Dengue fever (DF), DHF, and DSS are caused by four closely related but antigenically distinct single-stranded RNA viruses (DEN-1, 2, 3, and 4) in the genus Flavivirus, family Flaviridae. All four serotypes cause a range of human disease, including asymptomatic infections; undifferentiated fever; classic DF, an acute febrile illness with headache, body aches, and rash; DHF; and DSS. Sequential infections with different serotypes are possible because infection with one serotype provides lifelong protection from a homologous infection, but is only briefly cross-protective against heterologous serotypes. Even though most infections, especially in children under 15 years of age, are asymptomatic, it is estimated that annually there are between 50 and 100 million DF cases and between 250,000 and 500,000 DHF/DSS cases worldwide. If untreated, the case fatality rate for DHF/DSS can approach 20%; however, with supportive therapy (fluid and electrolyte management and oxygen) fewer than 1% of severely ill patients die.
The etiology of serious illness is not completely understood. Risk of DHF/DSS is highest in places where two or more viral serotypes are simultaneously transmitted. People with preexisting dengue antibodies, which can be obtained actively from a previous infection or passively by infants from their mothers, are 100-fold more likely to experience severe disease following infection with a heterologous virus serotype than are people without preexisting anti-dengue antibodies. The mechanism most commonly attributed to severe dengue is immune enhancement. Preexisting nonneutralizing antibodies complex with the infecting heterologous serotype virus, which enhances phagocytosis (entry) and replication of virus in mononuclear cells, which then leads to increased vascular permeability and hemorrhaging. An alternative explanation for severe disease is that different serotypes or strains of virus vary in virulence. Severe disease and death have been reported following primary dengue infections. Recent studies in the Americas suggest that the two hypotheses are not mutually exclusive. Immune enhancement may require secondary infection by genotypes of virus from Southeast Asia.
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