2B-NS3 protease, which is essen- A serological test can be used up to 7 days after symptoms
tial for viral replication. This enzyme complex cleaves the start to appear to diagnose dengue fever and to determine the
viral polyprotein into the functional proteins necessary for serotype of the virus. These tests are sufficiently sensitive to
genome replication and the assembly of new virions and is detect IgM and IgG at least four days after infection. Numer-
therefore a potential target for antiviral drug development ous methods for diagnosis of dengue have been described
[65]. Inhibitors of the NS2B-NS3 protease have shown in the WHO guidelines, including serological tests, nucleic
promise in preclinical studies, highlighting the potential acid detection, antigen detection, and haematological tests.
for therapeutic interventions that could mitigate the impact Although these methods can be used for rapid diagnosis in
of dengue fever [66]. In addition to viral enzymes, cellular the field, they require expertise, advanced facilities, profi-
enzymes also play a significant role in the host's immune ciency in lab work, and a considerable amount of time and
response. For example, the presence of dengue virus can effort for processing of serum samples for confirmation of
trigger the activation of host enzymes such as cyclooxygen- positive cases [6].
ases (COX) and lipoxygenases (LOX), which are involved The initial laboratory diagnosis of dengue is made by
in the inflammatory response. This inflammatory cascade direct detection of viral components in serum or by sero-
can lead to symptoms associated with dengue, such as fever, logical analysis. Confirmatory tests include molecular diag-
pain, and, in severe cases, haemorrhagic manifestations nostics methods such as polymerase chain reaction (PCR)
[67]. Understanding the interactions between viral enzymes and quantitative reverse transcription PCR (qRT-PCR). The
and host enzymes is crucial for developing effective treat- sensitivity of these methods depends on the time since the
ments and vaccines, and the pattern of enzymatic activity onset of disease [71]. The primary serological tests used for

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Fig. 6 Overview of diagnostic

methods for detection of DENV
infection

diagnosis are ELISA (enzyme-linked immunosorbent assay) haematocrit, and red blood cell counts also need to be moni-
hemagglutination inhibition (HI), neutralization (NT), com- tored [10].
plement fixation (CF), IgM capture ELISA (MAC-ELISA), The HI assay is dependent on the agglutination of red
and indirect IgG ELISA. However, these rapid diagnostic blood cells (RBCs) by the virus, which is mediated by the
tests are not completely reliable due to the cross-reactivity viral E protein, and allows the presence of anti-DENV
of other flaviviruses [72]. Antibodies that are produced in antibodies in serum to be detected based on their ability
response to infection are measured by ELISA-IgM capture to inhibit hemagglutination. However, ELISA-based tech-
and indirect IgG assays, but due to the cross-reactivity with niques for detecting dengue-specific IgM and IgG have
closely related viruses, confirmatory tests such as the plaque largely replaced this assay. IgM can be detected in serum
reduction neutralization test (PRNT) are necessary. A sum- about one week after the onset of fever, but the IgM ELISA
mary of dengue diagnosis methods is shown in Fig. 6. has low sensitivity and specificity [73]. A recent study
showed that the sensitivity and specificity of commercially
Serological tests available IgM kits differ greatly, depending on the quality
of the antigen used [73, 74]. The plaque reduction neutral-
Dengue is most frequently diagnosed using serological tests ization test (PRNT) is another method for antibody detec-
for detection of IgM and IgG antibodies and HI tests, which tion. This assay is designed to detect neutralizing antibodies
are easy to perform, relatively inexpensive, and can be per- that block the infection of cultured cells. This assay has the
formed at room temperature. IgM can be detected around advantage of differentiating between specific antibodies
7–10 days after the first exposure to the virus. During an against DENV and cross-reacting antibodies against other
acute infection, IgG levels tend to rise and then remain sta- flaviviruses [75].
ble for an extended period. Complete blood cell counts are Recently developed ELISA and rapid immunochromato-
performed to test for low platelet levels, which is a com- graphic (IC) assays have demonstrated the ability to identify
mon indication of late-onset dengue. Severe dengue fever primary and secondary DENV infections about 9 days after
is associated with blood loss, and therefore, haemoglobin, the onset of illness, by targeting the NS1 protein. The NS1

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antigen is detectable within the first week of infection and not yet approved any particular drugs for the treatment of
can be used to confirm an active DENV infection [74]. dengue fever. Numerous potential anti-dengue therapeutic
A meta-analysis of 30 studies showed that the PanBio agents have undergone medical trials, including oral pred-
NS1 ELISA kit is 66% sensitive and 99% specific. The nisolone, carbazochrome sodium sulfonate, and lovastatin
Platelia NS1 ELISA kit displayed a sensitivity of 74% and [85, 86]. Trials have also explored treatments to reduce
a specificity of 99%, which is different from the results severe bleeding, particularly infusions of donated plate-
obtained by other techniques [76]. A meta-analysis con- lets or recombinant human (rh) IL-11 [87, 88]. Progress in
ducted by another researcher showed the IC assay to be the development of effective therapeutics has been slug-
slightly more sensitive than ELISA, achieving a sensitiv- gish, and there remains an unsatisfied need for a successful
ity of 71% compared to 67% for ELISA [77]. NS1-based anti-dengue drug [5, 89]. Ideally, therapeutic drugs against
assays have been found to be especially useful for verifying dengue should be effective against all serotypes, should be
DENV infections [77], but their low sensitivity makes them fast-acting and well tolerated, and should have minimal tox-
unreliable for initial diagnosis [78]. The first four to six days icity. They should be easy to distribute, have few interac-
after infection are the best time to test for anti-dengue IgM tions with other medications, and be suitable for use in both
antibodies. However, in secondary infections, IgM levels children and adults, as well as in pregnant women and indi-
are sometimes too low to be detectable. Furthermore, as a viduals with co-morbidities [89].
result of cross-reactivity amongst flaviviruses, the specific-
ity of IgG assays can also be reduced [73, 79]. Vector control

Nucleic acid amplification tests The chief method for prevention of DENV infection is
through vector control, which can be done using chemical
Nucleic acid amplification tests performed on different or biological agents, such as larvicides or insecticides, or
components of whole blood of symptomatic dengue patients environmental interference, including the elimination of
demonstrate great sensitivity and specificity for the detec- potential vector breeding sites such as containers and waste
tion of DENV RNA within the first 7 days of illness [80]. disposal areas [90]. Chemical control using insecticides is
Nucleic acid amplification tests are effective for diag- used in many regions [91], especially during dengue out-
nosing dengue within the first 7 days of infection, and viral breaks [92]. Recently, novel biological control methods
RNA in a clinical sample can be detected within 1–2 days have been developed, including paratransgenesis, sterile
after infection. RT-PCR-based methods for DENV detection insect techniques, and genetically modified vectors [91,
include one-step quantitative RT-PCR, multiplex RT-PCR 93–97]. Social measures to prevent human exposure to mos-
[81], and nested RT-PCR [82]. The specificity of RT-PCR- quitoes include the use of insect repellents, wearing sleeved
based methods can vary between 80% and 100%, depend- clothes, and the use of mosquito nets for windows and beds
ing on the genome region targeted and the amplification or [98, 99]. The majority of these approaches rely extensively
detection method used [6]. The multiplex RT-PCR test can on community involvement and compliance [100–102].
be performed quickly, but it requires expensive equipment
and reagents as well as skilled practitioners [6]. The single- Vaccine
step RT-PCR assay and species-specific RT-PCR assay have
similar features [82, 83]. Government officials and policymakers in regions with
Molecular diagnostic assays for the detection of individ- a high incidence of dengue fever are now considering the
ual DENV serotypes are not available in many countries, potential benefits of using vaccination strategies for den-
especially in underdeveloped countries. gue prevention programs [103]. Historically, dengue vac-
cine development has been hampered by the need for a
Treatment tetravalent vaccine that is capable of eliciting protective
immunity against all four serotypes in order to prevent anti-
At present, there is no specific treatment or remedy for den- body-dependent enhancement. The first licensed vaccine,
gue. The existing supportive treatment options aim to miti- Dengvaxia (CYD-TDV), developed by Sanofi Pasteur, was
gate symptom severity and complications. Fluid therapy, found to be only partially successful due to its variable effi-
especially intravenous fluid replacement in severe cases, cacy and safety in seronegative individuals, leading to very
is a crucial component of dengue management, intended to restricted usage recommendations [104]. Another recently
prevent shock [84]. The updated WHO guidelines offer spe- developed dengue vaccine, CYD-TDV (chimeric yellow
cific details for managing dengue cases of differing sever- fever virus-DENV-tetravalent dengue vaccine), produced
ity. The U.S. Food and Drug Administration (FDA) has by Sanofi Pasteur, has been approved in numerous countries

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 48 Page 10 of 14 D. Kothari et al.

and has undergone phase II clinical trials in Colombia, Bra- D1ME100 is a nucleic acid vaccine developed by the
zil, Puerto Rico, Honduras, Mexico, Peru, Thailand, and Naval Medical Research Center in the United States that
Singapore [105–108]. TDV, previously called DENVax, is consists of plasmid DNA for expression of the E and prM
a chimeric vaccine developed by Takeda Vaccines Inc. TDV genes [117]. DNA vaccines against DENV-1 and DENV-2
is built upon a DENV-2 a dengue-2 PDK-53 backbone and is induce anti-dengue neutralizing antibody responses in pri-
effective against all four dengue serotypes. Recently, Take- mates, and the DENV-1 vaccine in particular demonstrated
da's TAK-003 (QDENGA) has completed phase III trials 80–95% protection against live virus challenge in rhesus
and has shown promising efficacy and safety results across macaques and Aotus monkeys [118].
diverse age groups and geographical regions [85]. TAK- Future dengue vaccines will need to generate a long-last-
003 demonstrated sustained protection against symptomatic ing, highly effective neutralizing antibody response against
dengue and hospitalizations for up to three years post-vacci- all four serotypes [5, 119]. This goal is made more challeng-
nation, with an overall efficacy rate of approximately 80%. ing by the fact that DENV undergoes rapid evolution, result-
Although it is most effective against DENV-2, it is also pro- ing in numerous strains within each serotype, and there is
tective against DENV-1 and DENV-3 in both seropositive considerable genetic divergence among the four serotypes,
and seronegative individuals. Currently, however, its effi- and even within each serotype. Therefore, further research
cacy against DENV-4 has not been determined conclusively on the development of a nontoxic and efficient vaccine that
[85]. This vaccine's favourable profile positions it as a strong provides efficient cross-protection remains a global priority
contender for widespread immunization programs, particu- [119].
larly in endemic regions [109]. Flavivirus-naive adults have
been studied in two phase I studies to assess the safety and
immunogenicity of TDV. No adverse effects were observed Conclusions and future aspects
in either study. In addition, it was found that TDV induces
high levels of antibodies against all four dengue serotypes in The global burden of dengue is rising steadily, affecting
dengue-naïve adults [110, 111]. Vaccines stimulate immu- over 100 countries with endemic transmission and causing
nity for up to four years, but their efficacy is affected by significant outbreaks in various regions. DENV has four dis-
many factors, including the virus serotype as well as the age tinct serotypes that cause illness ranging from minor febrile
and the serostatus of the individual [112]. CYD-TDV has infections to severe dengue with a fatal outcome. The patho-
been shown to be protective in seropositive subjects over physiology of DENV infection is influenced by multiple
nine years of age. As recommended by the WHO Strategic viral and host factors, with severe disease frequently linked
Advisory Panel, seronegative patients should not be vac- to secondary infections and the genetic traits of the host.
cinated with CYD-TDV, because vaccination increases the Despite the use of laboratory tests including serological and
risk of severe dengue in these individuals [113]. nucleic acid amplification methods, accurate diagnosis is
Two live-attenuated tetravalent dengue vaccines hindered by challenges such as cross-reactivity with other
(LATVs), TV003 and TV005, developed by the U.S. flaviviruses and the need for specialized equipment and
National Institutes of Health (NIH), continue to show robust expertise. Molecular diagnostic tests are not readily avail-
immunogenicity and long-term protection in various phase able worldwide and are expensive. Affordable and efficient
II trials and have been shown to induce a better immune kits for the detection of the individual DENV serotypes are
response than inactivated vaccines, subunit vaccines, or still needed.
DNA vaccines [114]. The LATVs are more effective at Although there is still a need for specific antiviral ther-
inducing humoral and cellular immunity, they present viral apy for dengue, supportive care and preventive measures
epitopes in their native state, and they are less expensive are available, and it is very important to manage the effects
to produce. In a randomized, double-blind trial including of the disease and prevent complications. Vaccination is a
[115] flavivirus-naïve individuals, five tetravalent admix- promising approach for preventing dengue, with several vac-
tures (TV001-TV005) were evaluated. The results showed cines in development and some already approved for use in
an insignificant difference in the occurrence of antagonistic certain regions. A comprehensive approach to surveillance,
effects between vaccine and placebo recipients [116]. In fla- diagnosis, treatment, and prevention is necessary to reduce
vivirus-naive individuals, the vaccine stimulated a trivalent the public health risk of dengue. We need to work across dis-
antibody response in 90% of the cases, and after a single ciplines, regions, and sectors to mitigate its impact on global
dose, seroconversion against all four DENV serotypes was health. Climate change is projected to increase the disease
observed in 45% of the subjects. The seroconversion rates burden of dengue, expand its geographical distribution, and
were 85–100% for DENV-1, DENV-3, and DENV-4, but cause more people to be exposed to the virus. While prog-
only 50% for DENV-2 [116]. ress has been made in laboratory-based diagnosis, including

13
Dengue: epidemiology, diagnosis methods, treatment options, and prevention strategies Page 11 of 14 48

11. Tuiskunen Bäck A, Lundkvist Å (2013) Dengue viruses– an over-

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Dimple Kothari and Niralee Patel. Methodology: Dimple Kothari. Su- of dengue shock syndrome in vietnamese children: A 10-year pro-
pervision: Niralee Patel. First draft: Dimple Kothari. Review, correc- spective study in a single hospital. Clin Infect Dis 57:1577–1586.​
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