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Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Pathogenesis of dengue virus infection

Author
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: Jul 2015. | This topic last updated: Feb 19, 2014.
INTRODUCTION Substantial gaps remain in the basic understanding of the pathogenesis of dengue infection. In
large part this limitation is related to the lack of a suitable animal model [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 [3]. The determination of the three-dimensional structures of the dengue E glycoprotein and the intact
virion has facilitated the understanding of this process [4-6]. Dengue viruses bind via the E glycoprotein to viral
receptors on the cell surface, which may include heparan sulfate or the lectin DC-SIGN [7,8]; they can also bind to
cell surface immunoglobulin receptors in the presence of antibodies to the E glycoprotein or membrane precursor
(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 [10]. 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 by the bite of an infected mosquito, most commonly Aedes
aegypti. The spread of virus early after subcutaneous injection has been studied in rhesus monkeys [11]. During the

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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 [12]. In rhesus monkeys, virus was
detected in regional lymph nodes 24 hours after infection [11]. 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 [13].
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 [14]. Viremia is detectable in humans 6 to 18 hours
before the onset of symptoms and ends as the fever resolves [15].
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 [11]. 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 [16-18]. 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 [16]. 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 [18]. However, an earlier study using flow cytometry reported that the
majority of cell-associated virus was contained in the CD20+ (B lymphocyte) fraction [17].
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 fibroblasts and monocytes in vitro
induces production of interferon-beta and -alpha, respectively [25,26]. Consistent with these observations, elevated
serum levels of interferon alpha have been demonstrated in children with dengue virus infection in Thailand [27].
The role of these cytokine responses is uncertain. Interferon inhibits dengue virus infection in monocytes in vitro [26].
In addition, dengue virusinfected cells are susceptible to lysis by natural killer cells in vitro [28]. However, dengue
viral proteins are able to block the antiviral function of type I interferons in infected cells [29,30]. 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 [31]. 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-crossreactive antibodies. E, pre-M, and NS1 are the principal viral proteins that are
targeted. In vitro, E proteinspecific antibodies can mediate neutralization of infection, direct complement-mediated
lysis or antibody-dependent cellular cytotoxicity of dengue virusinfected cells, and block virus attachment to cell
receptors [28,32,33]. Pre-Mspecific 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 [32]. In mice, passive
transfer of antibodies specific for E, pre-M, or NS1 was sufficient for protection against lethal dengue virus infection
[32,34,35].

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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 receptors is paradoxically increased, a process termed antibody-dependent
enhancement (ADE) of infection [9,36]. 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 virusspecific monoclonal antibody resulted in a 2- to 100-fold
increase in dengue-2 or dengue-4 viremia titers as compared with control animals [37,38]. An increase in viral titers
in blood and tissues and enhanced disease were also observed after passive transfer of low levels of dengue virusspecific antibody in mice lacking interferon receptors [39].
One study characterized 301 human dengue virus-specific monoclonal antibodies [40]. Pre-Mspecific 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 serotypecrossreactive responses [41]. Dengue virusspecific CD4+ and CD8+ T cells can lyse dengue virusinfected cells in
vitro and produce cytokines such as interferon-gamma, tumor necrosis factor (TNF)-alpha, and lymphotoxin [41,42].
In vitro, interferon-gamma can inhibit dengue virus infection of monocytes. However, interferon-gamma also
enhances the expression of immunoglobulin receptors, which can augment the antibody-dependent enhancement of
infection [43].
Primary versus secondary infection Infection with one of the four serotypes of dengue virus (primary infection)
provides lifelong immunity to infection with a virus of the same serotype [14]. 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 [44,45].
In one report, the distribution of dengue virus in secondary infections was evaluated in eight rhesus monkeys [11].
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 [46].
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 [47-49]. Two studies failed to demonstrate higher viremia titers in
patients with secondary dengue infections than in patients with primary dengue infections [50,51], but a study using
quantitative RT-PCR reported higher viral RNA levels in CD14+ monocytes among dengue fever patients with
secondary infections compared with dengue fever patients with primary infections [52].
The kinetics of dengue virusspecific 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.
Concentrations of dengue virusspecific 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
virusspecific 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.

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The kinetics of the T lymphocyte response in secondary infections also differ from those of primary infections. The
frequency of dengue virusspecific T lymphocytes is much higher prior to secondary infection than primary infection.
Furthermore, these memory T cells respond much more rapidly after contact with antigen-presenting cells than nave
T cells. As a result, dengue virusspecific T lymphocyte proliferation and cytokine production would be expected to
occur earlier and reach higher levels 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 antigenspecific cells, consistent with this hypothesis [53-56]. However, a study that compared the
frequencies of T cells specific for an immunodominant dengue epitope between primary and secondary dengue virus
infections found no significant differences, perhaps due to the variation in responses between subjects [57].
The severity of dengue disease has been correlated with the level and quality of the dengue virusspecific T
lymphocyte responses in some studies but not in others. In two studies, the frequency of dengue virusspecific
CD8+ T cells was higher after dengue hemorrhagic fever (DHF) than after dengue fever (DF) among subjects
experiencing secondary infections [54,55]. One study using HLA-peptide tetramers found that a high proportion of
the dengue virusspecific CD8+ T lymphocytes had higher affinity for dengue viral serotypes other than the infecting
serotype; a very high percentage of the tetramer-positive cells were apparently primed to undergo apoptosis [54].
However, two subsequent studies found no associations between the frequencies of dengue virusspecific T cells
and disease severity [57,58]; in one of those studies, dengue virusspecific CD8+ T cells were not detected by
human leukocyte antigen (HLA)-peptide tetramer staining until after the development of plasma leakage [58].
Some serotype-crossreactive T cells present after primary infection display qualitatively altered functional responses
to other dengue serotypes [59]. In one prospective cohort study, specific T cell responses prior to secondary dengue
virus infection were associated with the subsequent occurrence of DHF, such as production of TNF-alpha in
response to stimulation with dengue antigens [60]. In contrast, higher frequencies of CD4+ T cells producing
IFN-gamma or interleukin (IL)-2 in response to stimulation with dengue antigens were associated with subclinical
dengue infection, suggesting a protective effect as well [61].
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 [15,62-64]. 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 [65,66]. 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 [67,68], but it is not clear that this difference in in vitro replication is
the factor responsible for virulence.
Prior dengue exposure Epidemiologic studies have shown that the risk of severe disease (DHF/DSS) is
significantly higher during a secondary dengue virus infection than during a primary infection. This relationship can
be illustrated by the following observations:
An outbreak of dengue-2 virus infections in Cuba in 1981 followed an outbreak of dengue 1 virus infections in
1977 that involved 45 percent of the island's population; 98 percent of cases of DHF/DSS in children and adults
were associated with secondary infections [69,70].
In a prospective study in Bangkok in 1980, hospitalization for DHF was required in none of 47 children with
primary infections compared with 7 of 56 with secondary infections [62].
A prospective study in Myanmar from 1984 to 1988 found a relative risk of DSS in secondary infections of 82 to
103 [71].
The increased risk of DHF in secondary dengue virus infections is felt to reflect the differences in immune responses

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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 Iquitos, 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 [66].
At least 880 cases of DHF would have been expected based upon previous studies in Thailand [62,63].
Furthermore, there are numerous documented cases of dengue hemorrhagic fever occurring during primary
infection, suggesting that differences in viral virulence, as discussed above, are also important [1,15].
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 four years, although the frequency of secondary
dengue-2 infections was similar in those 4 to 40 years of age [72,73].
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 virusspecific antibodies transplacentally and become susceptible to primary
dengue virus infection when antibody levels decline below the neutralization threshold [74,75]. 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 ADE activity of preinfection serum and the severity of infection has not
been demonstrated, however [76].
Nutritional status Unlike other infectious diseases, DHF/DSS is less common in malnourished children than in
well-nourished children. As an example, malnutrition, as determined by weight for age, was noted in 13 percent of
100 Thai children with DHF compared with 33 percent of 184 healthy Thai children and 71 percent of 125 Thai
children with other infectious diseases admitted to the same hospital [77]. This negative association may be related
to suppression of cellular immunity in malnutrition.
Genetic factors Epidemiologic studies in Cuba showed that DHF occurred more often in whites than in blacks
[73], and a similar genetic resistance to DHF in blacks has been reported from Haiti [78]. Racial differences have
been described in viral replication in primary monocytes and in the level of dengue serotype-crossreactive T cell
responses [79], but it is unclear if either of these explains the genetic association.
DHF has been associated with specific human leukocyte antigen (HLA) genes in studies from Thailand [80,81],
Cuba [82], and Vietnam [83]. Other genetic factors that may be associated with varying degrees of susceptibility to
DHF include receptor polymorphisms of tumor necrosis factoralpha, vitamin D, Fc gamma IIa, blood group type,
and DC-SIGN genes [84-87].
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 [88]. Dengue virus infects human endothelial cells in vitro and causes cellular activation
[89]. Additionally, soluble NS1 protein, which can be detected in the serum during acute infection, has been reported
to bind to endothelial cells and may serve as a target for antibody binding and complement activation [90]. However,
the effects on endothelial cell function during infection are most likely to be indirectly caused by dengue virus
infection for the following reasons:
Histologic studies show little structural damage to capillaries [91].
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

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have been demonstrated in experimental animals. The most important mediators are thought to include tumor
necrosis factor (TNF)-alpha (released from virus-infected monocytes and activated T cells), interferon (IFN)-gamma
and interleukin (IL)-2 (released from activated T cells), IL-8 (produced by virus-infected cells), vascular endothelial
growth factor (VEGF, potentially produced by monocytes and endothelial cells), and complement (activated by virusantibody complexes) (figure 2).
Dengue virusinfected monocytic cells produce TNF-alpha and IL-8, and these affect endothelial cell permeability in
vitro [92-94]. Elevated serum levels of TNF-alpha [95,96], IL-8 [97], IFN-gamma [98,99], IL-2 [98], and free VEGF
[89] have also been observed in patients with DHF. Other studies from Thailand have found reduced serum levels of
the complement proteins C3 and C5 in children with DHF [100], with a corresponding increase in the serum
concentrations of anaphylatoxins C3a and C5a [101].
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 [98,99], CD4 [98], IL-2 receptors [98,99], and TNF receptors
[96,99,102]. Increased plasma concentrations of soluble TNF receptor II were found to correlate with the subsequent
development of shock in Vietnamese children with DHF [96] 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 [27].
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 [103]. 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 [104]. In vitro studies have
shown that dengue virus infects human bone marrow stromal cells and hematopoietic progenitor cells [105,106] and
inhibits progenitor cell growth [107].
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 [103]. 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 [108]. 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 [91]. (See "Clinical manifestations and diagnosis of dengue virus
infection".)
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 [103]. 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 [109], elevated levels of von Willebrand factor, tissue factor, tissue plasminogen activator, and
platelet activator inhibitor [110], and an increased fractional catabolic rate of fibrinogen [111]. 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.

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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 crossreacted with plasminogen; these antibodies correlated with the occurrence of
hemorrhagic signs (including petechiae) but not with thrombocytopenia or shock [112]. 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 [113].
Liver Elevations of serum aminotransferases that are usually mild are common in dengue virus infections [103].
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 [91].
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
[114]. However, immune-mediated hepatocyte injury, for example, bystander destruction of uninfected hepatocytes
by activated CD4+ T lymphocytes, is a potential alternative mechanism [41].
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 [115,116], but this is clearly the
exception in humans, whereas encephalitis is the only disease caused by dengue viruses in mice. In one series of
100 fatal cases of dengue, no evidence of central nervous system inflammation was found [91].
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 e-mail 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 information: 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 by the bite of an infected mosquito, most commonly Aedes aegypti.
(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 lifelong immunity to
infection with a virus of the same serotype [14]. 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.)

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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 (ADE).
(See 'Immune response and viral clearance' above.)
The severity of dengue disease has been correlated with both the level and quality of the dengue virusspecific
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.)
The risk for DHF appears to decline with age, especially after age 11 years. (See 'Age' above.)
Plasma leakage, due to an increase in capillary permeability, is a cardinal feature of DHF but is absent in
dengue fever (DF). The enhanced capillary permeability appears to be due to endothelial cell dysfunction
rather than injury. (See 'Pathophysiology of disease manifestations' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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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

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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

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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 (FcR), 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 (IFN) 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.
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Disclosures
Disclosures: Alan L Rothman, MD Consultant/Advisory Boards: Sanofi Pasteur [Prevention and treatment of dengue virus infections
(Tetravalent live-attenuated dengue vaccine Chimerivax-DEN)]. Martin S Hirsch, MD Nothing to disclose. Elinor L Baron, MD, DTMH
Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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