Dengue Viruses and Mononuclear Phagocytes

During the past two decades, dengue viruses have been a major cause of severe illness and death among children in tropical Asia (1). Dengue viruses are mosquito-borne flaviviruses which occur as four antigenically distinct types. Homotypic immunity is thought to be life long, but after a brief period of crossprotection, heterotypic infections occur and are accompanied by secondary-type antibody responses (2, 3). Severe dengue, the shock syndrome (DSS), 1 is characterized by abnormalities of hemostasis, and hypovolemic shock (4-7). Studies in Thailand have documented a significant correlation between disease severity and the immune status of the host before infection. The risk of shock is greater during secondary compared with primary dengue infections (6, 8, 9). In a large experience, more than 95% of shock cases over the age of 1-yr had secondarytype dengue antibody responses (4, 6). DSS and the milder, but pathogenetically similar dengue hemorrhagic fever without shock also occur frequently in infants in dengue endemic areas (8). Usually these infections are of the primary type (6). In a few instances the mothers of such infants have been studied and all have had dengue antibodies presumably from infections which antedated pregnancy (7, 10). From these and similar observations it was hypothesized that severe dengue illness is the result of a hypersensitivity phenomenon, pre-illness antibody "sensitizing" individuals to subsequent dengue infection (11). Clinical and experimental studies on humans and monkeys have provided data from which were developed new and provocative concepts of possible immunopathologic mechanisms resulting in vascular permeability and hemorrhage in dengue infection. Several groups of workers have shown that during the shock stage of dengue, complement (C) is activated, in some instances by both the alternate and classical pathways (7, 10). In the heterologously immune host, virus replication occurs in the presence of cross-reacting antibody. Under these conditions large amounts of C-fixing virus-anti-dengue IgG complexes should be produced. In this model, it has been predicted that vascular permeability is mediated by histamine released by immune complex-activated peptides,