Dengue Fever

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Electron photomicrograph of Dengue virus. Source: CDC.
Dengue fever (often called just dengue) is a mosquito-borne, viral infection that causes a severe, flu-like illness. In some people, a potentially life-threatening complication called dengue hemorrhagic fever can occur. Dengue is the most common mosquito-borne viral illness of humans that in recent years has become a major worldwide public health threat. Approximately 2.5 billion people throughout the world are at risk from dengue, and explosive outbreaks are occurring in the Americas and South-East Asia.[1]

Contents

History

A disease consistent with the symptoms of dengue fever was reported in a Chinese encyclopedia of disease, published as early as the Chin Dynasty (third or fourth century A.D.)[2] The Chinese called the disease water poison, and it was thought to be connected with insects associated with water. Outbreaks likely to be dengue were reported in the seventeenth and eighteenth centuries. Epidemics of dengue occurred in 1779 and 1780 on three continents (Asia, Africa, and North America) making these outbreaks a pandemic.[3][4]

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.

Epidemiology

World Distribution of Dengue - 2005. Source: CDC
Dengue fever occurs mostly during and shortly after the rainy season in tropical and subtropical areas of
  • Africa
  • Southeast Asia and China
  • India
  • Middle East
  • Caribbean and Central and South America
  • Australia and the South and Central Pacific

Worldwide, 50 to 100 million cases of dengue infection occur each year. This includes 100 to 200 cases yearly in the United States, mostly in people who have recently traveled abroad. Many more cases likely go unreported because some health care providers do not recognize the disease.

During the last part of the 20th century, many tropical regions of the world saw an increase in dengue cases. Epidemics also occurred more frequently and with more severity. In addition to typical dengue, dengue hemorrhagic fever (DHF) and dengue shock syndrome also have increased in many parts of the world. Globally, there are an estimated several hundred thousand cases of DHF per year.

In 2005, dengue was the most important mosquito-borne viral disease affecting humans.[5]

There is currently a worldwide pandemic of dengue fever.[5] Dengue is making its comeback most notably in Central and South America, with Dengue in Argentina becoming a growing concern. The reasons for this may include:

  • Deteriorating public-health facilities and lack of expensive active surveillance programs
  • More people living in cities under squalid conditions where mosquitoes can breed
  • Increased air travel, allowing infected people to introduce the disease to mosquitoes at their destination
  • Ineffective mosquito control compared with past decades
Dengue along the US-Mexico border. Source: US Global Climate Change Research Project
An epidemic in Hawaii in 2001 was a reminder that some parts of the United States are susceptible to dengue epidemics, since they harbor the particular types of mosquitoes that transmit dengue virus. In fact, thousands of cases of dengue have been seen in the U.S. in recent decades, most of them imported by travelers returning from abroad. Officials of the National Institute of Allergy and Infectious Diseases (NIAID) branch of the NIH are concerned that dengue fever could become more of a problem in the United States.[6]

Surveillance is extremely important in countries affected by dengue to quickly recognize and move to control local epidemics. Active surveillance is going on in Puerto Rico and the U.S. Virgin Islands, while passive surveillance, which is an inexpensive but much less effective method, is relied upon elsewhere.

The Texas-Mexico border area is of particular concern, as dengue virus is endemic in parts of Mexico, but not in the United States. Dengue was once common in Texas (where there were an estimated 500,000 cases in 1922), and the mosquito that transmits it remains abundant in Texas and much of the United States. There is a striking contrast in the incidence of dengue in Texas versus three Mexican states that border Texas (43 cases vs. 50,333) in the period from 1980-1996. Clearly, factors other than temperature or availability of the mosquito vector, are of great importance, such as poverty, public health infrastructure, use of air conditioning and window screen.

Other Names

  • Dengue
  • Break-bone fever

Causes

Dengue virus its a spherical 45-50 nm diameter RNA positive single strand virus, of the genus flavirus of the flaviviridae family, there are 4 different dengue serotypes named DEN-1, DEN-2, DEN-3, and DEN-4 each one having different genotypes. Other viruses in this group include those that cause yellow fever, St. Louis encephalitis, and West Nile virus disease. Infection with one type of dengue virus confers life-long immunity to that type of virus, but not to the other types of dengue virus.

The severe forms of dengue, hemorrhagic fever and shock syndrome, appear to occur primarily in people who are infected for a second time by a different type of dengue virus. The first episode of dengue infection causes the body to produce antibodies to that particular type of dengue virus, for example DEN-1. If infection occurs again with a different type of virus, for example DEN-3, the antibodies are not able to neutralize this new dengue virus and may actually cause the immune system to overreact, resulting in the severe forms of the disease.[7]

How Dengue Fever is Spread

Aedes aegypti, the mosquito that transmits dengue fever. Source: Wikimedia Commons

Dengue virus infections are transmitted by the bite of an infected Aedes mosquito. Mosquitoes become infected when they bite infected humans, and then they transmit that infection to other people they bite. Two main species of mosquito, Aedes aegypti and Aedes albopictus, are responsible for all cases of dengue transmitted in this country.

Dengue is not contagious from person to person.

Viral Replication

1) Virus attaches to host receptors through E glycoprotein fusing with it and enters the host cell by receptor mediated endocytosis.

2) Fusion of virus membrane with the vesicle membrane its transported to the cytoplasm where ; RNA genome is released.

3) The positive-sense genomic ssRNA is translated into a polyproteinco and post-translationally cleaved by cell signal peptidase and at dibasic sites by the viral protease; replicase complex: NS1, NS2A, NS3, NS4A, NS5, which is cleaved into all structural and non structural proteins.

4) Replication takes place at the surface of endoplasmic reticulum. A negative-sense complementary ssRNA is synthesized using the genomic RNA as a template.

5) New genomic RNA is synthesized using the negative-sense RNA as a template.

6) Virions assembly occurs at the endoplasmic reticulum. The virion buds at the endoplasmic reticulum, is transported to the Golgi apparatus, and then realesed from the cell membrane by exocytosis.[8] [9] [10]

Types

Illness from dengue virus can present in three major forms as follows:

Signs and Symptoms

Infection by dengue viruses may cause a spectrum of illness ranging from symptom-free infection, [11] to fever and general unwellness, to life-threatening bleeding and low blood pressure (shock). Which syndrome a person gets depends on their age, which virus they're infected with, and whether they've had dengue before. Previous infection with dengue makes a person immune to that particular virus strain, but raises the chance that if infection occurs with another strain, the resulting illness will be lethal.

Classic dengue fever

Symptoms of typical, uncomplicated (classic) dengue usually start suddenly within four to seven days after a person is bitten by an infected mosquito and can include the following:

    • High fever, up to 105° F (40.5° C)
    • Severe headache
    • Pain behind the eyes, called retro-orbital pain
    • Severe joint and muscle pain
    • Nausea and vomiting
    • Loss of appetite
    • Rash
  • The rash may appear over most of the body three to four days after the fever begins, and then subside after one to two days. A second rash may appear a few days later.
  • Young children generally experience a milder case of this classic form of dengue with only fever and rash.
  • Most symptoms of classic dengue resolve within one to two weeks, but weakness, tiredness, and loss of appetite my persist for several weeks.


Dengue hemorrhagic fever

Symptoms of dengue hemorrhagic fever include the symptoms of classic dengue (fever, pain, and headache) plus, after several days:

  • The blood and lymph vessels become leaky and allow vital fluids to seep out of the circulatory system.
  • Tiny spots can form on the skin that represent leaking of blood into the skin (petechiae). These areas of bleeding can become larger.
  • Easy bruising and bleeding, especially from the nose and gums, and under the skin, owing to a drop in levels of blood platelets which normally help form clots.
  • Enlargement of the liver can be seen.
  • Blood in the urine and vomiting blood may occur.

Dengue hemorrhagic fever can be fatal.

Dengue shock syndrome

Symptoms of dengue shock syndrome—the most severe form of dengue disease—include all of the symptoms of classic dengue and dengue hemorrhagic fever, plus the following:

  • Fluids leaking outside of blood vessels
  • Massive bleeding
  • Shock (very low blood pressure)

Warning signs of dengue shock syndrome include the following:

  • Severe abdominal pain
  • Protracted vomiting
  • Marked changes in body temperature, from fever to low temperatures
  • Change in mental status such as irritability, lethargy, or coma

Dengue hemorrhagic fever and shock syndrome usually occur in children less than 15 years of age who are experiencing their second dengue infection. It can be fatal in over 10% of cases, especially in children and young adults.


Diagnosis

Dengue fever can be diagnosed with two blood tests, two to three weeks apart. The tests can show whether a sample of blood contains antibodies to the virus. During an epidemic, when many people are falling ill with dengue, a health care provider often can diagnose dengue based on the typical signs and symptoms.

The dengue virus can sometimes be isolated from blood samples or tissue biopsies, but usually only when symptoms are of recent onset.

Treatment

There is no specific treatment for classic dengue fever, and most people recover within 2 weeks. To help with recovery, health care experts recommend the following:

  • Getting plenty of bed rest.
  • Drinking lots of fluids.
  • Taking medicine to reduce fever.

The Centers for Disease Control (CDC) advises people with dengue fever not to take aspirin due to the increased risk of bleeding. Acetaminophen or other over-the-counter pain-reducing medicines are safe for most people.

For severe dengue illness, including shock and coma, emergency treatment with fluid and electrolyte replacement can be lifesaving. In dengue hemorrhagic fever and shock syndrome, blood product transfusions may also be necessary, especially platelets, to treat bleeding complications.

Prevention

A poster reminding people to clean out pools of standing water where mosquitoes can breed. Source: National Library of Medicine

The best way to prevent dengue virus infection is to take special precautions to avoid being bitten by mosquitoes.[12] Several dengue vaccines are being developed, but none is likely to be licensed by the Food and Drug Administration (FDA) in the next few years. [13]

Because Aedes mosquitoes usually bite during the day, be sure to take precautions not to be bitten, especially during early morning hours before daybreak and in the late afternoon before dark. When outdoors in an area where dengue fever has been found, the following are recommended:

  • Use a mosquito repellent containing 10% to 20% DEET, picaridin, or oil of lemon eucalyptus.
  • Dress in protective clothing - long-sleeved shirts, long pants, socks, and shoes.

Other precautions include the following:

  • Keep unscreened windows and doors closed.
  • Keep window and door screens repaired.
  • Get rid of areas where mosquitoes breed, such as standing water in flower pots, containers, birdbaths, and old tires.

The CDC recommends that "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."[14]

Expected Outcome

Most people who develop dengue fever recover completely within two weeks. Some, especially adults, may be tired and/or depressed for several weeks to months after being infected with the virus. The more severe dengue hemorrhagic fever and dengue shock syndromes can result in blood vessel and liver damage, and can be life-threatening.

The mortality rate of dengue fever varies from less than 1% for the classic syndrome to as high as 44% in dengue hemorrhagic fever.[15]

Research

Scientists around the world are trying various approaches to develop vaccines against dengue. Researchers are using weakened and harmless versions of dengue viruses as potential vaccine candidates against dengue and related viruses. Several projects are currently ongoing to identify what determines the virulence and transmissibility of different dengue virus strains. Other researchers are investigating ways to treat infected individuals and to prevent dengue viruses from reproducing inside mosquitoes.

Although dengue virus has emerged as a growing global threat, scientists know little about how the virus infects cells and causes disease. New research is beginning to shed light on how the virus interacts with humans; for example, how dengue virus damages cells and how the human immune system responds to dengue virus infection.

Building a dengue-resistant mosquito

Researchers at the University of Colorado and the University of California, Irvine, have been attempting to engineer a dengue-resistant mosquito.[16] Thousands of mosquito eggs have been injected with an altered dengue virus gene that triggers a defense mechanism in mosquitoes. The result has been the production of mosquitoes that are resistant to dengue virus infection and that can pass this characteristic on to succeeding generations.

Source

http://www.cdc.gov/ncidod/eid/vol5no4/aviles.htm

References

  1. World Health Organization. WHO ALERT: Prompt action needed on dengue. 2007 Aug 9. Press Release
  2. Nobuchi, H. The symptoms of a dengue-like illness recorded in a Chinese medical encyclopedia. Kanpo Rinsho. 26:422-425. 1979. (In Japanese.) Cited in Gubler, Duane J. Dengue and Dengue Hemorrhagic Fever. Clin. Microbiol. Rev. 1998 11: 480-496
  3. Gubler, Duane J. Dengue and Dengue Hemorrhagic Fever. Clin. Microbiol. Rev. 1998. 11: 480-496.
  4. Gubler, D. J. 1997. Dengue and dengue hemorrhagic fever: its history and resurgence as a global public health problem, p. 1-22. In D. J. Gubler, and G. Kuno (ed.), Dengue and dengue hemorrhagic fever. CAB International, London, United Kingdom.
  5. 5.0 5.1 CDC. Dengue Fever Fact Sheet
  6. NIH News. NIAID Experts See Dengue as Potential Threat to U.S. Public Health. Full Text
  7. World Health Organization. Technical Guide for Diagnosis, Treatment, Surveillance, Prevention, and Control of Dengue Haemorrhagic Fever. 2nd ed. Geneva: World Health Organization. 1997. Full Text
  8. *Tidona, Christian A.; Darai, Gholamreza. The Springer Index of Viruses. Springer -Verlag Berlin Heidelberg 2002
  9. *Virus Taxonomy: Classification and Nomenclature of Viruses Eighth Report of the International Committe on the Taxonomy of Viruses 2005, Elsevier Inc.
  10. *NEW TREATMENT STRATEGIES FOR DENGUE AND OTHER FLAVIVIRAL DISEASES. Novartis Foundation Symposium 277. John Wiley & Sons Ltd. 2006.
  11. Endy, TP, Chunsuttiwat S, Nisalak A, et al. Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am. J. Epidemiol. 2002. 156:40-51. Abstract | Full Text | PDF
  12. CDC. Protection against mosquitoes, ticks, fleas and other insects and arthropods. Travelers' Health: Yellow Book. Full Text
  13. Fuller, Thomas. "The War on Dengue Fever." New York Times, November 4, 2008, page D1 of the New York edition; Available [online]
  14. CDC. Dengue Q&A
  15. Jelinek T. Dengue fever in international travelers. Clin Infect Dis. July 2000;31(1):144–147.
  16. Franz AW, Sanchez-Vargas I, Adelman ZN, et al. Engineering RNA interference-based resistance to dengue virus type 2 in genetically modified Aedes aegypti. Proc Natl Acad Sci USA. 2006 Mar 14;103(11):4198-203. Abstract | Full Text | PDF

External links

Centers for Disease Control and Prevention (CDC):

World Health Organization (WHO)

ViralZone

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