Differing Influences of Virus Burden and Immune Activation on Disease Severity in Secondary Dengue‐3 Virus Infections

Abstract

Dengue hemorrhagic fever (DHF), the most severe form of illness following infection with a dengue virus, is characterized by plasma leakage, thrombocytopenia, and hepatic inflammation. The interrelationships among virus burden, immune activation, and development of DHF were examined in 54 children with secondary dengue-3 virus infections participating in a prospective, hospital-based study. DHF was associated with higher mean plasma viremia early in illness and earlier peak plasma interferon-gamma levels. Maximum plasma viremia levels correlated with the degree of plasma leakage and thrombocytopenia. Maximum plasma levels of interleukin (IL)-10 and soluble tumor necrosis factor receptor-II correlated with the degree of thrombocytopenia, independently of viremia levels. Hepatic transaminase elevation correlated with plasma soluble IL-2 receptor levels and not with viremia levels. Quantitative differences in virus burden and host immune responses, and the timing of type 1 cytokine responses, have differing influences on the severity of disease manifestations during secondary dengue-3 virus infections.

Virus-Induced Decline in Soluble Vascular Endothelial Growth Receptor 2 Is Associated with Plasma Leakage in Dengue Hemorrhagic Fever

“…Several studies have demonstrated greater viral loads in patients with DHF compared to those with DF, suggesting that direct viral effects, or the magnitude of the host response to the virus, may be critical in determining disease severity (29,45). Dengue virus has been shown to infect endothelial cells in vitro (5).…”

Elevated levels of soluble ST2 protein in dengue virus infected patients

“…Serum levels of sST2 protein were found to be elevated at the end of the febrile stage of the disease, reaching a peak between fever days −1 and 0 followed by a decrease of the levels to normal values in convalescence. The viremia tendency is to rapidly decrease at late febrile stage of the disease through defervescence [16]. The levels of sST2 tend to increase at late febrile stage and at defervescence.…”

“…Cross reactivity also generates a dysfunctional T cell response that results in suboptimal clearance of the virus and an uncontrolled production of soluble mediators [9]. Elevated circulating levels of both type 1 (Th1) and type 2 (Th2) cytokines and various chemokines including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1beta (IL-1β), IL-6, IL-10, IL-13, IL-8, macrophage chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein 1 beta (MIP-1β) have been detected in dengue infected patients [10][11][12][13][14][15][16][17][18], and the kinetics and persistence of some of these mediators seem to be related to the severity of the disease.…”

The pathogenesis of dengue

“…73 In addition it is known that increased IL-10 levels correlate to reduced levels of platelets and reduced platelet function. 74 This phenomenon could, in part, contribute to the development of the bleeding complications observed in severe disease.…”

“…Each of the DEN virus serotypes is capable of causing severe dengue and early viral burdens in the course of illness are associated with severe disease. 74,82,115 Oscillations in the prevalence of each serotype are common in endemic settings. Typically, one serotype is dominant for a period of 2-4 years, after which it declines in prevalence as a different serotype(s) emerges to replace it.…”