Dengue Dengue Hemorrhagic Fever

The dengue viruses (DENVs) are also members of the family Flaviviridae; there are four2 dengue serotypes (DENV-1, DENV-2, DENV-3, DENV-4), which make up the dengue complex within the genus Flavivirus. While the DENVs have a primitive sylvatic maintenance cycle involving lower primates and canopy-dwelling mosquitoes in Asia and Africa, they have also established an endemic/epidemic cycle involving the highly domesticated Ae. aegypti mosquito and humans in the large urban centers of the tropics. They have become completely adapted to humans and current evidence suggests that the sylvatic cycle is not a major factor in the current emergence of epidemic disease (Gubler 1997; Rico-Hesse 1990).

The DENVs cause a spectrum of illness in humans ranging from inapparent infection and mild febrile illness to classic DF to severe and fatal hemorrhagic disease (WHO 1997). All age groups are affected, but in endemic areas, most illness is seen in children, who tend to have either a mild viral syndrome or the more severe dengue hemorrhagic fever (DHF), a vascular leak syndrome. DENV infection has also been associated with severe and fatal neurologic disease and massive hemorrhaging with organ failure (Sumarmo et al. 1983).

Dengue is an old disease; the principal urban vector, Aedes aegypti, and the viruses were spread around the world as commerce and the shipping industry expanded in the 17th, 18th, and 19th centuries. Major epidemics of DF occurred as port cities were urbanized and became infested with Ae. aegypti. Because the viruses depended on the shipping industry for spread, however, epidemics in different geographic regions were sporadic, occurring at 10-40-year intervals. The disease pattern changed with the ecological disruption in Southeast Asia during and after World War II. The economic development, population growth and uncontrolled urbanization in the post-war years created ideal conditions for increased transmission and spread of urban mosquito-borne diseases, initiating a global pandemic of dengue. With increased epidemic transmission, and the movement of people within and between countries, hyperendemicity (the co-circulation of multiple DENV serotypes) developed in Southeast Asian cities, and epidemic DHF, a newly described disease, emerged (Gubler 1997; Halstead 1980; WHO 1997).

By the mid-1970s, DHF had become a leading cause of hospitalization and death among children in the region (WHO 1997, 2000). In the 1980s and 1990s, dengue transmission in Asia further intensified; epidemic DHF increased in frequency and expanded geographically west into India, Pakistan, Sri Lanka, and the Maldives, and east into China (Gubler 1997). At the same time, the geographic distribution of epidemic DHF was expanding into the Pacific islands in the 1970s and 1980s and to the American tropics in the 1980s and 1990s (Gubler 1989, 1993, 1997; Gubler and Trent 1994; Halstead 1992).

Epidemiologic changes in the Americas have been the most dramatic. In the 1950s, 1960s, and most of the 1970s, epidemic dengue was rare in the American region because the principal mosquito vector, Aedes aegypti, had been eradicated from most of Central and South America (Gubler 1989; Gubler and Trent 1994; Schliessman and Calheiros 1974). The eradication program was discontinued in the early 1970s, and the mosquito then began to reinvade those countries from which it had been eliminated. By the 1990s, Aedes aegypti had regained the geographic distribution it had before eradication was initiated (Fig. 8). This was another classic case of "success breeding failure."

Epidemic dengue invariably followed after reinfestation of a country by Aedes aegypti. By the 1980s, the American region was experiencing major epidemics of DF in countries that had been free of the disease for more than 35 years (Gubler 1989,1993; Gubler and Trent 1994; Pinheiro 1989). With the introduction of new viruses and increased epidemic activity came the development of hyperendemicity in American countries and the emergence of epidemic DHF, much as had occurred in Southeast Asia 25 years earlier (Gubler 1989). From 1981 to 2006, 28 American countries reported laboratory-confirmed DHF (Gubler 2002b) (Fig. 9).

While Africa has not yet had a major epidemic of DHF, sporadic cases of severe disease have occurred as epidemic DF has increased in the past 25 years. Before the

Fig. 8 Distribution of Aedes aegypti in American countries in 1930, 1970, and 2007. Source: Courtesy, Division of Vector-Borne Infectious Diseases, CDC, Fort Collins, CO; adapted from Gubler (1998)
Fig. 9 Countries reporting confirmed DHF prior to 1981 and 1981-2007. Source: Courtesy, Division of Vector-Borne Infectious Diseases, CDC, Fort Collins, CO; adapted from Gubler (1998)

1980s, little was known of the distribution of DENVs in Africa (Carey et al. 1971). Since then, however, major epidemics caused by all four serotypes have occurred in both East and West Africa (Gubler 1997; Monath 1994).

In 2007, dengue viruses and Ae. aegypti mosquitoes have a worldwide distribution in the tropics with 2.5-3.0 billion people living in dengue-endemic areas. Currently, DF causes more illness and death than any other arboviral disease of humans. The number of cases of DF/DHF reported to the World Health Organization (WHO) has increased dramatically in the past 3 decades (Fig. 10). Each year, an estimated 100 million dengue infections and several hundred thousand cases of DHF occur, depending on epidemic activity (Gubler 1997, 2002b, 2004; WHO 2000).

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