Pathogenesis of Dengue Virus Infection

8/10/2019 Pathogenesis of Dengue Virus Infection

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12/23/2014 Pathogenesis of dengue virus infection

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Official reprint from UpToDate

www.uptodate.com 2014 UpToDate

AuthorAlan L Rothman, MD

Section EditorMartin S Hirsch, MD

Deputy EditorElinor L Baron, MD, DTMH

Pathogenesis of dengue virus infection

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Nov 2014. | 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 isavailable 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:

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 iscleaved 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

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
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[11]. 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 [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 injectionand 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 insome 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, andblock 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
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protection against lethal dengue virus infection [32,34,35].

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 virus-specific 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-Mspecific 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-

crossreactive 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 heterotypicprotective 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 higherpeak 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 thevariation 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 virus

specific 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:

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

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].
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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 andcauses 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:

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. 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

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.
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cells), vascular endothelial growth factor (VEGF, potentially produced by monocytes and endothelial cells), and

complement (activated by virus-antibody 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

(


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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 5 to 6

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 10 to 12 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.)

SUMMARY AND RECOMMENDATIONS

th th

th th

Basics topic (see "Patient information: Dengue fever (The Basics)")

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 commonlyAedes

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 inthe 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.)

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.
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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 Den gu e-2 virus

Viral genotype "Asian" genotypes

Host factors

Immunity Prior dengue virus infection

Age Adult

Nutrition Malnourished

Genetics Black



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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:Alan L Rothman, MD Grant/Researc h/Clinical Trial Support: Sanofi-Pasteur (Denguevaccine [dengue vaccine]). Consultant/Advisory Boards: Sanofi-Pasteur (Dengue vaccine [dengue

vaccine]). Martin S Hirsch, MD Nothing to disclose. Elinor L Baron, MD, DTMH Employee of

UpToDate, Inc.

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 forreferences to be provided to support the content. Appropriately referenced content is required of all

authors and must conform to UpToDate standards of evidence.

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