Dengue fever

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

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Dengue fever (Template:IPA2) and dengue hemorrhagic fever (DHF) are acute febrile diseases, found in the tropics and Africa, with a geographical spread similar to malaria. One major difference, however, is that malaria is often eradicated in major cities, where as dengue is often found in urban areas of developed tropical nations, like Singapore. 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.

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. 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 receive instead acetaminophen preparations to deal with these symptoms [3] if dengue is suspected.

Having a strong immune system also benefits recovery from dengue.

Emerging treatments

Emerging evidence suggests that mycophenolic acid and ribivirin inhibit dengue replication. Initial experiments showed a fivefold increase in defective viral RNA production by cells treated with each drug.^[4] In vivo studies, however, have not yet been done.

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.

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 (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. 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. 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

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.

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, covering exposed skin, use of DEET-impregnated bednets, and avoiding endemic areas. This is also important for malaria prevention.

Potential antiviral approaches

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

The yellow fever vaccine (YF-17D) is a related Flavivirus, thus the chimeric replacement of yellow fever vaccine with dengue has been often suggested but no full scale studies have been conducted to date.^[5]

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.

In 2007 the World Community Grid launched a project where by computer modeling of the Dengue Fever Virus (and related viruses) thousands of small molecules are screened for their potential anti-viral properties in fighting the Dengue Fever Virus. This project by use of computer simulations seeks out medicines to directly attack the virus once a person is infected. This is a distributed process project similar to SETI@Home where the general public downloads the World Community Grid agent and the program (along with thousands of other users) screens thousands of molecules while their computer would be otherwise idle. If the user needs to use the computer the program sleeps. There are several different projects running, including a similar one screening for anti-AIDS drugs. The project covering the Dengue Fever virus is called "Discovering Dengue Drugs – Together." The software and information about the project can be found at:

• World Community Grid web site

Recent outbreaks

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

2005 dengue outbreak

Country	Cases	Deaths	Date of Information	Sources
Cambodia	20,000	38	Sep.	[6]
Costa Rica	19,000	1	7 Sep.	[7]
India, (West Bengal)	90,000	1,500	Sep.	[8]
Indonesia	80,837	1,099	Jan. 2006	[9]
Malaysia	32,950	83	1 Nov.	[10]
Martinique	6,000	2	26 Sep.	[11]
Philippines	21,537	280	2 Oct.	[12]
Singapore	12,700	19	22 Oct.	[13]
Sri Lanka	3,000	-	16 Sep.	[14]
Thailand	31,000	58	Sep.	[15]
Vietnam	20,000	28	4 Oct.	[16]
Pakistan	4,800	50	11 Dec 2006.	[17]
Total†	232,724	16,673	—	—
†For listed countries only. World Health Organization estimates that there may be 50 million cases of dengue infection worldwide each year. [18]

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. The disease has propagated to Argentina (where it is not considered endemic), in almost all cases by people who recently arrived from Paraguay. 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. 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

• Puerto Rico: (August 2007) 2,343 confirmed cases of dengue.
• Dominican Republic: (August – October 2006) 4,968 cases with 44 dead.
• Cuba: Media reports (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 Gordonvale, Cairns, Queensland.
• China: September 2006, 70 cases since June in Guangzhou,Guangdong.
• Cook Islands: (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. By October 7, 2006, reports were of 3,331 cases of the mosquito-borne virus and a death toll of 49.
• 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: (January - August 2006) 13,468 cases with 167 dead.
• Singapore: 2007 more than 4029 cases, 8 deaths at 29 Sept.. 2005 at least 13 deaths. 2004 9460 cases. 2003, 4788 cases.
• Thailand: 2005 May, 7200 infected. At least 12 dead.

History

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. 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, or, alternatively, the Spanish word may derive from the Swahili.

History of the Disease

Outbreaks resembling dengue fever have been reported throughout history. 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.

See also

• Tropical disease
• 2006 dengue outbreak in Pakistan
• 2005 dengue outbreak in Singapore
• 2006 dengue outbreak in India
• Chikungunya
• Joseph Franklin Siler

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.

External links

• CDC site on Dengue Fever.
• Dengueinfo.org - Resources & depository of Dengue Virus genomic sequences for biomedical researchers.
• M.I. Dengue - Brazilian world awarded system to monitor and control the Dengue Mosquito