Dengue fever

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Dengue virus
A TEM micrograph showing dengue virus
Virus classification
Group: Group IV ((+)ssRNA) Family: Flaviviridae Genus: Flavivirus Species: Dengue virus

Dengue fever (IPA: /ˈdɛŋgeɪ/) and dengue hemorrhagic fever (DHF) are acute febrile diseases, found in the tropics and Africa, and caused by four closely related virus serotypes of the genus Flavivirus, family Flaviviridae.^[1] The geographical spread is similar to malaria, but unlike malaria, dengue is often found in urban areas of tropical nations, including Puerto Rico,Singapore, Taiwan, Indonesia, Philippines, India and Brazil. 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.^[2]

[edit] Signs and symptoms

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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 petechiae 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.

Other symptoms include:

• fever;
• bladder problems;
• constant headaches;
• severe dizziness; and,
• loss of appetite.

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 pass on the infection only through mosquitoes or blood products and only 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 disease (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.

[edit] 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.

The WHO definition of dengue haemorrhagic fever has been in use since 1975; all four criteria must be fulfilled:^[3]

1. Fever, bladder problem, constant headaches, severe dizziness and loss of appetite.
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 haematocrit of 20% or more from baseline following IV fluid, pleural effusion, ascites, hypoproteinemia)

Dengue shock syndrome is defined as dengue hemorrhagic fever plus:

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

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

[edit] Treatment

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 concentration of the blood 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 drugs; these drugs may aggravate the bleeding tendency associated with some of these infections. Patients should receive instead paracetamol preparations to deal with these symptoms if dengue is suspected.^[4]

[edit] Emerging treatments

Emerging evidence suggests that mycophenolic acid and ribavirin inhibit dengue replication. Initial experiments showed a fivefold increase in defective viral RNA production by cells treated with each drug.^[5] In vivo studies, however, have not yet been done.

[edit] Epidemiology

World-wide dengue distribution, 2006. Red: Epidemic dengue. Blue: Aedes aegypti.

World-wide dengue distribution, 2000

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.

On March 20, 2008, the secretary of health of the state of Rio de Janeiro, Sérgio Côrtes, announced that 23,555 cases of dengue, including 30 deaths, had been recorded in the state in less than three months. Côrtes said, "I am treating this as an epidemic because the number of cases is extremely high." Federal Minister of Health José Gomes Temporão also announced that he was forming a panel to respond to the situation. Cesar Maia, mayor of the city of Rio de Janeiro, denied that there was serious cause for concern, saying that the incidence of cases was in fact declining from a peak at the beginning of February. ^[6] By April 3, 2008, the number of cases reported rose to 55,000 ^[7]

Significant outbreaks of dengue fever tend to occur every five or six years. The cyclicity in numbers of dengue cases is thought to be the result of seasonal cycles interacting with a short-lived cross-immunity for all four strains, in people who have had dengue (Wearing and Rohani 2006). When the cross-immunity wears off, the population is then more susceptible to transmission whenever the next seasonal peak occurs. Thus in the longer term of several 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 phenomenon, 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.^[8] 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 six 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.^{[citation needed]}

[edit] Prevention

[edit] 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.^[9] Thai researchers are testing a dengue fever vaccine on 3,000–5,000 human volunteers after having successfully conducted tests on animals and a small group of human volunteers.^[10] A number of other vaccine candidates are entering phase I or II testing.^[11]

[edit] 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, Aedes aegypti, from southeast United States. Courtesy: Centers for Disease Control and Prevention Public Health Image Library

Primary prevention of dengue mainly resides in mosquito control. There are two primary methods: larval control and adult mosquito control. In urban areas, Aedes mosquitos breed on water collections in artificial containers such as plastic cups, used tires, broken bottles, flower pots, etc. Continued and sustained artificial container reduction or periodic draining of artificial containers is the most effective way of reducing the larva and thereby the aedes mosquito load in the community. For reducing the adult mosquito load, fogging with insecticide is somewhat effective.

Prevention of mosquito bites is another way of preventing disease. This can be achieved either by personal protection or by using mosquito nets. In 1998, scientists from the Queensland Institute of Research in Australia and Vietnam's Ministry of Health introduced a scheme that encouraged children to place a water bug, the crustacean Mesocyclops, in water tanks and discarded containers where the Aedes aegypti mosquito was known to thrive. This method is viewed as being more cost-effective and more environmentally friendly than pesticides, though not as effective, and requires the ongoing participation of the community.^[12]

[edit] Personal protection

Personal prevention consists of the use of mosquito nets, repellents containing NNDB or DEET, covering exposed skin, use of DEET-impregnated bednets, and avoiding endemic areas.

[edit] Potential antiviral approaches

In cell culture experiments^[13] and mice ^[14] Morpholino antisense oligos have shown specific activity against Dengue virus.

The yellow fever vaccine (YF-17D) is a related Flavivirus,^[clarify] thus the chimeric replacement of yellow fever vaccine with dengue has been often suggested^[clarify] but no full scale studies have been conducted to date.^[15]

In 2006, a group of Argentine scientists discovered the molecular replication mechanism of the virus, which could be attacked by disruption of the polymerase's work.^[16]

[edit] Recent outbreaks

A public service ad teaching people how to prevent dengue and yellow fever in Encarnación, Paraguay (2007)

During the first months of 2007, over 16,000 cases have been reported in Paraguay and in the end of the year, more than 100.000, of which around 300 or 400 have been detected as DHF cases. Ten deaths have also been reported, including a high ranking member of the Ministry of Health. One Department of Health official resigned because he had approved the use of expired batches of insecticide to control the mosquito vectors of dengue.^[17][18] The disease has propagated to Argentina (where it is not considered endemic) by people who recently arrived from Paraguay.^[19] 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.^[18] Epidemics in the states of Ceará, Pará, São Paulo, and Rio de Janeiro have taken the Brazilian national tally of cases to over 70,000, with upwards of 80 deaths.^[20] Larvae have also been found in Parana state. The proportion of cases registered as DHF is reported to be higher than in previous years.^{[citation needed]}

[edit] Americas

• Puerto Rico: ^[21](August 2007) 2,343 confirmed cases of dengue in 2007.
• Dominican Republic:^{[not in citation given][22]}(August – October 2006) 4,968 cases with 44 dead
• Cuba: Media reports ^{[23][24][25][26]} (dated September and October 2006) speculate on an outbreak although there is no official report
• Brazil: 2008 Health officials say an outbreak of dengue fever has infected more than 110,000 people in Rio de Janeiro state and claimed at least 95 lives since January 1st. An outbreak of Dengue in the first seven months of 2007 reported more than 438,000 cases of dengue fever, with 97 deaths.^[27]
• Mexico: As of October 2007 there is a serious problem in Monterrey, Nuevo Leon almost reaching epidemic proportions.^{[citation needed]}

[edit] Asia Pacific

See also: 2006 dengue outbreak in Pakistan, 2005 dengue outbreak in Singapore, and 2006 dengue outbreak in India

• Australia: 2006 March 15, 2 confirmed cases at Gordonvale, Cairns, Queensland.
• China: September 2006, 70 cases since June in Guangzhou,Guangdong.^[28]
• Cook Islands: ^[29](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.^[30] By October 7, 2006, reports were of 3,331 cases of the mosquito-borne virus and a death toll of 49.^[31]
• Indonesia: 2004 80,000 infected with 800 deaths.
• Malaysia: January 2005 33,203 cases.
• Pakistan: 2006 Over 3,230 cases, 50 deaths.
  • Karachi 2006 October, the number of infected patients rose to 1,836 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: ^[32](January – August 2006) 13,468 cases with 167 dead.
• Singapore: 2007 more than 4029 cases, 8 deaths at 29 September 2005 at least 13 deaths. 2004 9,460 cases. 2003, 4,788 cases.
• Thailand: May 2005 , 7,200 infected. At least 12 dead.

[edit] History

The origins of the word dengue 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.^[33] 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^[34] or, alternatively, the Spanish word may derive from the Swahili.^[35] It may also be attributed to the phrase meaning "Break bone fever", referencing the fact that pain in the bones is a common symptom.

Outbreaks resembling dengue fever have been reported throughout history.^[36] 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 deciphered only in the 20th century. Population movements during World War II spread the disease globally.

In 2007 replication mechanism of the virus was interrupted by interception of the viral protease [14], and currently a project to identify new protease interception mechanisms of the whole familly of the virus has been launched (Dengue virus belong to the familly Flaviviridae, which includes among others HCV, West Nile and Yellow fever viruses). The software and information about the project can be found at the World Community Grid web site.[15]

[edit] Footnotes

[edit] References

• Manson's Tropical Diseases
• Mandell's Principles and Practices of Infection Diseases
• Cecil Textbook of Medicine
• The Oxford Textbook of Medicine
• Harrison's Principles of Internal Medicine
• Theiler, Max and Downs, W. G. 1973. The Arthropod-Borne Viruses of Vertebrates: An Account of The Rockefeller Foundation Virus Program 1951-1970. Yale University Press.
• Downs, Wilbur H., et al. 1965. Virus diseases in the West Indies. Special edition of the Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, 1965.
• Earle, k. Vigors. 1965. "Notes on the Dengue epidemic at Point Fortin." The Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, pp. 157-164.
• Hill, A. Edward. 1965. "Isolation of Dengue Virus from a Human Being in Trinidad." Virus diseases in the West Indies. The Caribbean Medical Journal, Vol. XXVI, Nos. 1-4, pp. 83-84; "Dengue and Related Fevers in Trinidad and Tobago." Ibid, pp. 91-96.

[edit] External links

• CDC site on Dengue Fever.
• Dengueinfo.org - Resources & depository of Dengue Virus genomic sequences for biomedical researchers.
• [16].
• gmanews.tv/story,Valenzuela troubled by steep rise in dengue cases
• www.gmanews.tv/largevideo, Can camote tops cure dengue? - 01/25/2008