Dengue in Thailand and Cambodia: An Assessment of the Degree of Underrecognized Disease Burden Based on Reported Cases

Dengue is a major public health problem especially in tropical and subtropical countries of Asia and Latin-America. An effective dengue vaccine is not yet available, but several vaccine candidates are currently being evaluated in clinical trials. Accurate country-level incidence data are crucial to assess the cost-effectiveness of such vaccines and will assist policy-makers in making vaccine introduction decisions. Existing national surveillance systems are often passive and are designed to monitor trends and to detect disease outbreaks. Our analyses of data from prospectively followed cohorts with laboratory confirmation of dengue cases show that, in Thailand and Cambodia, dengue incidence is underrecognized by more than 8-fold. The magnitude of the outpatient burden caused by dengue is not assessed or reflected by the national surveillance data. We estimate that a median of more than 340,000 symptomatic dengue virus infections occurred annually in children less than 15 years of age in Thailand in Cambodia between 2003 and 2007

Results of literature search and evaluation of identified data sources according PRISMA.

<p>Duplicates and articles that did not satisfy the inclusion criteria were removed following evaluation of the titles and abstracts. The full text of these documents was examined to facilitate the final selection of relevant articles. Included publications were collated and summarized using a data extraction instrument developed as a series of spreadsheets, as described in the protocol.</p

Change in pattern of circulating dengue virus serotypes by year and region, Thailand, 2005–2010 [28]–[33].

<p>Regional DENV serotype data for the period 2005–2010 show similar patterns in each region. Broadly, there was a reduction in the proportion of DENV-1 and an increase in the proportion of DENV-2 in all regions. The proportion of DENV-3 was variable by time and between regions, whereas DENV-4 only remained in circulation throughout this 5-year period in the Central region. DENV, dengue virus. *Data for 2000–2004 not available from source material.</p

Reported dengue disease incidence by region, Thailand, 2000–2011 [23]–[34].

<p>The patterns of regional dengue disease case numbers broadly reflected those observed nationally. The reported incidence of dengue disease was highest in the South region in 2001, 2002, 2005, 2007 and 2010.</p

Reported cases of dengue fever, dengue haemorrhagic fever and dengue shock syndrome, Thailand, 2000–2011 [23]–[34].

<p>The contribution of DSS to the total number of dengue disease cases remained relatively stable over the decade. Over the same period, the proportion of the total dengue disease cases classified as DF tended to increase year-on-year (with the exception of 2010–2011) whereas the contribution of DHF to the total number of dengue disease cases decreased. DF, dengue fever; DHF, dengue haemorrhagic fever; DSS, dengue shock syndrome.</p

Activation of dengue virus-specific T cells modulates vascular endothelial growth factor receptor 2 expression

Background: The pathogenic mechanisms underlying the increased vascular permeability in dengue hemorrhagic fever (DHF) are not well understood. Enhanced cellular immune activation, especially activation of serotype-cross reactive T cells, has been implicated in plasma leakage in DHF. Changes in several biological markers and mediators including cytokines, chemokines, angiogenic factors and their receptors have been shown to correlate with disease severity. A decline in plasma levels of a soluble form of vascular endothelial growth factor receptor 2 (VEGFR2), a receptor of vascular endothelial growth factor (VEGF), has been associated with plasma leakage in dengue patients. Objective: We aimed to investigate the effect of dengue virus (DV)-specific CD8 + T cells on the expression of VEGFR2 on endothelial cells. Method: An in vitro model was developed in which dengue virus-specific CD8 + T cells generated from peripheral blood mononuclear cells (PBMCs) of DHF patients were co-cultured with antigen-presenting cells, human umbilical vein endothelial cells (HUVECs) and activated with DV non-structural protein 3 (NS3) peptides. The expression of VEGFR2 by endothelial cells was measured. Results: DV-specific CD8 + T cells were serotype cross-reactive. Activation of DV-specific CD8 + T cells resulted in down-regulation of soluble VEGFR2 production and an up-regulation of cell-associated VEGFR2. Conclusions: Our findings indicate that activation of DV-specific T cell is associated with modulation of VEGFR2 expression that may contribute to increased VEGF responsiveness and vascular permeabilit

Acute Systemic Infection with Dengue Virus Leads to Vascular Leakage and Death through Tumor Necrosis Factor-α and Tie2/Angiopoietin Signaling in Mice Lacking Type I and II Interferon Receptors.

Severe dengue is caused by host responses to viral infection, but the pathogenesis remains unknown. This is, in part, due to the lack of suitable animal models. Here, we report a non-mouse-adapted low-passage DENV-3 clinical isolate, DV3P12/08, derived from recently infected patients. DV3P12/08 caused a lethal systemic infection in type I and II IFN receptor KO mice (IFN-α/β/γR KO mice), which have the C57/BL6 background. Infection with DV3P12/08 induced a cytokine storm, resulting in severe vascular leakage (mainly in the liver, kidney and intestine) and organ damage, leading to extensive hemorrhage and rapid death. DV3P12/08 infection triggered the release of large amounts of TNF-α, IL-6, and MCP-1. Treatment with a neutralizing anti-TNF-α antibody (Ab) extended survival and reduced liver damage without affecting virus production. Anti-IL-6 neutralizing Ab partly prolonged mouse survival. The anti-TNF-α Ab suppressed IL-6, MCP-1, and IFN-γ levels, suggesting that the severe response to infection was triggered by TNF-α. High levels of TNF-α mRNA were expressed in the liver and kidneys, but not in the small intestine, of infected mice. Conversely, high levels of IL-6 mRNA were expressed in the intestine. Importantly, treatment with Angiopoietin-1, which is known to stabilize blood vessels, prolonged the survival of DV3P12/08-infected mice. Taken together, the results suggest that an increased level of TNF-α together with concomitant upregulation of Tie2/Angiopoietin signaling have critical roles in severe dengue infection