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Dengue Hemorrhagic Fever



Dengue Fever

A TEM micrograph showing Dengue virus virions (the cluster of dark dots near the center).

Other names: Breakbone fever

Dengue fever (IPA: /ˈdɛŋgeɪ/) and dengue hemorrhagic fever (DHF) are acute febrile diseases, that occurs in the tropics. 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, which feeds during the day.

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. There was a serious outbreak in Rio de Janeiro in February, 2002 affecting around one million people and 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. This process is also known as superinfection.

Contents

Signs and Symptoms
Causative Agent
Mode of Transmission
Diagnosis
Incubation Period
Pathogenesis/Pathophysiology
Prevention
Treatment
Complications
References

Signs and Symptoms

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petechia

Petechia

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, hemorrhagic phenomena, thrombocytopenia, and hemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate.

Causative Agent

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Arthropod-borne virus belonging to the family Flaviviridae. There are four known serotypes: DEN-1, DEN-2, DEN-3, and DEN-4.

Mode of Transmission

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Aedes aegypti

The viruses are transmitted via the bite of various day-feeding mosquitoes of the subgenus Stegomyia. The principal vector is Aedes aegypti. Once infected, a mosquito remains infective for life. Infected humans circulate the virus in their blood, mosquitoes ingest viruses when feeding on the infective individual. Humans serve as an amplifying host, though some monkeys may also serve as a source of the virus. Female mosquitoes can also transmit the virus transovarially, passing it down to the next generation.

Diagnosis

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

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

  1. Fever
  2. Hemorrhagic tendency (positive tourniquet test, spontaneous bruising, bleeding from mucosa, gingiva, injection sites, etc.; vomiting blood, or bloody diarrhea)
  3. Thrombocytopenia (<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 hematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)
  5. Encephalitic occurrences

Dengue shock syndrome is defined as dengue hemorrhagic fever plus:

  • Weak rapid pulse
  • Narrow pulse pressure (less than 20 mm Hg)
  • Cold, clammy skin and restlessness

Dependable, immediate diagnosis of dengue can be performed in rural areas by the use of Rapid Diagnostic Test kits, which also differentiate between primary and secondary dengue infections. Serology and polymerase chain reaction (PCR) studies are available to confirm the diagnosis of dengue if clinically indicated.

Incubation Period

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The incubation period of dengue fever is approximately four days.

Pathogenesis/Pathophysiology

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Dengue infection is caused by 1 of 4 related, but antigenically distinct, viral serotypes: dengue virus 1 (DENV-1), dengue virus 2 (DENV-2), dengue virus 3 (DENV-3), and dengue virus 4 (DENV-4). Albert Sabin speciated these in 1944. Each serotype is known to have several different genotypes. Dengue viruses are small, spherical, single-stranded enveloped RNA viruses of the family Flaviviridae, genus Flavivirus.

Infection with one dengue serotype confers lifelong homotypic immunity and a very brief period of partial heterotypic immunity, but each individual can eventually be infected by all 4 serotypes. Several serotypes can be in circulation during an epidemic.

Dengue viruses are transmitted by the bite of an infected Aedes mosquito. Globally, a aegypti is the predominant highly efficient mosquito vector for dengue infection, but A albopictus and other Aedes species can also transmit dengue with varying degrees of efficiency.

Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite and are easily disturbed during a blood meal, causing them to move on to finish a meal on another individual, making them efficient vectors. Entire families who develop infection within a 24- to 36-hour period, presumably from the bites of a single infected vector, is not unusual.

Humans serve as the primary reservoir for dengue; however, certain nonhuman primates in Africa and Asia also serve as hosts. Mosquitoes acquire the virus when they feed on a carrier of the virus. The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 8-12 days of viral replication in the mosquito’s salivary glands (extrinsic incubation period). The mosquito remains infected for the remainder of its 15- to 65-day lifespan. Vertical transmission of dengue virus in mosquitoes has been documented. The eggs of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C.

Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 d). Following incubation, a 5- to 7-day acute febrile illness ensues. Recovery is usually complete by 7-10 days. DHF or DSS usually develops around the third to seventh day of illness, approximately at the time of defervescence. The major pathophysiological abnormalities that occur in DHF and DSS are plasma leakage and bleeding. Plasma leakage is caused by increased capillary permeability and may be manifested by hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may present various ways, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.

Most patients who develop DHF or DSS have had prior infection with one or more dengue serotypes. In individuals with low levels of neutralizing antibodies, nonneutralizing antibodies to one dengue serotype, when bound by macrophage and monocyte Fc receptors, have been proposed to result in increased viral entry and replication, and increased cytokine production and complement activation. This phenomenon is called antibody-dependent enhancement. In addition, certain dengue strains, particularly those of DEN-2, have been proposed to be more virulent, in part because more epidemics of DHF have been associated with DEN-2 than with the other serotypes.

Prevention

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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. 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. And, a number of other vaccine candidates are entering phase I or II testing.

Mosquito control

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. US and British researchers have also genetically engineered a strain of flightless mosquito that may help curb the spread of Dengue fever.

Recently, researchers at the Federal University of Minas Gerais, in Brazil, have developed a world-awarded new technology to monitor and control the mosquito, using traps, chemical attractants, handheld computers and GPS georeferenced maps. The MI Dengue system can show precisely where the mosquitoes are inside the urban area, in a very short period of time.

Personal protection

Personal prevention consists of the use of mosquito nets, repellents containing NNDB or DEET ((N,N-Diethyl-meta-toluamide; also known as N,N’-Diethyl-3-methylbenzamide), covering exposed skin, use of DEET-impregnated bednets, and avoiding endemic areas.

Treatment

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

The presence of melena 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 though in this case they may actually aggravate the bleeding tendency associated with some of these infections. Patients should instead receive acetaminophen preparations to deal with these symptoms if dengue is suspected.

Having a strong immune system also benefits recovery from dengue.

Complications

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Neurologic manifestations such as seizures and encephalitis/encephalopathy have been reported in rare cases of dengue infection. Some of these cases did not manifest other typical features of dengue infection. Other neurological complications associated with dengue infection include neuropathies, Guillain-Barré syndrome, and transverse myelitis.

Liver failure has been associated with DHF/DSS epidemics. Whether this is a viral effect or a product of prolonged liver hypoperfusion remains unclear.

Overhydration is a well-recognized complication of DF and DHF/DSS.

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References

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1. “Dengue Fever, Wikipedia”

2. “WHO – Dengue and Dengue Haemorrhagic Fever”

3. “Dengue, Stanford University”

4. “Dengue Fever: eMedicine Emergency Medicine”

5. “Pediatric Dengue Vaccine Initiative”. 2008. Retrieved 2008-10-05.

6. “Thailand to test Mahidol-developed dengue vaccine prototype”. People’s Daily Online. 2005-09-05. Retrieved 2006-10-08.

7. Edelman R (July 2007). “Dengue vaccines approach the finish line”. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 45 Suppl 1: S56–60. doi:10.1086/518148. PMID 17582571

8. “Flightless Mosquito engineered to fight Dengue, Medical News Today”

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