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based on the expectation of a 10-percent annual infection rate among children in endemic areas.

The far more severe form of dengue hemorrhagic fever (DHF) has been recognized as a problem in Southeast Asia for the past 40 years. During the 25-year period 1956–1980, there were 3 million cases of DHF in Southeast Asia and 20,000 deaths (0.67 percent). During the first half of the 1980s there were 800,000 cases and 10,000 deaths (1.25 percent). During the second half of the 1980s, there were 900,000 to 1 million cases and 10,000 to 11,000 deaths (1.00 to 1.22 percent).

In the past few years, DHF has been occurring with increasing frequency in other parts of the world, including Cuba and the Caribbean, Central America, and South America—areas that previously had DF but not DHF. The reasons for this are not known. One possibility is a change in the virulence of the various strains of the virus. For example, the dengue type 2 virus that is present in the Caribbean today is different from what was there in the past and more closely resembles the type 2 genotype of Southeast Asia, which may have been transported to the Western Hemisphere.

Epidemiology. However, the current hypothesis, based on epidemiological data, suggests that increased risk of DHF comes from pre-existing infection rather than a more virulent virus. Studies of children aged 1–14 in Thailand indicate that there is an extremely small risk of developing DHF during primary infection with any of the four serotypes. In secondary infection, the vast majority have asymptomatic, self-limited DF, but there is about a 50-fold increased risk of developing the more severe form of DHF. However, DHF is very seldom seen during the first 2 years of life.

This is confirmed by data from Cuba. The island had been free of dengue for generations until an outbreak of dengue type 1 in 1976–1977. The country mobilized in anticipation of an outbreak of DHF, but they observed very little serious illness and no deaths. Then, in 1981, there was an outbreak of dengue type 2 and many cases of DHF, mostly of which occurred in children aged 3 to 12—those who had been sensitized by the preceding type 1 infection. Only one child born between the two outbreaks developed serious disease.

Immunopathogenesis. Recent research has emphasized the immunopathogenesis of dengue, and specifically the concept of antibody-dependent enhancement, rather than vaccine development per se. The current hypothesis is that, during secondary infection, previously existing crossreactive antibodies are binding the dengue virus and helping it into FC receptor-bearing cells. The receptor hasn’t been defined yet, but it seems clear that human monocytes would be the most permissive cell, and that binding with non-neutralizing antibodies will increase the number of infected cells about tenfold. That is, only about 2 percent of human monocytes will normally become infected with dengue virus, but if the virus is bound with crossreactive non-neutralizing antibodies, about 20 percent become infected, and if FC receptors are up-regulated by exposure to



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