Early Immune Activation in Acute Dengue Illness Is Related to Development of Plasma Leakage and Disease Severity

Green, Sharone; Vaughn, David W.; Kalayanarooj, Siripen; Nimmannitya, Suchitra; Suntayakorn, Saroj; Nisalak, Ananda; Lew, Robert; Innis, Bruce L.; Kurane, Ichiro; Rothman, Alan L.; Ennis, Francis A.

doi:10.1086/314680

Cited by 337 publications

(283 citation statements)

References 40 publications

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“…As predictors of DHF, previous studies have proposed certain host factors such as soluble tumour necrosis factor receptors and soluble vascular cell adhesion molecule-1 and dengue virus non-structural protein NS1 [26][27][28]. An increased level of PAIgM during the acute phase of a secondary infection was highly specific for the development of DHF (92·1%) in this study, although its sensitivity was relatively low (48·6%).…”

Section: Discussioncontrasting

confidence: 43%

Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections

Saito¹,

Oishi²,

Inoue

et al. 2004

Clinical and Experimental Immunology

106

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SUMMARY Severe thrombocytopenia and increased vascular permeability are two major characteristics of dengue haemorrhagic fever (DHF). To develop a better understanding of the roles of platelet-associated IgG (PAIgG) and IgM (PAIgM) in inducing thrombocytopenia and its severity of disease in patients with secondary dengue virus infection, the relationship between the PAIgG or PAIgM levels and disease severity as well as thrombocytopenia was examined in 78 patients with acute phase secondary infection in a prospective hospital-based study. The decrease in platelet count during the acute phase recovered significantly during the convalescent phase. In contrast, the increased levels of PAIgG or PAIgM that occurred during the acute phase of these patients decreased significantly during the convalescent phase. An inverse correlation between platelet count and PAIgG or PAIgM levels was found in these patients. Anti-dengue virus IgG and IgM activity was found in platelet eluates from 10 patients in an acute phase of secondary infection. Increased levels of PAIgG or PAIgM were significantly higher in DHF than those in dengue fever (DF). An increased level of PAIgM was associated independently with the development of DHF, representing a possible predictor of DHF with a high specificity. Our present data suggest that platelet-associated immunoglobulins involving antidengue virus activity play a pivotal role in the induction of thrombocytopenia and the severity of the disease in secondary dengue virus infections.

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Section: Discussioncontrasting

confidence: 43%

Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections

Saito¹,

Oishi²,

Inoue

et al. 2004

Clinical and Experimental Immunology

106

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“…Lack of iNKT cells greatly ameliorated DENV-associated disease including vascular leakage syndrome, a hallmark of se-vere DENV infection in humans. 6,8 Increased hematocrit, a marker of hemoconcentration, and Evans blue leakage were strongly reduced in DENV-infected J␣18 Ϫ/Ϫ mice compared with infected WT mice. In parallel, histologic examination of liver sections revealed that, compared with WT mice, infected J␣18 Ϫ/Ϫ developed less acute disease.…”

Section: Discussionmentioning

confidence: 98%

“…1,5,6,8 -10,56 Inasmuch as vascular leak syndrome is a hallmark of severe DENV infection in humans, 6,8 we measured hematocrit and Evans blue permeability in DENV-infected WT and J␣18 Ϫ/Ϫ mice. Compared with mock-treated mice, the hematocrit concentration was higher at day 5 after infection in DENV-infected WT animals ( Figure 3A).…”

Section: Mice Deficient In Inkt Cells Survive To Lethal Denv Challengementioning

confidence: 99%

“…4 Severe forms are life-threatening and are characterized by hemorrhagic manifestations, hemoconcentration, thrombocytopenia, and increased vascular permeability. 1,[5][6][7][8][9][10] Despite growing public health concerns, currently there is no vaccine and no specific thera-peutic agents. Treatment is supportive and may require administration of intravenous fluids, which places a serious burden on health systems in low-income countries.…”

mentioning

confidence: 99%

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A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

Renneson¹,

Guabiraba²,

Maillet³

et al. 2011

The American Journal of Pathology

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Dengue virus (DENV), a member of the mosquitoborne flaviviruses, is a serious public health problem in many tropical countries. We assessed the in vivo physiologic contribution of invariant natural killer T (iNKT) cells, a population of nonconventional lipidreactive ␣␤ T lymphocytes, to the host response during experimental DENV infection. We used a mouseadapted DENV serotype 2 strain that causes a disease that resembles severe dengue in humans. On DENV challenge, splenic and hepatic iNKT cells became activated insofar as CD69 and Fas ligand up-regulation and interferon-␥ production. C57BL/6 mice deficient in iNKT cells (J␣18 ؊/؊ ) were more resistant to lethal infection than were wild-type animals, and the phe Dengue virus (DENV), a flavivirus of the Flaviviridae family, is a serious public health problem in tropical and subtropical areas. In the last 60 years, the incidence, distribution, and clinical severity of dengue-related diseases have increased dramatically. 1,2 There are an estimated 50 million to 100 million DENV infections each year, of which approximately 500,000 are severe dengue hemorrhagic fever, and 24,000 result in death. 2,3 DENV is a single-stranded RNA virus that is transmitted to humans by Aedes mosquitoes, primarily Aedes aegypti. Infection with any of the four serotypes of DENV results in clinical symptoms that range from classic dengue fever to severe dengue hemorrhagic fever and shock syndrome, as defined by the World Health Organization. 4 Severe forms are life-threatening and are characterized by hemorrhagic manifestations, hemoconcentration, thrombocytopenia, and increased vascular permeability. 1,5-10 Despite growing public health concerns, currently there is no vaccine and no specific theraSupported in part by the

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“…Another study found the ratio of TNF-α-to IFN-γ-producing cells was higher when DENV-specific CD4 + T cells were stimulated ex vivo with antigens from the heterologous vs. homologous serotype (18). Increased TNF-α production by T cells could facilitate vascular leakage, as TNF-α has been detected more frequently and at higher levels in the serum of patients with DHF/DSS than with DF (19). Overall, studies in human DENV infections thus far have mostly focused on the potential role of T cells in pathogenesis and the association between HLA alleles and disease severity.…”

Section: A Protective Role For Original Antigenic Sinmentioning

confidence: 99%

Original antigenic sin in dengue revisited

Zompì

Harris

2013

Proc. Natl. Acad. Sci. U.S.A.

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The four dengue virus serotypes (DENV-1 to -4) cause the most important arthropod-borne viral disease of humans, with ∼100 million cases each year and over 3 billion people at risk for infection (1). The immune response to DENV infection is complex, because it can be either protective or pathogenic. The "original antigenic sin" in secondary (2°) DENV infections is defined as the dominance of cross-reactive antibodies or T-cell responses to a first infecting DENV serotype (the "original antigen") over the current infecting serotype. In acute DENV infections, cross-reactive T-cell responses have been associated with more severe disease, consigning cross-reactive T-cell responses to a pathogenic role (2, 3). In this issue of PNAS, Weiskopf et al. (4) challenge the idea that cross-reactive T-cell responses are only associated with pathogenesis by demonstrating that although CD8 + T-cell responses were indeed skewed toward the first DENV infection, this did not result in impaired responses, either qualitatively or quantitatively. Furthermore, they found that higher magnitude T-cell responses were associated with HLA alleles that have been linked to reduced susceptibility to severe dengue. Thus, these results suggest that human cross-reactive T-cell responses can be associated with a robust and multifunctional response that can induce protection, as has been shown in dengue mouse models (5-7). Dengue epidemiology and immune responseDengue is endemic throughout the world's subtropical and tropical regions, especially in Asia and Latin America, and it is considered an emerging infectious disease threat in the United States and a category A pathogen. Increased urbanization, globalization, and travel, as well as climate change, all contribute to its uncontrolled expansion (8). The acute febrile illness dengue fever (DF) can progress to a potentially life-threatening vascular leakage syndrome, known as dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the latter characterized by hypotension and circulatory failure, most often affecting children (9). There are ∼500,000 hospitalizations attributable to dengue each year, with case fatality rates as high as 10-20% without appropriate treatment (9). Dengue constitutes a substantial economic burden in endemic countries (10), which are mostly low-and middle-income countries. No specific treatment exists, and an incomplete understanding of the immune response has hindered vaccine development.Primary (1°) infection with any of the four DENV serotypes is believed to confer lifelong protection to the homologous serotype; however, 2°infection with a different DENV serotype is the major risk factor for severe disease (11). This may be attributable to cross-reactive T cells (3) or to "antibodydependent enhancement" (12), where crossreactive anti-DENV antibodies facilitate entry of DENV into constant fragment receptorbearing cells. However, the majority of 2°D ENV infections are asymptomatic or result in only mild disease. The immune mechanisms underlying protection against a het...

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Early Immune Activation in Acute Dengue Illness Is Related to Development of Plasma Leakage and Disease Severity

Cited by 337 publications

References 40 publications

Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections

Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

Original antigenic sin in dengue revisited

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