Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome

Dengue virus, first isolated in 1943, is morphologically indistinguishable from the agent causing yellow fever. Four dengue virus serotypes cause an acute febrile, generally self-limited disease, but a minority of patients (1%) may progress to complicated disease classified according to the WHO shema (See Table). Dengue fever has been recognized for at least several hundred years since Benjamin Rush from Philadelphia first described it as “breakbone fever” in 1780. Frequently occurring as an epidemic in tropical and subtropical regions of Asia and Africa, transmission has been geographically increasing during the past few decades. Successive introduction and circulation of all four serotypes into Central, South America and the Caribbean has occurred since 1977. A dengue hemorrhagic fever (DHF) epidemic was first reported in the Caribbean in 1981, and since 1982 epidemics have occurred in 14 Central or South American countries. Evolving transmission patterns are probably the result of a combination of changing human demographics, expanding vector populations, and alterations in viral virulence. Dengue fever can be found wherever the mosquito vector (Aedes aegypti) is present and introduced, whether in rural or urban areas. One hundred million cases of dengue fever are reported yearly by the WHO, making it one of the most important viral diseases in the world. Cases seen in the US are imported from the Caribbean region, the others arriving from South America, Africa or Asia. Transmission of dengue virus is often seasonal, with rates increasing during hot, humid months. The vector A. aegypti breeds in peridomestic fresh water as might be stored in natural and artificial containers in and around human dwellings (e.g., old tires, flowerpots, water storage containers). This day-bitting species is most active in the early morning and late afternoon.

SUSCEPTIBILITY AND RESISTANCE

Susceptibility is universal, but children generally have milder illness than adults. All four dengue serotypes produce clinically identical disease, and all can produce DHF and dengue shock syndrome (DSS) in decreasing order of frequency: serotypes 2, 3, 4, and 1. Individuals infected with one strain maintain lifelong homotypic immunity while remaining susceptible to infections with other heterotypic strains. Interestingly, DHF/DSS is more likely to develop if an individual previously infected with one serotype is later inoculated with a different viral strain. DHF and DSS usually occur as a second dengue infection in children and in infants born to dengue-immune mothers. Repeated episodes of DHS/DSS have not been described in the same individual.

CLINICAL FEATURES

Dengue fever is usually mild and nonspecific in most children, associated with pharyngitis, rhinitis, mild cough, and fever for several days to a week. Classic dengue fever, most likely to occur in older children and adults, is a febrile viral syndrome of sudden onset, characterized by fever for 2-5 days (often biphasic and rarely lasting more than 7 days), severe headache, intense myalgias, arthralgias, retro-orbital pain, anorexia, and rash. The initial fever begins abruptly with frontal or retro-orbital headache and low back pain. Severe limb or “breakbone” pain develops in the first 1 or 2 days, often concurrent with an evanescent generalized erythroderma. Nausea and vomiting are common between days 2 and 5. Objective physical and lab findings during this acute febrile phase include a relative bradycardia, lymphadenopathy, conjunctival injection with ocular globe tenderness, and leukopenia (to 1500 WBCs/mm3) with relative lymphocytosis. About day 5 or 6, fever subsides and a diffuse morbilliform rash appears; the rash may be pruritic and heals with desquamation. After a 2-day absence, fever recurs. Minor bleeding phenomena such as epistaxis, petechiae, and gingival bleeding may occur at any time during the febrile phase. Major bleeding phenomena such as menorrhagia and GI hemorrhage can occur, this has been associated with pathologic changes of peptic ulcer disease.

DENGUE HEMORRHAGIC FEVER AND DENGUE SHOCK SYNDROME

Clinical criteria for DHF and DSS are shown on the Table on the previous page and include hemoconcentration (Hct > 20% of baseline), thrombocytopenia, and circulatory collapse, often associated with severe end-organ dysfunction. DHF and DSS are recognized primarily in children; in tropical Asia, DSS is observed almost exclusively among indigenous children 15 years of age and younger. Ilness is often biphasic, beginning abruptly with fever, malaise, headache, anorexia, nausea and vomiting, cough, and facial flushing. Severe bone and limb pain are often absent. Coincident with defervescence, the patient’s condition worsens with profound weakness and prostration, diaphoresis, restlessness, facial pallor and circumoral cyanosis, cool and clammy extremities, rapid but thready pulse, and a narrow pulse pressure (< 20 mmHg). The liver may be enlarged in 10% of children. In this setting hemorrhagic phenomena are frequent with bleeding from the nose, gums, venipuncture sites, and the GI, GU and respiratory tracts. Elevated transaminase levels (and occasionally hepatic failure and encephalopathy), hypoalbuminemia, hyponatremia (especially in adults) and DIC are common features. In severe cases, pleural effusions and ascites correlate with hypoproteinemia and marked liver dysfunction. Platelet counts less than 50,000 mm3 and prolonged prothrombin times are poor prognostic indicators. Adequate treatment with physiologic fluid replacement and supportive care can reduce mortality from 40-50% to 1-2%. The diagnosis is generally made serologically, which distinguishes it from other entities. Acute-phase IgM antibody can be detected by ELISA within 6 or 7 days of onset of illness. Virus-specific nucleic acid sequences can be detected with PCR.

TREATMENT AND CONTROL

Treatment of dengue fever is nonspecific and supportive. For patients with DHF/DSS, measures to correct hypovolemia, hypoxia, shock and DIC can reduce complications and death. Modalities include nonsalicylate antipyretics, oxygen, and electrolyte and crystalloid and/or colloid fluid replacement (plasma or plasma expanders for severe shock or for continued rise in hematocrit despite vigorous IV fluid administration). The rate of fluid (initially 10-20 mL/kg/hr for hypovolemic shock) should be determined by serial microhematocrits). Red blood cell and platelet transfusions and fresh plasma are indicated for severe bleeding and decreasing hematocrit values. Anticoagulation with heparin is risky and not of proven benefit in patients with DIC. The use of high dose methylprednisolone has not been shown to alter mortality in children with DSS. Live-attenuated vaccines for dengue types 1, 2, and 4 have been developed but are not yet commercially available. To eliminate the potential for severe disease in individuals infected by a nonvaccine strain, a vaccine effective against all serotypes will ultimately be required. Prevention and control of dengue virus infection and its arthropod vector relies on insecticides, barrier measures protective clothing, bednetting, and insect repellents are advised.

WHO Classification of Dengue Fever

Grade I	Fever, constitutional symptoms, positive tourniquet test
Grade II	Grade I + spontaneous bleeding (skin, gums, GI tract)
Grade III*	Grade II + circulatory failure and agitation
Grade IV*	Grade III + profound shock (unrecordable blood pressure)

Clinical Features accompanied by thrombocytopenia and hemoconcentration. * Dengue Shock Syndrome