Several hypotheses have been explained as pathogenetic mechanism for dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS).

Antibody dependent enhancement (ADE): The phenomenon of ADE was observed with dengue virus when it was found that dengue virus grows better in culture of peripheral blood mononuclear cells (PBMC) from human or monkeys who were immune to dengue, as compared to that from non-immune hosts.

The role of ADE in disease pathogenesis is evidenced by increased risk of developing DHF/DSS after a secondary dengue viral infection with a heterologous dengue virus serotype.

Mechanism of ADE: During the primary dengue infection, both homotypic neutralizing antibodies as well as cross-protective heterotypic neutralizing antibodies are developed. Homotypic antibodies persist for a long time but the level of heterotypic antibodies decreases to sub-neutralizing level after a few months to years. Therefore, secondary infection with a different serotype when occurs within a short span of time significant cross-protection occurs due to the presence of heterotypic antibodies developed during the previous infection.

Thus, during the initial period, heterotypic antibodies provide cross-protection against the infection and for a further more period against the severe disease. However, the level of cross-protection decreases with increase in gap between the primary and secondary infections.

When sequential infection occurs after a few years with a different serotype, the pre-existing heterotypic sub-neutralizing antibodies bind to the virus but not able to neutralize it. This antibody–virus (antigen) complex attaches to the Fcg receptor present on the circulating monocytes, facilitating the entry of virus to its target cells. This in turn leads to infection of more number of target cells, high viral replication leading to high viral load and thereby increase in NS1 antigen level, release of cytokines and contributing to pathogenesis of severity (Table1).

Table1. Mechanism of antibody dependent enhancement

In addition to the ADE mechanism, it is also thought that entry of virus through Fcg receptor inhibits the innate antiviral response.

Cross-reactive memory T cell response: Cross reactive memory CD8 cells are present in previously infected individual. These memory cells recognize the viral antigen and get activated but not capable of clearing the virus. CD8 memory T cells may have high avidity or low avidity to the heterologous antigen.

CD8 T cells having low avidity for the heterologous dengue virus epitopes, produce high level of proinflammatory cytokines such as TNF-a, IL-6 and other soluble factors. These cytokines cause endothelial damage and lead to increase of vascular permeability.

Complement mediated damage: During secondary infection with heterologous dengue virus, reaction between viral antigen and preexisting antibody activates the complement through C3 activator and initiating C1, C2 and C4 cascade. This leads to increase in the level of C3a and C5a anaphylotoxins which mediates the endothelial damage and leads to increase in vascular permeability.

Heterophile immune response: Antibody produced against the viral protein NS1 cross reacts with several host cell proteins such as endothelial cell, liver cell and blood clotting proteins. The level of this antibody reaches pathologic level during secondary infection and is believed to cause damage to the cross reactive host cells.

Soluble factors: Several studies have shown association of severity with increased level of various proinflammatory cytokines. However, the role of TNF-a, IL-10 and IL-6 has been extensively elucidated. These cytokines lead to increase in endothelial cell permeability, thrombocytopenia, derangement of coagulation and fibrinolysis.

Viral factors: No specific dengue virus serotype or genotype has been exclusively associated with severe disease. A recent meta analysis study has shown secondary infection with DEN-2, DEN-3 and DEN-4 and primary infection with DEN-3 serotypes are associated with more severe disease in South East Asian (SEA) countries and secondary infection with DEN-2 and DEN-3 are associated more with severe diseases in non-SEA countries.

Heterotypic infection with Asian genotype of DEN2 has been observed to cause more severe disease of DHF and DSS in Southeast Asia as compared to the American genotype of DEN-2 which causes mild disease.

The sequential infection with different dengue virus serotypes is responsible for development of severe dengue viral disease. Primary infection with DENV-1 followed by secondary infection with DEN-2 or DEN-3 has been associated with DHF epidemics. The evolution of dengue virus strain during a particular epidemic (intraepidemic) has also been associated with severe dengue disease.

Role of dengue virus NS1 antigen: High level of dengue virus NS1 antigenemia has been correlated with disease severity. NS1 antigen along with virus envelop (E) protein binds to the heparin sulfate which is the major glycosaminoglycan of the endothelial cell layer. This adherence alters the endothelial cell permeability leading to vascular leakage.

Dengue NS1 antigen has also been shown to interact with toll-like receptor 4 (TLR4) present on the surface of monocyte, macrophage and endothelial cells. This induces the release of cytokines responsible for disease severity and endothelial cell damage.

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