Dengue Fever and Dengue Hemorrhagic Fever

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Chapter 261 Dengue Fever and Dengue Hemorrhagic Fever

Scott B. Halstead

Dengue fever, a benign syndrome caused by several arthropod-borne viruses, is characterized by biphasic fever, myalgia or arthralgia, rash, leukopenia, and lymphadenopathy. Dengue hemorrhagic fever (Philippine, Thai, or Singapore hemorrhagic fever; hemorrhagic dengue; acute infectious thrombocytopenic purpura) is a severe, often fatal, febrile disease caused by dengue viruses. It is characterized by capillary permeability, abnormalities of hemostasis, and, in severe cases, a protein-losing shock syndrome (dengue shock syndrome), which is thought to have an immunopathologic basis.

Etiology

There are at least 4 distinct antigenic types of dengue virus, which is a member of the family Flaviviridae. In addition, 3 other arthropod-borne viruses (arboviruses) cause similar or identical febrile diseases with rash (Table 261-1).

Table 261-1 VECTORS AND GEOGRAPHIC DISTRIBUTION OF DENGUE-LIKE DISEASES

Epidemiology

Dengue viruses are transmitted by mosquitoes of the Stegomyia family. Aedes aegypti, a daytime biting mosquito, is the principal vector, and all 4 virus types have been recovered from it. In most tropical areas, A. aegypti is highly urbanized, breeding in water stored for drinking or bathing and in rainwater collected in any container. Dengue viruses have also been recovered from Aedes albopictus, as in the 2001 Hawaiian epidemic, whereas outbreaks in the Pacific area have been attributed to several other Aedes species. These species breed in water trapped in vegetation. In Southeast Asia and West Africa, dengue virus may be maintained in a cycle involving canopy-feeding jungle monkeys and Aedes species, which feed on monkeys.

Epidemics were common in temperate areas of the Americas, Europe, Australia, and Asia until early in the 20th century. Dengue fever and dengue-like disease are now endemic in tropical Asia, the South Pacific Islands, northern Australia, tropical Africa, the Caribbean, and Central and South America. Dengue fever occurs frequently among travelers to these areas. Locally acquired disease has been reported in Florida and Texas, and imported cases in the USA occur in travelers to endemic areas.

Dengue outbreaks in urban areas infested with A. aegypti may be explosive; up to 70-80% of the population may be involved. Most disease occurs in older children and adults. Because A. aegypti has a limited flight range, spread of an epidemic occurs mainly through viremic human beings and follows the main lines of transportation. Sentinel cases may infect household mosquitoes; a large number of nearly simultaneous secondary infections give the appearance of a contagious disease. Where dengue is endemic, children and susceptible foreigners may be the only persons to acquire overt disease, adults having become immune.

Dengue-Like Diseases

Dengue-like diseases may also occur in epidemics. Epidemiologic features depend on the vectors and their geographic distribution (see Table 261-1). Chikungunya virus is widespread in the most populous areas of the world. In Asia, A. aegypti is the principal vector; in Africa, other Stegomyia species may be important vectors. In Southeast Asia, dengue and chikungunya outbreaks occur concurrently. Outbreaks of o’nyong-nyong and West Nile fever usually involve villages or small towns, in contrast to the urban outbreaks of dengue and chikungunya.

Dengue Hemorrhagic Fever

Dengue hemorrhagic fever occurs where multiple types of dengue virus are simultaneously or sequentially transmitted. It is endemic in all of tropical America and Asia, where warm temperatures and the practices of water storage in homes plus outdoor breeding sites result in large, permanent populations of A. aegypti. Under these conditions, infections with dengue viruses of all types are common, and 2nd infections with heterologous types are frequent.

Second dengue infections are relatively mild in the majority of instances, ranging from an inapparent infection through an undifferentiated upper respiratory tract or dengue-like disease, but may also progress to dengue hemorrhagic fever. Nonimmune foreigners, both adults and children, who are exposed to dengue virus during outbreaks of hemorrhagic fever have classic dengue fever or even milder disease. The differences in clinical manifestations of dengue infections between natives and foreigners in Southeast Asia are related more to immunologic status than to racial susceptibility. Dengue hemorrhagic fever can occur during primary dengue infections, most frequently in infants whose mothers are immune to dengue.

Dengue 3 virus strains circulating in mainland Southeast Asia since 1983 are associated with a particularly severe clinical syndrome, characterized by encephalopathy, hypoglycemia, markedly elevated liver enzyme values, and, occasionally, jaundice.

Pathogenesis

Fatalities with chikungunya and West Nile fever infections have been ascribed to hemorrhage or viral encephalitis.

The pathogenesis of dengue hemorrhagic fever is incompletely understood, but epidemiologic studies suggest that it is usually associated with 2nd infections with dengue types 1-4. Retrospective studies of sera from human mothers whose infants acquired dengue hemorrhagic fever and prospective studies in children acquiring sequential dengue infections have shown that the circulation of infection-enhancing antibodies at the time of infection is the strongest risk factor for development of severe disease. Absence of cross-reactive neutralizing antibodies and presence of enhancing antibodies from passive transfer or active production are the best correlates of risk for dengue hemorrhagic fever. Monkeys that are infected sequentially or are receiving small quantities of enhancing antibodies have enhanced viremias. In humans studied early during the course of secondary dengue infections, viremia levels directly predicted disease severity. When dengue virus immune complexes attach to macrophage Fc receptors, a signal is sent that suppresses innate immunity, resulting in enhanced viral production. In the Americas, dengue hemorrhagic fever and dengue shock syndrome have been associated with dengue types 1-4 strains of recent Southeast Asian origin. Recent occurrences of sizable dengue hemorrhagic fever outbreaks in India, Pakistan, and Bangladesh also appear to be related to imported dengue strains.

Early in the acute stage of secondary dengue infections, there is rapid activation of the complement system. Shortly before or during shock, blood levels of soluble tumor necrosis factor receptor, interferon-γ, and interleukin-2 are elevated. C1q, C3, C4, C5-C8, and C3 proactivators are depressed, and C3 catabolic rates are elevated. These factors or virus itself may interact with endothelial cells to produce increased vascular permeability through the nitric oxide final pathway. The blood clotting and fibrinolytic systems are activated, and levels of factor XII (Hageman factor) are depressed. The mechanism of bleeding in dengue hemorrhagic fever is not known, but a mild degree of disseminated intravascular coagulopathy, liver damage, and thrombocytopenia may operate synergistically. Capillary damage allows fluid, electrolytes, small proteins, and, in some instances, red blood cells to leak into extravascular spaces. This internal redistribution of fluid, together with deficits caused by fasting, thirsting, and vomiting, results in hemoconcentration, hypovolemia, increased cardiac work, tissue hypoxia, metabolic acidosis, and hyponatremia.

Usually no pathologic lesions are found to account for death. In rare instances, death may be due to gastrointestinal or intracranial hemorrhages. Minimal to moderate hemorrhages are seen in the upper gastrointestinal tract, and petechial hemorrhages are common in the interventricular septum of the heart, on the pericardium, and on the subserosal surfaces of major viscera. Focal hemorrhages are occasionally seen in the lungs, liver, adrenals, and subarachnoid space. The liver is usually enlarged, often with fatty changes. Yellow, watery, and at times blood-tinged effusions are present in serous cavities in about 75% of patients.

Dengue virus is frequently absent in tissues at the time of death; viral antigens or RNA have been localized to macrophages in liver, spleen, lung, and lymphatic tissues.

Clinical Manifestations

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