Dengue fever

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Virus classification

Group: Group IV ((+)ssRNA)

Family: Flaviviridae

Genus: Flavivirus

Species: Dengue virus

Dengue fever (IPA: ['deŋgeɪ]) and dengue hemorrhagic fever (DHF) are acute febrile diseases, found in the tropics, with a geographical spread similar to malaria.[1] Caused by one of four closely related virus serotypes of the genus Flavivirus, family Flaviviridae, each serotype is sufficiently different that there is no cross-protection and epidemics caused by multiple serotypes (hyperendemicity) can occur. Dengue is transmitted to humans by the Aedes aegypti (rarely Aedes albopictus) mosquito.This mosquito tends to bite just after dawn and just before sunset.

Etymology of "dengue"

The origins of the word are not clear, but one theory is that it is derived from the Swahili phrase "Ka-dinga pepo", which describes the disease as being caused by an evil spirit.[2] The Swahili word "dinga" may possibly have its origin in the Spanish word "dengue" (fastidious or careful), describing the gait of a person suffering dengue fever,[3] or, alternatively, the Spanish word may derive from the Swahili.[4]

Signs and symptoms

This infectious disease is manifested by a sudden onset of fever, with severe headache, muscle and joint pains (myalgias and arthralgias - severe pain gives it the name break-bone fever or bonecrusher disease) and rashes; the dengue rash is characteristically bright red petechia and usually appears first on the lower limbs and the chest - in some patients, it spreads to cover most of the body. There may also be gastritis with some combination of associated abdominal pain, nausea, vomiting or diarrhea.

Some cases develop much milder symptoms, which can, when no rash is present, be misdiagnosed as influenza or other viral infection. Thus, travelers from tropical areas may inadvertently pass on dengue in their home countries, having not been properly diagnosed at the height of their illness. Patients with dengue can only pass on the infection through mosquitoes or blood products while they are still febrile.

The classic dengue fever lasts about six to seven days, with a smaller peak of fever at the trailing end of the fever (the so-called "biphasic pattern"). Clinically, the platelet count will drop until the patient's temperature is normal.

Cases of DHF also show higher fever, haemorrhagic phenomena, thrombocytopenia and haemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate.

Diagnosis

The diagnosis of dengue is usually made clinically. The classic picture is high fever with no localising source of infection, a petechial rash with thrombocytopenia and relative leukopenia.

There exists a WHO definition of dengue haemorrhagic fever that has been in use since 1975; all four criteria must be fulfilled:

1. Fever
2. Haemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
3. Thrombocytopaenia (<100,000 platelets per mm³ or estimated as less than 3 platelets per high power field)
4. Evidence of plasma leakage (hematocrit more than 20% higher than expected, or drop in haematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinaemia)

Dengue shock syndrome is defined as dengue haemorrhagic fever plus:

• Weak rapid pulse,
• Narrow pulse pressure (less than 20 mm Hg)

or,

• Hypotension for age;
• Cold, clammy skin and restlessness.

Serology and PCR (polymerase chain reaction) studies are available to confirm the diagnosis of dengue if clinically indicated.

Treatment

The mainstay of treatment is supportive therapy. Increased oral fluid intake is recommended to prevent dehydration. If the patient is unable to maintain oral intake, supplementation with intravenous fluids may be necessary to prevent dehydration and significant hemoconcentration. A platelet transfusion is rarely indicated if the platelet level drops significantly (below 20,000) or if there is significant bleeding.

The presence of malaena may indicate internal gastrointestinal bleeding requiring platelet and/or red blood cell transfusion.

It is very important to avoid Aspirin and non-steroidal anti-inflammatory medications. These drugs are often used to treat pain and fever, but in this case, they may actually aggravate the bleeding tendency associated with some of these infections. If dengue is suspected, patients should receive instead acetaminophen preparations to deal with these symptoms [1].

The first epidemics occurred almost simultaneously, in Asia, Africa and North America in the 1780s. The disease was identified and named in 1779. A global pandemic began in Southeast Asia in the 1950s and by 1975 DHF had become a leading cause of death among children in many countries in that region. Epidemic dengue has become more common since the 1980s - by the late 1990s, dengue was the most important mosquito-borne disease affecting humans after malaria, there being around 40 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever each year.

In February 2002 there was a serious outbreak in Rio de Janeiro, affecting around one million people but only killing sixteen.

Significant outbreaks of dengue fever tend to occur every five or six years. There tend to remain large numbers of susceptible people in the population despite previous outbreaks because there are four different strains of the dengue virus and because of new susceptible individuals entering the target population, either through childbirth or immigration.

There is significant evidence, originally suggested by S.B. Halstead in the 1970s, that dengue hemorrhagic fever is more likely to occur in patients who have secondary infections by serotypes different from the primary infection. One model to explain this process is known as antibody-dependent enhancement (ADE), which allows for increased uptake and virion replication during a secondary infection with a different strain. Through an immunological phenomena, known as original antigenic sin, the immune system is not able to adequately respond to the stronger infection, and the secondary infection becomes far more serious.[5] This process is also known as superinfection (Nowak and May 1994; Levin and Pimentel 1981).

In Singapore, there are about 4,000-5,000 reported cases of dengue fever or dengue haemorrhagic fever every year. In the year 2003, there were 6 deaths from dengue shock syndrome.[citation needed] It is believed that the reported cases of dengue are an underrepresentation of all the cases of dengue as it would ignore subclinical cases and cases where the patient did not present for medical treatment. With proper medical treatment, the mortality rate for dengue can therefore be brought down to less than 1 in 1000.

Prevention

Vaccine development

There is no commercially available vaccine for the dengue flavivirus. However, one of the many ongoing vaccine development programs is the Pediatric Dengue Vaccine Initiative which was set up in 2003 with the aim of accelerating the development and introduction of dengue vaccine(s) that are affordable and accessible to poor children in endemic countries.[6] Thai researchers are testing a dengue fever vaccine on 3,000-5,000 human volunteers within the next three years after having successfully conducted tests on animals and a small group of human volunteers.[7] and a number of other vaccine candidates are entering phase I or II testing.[8]

Mosquito control

A field technician looking for larvae in standing water containers during the 1965 Aedes aegypti eradication program in Miami, Florida. In the 1960s, a major effort was made to eradicate the principal urban vector mosquito of dengue and yellow fever viruses, A. aegypti, from southeast United States.

Courtesy: Centers for Disease Control and Prevention Publich Health Image Library

Primary prevention of dengue mainly resides in eliminating or reducing the mosquito vector for dengue. Public spraying for mosquitoes is the most important aspect of this vector. Application of larvicides such as Abate® to standing water is more effective in the long term control of mosquitoes. Initiatives to eradicate pools of standing water (such as in flowerpots) have proven useful in controlling mosquito-borne diseases. Promising new techniques have been recently reported from Oxford University on rendering the Aedes mosquito pest sterile.

Personal protection

Personal prevention consists of the use of mosquito nets, repellents containing NNDB or DEET, cover exposed skin, use DEET-impregnated bednets, and avoiding endemic areas. This is also important for malaria prevention.

Potential antiviral approaches

In cell culture experiments[9] and mice [10] Morpholino antisense oligos have shown specific activity against Dengue virus.

In 2002 the Swiss pharmaceutical company Novartis and the Singapore Economic Development board created the Novartis Institute for Tropical Diseases (NITD). NITD is a public-private partnership that researches neglected tropical diseases. NITD's dengue unit is researching an anti-viral drug to treat or prevent dengue fever.

In 2006, a group of Argentine scientists directed by Andrea Gamarnik discovered the molecular replication mechanism of the virus, which could be attacked by disruption of the polymerase's work.[11]

During the first months of 2007 over 16,000 cases have been reported in Paraguay, of which around 100 have been detected as DHF cases. This new epidemic is expected to continue in Paraguay for several months, given the forecast of continuous rain all through the summer. Ten deaths have also been reported, including recently a high ranking member of the Ministry of Health. The epidemic has been the root of a scandal in the Paraguayan Department of Health, where one official has resigned because he had approved the use of expired batches of insecticide to control the mosquito vectors of dengue.[12][13] The disease has propagated to Argentina (where it is not considered endemic), in almost all cases by people who recently arrived from Paraguay.[14] In the Brazilian state of Mato Grosso do Sul, which borders on Paraguay, the number of cases in March 2007 is estimated to be more than 45,000.[13] Epidemics in the states of Ceará, Pará, São Paulo, and Rio de Janeiro have taken the Brazilian national tally of cases this year to over 70,000, with upwards of 20 deaths. The proportion of cases registered as DHF is reported to be higher than in previous years.

Americas

• Dominican Republic: [15](August - October 2006) 4,968 cases with 44 dead.
• Cuba: Media reports [16][17][18][19] (dated September and October 2006) speculate on an outbreak although there is no official report.

Asia Pacific

• Australia: 2006 March 15, 2 confirmed cases at Gordon Vale, Cairns, Queensland.
• China: September 2006, 70 cases since June in Guangzhou,Guangdong.[20]
• Cook Islands: [21](October 2006-January 2007) 460 cases.
• India: 2006 September, more than 400 cases and 22 deaths were reported due to dengue fever in New Delhi. [22] By October 7, 2006, reports were of 3,331 cases of the mosquito-borne virus and a death toll of 49. [23]
• Indonesia: 2004 80,000 infected with 800 deaths.
• Malaysia: January 2005 33,203 cases.
• Pakistan: 2006 Over 3230 cases, 50 deaths.
  • Karachi 2006 October, the number of infected patients rose to 1836 of which 30 had died.
  • Lahore, 2006 October 23, the disease shifted to Lahore during the holidays with the luggage of some people travelling to their homes to celebrate Eid. The number of infected patients is 400 by October 31, of which 4 had died.
• Philippines: [24](January - August 2006) 13,468 cases with 167 dead.
• Singapore: 2007 4029 cases, 3 deaths. 2005 at least 13 deaths. 2004 9460 cases. 2003, 4788 cases.
• Thailand: 2005 May, 7200 infected. At least 12 dead.

History

Outbreaks resembling dengue fever have been reported throughout history.[25] The first definitive case report dates from 1789 and is attributed to Benjamin Rush, who coined the term "breakbone fever" (because of the symptoms of myalgia and arthralgia). The viral etiology and the transmission by mosquitoes were only deciphered in the 20th century. Population movements during World War II spread the disease globally.

CDC DENGUE FEVER

Perspectives

Dengue (DF) 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 provides immunity to only that serotype for life, so persons living in a dengue-endemic area can have more than one dengue infection during their lifetime. DF and DHF are primarily diseases of tropical and sub tropical areas, and the four different dengue serotypes are maintained in a cycle that involves humans and the Aedes mosquito. However, Aedes aegypti, a domestic, day-biting mosquito that prefers to feed on humans, is the most common Aedes species. Infections produce 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 of the infecting virus, as well as the age, and especially the prior dengue infection history of the patient.

History of Dengue

The first reported epidemics of DF 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, DF was considered a mild, nonfatal disease of visitors to the tropics. Generally, there were long intervals (10-40 years) between major epidemics, mainly because the introduction of a new serotype in a susceptible population occurred only if viruses and their mosquito vector could survive the slow transport between population centers by sailing vessels.

A pandemic of dengue began in Southeast Asia after World War II and has spread around the globe since then. 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 frequent cause of hospitalization and death among children in many countries in that region.

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 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 reemerged 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 not been reported in Africa or 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 started 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 weakened elsewhere, and the mosquito began to reinfest countries from which it had been eradicated. As a result, the geographic distribution of Ae. aegypti in 2002 was much wider than that before the eradication program (Figure 1).

Figure 1. Distribution of Aedes aegypti (red shaded areas) in the Americas in 1970, at the end of the mosquito eradication program, and in 2002.

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 2003, 24 countries in the American region had reported confirmed DHF cases (Figure 2), and DHF is now endemic in many of these countries.

Figure 2. American countries with laboratory-confirmed dengue hemorrhagic fever (red shaded areas), prior to 1981 and from 1981 to 2003.

DEN-3 virus 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.

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 causing major epidemics of dengue/DHF in Central America in 1995.

Figure 3. Presence of DEN-3 in the Americas from 1994 to 2003

In 2005, 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 4). Each year, tens of millions of cases of DF 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%, but this can be reduced to less than 1% with proper treatment. Most fatal cases are among children and young adults.

Figure 4. World distribution of dengue viruses and their mosquito vector, Aedes aegypti, in 2005.

There is a small 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 six times in the last 25 years in south Texas (1980 -2004) and has been associated with dengue epidemics in northern Mexico by Aedes aegypti and in Hawaii (2001-02) due to Ae. albopictus. Moreover, numerous viruses are introduced annually by travelers returning from tropical areas where dengue viruses are endemic. From 1977 to 2004, a total of 3,806 suspected cases of imported dengue were reported in the United States. Although some specimens collected were not adequate for laboratory diagnosis, 864 (23%) 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 states in southern and southeastern United States, where Ae. aegypti is found, are at risk for dengue transmission and sporadic outbreaks.

Although travel-associated dengue and limited outbreaks do occur in the continental United States, most dengue cases in US citizens occur as endemic transmission among residents in some of the US territories. CDC conducts laboratory-based passive surveillance in Puerto Rico in collaboration with the Puerto Rico Department of Health. The weekly surveillance report from this collaboration can be found at: Dengue Surveillance Report

The reasons for the dramatic global emergence of DF/DHF as a major public health problem are complex and not well understood. However, several important factors can be identified.

1. First, 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.
2. 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.) passive; 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 its peak before it is recognized.
3. Increased travel by airplane provides the ideal mechanism for infected human transport of dengue viruses between population centers of the tropics, resulting in a frequent exchange of dengue viruses and other pathogens.
4. Lastly, effective mosquito control is virtually nonexistent in most dengue-endemic countries. Considerable emphasis in the past has been placed on ultra-low-volume insecticide space sprays for adult mosquito control, a relatively ineffective approach for controlling Ae. aegypti.

Future Outlook

Return to top of page No dengue vaccine is available. Recently, however, attenuated candidate vaccine viruses have been developed. Efficacy trials in human volunteers have yet to be initiated. Research is also being conducted to develop second-generation recombinant vaccine viruses. 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 DF/DHF cases.

Glossary of terms

Endemic - means a disease occurs continuously and with predictable regularity in a specific area or population .

Epidemic - a widespread outbreak of an infectious disease where many people are infected at the same time.

Igm - a protein that recognizes a particular epitope on an antigen and facilitates clearance of that antigen and is the primary antibody response to a viral infection

Outbreak - an epidemic limited to localized increase in the incidence of a disease, e.g., in a village, town, or closed institution

Pandemic - an epidemic occurring worldwide, or over a very wide area, crossing international boundaries, and usually affecting a large number of people.

Recombinant vaccine - using the technique of recombination to create an attenuated virus which elicits an immune response against the viral strain of interest in order to use as a vaccine in humans.

Seroytpe - a closely related set of viruses that can be differiented by the immune response they produce.

Viral envelope gene sequence - the nucleic acid composition in the envelope gene

Fact Sheet: Dengue and Dengue Hemorrhagic Fever

CLINICAL FEATURES

• Sudden onset of fever, severe headache, myalgias and arthralgias, leukopenia, thrombocytopenia and hemorrhagic manifestations
• Occasionally produces shock and hemorrhage, leading to death

ETIOLOGIC AGENT

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

INCIDENCE

• Variable, depending on epidemic activity.
• Globally, there are an estimated 50 to 100 million cases of dengue fever (DF) and several hundred thousand cases of dengue hemorrhagic fever (DHF) per year
• Average case fatality rate of DHF is about 5%
• In 1995, 250,000 cases of DF and 7,000 cases of DHF reported in Americas
• Between 100 to 200 suspected cases introduced into U.S. each year by travelers

SEQUELAE

• None

COSTS

• $250 million estimated in Puerto Rico in past 10 years

TRANSMISSION

• Mosquito-borne (Aedes aegypti)

RISK GROUPS

• Residents of or visitors to tropical urban areas
• Increased severe and fatal disease in children under 15 years
• No cross-immunity from each serotype
• A person can theoretically experience four dengue infections

SURVEILLANCE

• Active, laboratory-based surveillance in Puerto Rico and the U.S. Virgin Islands
• In U.S., passive surveillance of imported cases reported to CDC and other reference laboratories
• Laboratory-based, passive surveillance in endemic areas

TRENDS

• Resurgent disease worldwide in the tropics
• Epidemics are larger and more frequent
• Transmission in continental U.S. in 1995; first since 1986
• Since first epidemic in 1981, DHF now reported from 18 countries in the Americas
• Evolution of disease pattern in Americas similar to SE Asia in 1950s and 1960s

CHALLENGES

• Increased incidence associated with increased urbanization
• Rapid dispersal of viruses via air travel
• Emergency control methods ineffective
• Severe hemorrhagic disease poorly understood by physicians in Americas
• Change emphasis from emergency response to prevention of epidemics
• Develop better government-based programs
• Encourage community participation in prevention and control programs

OPPORTUNITIES

• Dengue Branch, NCID, designated WHO Reference Center
• Improve laboratory-based international surveillance
• Educate medical community
• Develop community-based, integrated prevention programs

RESEARCH PRIORITIES

• Develop improved laboratory-based international surveillance
• Develop rapid, sensitive and specific diagnostic tests
• Develop more effective community-based prevention programs
• Develop tetravalent dengue vaccine

Dengue and Dengue Hemorrhagic Fever:

Questions and Answers

Q. What is dengue?

A. Dengue (pronounced den' gee) is a disease caused by any one of four closely related viruses (DEN-1, DEN-2, DEN-3, or DEN-4). The viruses are transmitted to humans by the bite of an infected mosquito. In the Western Hemisphere, the Aedes aegypti mosquito is the most important transmitter or vector of dengue viruses, although a 2001 outbreak in Hawaii was transmitted by Aedes albopictus. It is estimated that there are over 100 million cases of dengue worldwide each year.

Q. What is dengue hemorrhagic fever (DHF)?

A. DHF is a more severe form of dengue. It can be fatal if unrecognized and not properly treated. DHF is caused by infection with the same viruses that cause dengue. With good medical management, mortality due to DHF can be less than 1%.

Q. How are dengue and dengue hemorrhagic fever (DHF) spread?

A. Dengue is transmitted to people by the bite of an Aedes mosquito that is infected with a dengue virus. The mosquito becomes infected with dengue virus when it bites a person who has dengue or DHF and after about a week can transmit the virus while biting a healthy person. Dengue cannot be spread directly from person to person.

Q. What are the symptoms of the disease?

A. The principal symptoms of dengue are high fever, severe headache, backache, joint pains, nausea and vomiting, eye pain, and rash. Generally, younger children have a milder illness than older children and adults.

Dengue hemorrhagic fever is characterized by a fever that lasts from 2 to 7 days, with general signs and symptoms that could occur with many other illnesses (e.g., nausea, vomiting, abdominal pain, and headache). This stage is followed by hemorrhagic manifestations, tendency to bruise easily or other types of skin hemorrhages, bleeding nose or gums, and possibly internal bleeding. The smallest blood vessels (capillaries) become excessively permeable ("leaky"), allowing the fluid component to escape from the blood vessels. This may lead to failure of the circulatory system and shock, followed by death, if circulatory failure is not corrected.

Q. What is the treatment for dengue?

A. There is no specific medication for treatment of a dengue infection. Persons who think they have dengue should use analgesics (pain relievers) with acetaminophen and avoid those containing aspirin. They should also rest, drink plenty of fluids, and consult a physician.

Q. Is there an effective treatment for dengue hemorrhagic fever (DHF)?

A. As with dengue, there is no specific medication for DHF. It can however be effectively treated by fluid replacement therapy if an early clinical diagnosis is made. Hospitalization is frequently required in order to adequately manage DHF. Physicians who suspect that a patient has DHF may want to consult the Dengue Branch at CDC, for more information.

Q. Where can outbreaks of dengue occur?

A. Outbreaks of dengue occur primarily in areas where Aedes aegypti (sometimes also Aedes albopictus) mosquitoes live. This includes most tropical urban areas of the world. Dengue viruses may be introduced into areas by travelers who become infected while visiting other areas of the tropics where dengue commonly exists.

In the America region, all dengue virus serotypes are now present. DEN-3 was reintroduced into Central America in 1994 and is now found in several countries in the region. Since this serotype has been absent from the Americas for almost 20 years, the population has a low level of immunity and the virus is expected to spread rapidly.

Q. What can be done to reduce the risk of acquiring dengue?

A. There is no vaccine for preventing dengue. The best preventive measure for residents living in areas infested with Aedes aegypti is to eliminate the places where the mosquito lays her eggs, primarily artificial containers that hold water.

Items that collect rainwater or are used to store water (for example, plastic containers, 55-gallon drums, buckets, or used automobile tires) should be covered or properly discarded. Pet and animal watering containers and vases with fresh flowers should be emptied and scoured at least once a week. This will eliminate the mosquito eggs and larvae and reduce the number of mosquitoes present in these areas.

For travelers to areas with dengue, a well as people living in areas with dengue, the risk of being bitten by mosquitoes indoors is reduced by utilization of air conditioning or windows and doors that are screened. Proper application of mosquito repellents containing 20% to 30% DEET as the active ingredient on exposed skin and clothing decreases the risk of being bitten by mosquitoes. The risk of dengue infection for international travelers appears to be small, unless an epidemic is in progress.

Q. How can we prevent epidemics of dengue hemorrhagic fever (DHF)?

A. The emphasis for dengue prevention is on sustainable, community-based, integrated mosquito control, with limited reliance on insecticides (chemical larvicides and adulticides). Preventing epidemic disease requires a coordinated community effort to increase awareness about dengue/DHF, how to recognize it, and how to control the mosquito that transmits it. Residents are responsible for keeping their yards and patios free of sites where mosquitoes can be produced.

Dengue and Dengue Hemorrhagic Fever:

Information for Health Care Practitioners

Introduction

Dengue is an arthropod-borne disease caused by any one of four closely related viruses. Infection with one serotype of dengue virus provides immunity to that serotype for life. A person can be infected as many as four times, once with each serotype. Dengue viruses are transmitted from person to person by Aedes mosquitoes (most often Aedes aegypti) in the domestic environment. Periodic epidemics have occurred in the Western Hemisphere for over 200 years. In the past 20 years, dengue transmission and the frequency of dengue epidemics has increased greatly in most tropical countries of the American region.

Clinical Diagnosis

Dengue

Classic dengue fever or "break bone fever" is characterized by acute onset of high fever, 3-14 days after the bite of an infected mosquito. Patients develop frontal headache, retro-orbital pain, myalgias, arthralgias, nausea, vomiting, and often a maculopapular rash. Many patients notice a change in taste sensation. Acute symptoms, when present, usually last about 1 week, but weakness, malaise, and anorexia may persist for several weeks. A high proportion of infections produce no or minimal symptoms, especially in children. Treatment emphasizes relief of symptoms, avoiding aspirin and other non steroidal anti-inflamatory medications and encouraging oral fluid intake (see Treatment below).

Dengue Hemorrhagic Fever/Dengue Shock Syndrome

Some patients with dengue fever go on to develop dengue hemorrhagic fever (DHF), a severe and sometimes fatal form of the disease. At about the time the fever begins to subside, the patient may become restless or lethargic, show signs of circulatory failure, and experience hemorrhagic manifestations. The most common of these manifestations are mild, such as skin hemorrhages as petechiae or microscopic hematuria, but may also include epistaxis, bleeding gums, hematemesis, and melena. DHF patients develop thrombocytopenia and hemoconcentration, the latter as a result of the leakage of plasma from the intravascular compartment. These patients may rapidly progress into dengue shock syndrome (DSS), which, if not treated correctly, can lead to profound shock and death. Despite the name, it is the loss of intravascular volume from leaky capillaries rather than hemorrhage, which results in shock. Advance warning signs of DSS include severe abdominal pain, protracted vomiting, marked change in temperature (from fever to hypothermia), or change in mental status (irritability or obtundation). Early signs of shock include restlessness, cold clammy skin, rapid weak pulse, narrowing of pulse pressure, and hypotension. Fatality rates among those with DSS may be higher than 10%. DHF/DSS can occur in children and adults.

Treatment

Even for outpatients, the need for maintaining adequate hydration should be stressed. In addition, monitoring for signs of hemorrhagic fever and early appropriate treatment are key to ensure survival if the patient progresses to a more severe form of dengue infection. DHF/DSS can be effectively managed by intravenous fluid replacement therapy, and if diagnosed early, fatality rates can be kept below 1%. It is very important that physicians and other health care providers learn to recognize this disease.

To manage the pain and fever, patients suspected of having a dengue infection should be given acetaminophen preparations. Aspirin and non-steroidal anti-inflammatory medications may aggravate the bleeding tendency associated with some dengue infections and in children can be associated with the development of Reyes syndrome.

Laboratory Diagnosis

Unequivocal diagnosis of dengue infection requires laboratory confirmation, either by isolating the virus or detecting specific antibodies. For virus isolation, an acute-phase serum specimen should be collected within 5 days after onset of fever. If virus cannot be isolated, a convalescent-phase serum specimen is needed at least 6 days after onset of symptoms to make a serologic diagnosis by enzyme-linked immunosorbent assay (ELISA). Acute-phase and convalescent-phase serum samples should be collected and sent to the state health department for testing or forwarded to CDC for testing. Acute-phase samples for virus diagnosis may be stored on dry ice (-70°C) or, if delivery can be made within 1 week, stored unfrozen in a refrigerator (4°C). Convalescent-phase samples should be sent in a rigid container without ice, if next-day delivery is assured. Otherwise they should be shipped on ice, in an insulated container to avoid heat exposure during transit.

It is important to note that most tests for anti-dengue antibodies are non-specific among the flaviviruses, including West Nile and St. Louis encephalitis viruses. Commercial kits may vary in sensitivity and specificity; therefore critical results may need confirmation by a reference laboratory.

Epidemiology

A dengue epidemic requires the presence of 1) the vector mosquito (usually Aedes aegypti), 2) the virus, and 3) a large number of susceptible human hosts. Outbreaks may be explosive or progressive, depending on the density and efficiency by which the vector can be infected, the serotype and strain of dengue virus, the number of susceptible humans in the population, and the amount of vector-human contact. Dengue should be considered as the possible etiology where influenza, rubella, or measles is suspected in a dengue-receptive area, i.e., at a time and place where vector mosquito populations are abundant and active. In most countries of the Caribbean Basin, Aedes aegypti is abundant year-round. In the United States, this species is seasonally abundant in some southwestern and southeastern states, including Texas (Brazoria, Brazos, Collin, Dallas, Denton, El Paso, Ellis, Fort Bend, Galveston, Hidalgo, Jefferson, McLennan, Midland, Montgomery, Nueces, Orange, San Patricio, Tarrant, Taylor, and Travis counties), Arizona (Maricopa, Pinal, Yavapai counties and Tucson, Nogales, Douglas), New Mexico (Las Cruces), Louisiana (New Orleans, Monroe, Lafayette), Mississippi, Alabama, Georgia, and mid to south Florida. It has been sporadically reported from limited areas of North Carolina (Swain, Haywood counties), South Carolina, Tennessee (Blount, Sevier counties), Arkansas (Jefferson county), Maryland, and New Jersey (Morris county). Given the competent vectors and susceptible population in the continental United States isolated dengue outbreaks may occur (last reported dengue in Texas in 1999).

In 1985, a mosquito from Asia, Aedes albopictus, was found in the U.S. This species is now found in most states in the eastern half of the U.S. and limited areas of Bolivia, Brazil, Cayman Islands, Colombia, Cuba, Dominican Republic, El Salvador, Guatemala, Honduras, and Mexico. Although its contact with humans and its density in urban areas are not as great as that of Aedes aegypti, this species can also transmit dengue viruses. From mid 2001 through early 2002, 122 Hawaii residents developed dengue infections due to autochthonous transmission by Aedes albopictus mosquitoes.

As noted previously, the frequency of epidemic disease has increased significantly in the past 20 years. Modern transportation makes it easy for travelers to visit virtually any location on the globe, including areas of the world where dengue is endemic.

Although travel-associated dengue and limited outbreaks do occur in the continental United States, most dengue cases in US citizens occur as a result of endemic transmission in some of the US territories. CDC conducts laboratory-based passive surveillance in Puerto Rico in collaboration with the Puerto Rico Department of Health. The weekly surveillance report produced by this collaboration can be found at: Dengue Surveillance Report for Puerto Rico.

If a dengue-like illness is observed in a person in the continental United States who has recently traveled to a tropical area, a blood specimen, associated clinical information (case form), and a brief travel history should be sent to the state public health laboratory with a request that the specimen be tested for dengue there or at the CDC's Dengue Branch in San Juan, Puerto Rico. If that is not possible, contact the Centers for Disease Control and Prevention at the address below.

In Puerto Rico and the U.S. Virgin Islands, specimens and clinical information can be sent through the respective Department of Health or directly to the address listed below (criteria for specimen testing at CDC).