**2.4 Pathogenesis of severe dengue disease**

There are two form of Severe disease, namely dengue shock syndrome (DSS) and DHF without shock. It is proposed that devastating coagulation derangements due to host immune response leads to heamorrhage and shock in severe cases. The concept of original antibody sin leading to immune enhancement is considered to be the main reason whereby infection with one type of dengue virus sensitizes an individual and that subsequent infection with different virus type elicits a hypersensitivity reaction (secondary infection). Various studies have been conducted to show the association of elevated cytokines in patients presenting with DHF and DSS. Elevated serum levels of cytokine and chemokines such as IL-2, IL-8, IL-6, IL-10, IL-13, TNF and INF-γ have been found to be significantly associated with patients presenting with DHF and DSS in clinical setting (Azeredo et al., 2001; Hung, et al., 2004, Clyde. K. et al., 2006). It has been proposed that the pro-inflammatory cytokines released by the cross reactive memory T-cellls, induce plasma leakage by its effects on the endothelial cells (Eva.H. et al 2004; Aviruntanan et al., 1998). In fact in-vitro studies have rendered endothelial cell monolayers permeable by the application of chemokine such as IL-1β (Cardier et al.,2005). In vitro-and in-vivo models of studies also suggest role of decreased nitric oxide levels and its relation with IL-10 and raised viral load (Simmons et al., 2007). There is evidence that suggests relation of increased expression of certain cytokines such as IL-1β, TNF-γ, and IL-6 with elevated NO production (Guzik et al., 2003).

With the advances in genomic and bioinformatics tools the scope of genetic studies has greatly expanded particularly in depth data on genomic changes and its association with disease epidemiology, seasonality and severity has been made available. Growing availability of comparative genome sequence data has provided important insights into the molecular evolution of dengue virus. Evidence strongly suggests appearance of new strains correlating with DHF/DSS epidemics. Despite the wealth of genomic data now available the exact cause and effect of viral virulence and clade changes is yet to be proven, however it is quite evident that different serotypes and viral linage is continually changing with local extinction and emergence of new clade and that the introduction of new clade in the region translates in form of outbreaks of DHF and DSS.
