DENGUE FEVER All four distinct dengue viruses (dengue 1-4) have A.

aegypti as their principal vector, and all cause a similar clinical syndrome. In rare cases, second infection with a serotype of dengue virus different from that involved in the primary infection leads to dengue HF with severe shock (see below). Sporadic cases are seen in the settings of endemic transmission and epidemic disease. Year-round transmission between latitudes 25N and 25S has been established, and seasonal forays of the viruses to points as far north as Philadelphia are thought to have taken place in the United States. With increasing spread of the vector mosquito throughout the tropics and subtropics, large areas of the world have become vulnerable to the introduction of dengue viruses, particularly through air travel by infected humans, and both dengue fever and the related dengue HF are becoming increasingly common. Conditions favorable to dengue transmission exist in the southern United States, and bursts of dengue fever activity are to be expected in this region, particularly along the Mexican border, where water may be stored in containers and A. aegypti numbers may therefore be greatest: this mosquito, which also is an efficient vector of the yellow fever and chikungunya viruses, typically breeds near human habitation, using relatively fresh water from sources such as water jars, vases, discarded containers, coconut husks, and old tires. A. aegypti usually inhabits dwellings and bites during the day. After an incubation period of 2 to 7 days, the typical patient experiences the sudden onset of fever, headache, retroorbital pain, and back pain along with the severe myalgia that gave rise to the colloquial designation "break-bone fever." There is often a macular rash on the first day as well as adenopathy, palatal vesicles, and scleral injection. The illness may last a week, with additional symptoms usually including anorexia, nausea or vomiting, marked cutaneous hypersensitivity, and near the time of defervescence maculopapular rash (Fig. 200-CD1) beginning on the trunk and spreading to the extremities and the a face. Epistaxis and scattered petechiae are often noted in uncomplicated dengue, and preexisting gastrointestinal lesions may bleed during the acute illness. Laboratory findings include leukopenia, thrombocytopenia, and, in many cases, serum aminotransferase elevations. The diagnosis is made by IgM ELISA or paired serology during recovery or by antigen-detection ELISA or RT-PCR during the acute phase. Virus is readily isolated from blood in the acute phase if mosquito inoculation or mosquito cell culture is used. DENGUE HEMORRHAGIC FEVER/DENGUE SHOCK SYNDROME A syndrome of HF noted in the 1950s among children in the Philippines and Southeast Asia was soon associated with dengue virus infections, particularly those occurring against a background of previous exposure to another serotype. The transient heterotypic protection after dengue virus infection is replaced within several weeks by the potential for heterotypic infection resulting in typical dengue fever (see above) or uncommonly enhanced disease (secondary DHF/DSS). In rare for instances, primary dengue infections lead to an HF syndrome, but much less is known about pathogenesis in this situation. In the past 20 years, A. aegypti has progressively reinvaded Latin America and other areas, and frequent travel by infected individuals has introduced multiple strains of dengue virus from many geographic areas. Thus the pattern of hyperendemic transmission of multiple dengue serotypes has now been established in the Americas and the Caribbean and has led to the emergence of DHF/DSS as a major problem there as well. Millions of dengue infections, including many thousands of cases of DHF/DSS, occur annually. The severe syndrome is unlikely to be seen in U.S. citizens since few children have the dengue antibodies that can trigger the pathogenetic cascade when a second infection is acquired. Macrophage/monocyte infection is central to the pathogenesis of dengue fever and to the origin of DHF/DSS. Previous infection with a heterologous dengue-virus serotype may result in the production of nonprotective antiviral antibodies that nevertheless bind to the virion's surface and through interaction with the Fc receptor focus secondary dengue viruses on the target cell, the result being enhanced infection. The host is also primed for a secondary antibody response when viral antigens are released and immune complexes lead to activation of the classic complement pathway, with consequent phlogistic effects. Cross-reactivity at the T cell level results in the release of physiologically active cytokines, including interferon and tumor necrosis factor alpha. The induction of vascular permeability and shock depends on multiple factors, including the following: 1. Presence of enhancing and nonneutralizing antibodies Transplacental maternal antibody may be present in infants <9 months old, or antibody elicited by previous heterologous dengue infection may be present in older individuals. 2. Age Susceptibility to DHF/DSS drops considerably after 12 years of age. 3. Sex Females are more often affected than males.

4. Race Caucasians are more often affected than blacks. 5. Nutritional status Malnutrition is protective. 6. Sequence of infection For example, serotype 1 followed by serotype 2 is more dangerous than serotype 4 followed by serotype 2. 7. Infecting serotype Type 2 is apparently more dangerous than other serotypes. In addition, there is considerable variation among strains of a given serotype, with Southeast Asian serotype 2 strains having more potential to cause DHF/DSS than others. Dengue HF is identified by the detection of bleeding tendencies (tourniquet test, petechiae) or overt bleeding in the absence of underlying causes such as preexisting gastrointestinal lesions. Dengue shock syndrome, usually accompanied by hemorrhagic signs, is much more serious and results from increased vascular permeability leading to shock. In mild DHF/DSS, restlessness, lethargy, thrombocytopenia (<100,000/uL), and hemoconcentration are detected 2 to 5 days after the onset of typical dengue fever, often at the time of defervescence. The maculopapular rash that often develops in dengue fever may also appear in DHF/DSS. In more severe cases, frank shock is apparent, with low pulse pressure, cyanosis, hepatomegaly, pleural effusions, ascites, and in some cases severe ecchymoses and gastrointestinal bleeding. The period of shock lasts only 1 or 2 days, and most patients respond promptly to close monitoring, oxygen administration, and infusion of crystalloid or severe casescolloid. The mortality rates reported vary greatly with case ascertainment and the quality of in treatment; however, most DHF/DSS patients respond well to supportive therapy, and overall mortality in an experienced center in the tropics is probably as low as 1 percent. A virologic diagnosis can be made by the usual means, although multiple flavivirus infections lead to a broad immune response to several members of the group, and this situation may result in a lack of virus specificity of the IgM and IgG immune responses. A secondary antibody response can be sought with tests against several flavivirus antigens to demonstrate the characteristic wide spectrum of reactivity. The key to control of both dengue fever and DHF/DSS is the control of A. aegypti, which also reduces the risk of urban yellow fever and chikungunya virus circulation. Control efforts have been handicapped by the presence of nondegradable tires and long-lived plastic containers in trash repositories, insecticide resistance, urban poverty, and an inability of the public health community to mobilize the populace to respond to the need to eliminate mosquito breeding sites. Live attenuated dengue vaccines are in the late stages of development and have produced promising results in early tests. Whether vaccines can provide safe, durable immunity to an immunopathologic disease such as DHF/DSS in endemic areas is an issue that will have to be tested, but it is hoped that vaccination will reduce transmission to negligible levels.