Dengue fever, a very old disease, has reemerged in the past 20 years with an expanded geographic distribution of both the viruses and the mosquito vectors, increased epidemic activity, the development of hyperendemicity (the cocirculation of multiple serotypes), and the emergence of dengue hemorrhagic fever in new geographic regions. In 1998 this mosquito-borne disease is the most important tropical infectious disease after malaria, with an estimated 100 million cases of dengue fever, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually. The reasons for this resurgence and emergence of dengue hemorrhagic fever in the waning years of the 20th century are complex and not fully understood, but demographic, societal, and public health infrastructure changes in the past 30 years have contributed greatly. This paper reviews the changing epidemiology of dengue and dengue hemorrhagic fever by geographic region, the natural history and transmission cycles, clinical diagnosis of both dengue fever and dengue hemorrhagic fever, serologic and virologic laboratory diagnoses, pathogenesis, surveillance, prevention, and control. A major challenge for public health officials in all tropical areas of the world is to devleop and implement sustainable prevention and control programs that will reverse the trend of emergent dengue hemorrhagic fever.

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Dengue and Dengue Hemorrhagic Fever

Dengue and dengue hemorrhagic fever.

Mosquito-borne flaviviruses provide some of the most important examples of emerging and resurging diseases of global significance. Here, we describe three of them: the resurgence of dengue in tropical and subtropical areas of the world, and the spread and establishment of Japanese encephalitis and West Nile viruses in new habitats and environments. These three examples also illustrate the complexity of the various factors that contribute to their emergence, resurgence and spread. Whereas some of these factors are natural, such as bird migration, most are due to human activities, such as changes in land use, water impoundments and transportation, which result in changed epidemiological patterns. The three examples also show the ease with which mosquito-borne viruses can spread to and colonize new areas, and the need for continued international surveillance and improved public health infrastructure to meet future emerging disease threats.

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Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses

Dengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries. Disturbingly, the geographic range of dengue is currently expanding and the severity of outbreaks is increasing. Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti. These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control. For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines. This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression.

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The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations.

Dengue virus is a single-stranded, enveloped RNA virus that productively infects human dendritic cells (DCs) primarily at the immature stage of their differentiation. We now find that all four serotypes of dengue use DC-SIGN (CD209), a C-type lectin, to infect dendritic cells. THP-1 cells become susceptible to dengue infection after transfection of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), or its homologue L-SIGN, whereas the infection of dendritic cells is blocked by anti–DC-SIGN antibodies and not by antibodies to other molecules on these cells. Viruses produced by dendritic cells are infectious for DC-SIGN– and L-SIGN–bearing THP-1 cells and other permissive cell lines. Therefore, DC-SIGN may be considered as a new target for designing therapies that block dengue infection.

https://rupress.org/jem/article-pdf/197/7/823/1144848/jem1977823.pdf

DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells

The comparative susceptibility of 13 geographic strains of Aedes aegypti to oral infection with dengue viruses was studied by feeding the mosquitoes on a virus-erythrocyte-sugar suspension. Significant variation in susceptibility to four dengue serotypes was observed among the geographic strains tested. Mosquito strains which were more susceptible to one serotype were also more susceptible to the other serotypes, suggesting that the factors controlling susceptibility were the same for all types. The amount of virus required to infect mosquitoes orally varied inversely with the susceptibility of the geographic strain. Thresholds of infection were not the same for dengue types 1, 2, 3 and 4. There was no apparent difference in infectivity between prototype and recently isolated strains of dengue types 1 and 3. Crossing experimentibility as the resistant parent. No difference was observed between resistant and susceptible mosquito strains in the rate or the amount of viral replication after infection by the parenteral route, or in their ability to transmit dengue 2 virus after infection by the oral route.

Variation in susceptibility to oral infection with dengue viruses among geographic strains of Aedes aegypti.

Virological studies were carried out during an epidemic of dengue hemorrhagic fever in Central Java, Indonesia in 1976. Dengue virus was isolated from the acute sera of 45 of 69 patients (65%). The isolation rate was higher in primary than secondary cases. Dengue 3 was the predominant serotype being transmitted (27 isolates), but both dengue 1 (8 isolates) and dengue 4 (10 isolates) were also being transmitted. A composite picture of magnitude and duration of viremia showed that many patients were circulating over 108 MID50 per milliliter dengue 3 virus for the first 3 days of illness and that viremia persisted for 5–6 days in some persons. If all shock cases were considered, there was no relationship between dengue serotype and severity of disease. All three confirmed fatal cases, however, were associated with dengue type 3 infections.

Epidemic dengue hemorrhagic fever in rural Indonesia. I. Virological and epidemiological studies.

Sera from lifetime residents in 16 localities of the Indo-Australian archipelago and adjacent areas were tested for hemagglutination-inhibition antibody against four alphaviruses (Sindbis, Getah, chikungunya, and Ross River) and for neutralizing antibody against six flaviviruses (dengue 2 and 3, Japanese encephalitis, Murray Valley encephalitis, Kunjin, and Edge Hill). Mosquito collections were carried out in some of the localities to study vector relationships to distribution of the arbovirus antibodies. Antibodies specific to Sindbis and Getah viruses were rare except in north Australia. Chikungunya virus-specific antibody was highly prevalent in localities of the Oriental zoogeographic region and Wallacea, rare in west New Guinea, and absent in north Australia. Age distribution of chikungunya antibody suggested that the antibody last occurred in most Indonesian localities about 30 years ago. Ross River virus-specific antibody was confined to localities of the Australian zoogeographic region. Antibodies reacting to dengue 2 and 3 viruses occurred in high frequency in the entire area of the archipelago. Antibodies specific to Murray Valley encephalitis and Kunjin viruses were also widespread although at a very low frequency. Japanese encephalitis virus-specific antibody was highly prevalent in areas west of Wallace's Line while it was absent in areas east of the line with the exception of Lombok. Antibody to Edge Hill virus was rare and confined to the Australian zoogeographic region. The distribution of arthropod vectors, vertebrate hosts, and of arboviruses are discussed in relation to zoogeographic divisions.

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J. Sulianti Saroso

Papers

Variation in susceptibility to oral infection with dengue viruses among geographic strains of Aedes aegypti.

Epidemic dengue hemorrhagic fever in rural Indonesia. I. Virological and epidemiological studies.

Geographic distribution of arbovirus antibodies in indigenous human populations in the Indo-Australian archipelago.