Patogenesis del Dengue virus

7/23/2019 Patogenesis del Dengue virus

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Official reprint from UpToDate

www.uptodate.com2015 UpToDate

Author

Alan L Rothman, MD

Section Editor

Martin S Hirsch, MD

Deputy Editor

Elinor L Baron, MD, DTMH

Pathogenesis of dengue virus infection

All topics are updated as new evidence becomes available and our peer review processis 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:

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 thetemplate 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 commonlyAedes

aegypti. The spread of virus early after subcutaneous injection has been studied in rhesus monkeys [ 11]. During the

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

genesis of dengue virus infection http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/patho

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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 andlasts 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 populationthan 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 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-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-

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 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 yieldedvirus 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 dengueinfections 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:

The increased risk of DHF in secondary dengue virus infections is felt to reflect the differences in immune responses

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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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:

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

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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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 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 ofthe 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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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 Councilmanbodies 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 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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REFERENCES

Rico-Hesse R. Dengue virus evolution and virulence models. Clin Infect Dis 2007; 44:1462.1.

Henchal EA, Putnak JR. The dengue viruses. Clin Microbiol Rev 1990; 3:376.2.

Anderson R, King AD, Innis BL. Correlation of E protein binding with cell susceptibility to dengue 4 virus

infection. J Gen Virol 1992; 73 ( Pt 8):2155.

3.

Modis Y, Ogata S, Clements D, Harrison SC. A ligand-binding pocket in the dengue virus envelope

glycoprotein. Proc Natl Acad Sci U S A 2003; 100:6986.

4.

Modis Y, Ogata S, Clements D, Harrison SC. Structure of the dengue virus envelope protein after membrane

fusion. Nature 2004; 427:313.

5.

Mukhopadhyay S, Kuhn RJ, Rossmann MG. A structural perspective of the flavivirus life cycle. Nat Rev

Microbiol 2005; 3:13.

6.

Chen Y, Maguire T, Hileman RE, et al. Dengue virus infectivity depends on envelope protein binding to target

cell heparan sulfate. Nat Med 1997; 3:866.

7.

Tassaneetrithep B, Burgess TH, Granelli-Piperno A, et al. DC-SIGN (CD209) mediates dengue virus infection

of human dendritic cells. J Exp Med 2003; 197:823.

8.

Morens DM. Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin Infect

Dis 1994; 19:500.

9.

Stadler K, Allison SL, Schalich J, Heinz FX. Proteolytic activation of tick-borne encephalitis virus by furin. J

Virol 1997; 71:8475.

10.

Marchette NJ, Halstead SB, Falkler WA Jr, et al. Studies on the pathogenesis of dengue infection in monkeys.

3. Sequential distribution of virus in primary and heterologous infections. J Infect Dis 1973; 128:23.

11.

Wu SJ, Grouard-Vogel G, Sun W, et al. Human skin Langerhans cells are targets of dengue virus infection. Nat

Med 2000; 6:816.

12.

Kyle JL, Beatty PR, Harris E. Dengue virus infects macrophages and dendritic cells in a mouse model of

infection. J Infect Dis 2007; 195:1808.

13.

SABIN AB. Research on dengue during World War II. Am J Trop Med Hyg 1952; 1:30.14.

Vaughn DW, Green S, Kalayanarooj S, et al. Dengue in the early febrile phase: viremia and antibody

responses. J Infect Dis 1997; 176:322.

15.

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.)


7 11/08/2015 1


9/17

Scott RM, Nisalak A, Cheamudon U, et al. Isolation of dengue viruses from peripheral blood leukocytes of

patients with hemorrhagic fever. J Infect Dis 1980; 141:1.

16.

King AD, Nisalak A, Kalayanrooj S, et al. B cells are the principal circulating mononuclear cells infected by

dengue virus. Southeast Asian J Trop Med Public Health 1999; 30:718.

17.

Durbin AP, Vargas MJ, Wanionek K, et al. Phenotyping of peripheral blood mononuclear cells during acute

dengue illness demonstrates infection and increased activation of monocytes in severe cases compared to

classic dengue fever. Virology 2008; 376:429.

18.

Rosen L, Khin MM, U T. Recovery of virus from the liver of children with fatal dengue: reflections on the

pathogenesis of the disease and its possible analogy with that of yellow fever. Res Virol 1989; 140:351.

19.

Boonpucknavig S, Boonpucknavig V, Bhamarapravati N, Nimmannitya S. Immunofluorescence study of skin

rash in patients with dengue hemorrhagic fever. Arch Pathol Lab Med 1979; 103:463.

20.

Hall WC, Crowell TP, Watts DM, et al. Demonstration of yellow fever and dengue antigens in formalin-fixed

paraffin-embedded human liver by immunohistochemical analysis. Am J Trop Med Hyg 1991; 45:408.

21.

Jessie K, Fong MY, Devi S, et al. Localization of dengue virus in naturally infected human tissues, by

immunohistochemistry and in situ hybridization. J Infect Dis 2004; 189:1411.

22.

Fresh JW, Reyes V, Clarke EJ, Uylangco CV. Philippine hemorrhagic fever: a clinical, laboratory, and necropsy

study. J Lab Clin Med 1969; 73:451.

23.

Schmidt AC. Response to dengue fever--the good, the bad, and the ugly? N Engl J Med 2010; 363:484.24.

Kurane I, Janus J, Ennis FA. Dengue virus infection of human skin fibroblasts in vitro production of IFN-beta,

IL-6 and GM-CSF. Arch Virol 1992; 124:21.

25.

Kurane I, Ennis FA. Production of interferon alpha by dengue virus-infected human monocytes. J Gen Virol

1988; 69 ( Pt 2):445.

26.

Libraty DH, Endy TP, Houng HS, et al. Differing influences of virus burden and immune activation on disease

severity in secondary dengue-3 virus infections. J Infect Dis 2002; 185:1213.

27.

Kurane I, Hebblewaite D, Brandt WE, Ennis FA. Lysis of dengue virus-infected cells by natural cell-mediated

cytotoxicity and antibody-dependent cell-mediated cytotoxicity. J Virol 1984; 52:223.

28.

Muoz-Jordan JL, Snchez-Burgos GG, Laurent-Rolle M, Garca-Sastre A. Inhibition of interferon signaling by

dengue virus. Proc Natl Acad Sci U S A 2003; 100:14333.

29.

Jones M, Davidson A, Hibbert L, et al. Dengue virus inhibits alpha interferon signaling by reducing STAT2expression. J Virol 2005; 79:5414.

30.

Simmons CP, Popper S, Dolocek C, et al. Patterns of host genome-wide gene transcript abundance in the

peripheral blood of patients with acute dengue hemorrhagic fever. J Infect Dis 2007; 195:1097.

31.

Schlesinger JJ, Brandriss MW, Walsh EE. Protection of mice against dengue 2 virus encephalitis by

immunization with the dengue 2 virus non-structural glycoprotein NS1. J Gen Virol 1987; 68 ( Pt 3):853.

32.

He RT, Innis BL, Nisalak A, et al. Antibodies that block virus attachment to Vero cells are a major component of

the human neutralizing antibody response against dengue virus type 2. J Med Virol 1995; 45:451.

33.

Kaufman BM, Summers PL, Dubois DR, Eckels KH. Monoclonal antibodies against dengue 2 virus

E-glycoprotein protect mice against lethal dengue infection. Am J Trop Med Hyg 1987; 36:427.

34.

Kaufman BM, Summers PL, Dubois DR, et al. Monoclonal antibodies for dengue virus prM glycoprotein protect

mice against lethal dengue infection. Am J Trop Med Hyg 1989; 41:576.

35.

Pierson TC, Diamond MS. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection.

Expert Rev Mol Med 2008; 10:e12.

36.

Halstead SB. In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred

antibody. J Infect Dis 1979; 140:527.

37.

Goncalvez AP, Engle RE, St Claire M, et al. Monoclonal antibody-mediated enhancement of dengue virus

infection in vitro and in vivo and strategies for prevention. Proc Natl Acad Sci U S A 2007; 104:9422.

38.

Balsitis SJ, Williams KL, Lachica R, et al. Lethal antibody enhancement of dengue disease in mice is

prevented by Fc modification. PLoS Pathog 2010; 6:e1000790.

39.


7 11/08/2015 1


10/17

Dejnirattisai W, Jumnainsong A, Onsirisakul N, et al. Cross-reacting antibodies enhance dengue virus infection

in humans. Science 2010; 328:745.

40.

Gagnon SJ, Ennis FA, Rothman AL. Bystander target cell lysis and cytokine production by dengue virus-

specific human CD4(+) cytotoxic T-lymphocyte clones. J Virol 1999; 73:3623.

41.

Mathew A, Kurane I, Rothman AL, et al. Dominant recognition by human CD8+ cytotoxic T lymphocytes of

dengue virus nonstructural proteins NS3 and NS1.2a. J Clin Invest 1996; 98:1684.

42.

Kontny U, Kurane I, Ennis FA. Gamma interferon augments Fc gamma receptor-mediated dengue virus

infection of human monocytic cells. J Virol 1988; 62:3928.

43.

Anderson KB, Gibbons RV, Cummings DA, et al. A shorter time interval between first and second dengue

infections is associated with protection from clinical illness in a school-based cohort in Thailand. J Infect Dis

2014; 209:360.

44.

Montoya M, Gresh L, Mercado JC, et al. Symptomatic versus inapparent outcome in repeat dengue virus

infections is influenced by the time interval between infections and study year. PLoS Negl Trop Dis 2013;

7:e2357.

45.

Halstead SB, Shotwell H, Casals J. Studies on the pathogenesis of dengue infection in monkeys. II. Clinical

laboratory responses to heterologous infection. J Infect Dis 1973; 128:15.

46.

Vaughn DW, Green S, Kalayanarooj S, et al. Dengue viremia titer, antibody response pattern, and virus

serotype correlate with disease severity. J Infect Dis 2000; 181:2.

47.

Murgue B, Roche C, Chungue E, Deparis X. Prospective study of the duration and magnitude of viraemia inchildren hospitalised during the 1996-1997 dengue-2 outbreak in French Polynesia. J Med Virol 2000; 60:432.

48.

Wang WK, Chen HL, Yang CF, et al. Slower rates of clearance of viral load and virus-containing immune

complexes in patients with dengue hemorrhagic fever. Clin Infect Dis 2006; 43:1023.

49.

Kuberski T, Rosen L, Reed D, Mataika J. Clinical and laboratory observations on patients with primary and

secondary dengue type 1 infections with hemorrhagic manifestations in Fiji. Am J Trop Med Hyg 1977; 26:775.

50.

Sudiro TM, Zivny J, Ishiko H, et al. Analysis of plasma viral RNA levels during acute dengue virus infection

using quantitative competitor reverse transcription-polymerase chain reaction. J Med Virol 2001; 63:29.

51.

Srikiatkhachorn A, Wichit S, Gibbons RV, et al. Dengue viral RNA levels in peripheral blood mononuclear cells

are associated with disease severity and preexisting dengue immune status. PLoS One 2012; 7:e51335.

52.

Green S, Pichyangkul S, Vaughn DW, et al. Early CD69 expression on peripheral blood lymphocytes fromchildren with dengue hemorrhagic fever. J Infect Dis 1999; 180:1429.53.

Mongkolsapaya J, Dejnirattisai W, Xu XN, et al. Original antigenic sin and apoptosis in the pathogenesis of

dengue hemorrhagic fever. Nat Med 2003; 9:921.

54.

Zivna I, Green S, Vaughn DW, et al. T cell responses to an HLA-B*07-restricted epitope on the dengue NS3

protein correlate with disease severity. J Immunol 2002; 168:5959.

55.

Simmons CP, Dong T, Chau NV, et al. Early T-cell responses to dengue virus epitopes in Vietnamese adults

with secondary dengue virus infections. J Virol 2005; 79:5665.

56.

Friberg H, Bashyam H, Toyosaki-Maeda T, et al. Cross-reactivity and expansion of dengue-specific T cells

during acute primary and secondary infections in humans. Sci Rep 2011; 1:51.

57.

Dung NT, Duyen HT, Thuy NT, et al. Timing of CD8+ T cell responses in relation to commencement of capillary

leakage in children with dengue. J Immunol 2010; 184:7281.

58.

Zivny J, DeFronzo M, Jarry W, et al. Partial agonist effect influences the CTL response to a heterologous

dengue virus serotype. J Immunol 1999; 163:2754.

59.

Mangada MM, Endy TP, Nisalak A, et al. Dengue-specific T cell responses in peripheral blood mononuclear

cells obtained prior to secondary dengue virus infections in Thai schoolchildren. J Infect Dis 2002; 185:1697.

60.

Hatch S, Endy TP, Thomas S, et al. Intracellular cytokine production by dengue virus-specific T cells correlates

with subclinical secondary infection. J Infect Dis 2011; 203:1282.

61.

Burke DS, Nisalak A, Johnson DE, Scott RM. A prospective study of dengue infections in Bangkok. Am J Trop

Med Hyg 1988; 38:172.

62.

Sangkawibha N, Rojanasuphot S, Ahandrik S, et al. Risk factors in dengue shock syndrome: a prospective63.


17 11/08/2015 1


11/17

epidemiologic study in Rayong, Thailand. I. The 1980 outbreak. Am J Epidemiol 1984; 120:653.

Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev

2009; 22:564.

64.

Rico-Hesse R, Harrison LM, Salas RA, et al. Origins of dengue type 2 viruses associated with increased

pathogenicity in the Americas. Virology 1997; 230:244.

65.

Watts DM, Porter KR, Putvatana P, et al. Failure of secondary infection with American genotype dengue 2 to

cause dengue haemorrhagic fever. Lancet 1999; 354:1431.

66.

Pryor MJ, Carr JM, Hocking H, et al. Replication of dengue virus type 2 in human monocyte-derivedmacrophages: comparisons of isolates and recombinant viruses with substitutions at amino acid 390 in the

envelope glycoprotein. Am J Trop Med Hyg 2001; 65:427.

67.

Cologna R, Rico-Hesse R. American genotype structures decrease dengue virus output from human

monocytes and dendritic cells. J Virol 2003; 77:3929.

68.

Guzmn MG, Kour G, Martnez E, et al. Clinical and serologic study of Cuban children with dengue

hemorrhagic fever/dengue shock syndrome (DHF/DSS). Bull Pan Am Health Organ 1987; 21:270.

69.

Daz A, Kour G, Guzmn MG, et al. Description of the clinical picture of dengue hemorrhagic fever/dengue

shock syndrome (DHF/DSS) in adults. Bull Pan Am Health Organ 1988; 22:133.

70.

Thein S, Aung MM, Shwe TN, et al. Risk factors in dengue shock syndrome. Am J Trop Med Hyg 1997;

56:566.

71.

Kour G, Guzmn MG, Bravo J. Hemorrhagic dengue in Cuba: history of an epidemic. Bull Pan Am HealthOrgan 1986; 20:24.

72.

Guzmn MG, Kouri GP, Bravo J, et al. Dengue hemorrhagic fever in Cuba, 1981: a retrospective

seroepidemiologic study. Am J Trop Med Hyg 1990; 42:179.

73.

Kliks SC, Nimmanitya S, Nisalak A, Burke DS. Evidence that maternal dengue antibodies are important in the

development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg 1988; 38:411.

74.

Simmons CP, Chau TN, Thuy TT, et al. Maternal antibody and viral factors in the pathogenesis of dengue virus

in infants. J Infect Dis 2007; 196:416.

75.

Libraty DH, Acosta LP, Tallo V, et al. A prospective nested case-control study of Dengue in infants: rethinking

and refining the antibody-dependent enhancement dengue hemorrhagic fever model. PLoS Med 2009;

6:e1000171.

76.

Thisyakorn U, Nimmannitya S. Nutritional status of children with dengue hemorrhagic fever. Clin Infect Dis

1993; 16:295.

77.

Halstead SB, Streit TG, Lafontant JG, et al. Haiti: absence of dengue hemorrhagic fever despite hyperendemic

dengue virus transmission. Am J Trop Med Hyg 2001; 65:180.

78.

de la C Sierra B, Kour G, Guzmn MG. Race: a risk factor for dengue hemorrhagic fever. Arch Virol 2007;

152:533.

79.

Chiewsilp P, Scott RM, Bhamarapravati N. Histocompatibility antigens and dengue hemorrhagic fever. Am J

Trop Med Hyg 1981; 30:1100.

80.

Stephens HA, Klaythong R, Sirikong M, et al. HLA-A and -B allele associations with secondary dengue virus

infections correlate with disease severity and the infecting viral serotype in ethnic Thais. Tissue Antigens 2002;

60:309.

81.

Paradoa Prez ML, Trujillo Y, Basanta P. Association of dengue hemorrhagic fever with the HLA system.

Haematologia (Budap) 1987; 20:83.

82.

Loke H, Bethell DB, Phuong CX, et al. Strong HLA class I--restricted T cell responses in dengue hemorrhagic

fever: a double-edged sword? J Infect Dis 2001; 184:1369.

83.

Fernndez-Mestre MT, Gendzekhadze K, Rivas-Vetencourt P, Layrisse Z. TNF-alpha-308A allele, a possible

severity risk factor of hemorrhagic manifestation in dengue fever patients. Tissue Antigens 2004; 64:469.

84.

Loke H, Bethell D, Phuong CX, et al. Susceptibility to dengue hemorrhagic fever in vietnam: evidence of an

association with variation in the vitamin d receptor and Fc gamma receptor IIa genes. Am J Trop Med Hyg

2002; 67:102.

85.


17 11/08/2015 1


12/17

Sakuntabhai A, Turbpaiboon C, Casadmont I, et al. A variant in the CD209 promoter is associated with

severity of dengue disease. Nat Genet 2005; 37:507.

86.

Kalayanarooj S, Gibbons RV, Vaughn D, et al. Blood group AB is associated with increased risk for severe

dengue disease in secondary infections. J Infect Dis 2007; 195:1014.

87.

Sahaphong S, Riengrojpitak S, Bhamarapravati N, Chirachariyavej T. Electron microscopic study of the

vascular endothelial cell in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1980;

11:194.

88.

Srikiatkhachorn A, Ajariyakhajorn C, Endy TP, et al. Virus-induced decline in soluble vascular endothelial

growth receptor 2 is associated with plasma leakage in dengue hemorrhagic Fever. J Virol 2007; 81:1592.

89.

Avirutnan P, Punyadee N, Noisakran S, et al. Vascular leakage in severe dengue virus infections: a potential

role for the nonstructural viral protein NS1 and complement. J Infect Dis 2006; 193:1078.

90.

Bhamarapravati N, Tuchinda P, Boonyapaknavik V. Pathology of Thailand haemorrhagic fever: a study of 100

autopsy cases. Ann Trop Med Parasitol 1967; 61:500.

91.

Anderson R, Wang S, Osiowy C, Issekutz AC. Activation of endothelial cells via antibody-enhanced dengue

virus infection of peripheral blood monocytes. J Virol 1997; 71:4226.

92.

Bosch I, Xhaja K, Estevez L, et al. Increased production of interleukin-8 in primary human monocytes and in

human epithelial and endothelial cell lines after dengue virus challenge. J Virol 2002; 76:5588.

93.

Talavera D, Castillo AM, Dominguez MC, et al. IL8 release, tight junction and cytoskeleton dynamic

reorganization conducive to permeability increase are induced by dengue virus infection of microvascularendothelial monolayers. J Gen Virol 2004; 85:1801.

94.

Hober D, Poli L, Roblin B, et al. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6),

and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg 1993; 48:324.

95.

Bethell DB, Flobbe K, Cao XT, et al. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic

fever. J Infect Dis 1998; 177:778.

96.

Juffrie M, van Der Meer GM, Hack CE, et al. Inflammatory mediators in dengue virus infection in children:

interleukin-8 and its relationship to neutrophil degranulation. Infect Immun 2000; 68:702.

97.

Kurane I, Innis BL, Nimmannitya S, et al. Activation of T lymphocytes in dengue virus infections. High levels of

soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of

children with dengue. J Clin Invest 1991; 88:1473.

98.

Green S, Vaughn DW, Kalayanarooj S, et al. Early immune activation in acute dengue illness is related to

development of plasma leakage and disease severity. J Infect Dis 1999; 179:755.

99.

Bokisch VA, Top FH Jr, Russell PK, et al. The potential pathogenic role of complement in dengue hemorrhagic

shock syndrome. N Engl J Med 1973; 289:996.

100.

Malasit P. Complement and dengue haemorrhagic fever/shock syndrome. Southeast Asian J Trop Med Public

Health 1987; 18:316.

101.

Hober D, Delannoy AS, Benyoucef S, et al. High levels of sTNFR p75 and TNF alpha in dengue-infected

patients. Microbiol Immunol 1996; 40:569.

102.

Kalayanarooj S, Vaughn DW, Nimmannitya S, et al. Early clinical and laboratory indicators of acute dengue

illness. J Infect Dis 1997; 176:313.

103.

BIERMAN HR, NELSON ER. HEMATODEPRESSIVE VIRUS DISEASES OF THAILAND. Ann Intern Med1965; 62:867.

104.

Rothwell SW, Putnak R, La Russa VF. Dengue-2 virus infection of human bone marrow: characterization of

dengue-2 antigen-positive stromal cells. Am J Trop Med Hyg 1996; 54:503.

105.

Nakao S, Lai CJ, Young NS. Dengue virus, a flavivirus, propagates in human bone marrow progenitors and

hematopoietic cell lines. Blood 1989; 74:1235.

106.

Murgue B, Cassar O, Guigon M, Chungue E. Dengue virus inhibits human hematopoietic progenitor growth in

vitro. J Infect Dis 1997; 175:1497.

107.

Mitrakul C, Poshyachinda M, Futrakul P, et al. Hemostatic and platelet kinetic studies in dengue hemorrhagic

fever. Am J Trop Med Hyg 1977; 26:975.

108.


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13/17

Cardier JE, Rivas B, Romano E, et al. Evidence of vascular damage in dengue disease: demonstration of high

levels of soluble cell adhesion molecules and circulating endothelial cells. Endothelium 2006; 13:335.

109.

Sosothikul D, Seksarn P, Pongsewalak S, et al. Activation of endothelial cells, coagulation and fibrinolysis in

children with Dengue virus infection. Thromb Haemost 2007; 97:627.

110.

Srichaikul T, Nimmanitaya S, Artchararit N, et al. Fibrinogen metabolism and disseminated intravascular

coagulation in dengue hemorrhagic fever. Am J Trop Med Hyg 1977; 26:525.

111.

Chungue E, Poli L, Roche C, et al. Correlation between detection of plasminogen cross-reactive antibodies

and hemorrhage in dengue virus infection. J Infect Dis 1994; 170:1304.

112.

Falconar AK. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on

human blood clotting, integrin/adhesin proteins and binds to human endothelial cells: potential implications in

haemorrhagic fever pathogenesis. Arch Virol 1997; 142:897.

113.

Marianneau P, Cardona A, Edelman L, et al. Dengue virus replication in human hepatoma cells activates

NF-kappaB which in turn induces apoptotic cell death. J Virol 1997; 71:3244.

114.

Solomon T, Dung NM, Vaughn DW, et al. Neurological manifestations of dengue infection. Lancet 2000;

355:1053.

115.

Ramos C, Snchez G, Pando RH, et al. Dengue virus in the brain of a fatal case of hemorrhagic dengue fever.

J Neurovirol 1998; 4:465.

116.

Topic 3029 Version 12.0


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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



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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 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

Disclosures


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Patogenesis del Dengue virus

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