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Dengue

Overview | Symptoms | Treatment | Prevention

Overview

Etiologic Agent

Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4) - flaviviruses

Currently, dengue is the most important viral disease transmitted by mosquitoes afflicting humans in a world context. Clinical symptoms range from mild fevers, to a severe and potentially life threatening haemorrhagic disease. Source reduction of the breeding habitats of the major mosquito vector, Aedes aegypti, is the best form of control.

Perspectives

Dengue and dengue hemorrhagic fever (DHF) are caused by one of four closely related, but antigenically distinct, virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4), of the genus Flavivirus. Infection with one of these serotypes does not provide cross-protective immunity, so persons living in a dengue-endemic area can have four dengue infections during their lifetimes. Dengue is primarily a disease of the tropics, and the viruses that cause it are maintained in a cycle that involves humans and Aedes aegypti, a domestic, day-biting mosquito that prefers to feed on humans. Infection with dengue viruses produces a spectrum of clinical illness ranging from a nonspecific viral syndrome to severe and fatal hemorrhagic disease. Important risk factors for DHF include the strain and serotype of the infecting virus, as well as the age, immune status, and genetic predisposition of the patient.

Clinical Features

Incidence

Sequelae

Costs

Transmission

Risk Groups

Surveillance

Trends

Challenges

Opportunities

Research Priorities

History of Dengue

The first reported epidemics of dengue fever occurred in 1779-1780 in Asia, Africa, and North America; the near simultaneous occurrence of outbreaks on three continents indicates that these viruses and their mosquito vector have had a worldwide distribution in the tropics for more than 200 years. During most of this time, dengue fever was considered a benign, nonfatal disease of visitors to the tropics. Generally, there were long intervals (10-40 years) between major epidemics, mainly because the viruses and their mosquito vector could only be transported between population centers by sailing vessels.

A global pandemic of dengue began in Southeast Asia after World War II and has intensified during the last 15 years. Epidemics caused by multiple serotypes (hyperendemicity) are more frequent, the geographic distribution of dengue viruses and their mosquito vectors has expanded, and DHF has emerged in the Pacific region and the Americas. In Southeast Asia, epidemic DHF first appeared in the 1950s, but by 1975 it had become a leading cause of hospitalization and death among children in many countries in that region.

Natural History

The normal cycle of dengue infection is considered to be human - mosquito - human. From feeding on an infected and viraemic human, the female mosquito is able to transmit the dengue virus after an incubation period of 8-10 days wherein virus infection, replication and dissemination result in infection of the salivary glands making the mosquito infective for life.

In Australia epidemics of dengue occurred in the late 19th century and early 20th century. Australia was considered to be free of local dengue following 1955 (when there had been a large outbreak in Townsville), but in 1981 a major outbreak with an estimated 3,000 infections occurred in northern Queensland, presumably initiated by an infected traveler.

In Australia, there are three possible vectors: Ae.aegypti, whose distribution is restricted to Queensland; Ae.scutellaris, which is present in north Queensland and is a known vector of dengue in Papua New Guinea; Ae.katherinensis, which is found in northern Queensland, the Northern Territory and northern Western Australia but appears to be not an effective vector. Additionally, Ae.albopictus, poses a threat to Australia. It is an important vector that has been introduced from Asia to many countries, as eggs or larvae transported in artificial container habitats such as used motor vehicle tyres, and water barrels on ships. If it was introduced to Australia it is likely it could readily establish and present a threat for dengue transmission.

It is assumed that Ae.aegypti is the vector of greatest concern because of its distribution and close association with humans. Ae.aegypti is predominantly a day-biting mosquito whose larvae may be found almost exclusively in clean water in man-made containers such as water-barrels, rainwater tanks, wells, vases, tyres, bottles, tins, and most other water-holding containers found in the domestic environment. Although the species is currently restricted to Queensland, there are past records of Ae.aegypti being found in NSW, the NT and WA.

Current Trends

In the 1980s, DHF began a second expansion into Asia when Sri Lanka, India, and the Maldive Islands had their first major DHF epidemics; Pakistan first reported an epidemic of dengue fever in 1994. The recent epidemics in Sri Lanka and India were associated with multiple dengue virus serotypes, but DEN-3 was predominant and was genetically distinct from DEN-3 viruses previously isolated from infected persons in those countries. After an absence of 35 years, epidemic dengue fever occurred in both Taiwan and the People's Republic of China in the 1980s. The People's Republic of China had a series of epidemics caused by all four serotypes, and its first major epidemic of DHF, caused by DEN-2, was reported on Hainan Island in 1985. Singapore also had a resurgence of dengue/DHF from 1990 to 1994 after a successful control program had prevented significant transmission for over 20 years. In other countries of Asia where DHF is endemic, the epidemics have become progressively larger in the last 15 years.

In the Pacific, dengue viruses were reintroduced in the early 1970s after an absence of more than 25 years. Epidemic activity caused by all four serotypes has intensified in recent years with major epidemics of DHF on several islands.

Despite poor surveillance for dengue in Africa, epidemic dengue fever caused by all four serotypes has increased dramatically since 1980. Most activity has occurred in East Africa, and major epidemics were reported for the first time in the Seychelles (1977), Kenya (1982, DEN-2), Mozambique (1985, DEN-3), Djibouti (1991-92, DEN-2), Somalia (1982, 1993, DEN-2), and Saudi Arabia (1994, DEN-2). Epidemic DHF has been reported in neither Africa nor the Middle East, but sporadic cases clinically compatible with DHF have been reported from Mozambique, Djibouti, and Saudi Arabia.

The emergence of dengue/DHF as a major public health problem has been most dramatic in the American region. In an effort to prevent urban yellow fever, which is also transmitted by Ae. aegypti, the Pan American Health Organization organized a campaign that eradicated Ae. aegypti from most Central and South American countries in the 1950s and 1960s. As a result, epidemic dengue occurred only sporadically in some Caribbean islands during this period. The Ae. aegypti eradication program, which was officially discontinued in the United States in 1970, gradually eroded elsewhere, and this species began to reinfest countries from which it had been eradicated. In 1997, the geographic distribution of Ae. aegypti is wider than its distribution before the eradication program.

In 1970, only DEN-2 virus was present in the Americas, although DEN-3 may have had a focal distribution in Colombia and Puerto Rico. In 1977, DEN-1 was introduced and caused major epidemics throughout the region over a 16-year period. DEN-4 was introduced in 1981 and caused similar widespread epidemics. Also in 1981, a new strain of DEN-2 from Southeast Asia caused the first major DHF epidemic in the Americas (Cuba). This strain has spread rapidly throughout the region and has caused outbreaks of DHF in Venezuela, Colombia, Brazil, French Guiana, Suriname, and Puerto Rico. By 1997, 18 countries in the American region had reported confirmed DHF cases, and DHF is now endemic in many of these countries.

DEN-3 virus recently reappeared in the Americas after an absence of 16 years. This serotype was first detected in association with a 1994 dengue/DHF epidemic in Nicaragua. Almost simultaneously, DEN-3 was confirmed in Panama and, in early 1995, in Costa Rica. In Nicaragua, considerable numbers of DHF cases were associated with the epidemic, which was apparently caused by DEN-3. In Panama and Costa Rica, the cases were classic dengue fever.

Viral envelope gene sequence data from the DEN-3 strains isolated from Panama and Nicaragua have shown that this new American DEN-3 virus strain was likely a recent introduction from Asia since it is genetically distinct from the DEN-3 strain found previously in the Americas, but is identical to the DEN-3 virus serotype that caused major DHF epidemics in Sri Lanka and India in the 1980s. As suggested by the finding of a new DEN-3 strain, and the susceptibility of the population in the American tropics to it DEN-3 spread rapidly throughout the region caused major epidemics of dengue/DHF in Central America in 1995.

In 1997, dengue is the most important mosquito-borne viral disease affecting humans; its global distribution is comparable to that of malaria, and an estimated 2.5 billion people live in areas at risk for epidemic transmission (Figure 3). Each year, tens of millions of cases of dengue fever occur and, depending on the year, up to hundreds of thousands of cases of DHF. The case-fatality rate of DHF in most countries is about 5%; most fatal cases are among children and young adults.

There is a small, but significant, risk for dengue outbreaks in the continental United States. Two competent mosquito vectors, Ae. aegypti and Aedes albopictus, are present and, under certain circumstances, each could transmit dengue viruses. This type of transmission has been detected three in the last 16 years in south Texas (1980, 1986, and 1995) and has been associated with dengue epidemics in northern Mexico. Moreover, numerous viruses are introduced annually by travelers returning from tropical areas where dengue viruses are endemic. From 1977 to 1994, a total of 2,248 suspected cases of imported dengue were reported in the United States. Although some specimens collected were not adequate for laboratory diagnosis, 481(21%) cases were confirmed as dengue. Many more cases probably go unreported each year because surveillance in the United States is passive and relies on physicians to recognize the disease, inquire about the patient's travel history, obtain proper diagnostic samples, and report the case. These data suggest that southern Texas and the southeastern United States, where Ae. aegypti is found, are at risk for dengue transmission and sporadic outbreaks.

The reasons for this dramatic global emergence of dengue/DHF as a major public health problem are complex and not well understood. However, several important factors can be identified. First, effective mosquito control is virtually nonexistent in most dengue-endemic countries. Considerable emphasis for the past 20 years has been placed on ultra-low-volume insecticide space sprays for adult mosquito control, a relatively ineffective approach for controlling Ae. aegypti. Second, major global demographic changes have occurred, the most important of which have been uncontrolled urbanization and concurrent population growth. These demographic changes have resulted in substandard housing and inadequate water, sewer, and waste management systems, all of which increase Ae. aegypti population densities and facilitate transmission of Ae. aegypti-borne disease. Third, increased travel by airplane provides the ideal mechanism for transporting dengue viruses between population centers of the tropics, resulting in a constant exchange of dengue viruses and other pathogens. Lastly, in most countries the public health infrastructure has deteriorated. Limited financial and human resources and competing priorities have resulted in a crisis mentality with emphasis on implementing so-called emergency control methods in response to epidemics rather than on developing programs to prevent epidemic transmission. This approach has been particularly detrimental to dengue control because, in most countries, surveillance is (just as in the U.S.) very inadequate; the system to detect increased transmission normally relies on reports by local physicians who often do not consider dengue in their differential diagnoses. As a result, an epidemic has often reached or passed transmission before it is detected.

Future Outlook

No dengue vaccine is available. Recently, however, attenuated candidate vaccine viruses have been developed in Thailand. These vaccines are safe and immunogenic when given in various formulations, including a quadrivalent vaccine for all four dengue virus serotypes. Efficacy trials in human volunteers have yet to be initiated. Research is also being conducted to develop second-generation recombinant vaccine viruses; the Thailand attenuated viruses are used as a template. Therefore, an effective dengue vaccine for public use will not be available for 5 to 10 years.

Prospects for reversing the recent trend of increased epidemic activity and geographic expansion of dengue are not promising. New dengue virus strains and serotypes will likely continue to be introduced into many areas where the population densities of Ae. aegypti are at high levels. With no new mosquito control technology available, in recent years public health authorities have emphasized disease prevention and mosquito control through community efforts to reduce larval breeding sources. Although this approach will probably be effective in the long run, it is unlikely to impact disease transmission in the near future. We must, therefore, develop improved, proactive, laboratory-based surveillance systems that can provide early warning of an impending dengue epidemic. At the very least, surveillance results can alert the public to take action and physicians to diagnose and properly treat dengue/DHF cases.

Symptoms

Dengue is a debilitating infection of comparatively short duration with a high attack rate but a low fatality rate. The so-called 'classical' Dengue Fever (DF) form usually affects older children and adults with fever, violent headache, and severe pains in the muscles and joints following an incubation period of 5-8 days, and lasts about 4-7 days; recovery is generally complete although convalescence may be long. A more severe form, Dengue Haemorrhagic Fever (DHF), involves internal bleeding and is sometimes associated with severe shock (the Dengue Shock Syndrome (DSS)), and occurs most frequently in infants and young children.

Dengue virus occurs as four serotypes, designated DEN 1, 2, 3 and 4; each has been involved in both uncomplicated dengue and in cases withhaemorrhagic syndrome.

Laboratory Diagnosis

A variety of blood tests are used to demonstrate the presence of specific antibodies to Dengue virus. Blood samples should be taken during the acute and convalescent phases of the illness, and a fourfold rise in antibody levels will confirm the clinical diagnosis.

Treatment

No specific antiviral treatments exists nor is there any vaccine available. For patients with DHF or DSS, treatment is supportive.

Prevention

Restricting the availability of potential breeding habitats for Ae. aegypti will help to reduce mosquito densities and therefore reduce the possibility of disease transmission. All containers capable of holding water in the domestic environment can provide habitat for the larval stage of the mosquito and this includes water-barrels, rainwater tanks, wells, vases, tyres, bottles, pot plants saucers and tins.

Personal protective measures include: avoiding known mosquito infested areas, especially at dawn and dusk when mosquitoes are most active; ensuring that houses are adequately fly screened (with small mesh); using insect repellents that contain the chemical DEET, and reapplying it regularly; and wearing long sleeved shirts and pants.

World Distribution of Dengue World distribution of dengue viruses and their mosquito vector, Aedes aegypti, in 1997

Note: The information provided herein should not be used for diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions. There is no warranty that the information is free from all errors and omissions or that it meets any particular standard.

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Resources compiled by Lim Chee Aun <cheeaun(at)phoenity(dot)com>