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Dengue virus infection: Pathogenesis

Authors: Stephen J Thomas, MD, Alan L Rothman, MD
Section Editor: Martin S Hirsch, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2019. | This topic last updated: Mar 08, 2018.

INTRODUCTION

Substantial gaps remain in the comprehensive understanding of the pathogenesis of

dengue virus infections. In large part, this limitation is related to the lack of a suitable
animal model of disease [1]. Rhesus monkeys develop viremia similar in pattern to
humans after dengue virus challenge but do not develop clinical disease. Careful
epidemiologic and experimental challenge studies in humans have provided valuable
information on dengue virus infection, but detailed data on virus distribution in vivo are
available only from small numbers of patients with more severe disease, unusual
manifestations, or the later stages of infection. Little pathogenetic information is available
concerning milder infections, which constitute the vast majority of cases.

THE DENGUE VIRAL REPLICATION CYCLE

Dengue viruses are members of the family Flaviviridae genus Flavivirus. They are small,
enveloped viruses containing a single-strand RNA genome of positive polarity [2].
Dengue viruses infect a wide range of human and nonhuman cell types in vitro. Viral
replication involves the following steps:

● Attachment to the cell surface

 ● Entry into the cytoplasm
● Translation of viral proteins
● Replication of the viral RNA genome
● Formation of virions (encapsidation)
● Release from the cell

Binding of dengue virions to cells, which is mediated by the major viral envelope (E)
glycoprotein, is critical for infectivity. The determination of the three-dimensional
structures of the dengue E glycoprotein and the intact virion has facilitated the
understanding of this process [3-5]. Dengue viruses bind via the E glycoprotein to viral
receptors on the cell surface, which may include heparan sulfate or lectins such as DC-
SIGN and CLEC5A [6-8]; they can also bind to cell surface immunoglobulin receptors in
the presence of antibodies to the E glycoprotein or precursor membrane (pre-M) protein,
as described further below [9].

Following fusion of viral and cell membranes in acidified endocytic vesicles, the viral RNA
enters the cytoplasm. The viral proteins are then translated directly from the viral RNA as
a single polyprotein, which is cleaved to yield the three structural and seven nonstructural
proteins [2]. Cleavage of several of the viral proteins requires a functional viral protease
encoded in the nonstructural protein NS3. The nonstructural protein NS5 is the viral RNA-
dependent RNA polymerase, which assembles with several other viral proteins and
several host proteins to form the replication complex. This complex transcribes the viral
RNA to produce negative-strand viral RNA, which serves as the template for the
production of the viral genomic RNA.

The assembly and budding of progeny virions is still poorly understood. The pre-M
structural protein is cleaved by a cellular enzyme, furin, as one of the final steps in
maturation of progeny virions [2]. Cleavage of the pre-M protein enhances the infectivity
of the virions 100-fold.

COURSE OF INFECTION

The course of dengue virus infection is characterized by early events, dissemination, and
the immune response and subsequent viral clearance (figure 1).

Early events — Dengue virus is introduced into the skin when an infected mosquito,
most commonly Aedes aegypti, takes a blood meal from a susceptible host. The spread
of virus early after subcutaneous injection has been studied in rhesus monkeys [10].
During the first 24 hours, virus could only be isolated from the injection site. The major
cell type infected was not defined; both Langerhans cells and dermal fibroblasts have
been proposed to be target cells for dengue virus infection in the skin. One study using
human skin dendritic cells demonstrated expression of dengue virus antigens following in
vitro exposure, suggesting that these cells are permissive for dengue viral infection [11].
In rhesus monkeys, virus was detected in regional lymph nodes 24 hours after infection
[10]. In one study using a mouse model deficient in both type I and type II interferon (IFN)
receptors, macrophages and dendritic cells were demonstrated to be early cellular
targets for infection [12].

Dissemination — Viremia begins in rhesus monkeys between two and six days after
subcutaneous injection and lasts for three to six days. In humans infected with "natural"
dengue viruses, viremia begins approximately one day later than in monkeys, but the
duration of viremia is similar [13]. Viremia is detectable in humans 6 to 18 hours before
the onset of symptoms and ends around the time fever resolves [14].

In rhesus monkeys during the period of viremia, virus was frequently detected in lymph
nodes distant from the site of inoculation and less commonly from spleen, thymus, lung,
and bone marrow [10]. Virus was also isolated from peripheral blood leukocytes at the
end of the viremic period and sometimes for one day after.

The distribution of virus in humans has been studied in blood, biopsy, and autopsy
specimens from patients with natural dengue virus infection. Infection of peripheral blood
mononuclear cells persists beyond the period of detectable viremia [15-17]. Conflicting
data have been published regarding the principal infected cell type in the peripheral
blood. An older study reported more frequent isolation of infectious virus from the
adherent cell population than the nonadherent population, suggesting that monocytes are
the primary target cell for infection [15]. A similar conclusion was reached in a study using
flow cytometry, which reported the detection of dengue viral antigen in a very high
percentage of circulating monocytes [17]. However, an earlier study using flow cytometry
reported that the majority of cell-associated virus was contained in the CD20+ (B
lymphocyte) fraction [16]. Another study using polymerase chain reaction found the
highest levels of dengue viral RNA in B cells but could not exclude passive binding as an
explanation [18].
The yield of dengue virus from tissues obtained at autopsy has generally been low.
However, in one study using the most sensitive techniques for virus isolation, virus was
isolated most often (4 of 16 cases) from liver tissue [19]. Antigen staining has suggested
that the predominant cell types infected are macrophages in the skin [20] and Kupffer
cells in the liver [21,22]; dengue viral antigens have also been detected in hepatocytes in
some cases [23].

Immune response and viral clearance — Both innate and adaptive immune responses
induced by dengue virus infection are likely to play a role in the clearance of infection
[24]. Infection of human cells in vitro induces antiviral responses, including the production
of interferons [25]. Consistent with these observations, elevated serum levels of IFN-
alpha have been demonstrated in children with dengue [26].

The role of these cytokine responses is uncertain. Interferon inhibits dengue virus
infection in vitro. In addition, dengue virus–infected cells are susceptible to lysis by
natural killer cells in vitro [27]. However, dengue viral proteins are able to inhibit both the
production of interferons and their antiviral function in infected cells [28,29]. In one study
of host cell gene expression by microarray analysis of blood samples obtained from 14
adults with dengue, a cluster of 24 gene transcripts, many reflecting type I interferon
signaling, was identified as significantly less abundant in the six patients with dengue
shock syndrome (DSS) than in the eight patients without DSS [30]. These subjects had
low to undetectable plasma viral RNA and IFN-alpha levels when studied. Whether
attenuated interferon responses are the result or cause of severe dengue disease is
unknown.

The antibody response to dengue virus infection is primarily directed at serotype-specific

determinants, but there is a substantial level of serotype–cross-reactive antibodies. E,
precursor membrane (pre-M), and NS1 are the principal viral proteins that are targeted.
In vitro, E protein–specific antibodies can mediate neutralization of infection, direct
complement-mediated lysis or antibody-dependent cellular cytotoxicity of dengue virus–
infected cells, and block virus attachment to cell receptors [2]. Pre-M–specific antibodies
only bind to virions that have not fully matured and have remaining uncleaved pre-M
protein. NS1 is not found in the virion; NS1-specific antibodies are therefore incapable of
neutralization of virus infection but can direct complement-mediated lysis of infected cells
[31].
The basis of neutralization of virus by antibody is not well understood. Neutralization
clearly requires a threshold level of antibodies; when the concentration of antibodies is
below this threshold, the uptake of antibody-bound virus by cells that express
immunoglobulin (Ig) receptors is paradoxically increased, a process termed antibody-
dependent enhancement (ADE) of infection [32,33]. Since monocytes, the putative
cellular targets of dengue virus infection in vivo, express immunoglobulin receptors and
manifest ADE in vitro, this phenomenon is thought to be highly relevant in natural dengue
virus infections (see below). In rhesus monkeys, passive transfer of low levels of dengue-
immune human sera or a humanized chimpanzee dengue virus–specific monoclonal
antibody resulted in a 2- to 100-fold increase in dengue-2 or dengue-4 viremia titers as
compared with control animals [34,35]. An increase in viral titers in blood and tissues and
enhanced disease were also observed after passive transfer of low levels of dengue
virus–specific antibody in mice lacking interferon receptors [36]. Dengue virus entry via
ADE has also been found to suppress innate immune responses in infected monocytes in
vitro [9].

One study characterized 301 human dengue virus–specific monoclonal antibodies [37].
Pre-M–specific antibodies represented a larger fraction of the monoclonal antibodies
detected than antibodies directed at E or NS1. Pre-M–specific antibodies showed poor
neutralization of infection in vitro but could mediate ADE.

The T lymphocyte response to dengue virus infection also includes both serotype-specific
and serotype–cross-reactive responses [38]. Dengue virus–specific CD4+ and CD8+ T
cells can lyse dengue virus–infected cells in vitro and produce cytokines such as IFN-
gamma, tumor necrosis factor (TNF)-alpha, and lymphotoxin. In vitro, IFN-gamma can
inhibit dengue virus infection of monocytes. However, IFN-gamma also enhances the
expression of immunoglobulin receptors, which can augment the antibody-dependent
enhancement of infection [39].

Primary versus secondary infection — Infection with one of the four serotypes of
dengue virus (primary infection) generally provides long-lasting immunity to infection with
a virus of the same serotype [13]. In contrast, immunity to the other dengue serotypes is
transient, and individuals can subsequently be infected with another dengue serotype
(secondary infection). Two prospective cohort studies found that the interval between
primary and secondary dengue virus infections was significantly longer among children
who experienced a symptomatic secondary infection than those who had a subclinical
secondary infection, suggesting that heterotypic protective immunity wanes gradually
over one to two years [40,41].

In one report, the distribution of dengue virus in secondary infections was evaluated in
eight rhesus monkeys [10]. The onset and duration of viremia were similar to primary
infections. Autopsy specimens from six monkeys yielded virus somewhat more frequently
from various tissues than specimens from primary infections. Another study found higher
plasma virus titers in secondary than primary dengue-2 virus infections but not in
secondary infections with dengue viruses of the other serotypes [42].

There is little information from human studies to allow comparisons of virus distribution or
titer in primary and secondary infections. Several studies have reported that higher peak
plasma virus titers in secondary dengue infections were associated with more severe
illness [43-45]. Two studies failed to demonstrate higher viremia titers in patients with
secondary dengue infections than in patients with primary dengue infections [46,47], but
a study using quantitative reverse-transcription polymerase chain reaction reported
higher viral RNA levels in CD14+ monocytes among dengue fever patients with
secondary infections compared with dengue fever patients with primary infections [18].

The kinetics of dengue virus–specific antibodies in secondary dengue infections differ

from those of primary dengue infections in several ways.

● Low concentrations of antibodies to the virus serotype causing the secondary

infection are present before exposure to the virus. As a result, antibody-dependent
enhancement of infection could occur early in secondary dengue virus infections.
Consistent with this hypothesis, an analysis of data from a longitudinal cohort study
of children in Nicaragua found that the risk of more severe dengue illness was
highest within a narrow range of preexisting anti-dengue virus antibody titers [48].

● Concentrations of dengue virus–specific antibodies increase earlier in secondary

infection, reach higher peak titers, and have a lower IgM:IgG ratio, suggestive of an
anamnestic response. Thus, the levels of dengue virus–specific antibodies are much
higher during the late stage of viremia in secondary infections, with greater potential
for forming immune complexes of dengue virions and activating complement.

The kinetics of the T lymphocyte response in secondary infections also would be

expected to differ from those of primary infections, with an earlier onset and higher level
of dengue virus–specific T lymphocyte proliferation and cytokine production in secondary
infections. Studies of circulating T lymphocytes during acute secondary infections have
shown a high percentage of cells expressing markers of activation and high frequencies
of dengue antigen–specific cells, consistent with this hypothesis [49-52]. However, a
study that compared the frequencies of T cells specific for an immunodominant dengue
epitope between symptomatic primary and secondary dengue virus infections found no
significant differences [53].

The severity of dengue disease has been correlated with the level and quality of the
dengue virus–specific T lymphocyte responses in some studies [50,51] but not in others
[53,54].

Some serotype–cross-reactive T cells present after primary infection display qualitatively

altered functional responses to other dengue serotypes [38]. In one prospective cohort
study, specific T cell responses prior to secondary dengue virus infection were associated
with the subsequent occurrence of dengue hemorrhagic fever, such as production of
TNF-alpha in response to stimulation with dengue antigens [55]. In contrast, higher
frequencies of CD4+ T cells producing IFN-gamma or interleukin 2 in response to
stimulation with dengue antigens were associated with subclinical dengue infection,
suggesting a protective effect as well [56].

FACTORS INFLUENCING DISEASE SEVERITY

Most dengue virus infections produce mild, nonspecific symptoms or classic dengue
fever (DF). The more severe manifestations, dengue hemorrhagic fever (DHF) and
dengue shock syndrome (DSS), occur in less than 1 percent of dengue virus infections.
Thus, considerable attention has been focused upon understanding the risk factors for
DHF (table 1).

Viral factors — DHF can occur during infection with any of the four dengue serotypes;
several prospective studies have suggested that the risk is highest with dengue-2 viruses
[14,57-59]. Genetic analyses of dengue virus isolates from the Western hemisphere
strongly suggest that DHF only occurs during infection with viruses that fall into specific
genotypes within each dengue serotype [60,61]. These "virulent" genotypes were
originally detected in Southeast Asia but are now widespread. Several studies have
suggested that "virulent" and "avirulent" genotypes differ in their ability to replicate in
monocytic cells [62,63], but it is not clear that this difference in in vitro replication is the
factor responsible for virulence.

Prior dengue exposure — Multiple epidemiologic studies have shown that the risk of
severe disease (DHF and DSS) is significantly higher during a secondary dengue virus
infection than during a primary infection [9,57,64,65].

The increased risk of DHF in secondary dengue virus infections is felt to reflect the
differences in immune responses between primary and secondary dengue virus
infections described above: antibody-dependent enhancement of infection, enhanced
immune complex formation, and/or accelerated T lymphocyte responses.

The increased risk for DHF associated with secondary dengue virus infections appears
not to apply to infections with "avirulent" genotypes (see above). A prospective study in
Peru found no cases of DHF or DSS during an outbreak of dengue-2 virus infections that
was estimated to involve over 49,000 secondary infections in children [61]. At least 880
cases of DHF would have been expected based upon previous studies in Thailand.
Furthermore, there are numerous documented cases of DHF occurring during primary
infection, suggesting that differences in viral virulence, as discussed above, are also
important [1,14].

Age — The risk for DHF appears to decline with age, especially after age 11 years.
During the 1981 epidemic of DHF in Cuba, the modal age of DHF cases and deaths was
4 years, although the frequency of secondary dengue-2 infections was similar in those 4
to 40 years of age [66,67].

A specific population at higher risk for DHF in endemic areas is infants, particularly those
between 6 and 12 months of age. These children acquire dengue virus–specific
antibodies transplacentally and become susceptible to primary dengue virus infection
when antibody levels decline below the neutralization threshold [68]. This observation is
taken to support the hypothesis of antibody-dependent enhancement of infection as a
primary factor in determining the risk for DHF. A direct correlation between antibody-
dependent enhancement (ADE) activity of preinfection serum and the severity of infection
has not been demonstrated, however [69].

Nutritional status — Some studies have reported that, unlike other infectious diseases,
DHF and DSS are less common in malnourished children than in well-nourished children
[70], and this has been taken to reflect the role of the immune response in disease
pathogenesis. A systematic review found no consistent association with nutritional status,
however [71].

Genetic factors — Epidemiologic studies in Cuba showed that DHF occurred more often
in whites than in blacks [67], and a similar genetic resistance to DHF in blacks has been
reported from Haiti [72]. Racial differences have been described in viral replication in
primary monocytes and in the level of dengue serotype–cross-reactive T cell responses
[73], but it is unclear if either of these explains the genetic association.

Genome-wide association studies conducted in Vietnam [74,75] and Thailand [76] have
found significant genetic associations of two single-nucleotide polymorphisms, one in the
major histocompatibility complex class I polypeptide-related sequence B (MICB) gene
and one in the phospholipase C epsilon 1 (PLCE1) genes, with both dengue shock
syndrome and less severe dengue. The mechanisms for these associations have not
been defined.

In focused studies, DHF has been associated with specific human leukocyte antigen
genes [77-80], with blood group [81], and with polymorphisms of tumor necrosis factor–
alpha, vitamin D, Fc gamma IIa, and DC-SIGN genes [82-84].

PATHOPHYSIOLOGY OF DISEASE MANIFESTATIONS

Capillary leak syndrome — Plasma leakage, due to an increase in capillary

permeability, is a cardinal feature of dengue hemorrhagic fever (DHF) but is absent in
dengue fever (DF). The enhanced capillary permeability appears to be due to endothelial
cell dysfunction rather than injury, as electron microscopy demonstrated a widening of the
endothelial tight junctions [85]. Dengue virus infects human endothelial cells in vitro and
causes cellular activation [86]. Additionally, soluble NS1 protein, which can be detected in
the serum during acute infection, has been reported to bind to endothelial cells, to
activate cells through toll-like receptor 4 signaling, and to serve as a target for antibody
binding and complement activation [87]. However, the effects on endothelial cell function
during infection are thought more likely to be indirectly caused by dengue virus infection
for the following reasons:
 ● Histologic studies show little structural damage to capillaries [88].

● Infection of endothelial cells by dengue virus is not apparent in tissues obtained at

autopsy [22].

● Increased capillary permeability is transient, with rapid resolution and no residual

pathology.

Most investigations have focused on the hypothesis that circulating factors induce the
transient increase in capillary permeability. Multiple mediators are likely to be involved in
vivo, and interactions between these different factors have been demonstrated in
experimental animals. Nitric oxide has been associated with increased vascular
permeability and severe dengue in two prospective studies in Asia [89,90]. However, the
most important mediators are still thought to include tumor necrosis factor (TNF)-alpha,
interferon (IFN)-gamma, interleukin (IL)-2, IL-8, vascular endothelial growth factor
(VEGF), and complement (figure 2) [91]. The sources of these cytokines have been
proposed to include virus-infected monocytes, dendritic cells and mast cells, activated
platelets, and dengue virus–specific CD4 and CD8 T lymphocytes.

Elevated serum levels of TNF-alpha, IL-8, IFN-gamma, IL-2, and free VEGF have been
observed in patients with DHF [91]. Other studies have found reduced serum levels of the
complement proteins C3 and C5 in patients with DHF, with a corresponding increase in
the serum concentrations of anaphylatoxins C3a and C5a [92,93].

It is difficult to detect elevated cytokine levels in the circulation, because of the short half-
life of these molecules. Analysis of more stable markers of immune activation has
provided additional, although indirect, support for the immunopathogenesis model of
plasma leakage. Several studies have shown that children with DHF have elevated
circulating levels of the soluble forms of CD8, CD4, IL-2 receptors, and TNF receptors
[91]. Increased plasma concentrations of soluble TNF receptor II were found to correlate
with the subsequent development of and with the magnitude of plasma leakage into the
pleural space. The intensity of the immune response may ultimately be determined by the
level of viral replication, however, as one study found that the plasma viremia titer was
the strongest independent factor that correlated with plasma leakage [26].

Blood and bone marrow — Leukopenia, thrombocytopenia, and a hemorrhagic

diathesis are the typical hematologic findings in dengue virus infections. Leukopenia is
apparent early in illness and is of similar degree in DHF and dengue fever [94]. It is
thought to represent a direct effect of dengue virus on the bone marrow. Bone marrow
biopsies of children in Thailand with DHF revealed suppression of hematopoiesis early in
the illness, with marrow recovery and hypercellularity in the late stage and during early
clinical recovery [95]. In vitro studies have shown that dengue virus infects human bone
marrow stromal cells and hematopoietic progenitor cells [96,97] and inhibits progenitor
cell growth [98].

Some degree of thrombocytopenia is common in both dengue fever and DHF, but marked
thrombocytopenia (<100,000 platelets/mm3) is one of the criteria used to define DHF.
Multiple factors are thought to contribute to the fall in platelet count, which is most severe
late in the illness [94]. Bone marrow suppression may play a role, but platelet destruction
is probably more important. In one study, 10 of 11 Thai children with DHF had a
shortened platelet survival time, ranging from 6.5 to 53 hours [99]. Adsorption of dengue
virions or virus-antibody immune complexes to the platelet surface, with subsequent
activation of complement, are thought to be responsible for the platelet destruction.

Manifestations of the hemorrhagic diathesis in dengue virus infections range from a

positive tourniquet test to life-threatening hemorrhage. Fatal DHF may be associated with
diffuse petechial hemorrhages involving the stomach, skin, heart, intestine, and lungs
[88]. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

Despite the nomenclature, however, the occurrence of hemorrhage does not define DHF
as compared with dengue fever since a positive tourniquet test may occur with equal
frequency in the two disorders [94]. Several different mechanisms, possibly acting
synergistically, contribute to bleeding tendency of dengue virus infections. Both the
vasculopathy and thrombocytopenia described above create a predisposition to bleeding.

Endothelial cell activation and injury and activation of coagulation and fibrinolysis have
been reported in dengue, particularly in severe infections. Abnormalities that have been
described include increased numbers of circulating endothelial cells [100], elevated levels
of von Willebrand factor, tissue factor, tissue plasminogen activator, and platelet activator
inhibitor [101], and an increased fractional catabolic rate of fibrinogen [102]. However,
most of these findings are based on small studies and comparison with non-dengue
controls. Frank coagulopathy is uncommon except in patients with shock.
A final etiologic factor may be molecular mimicry between dengue viral proteins and
coagulation factors. One study of 88 Tahitian children with dengue virus infection found
that antibody responses to homologous peptides derived from the dengue virus E protein
cross-reacted with plasminogen; these antibodies correlated with the occurrence of
hemorrhagic signs (including petechiae) but not with thrombocytopenia or shock [103].
Another study reported that monoclonal antibodies directed at the dengue virus NS1
protein bound in vitro to human fibrinogen, platelets, and endothelial cells and induced
hemorrhage in mice [104].

Liver — Elevations of serum aminotransferases that are usually mild are common in
dengue virus infections [94]. Typical pathologic findings in the livers of fatal cases of
dengue include hepatocellular necrosis and Councilman bodies with relatively little
inflammatory cell infiltration, similar to the findings in early yellow fever virus infection
[88]. The pathologic similarities between these two diseases and the relatively frequent
isolation of dengue virus from liver tissues of fatal cases suggest that liver injury is
directly mediated by dengue virus infection of hepatocytes and Kupffer cells. Dengue
virus has been shown to infect and induce apoptosis in a human hepatoma cell line in
vitro [105]. However, immune-mediated hepatocyte injury is a potential alternative
mechanism.

Central nervous system — Rare cases of encephalopathy have been attributed to

dengue virus infections. True encephalitis has been reported, with detection of dengue
virus in brain tissue [106], but this is clearly the exception in humans. In one series of 100
fatal cases of dengue, no evidence of central nervous system inflammation was found
[88].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to
6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you
to print or email these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)

● Basics topic (see "Patient education: Dengue fever (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Dengue viruses are small, enveloped viruses that are members of the family
Flaviviridae genus Flavivirus. Viral replication involves the following steps:
attachment to the cell surface, cellular entry, translation of viral proteins, replication
of the viral RNA genome, formation of virions by encapsidation, and cellular release.
(See 'The dengue viral replication cycle' above.)

● Dengue virus is introduced into the skin when an infected mosquito, most commonly
Aedes aegypti, takes a blood meal from a susceptible host. (See 'Early events'
above.)

● Viremia is detectable in humans 6 to 18 hours before the onset of symptoms and

ends as the fever resolves. (See 'Dissemination' above.)

● Both innate and adaptive immune responses induced by dengue virus infection are
likely to play a role in the clearance of infection. (See 'Immune response and viral
clearance' above.)

● Infection with one of the four serotypes of dengue virus (primary infection) provides
long-lasting immunity to infection with a virus of the same serotype [13]. However,
immunity to the other dengue serotypes is transient, and individuals can
subsequently be infected with another dengue serotype (secondary infection). (See
'Primary versus secondary infection' above.)

● Antibodies to proteins on the dengue virus surface can cause increased infection of
cells bearing immunoglobulin receptors, a phenomenon known as antibody-
dependent enhancement of infection. (See 'Immune response and viral clearance'
 above.)

● The severity of dengue disease has been correlated with both the level and quality of
the dengue virus–specific T lymphocyte responses. (See 'Primary versus secondary
infection' above.)

● Although dengue hemorrhagic fever (DHF) can occur during infection with any of the
four dengue serotypes, several prospective studies have suggested that the risk is
highest with dengue-2 viruses. (See 'Factors influencing disease severity' above.)

● Epidemiologic studies have shown that the risk of severe disease is significantly
higher during a secondary dengue virus infection than during a primary infection.
(See 'Prior dengue exposure' above.)

● Plasma leakage, due to an increase in capillary permeability, is a cardinal feature of

DHF but is absent in dengue fever. The enhanced capillary permeability appears to
be due to endothelial cell dysfunction rather than injury. (See 'Pathophysiology of
disease manifestations' above.)

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Topic 3029 Version 16.0

GRAPHICS

Acute dengue virus infection

Hypothetical schema of events in acute dengue virus infection. The kinetics and
general location of viral replication are diagrammed in relation to the presence of
detectable viremia, general symptoms (fever, myalgias, headache, rash), and the
period of risk for plasma leakage, shock, severe thrombocytopenia, and bleeding
in dengue hemorrhagic fever (DHF). Nonspecific immune responses include the
production of interferons (IFN) and natural killer (NK) cell activity. The kinetics of
dengue virus-specific T lymphocyte activation and the production of dengue virus-
specific antibodies occur later and are of lesser magnitude in primary infections
(first exposure to dengue viruses) than in secondary infections (later infection with
a second dengue virus serotype).

Graphic 63173 Version 1.0

Factors that influence the risk for dengue hemorrhagic fever

Factor Low risk High risk

Viral factors

Viral serotype Dengue-2 virus

Viral genotype "Asian" genotypes

Host factors

Immunity Prior dengue virus infection

Age Adult

Nutrition Malnourished

Genetics Black

Graphic 58587 Version 1.0

Capillary leak in dengue virus infection

Proposed model by which dengue virus (DV) produces a capillary leak syndrome. Monocytes
(Mo) are thought to be the primary cellular target for DV. Serotype crossreactive antibodies
(Ab), present at the time of second DV infection, bind to virions without neutralization and
then enhance the entry of virus into monocytic cells expressing immunoglobulin receptors
(FcγR), as show in the left side of the picture. Serotype crossreactive memory T cells, also
present at the time of secondary DV infection, recognize viral antigens in the context of
class I and II major histocompatibility complex (MHC) molecules. These T cells produce
cytokines, such as interferon-gamma (IFNγ) and tumor necrosis factors (TNF) alpha and
beta, and lyse DV-infected monocytes. TNF-alpha is also produced in monocytes in
response to DV infection and/or interactions with T cells. These cytokines have direct effects
on endothelial cells (EC) to induce plasma leakage. Interferon-gamma activates monocytes
to increase the expression of MHC molecules and immunoglobulin receptors and the
production of TNF-alpha. The complement cascade, activated by virus-antibody complexes
and by several cytokines, releases the complement anaphylatoxins C3a and C5a which
further increase capillary permeability. Interleukin-2 may contribute by facilitating T cell
proliferation.

Graphic 75407 Version 2.0

Contributor Disclosures
Stephen J Thomas, MD Consultant/Advisory Boards: Takeda [Dengue]; Merck [Dengue (vaccines)];
Sanofi [Dengue (vaccines)]; Chugai Pharma [Dengue (drug)]; Janssen [Dengue (drug)]; PrimeVax
[Dengue (immuno-oncolytic including dengue component)]. Patent Holder: USG/Army [Pan-flavivirus,
chikungunya, Zika virus (vaccines)]. Equity Ownership/Stock Options: PrimeVax SAB membership
[Cancer immunotherapy]. Alan L Rothman, MD Grant/Research/Clinical Trial Support: Sanofi
Pasteur [Prevention and treatment of dengue virus infections (Dengvaxia (dengue vaccine)].
Consultant/Advisory Boards: Sanofi Pasteur [Prevention and treatment of dengue virus infections
(Dengvaxia (dengue vaccine)]; Takeda [Prevention and treatment of dengue virus infections (dengue
vaccine)]; Merck [Prevention and treatment of dengue virus infections (dengue vaccine)] Martin S
Hirsch, MD Nothing to disclose Elinor L Baron, MD, DTMH Nothing to disclose

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