The immunopathology of severe dengue remains incompletely understood. Most patients who develop severe dengue have had prior infection with one or more dengue serotypes. When an individual is infected with another serotype (ie, secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor membrane protein and envelope protein), when bound by macrophage and monocyte Fc receptors, have been proposed to fail to neutralize virus and instead form an antigen-antibody complex.
This results in increased viral entry into macrophages bearing IgG receptors, allowing unchecked viral replication with higher viral titers and increased cytokine production and complement activation, a phenomenon called antibody-dependent enhancement. [33, 34]
The affected macrophages release vasoactive mediators that increase vascular permeability, leading to vascular leakage, hypovolemia, and shock. This mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis. Infants born to mothers who have had dengue, as maternally derived dengue neutralizing IgGs wane, are also thought to be at risk for enhanced disease. [33, 34]
Some researchers suggest that T-cell immunopathology may play a role, with increased T-cell activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days following fever onset during symptomatic secondary dengue infections.  The activation of cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has been correlated with disease severity.