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Infección por el virus del dengue: patogénesis

Autores: Stephen J Thomas, MD, Alan L Rothman, MD
Editor de sección: Martin S Hirsch, MD
Subdirector: Elinor L Baron, MD, DTMH

Todos los temas se actualizan a medida que hay nuevas pruebas disponibles y nuestro proceso de revisión por pares está
completo.

Revisión de literatura actualizada hasta:  diciembre de 2019. | Última actualización de este tema:  18 de septiembre de
2019.

INTRODUCCIÓN

Persisten lagunas sustanciales en la comprensión integral de la patogénesis de las infecciones por el

virus del dengue. En gran parte, esta limitación está relacionada con la falta de un modelo animal
adecuado de enfermedad [ 1 ]. Los monos rhesus desarrollan viremia similar en patrón a los
humanos después de la exposición al virus del dengue, pero no desarrollan enfermedad clínica. Los
cuidadosos estudios epidemiológicos y experimentales de desafío en humanos han proporcionado
información valiosa sobre la infección por el virus del dengue, pero los datos detallados sobre la
distribución del virus in vivo solo están disponibles en un pequeño número de pacientes con
enfermedades más graves, manifestaciones inusuales o las últimas etapas de la infección. Hay poca
información patogénica disponible sobre infecciones más leves, que constituyen la gran mayoría de
los casos.

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 several studies, the expression of genes associated with type I
interferon signaling was significantly lower in patients with dengue shock syndrome (DSS) than in
patients without DSS [30,31]. 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 (figure 2). 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 [32].

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 [33,34]. 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 [35,36]. 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 [37]. 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 [38]. 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 [39]. 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 Ig receptors, which can augment the antibody-
dependent enhancement of infection [40].

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 [41,42].

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 [43].

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 [44-46]. Two studies failed
to demonstrate higher viremia titers in patients with secondary dengue infections than in patients
with primary dengue infections [47,48], 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, two
separate analyses of data from longitudinal cohort studies of children in Nicaragua and Thailand
found that the risk of more severe dengue illness was highest within a narrow range of pre-
existing anti-dengue virus antibody titers [49,50].

● 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 [51-54]. 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 [55].

The severity of dengue disease has been correlated with the level and quality of the dengue virus-
specific T lymphocyte responses in some studies [52,53] but not in others [55,56].

Some serotype-cross-reactive T cells present after primary infection display qualitatively altered
functional responses to other dengue serotypes [39]. 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 [57]. 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 [58]. In a separate study, the secretion of IL-6,
IL-15, and macrophage chemotactic protein 1 in response to in vitro stimulation with dengue virus
was associated with symptomatic dengue infection whereas the secretion of other cytokines,
including IL-12 and regulated on activation, normally T cell expressed, and secreted (RANTES) was
associated with subclinical infection, pointing to the potential for either protective or pathologic
immune response profiles [59].

FACTORS INFLUENCING DISEASE SEVERITY

Most dengue virus infections produce mild, nonspecific symptoms or classic dengue fever (DF).
Severe dengue, dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS), occurs in less than
1 percent of all 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 [14,60-62]. 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
[63,64]. 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 [65,66], 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 [9,60,67,68].

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 [64]. 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 [69,70].

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 [71]. 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 [72].

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 [73], 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 [74].
Genetic factors — Epidemiologic studies in Cuba showed that DHF occurred more often in whites
than in blacks [70], and a similar genetic resistance to DHF in blacks has been reported from Haiti
[75]. Racial differences have been described in viral replication in primary monocytes and in the level
of dengue serotype-cross-reactive T cell responses [76], but it is unclear if either of these explains the
genetic association.

Genome-wide association studies conducted in Vietnam [77,78] and Thailand [79] 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 [80,81],
with blood group [82], and with polymorphisms of tumor necrosis factor-alpha, vitamin D, Fc gamma
IIa, and DC-SIGN genes [80].

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 [83]. Dengue virus infects
human endothelial cells in vitro and causes cellular activation [84]. 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, to induce endothelial permeability and
disrupt the glycocalyx, and to serve as a target for antibody binding and complement activation [85-
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 3) [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 18.0

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

Antibody responses to dengue virus protein targets and antibody functions

(Panel A) The dengue virus life cycle and sources of antigens are shown. Dengue virions bind to cell surface receptors (these have not been c
characterized), and the virions are internalized through endocytosis. Acidification of the endocytic vesicle leads to rearrangement of the surfa
glycoprotein, fusion of the viral and vesicle membranes and release of viral RNA into the cytoplasm. Viral genomic RNA is then translated to p
in endoplasmic reticulum (ER)‑derived membrane structures, and the viral proteins and newly synthesized viral RNA assemble into immature
lumen. Cleavage of the viral precursor membrane (pre‑M) protein by the host cell enzyme furin leads to the formation of mature virions, which
cell. In addition, some of the synthesized non-structural protein 1 (NS1) is expressed on the plasma membrane of the cell or secreted, and so
secreted in an immature form. Mature and immature virions induce antibody responses to the E protein, and these antibodies can function in
antibody-dependent enhancement of infection. Immature virions also induce antibody responses to the pre‑M protein. Antibodies specific for
membrane-bound NS1 and cause complement-dependent lysis of virus-infected cells.
(Panel B) The structure of the dengue virus E glycoprotein ectodomain and characteristics of E protein‑specific antibodies are shown. The thr
protein are coloured in red (domain I), yellow (domain II) and blue (domain III).
(Panel C) The mechanisms of neutralization and enhancement by dengue virus-specific antibodies are shown. At high levels of epitope occup
block the binding of virions to the cellular receptor or can block fusion at a post-binding stage. At lower epitope occupancy levels, antibodies
uptake of virions into cells by interacting with immunoglobulin (Fc) receptors.

Reprinted by permission from: Macmillan Publishers Ltd: Nature Reviews Immunology. Rothman AL. Immunity to dengue virus: a tale of original antigenic s
storms. Nat Rev Immunol 2011; 11:532. Copyright © 2011. https://www.nature.com/nri/.

Graphic 122397 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 Grant/Research/Clinical Trial Support: Congressionally Directed Medical Research
Programs [Dengue human infection model grant]; Janssen [Dengue human infection model study]; National
Institute on Drug Abuse [Heroin vaccine study]; Department of Defense [Dengue human infection model];
National Institutes of Health P01 [Dengue]. Consultant/Advisory Boards: Takeda [Dengue]; Merck [Dengue
(vaccines)]; Sanofi [Dengue (vaccines)]; PrimeVax [Dengue (immuno-oncolytic including dengue component)];
Tremeau Pharmaceuticals [Dengue]; Themisbio [Chikungunya (vaccines)]; Moderna [Zika]. Patent Holder:
USG/Army [Pan-flavivirus, chikungunya, Zika virus (vaccines)]. Equity Ownership/Stock Options: PrimeVax SAB
membership [Cancer immunotherapy]. Other Financial Interests: Cormac Life Sciences, LLC [veteran owned
small business]; Green Mark Partners [Director of Strategy & Cofounder]. Alan L Rothman, MD Consultor /
Consejos Asesores: Merck [Prevención y tratamiento de infecciones por virus del dengue (vacuna contra el
dengue)]. Martin S Hirsch, MD Nada que revelar Elinor L Baron, MD, DTMH Nada que revelar

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