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Copyright 2004 Tara K. Harper.  All rights reserved.

TKH Virology Notes:
Dengue Fever

•  Description     •  Mechanism     •  Outbreaks
•  Location     •  Incubation Period     •  Vaccine
•  Vector     •  Symptoms     •  Variants
    •  Diagnosis     •  Links
    •  Treatment

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NOTE:  This file is for information only.  It is not intended for diagnosis.

      Dengue virus infection
      Dengue fever
      Dengue hemorrhagic fever
      Dengue shock syndrome

Also known as:
     •  Breakbone fever, named by Dr. Benjamin Rush in Philadelphia, 1780;  a reference to the symptom of aching joints.
     •  Dandy fever
     •  Seven-day fever
     •  Duengero - from the Spanish duengo
     •  Ki denga pepo - Swahili:  "it is a sudden overtaking by a spirit"

Description.   Pronounced "deng-gee" or "deng-gay."   Dengue hemorrhagic fever first "emerged" in 1949, although clinical dengue fever was described more than 100 years earlier.  It is an acute, infectious, tropical viral disease characterized by fever, severe myalgias, and rash. 

As of the late 1990's, dengue has become the most notable mosquito-borne disease.  Each year, dengue affects tens of millions of people, and an estimated 2.5 billion live in areas which are at risk of epidemic transmission.  Each year, the hemorrhagic form of the disease affects up to hundreds of thousands of poeple.

Outbreaks are occurring with greater frequency in tropical countries.  This may be a result of increasing population density in cities, as well as other factors (such as open water storage for cities, irrigation canals, rain-filled tires, and plastic bottles), which provide breeding grounds for mosquitoes and allow the mosquito population to flourish.

Dengue, a flavivirus in the family Arboviridae, has four known serotypes (varieties recognized as distinct by the immune system).  The most severe form of the disease is dengue hemorrhagic fever, which is characterized by thrombocytopenia, bleeding, and shock.  The hemorrhagic form continues to be the leading viral hemorrhagic fever in the world.

Dengue hemorrhagic fever occurs in many areas where other dengue serotypes are localized.  Studies show that infection with and subsequent immunization from one dengue serotype actually increases the odds of developing dengue hemorrhagic fever during infection with a second serotype.  This is especially notable in areas where multiple serotypes have overlapping, endemic regions.  Essentially, exposure to a mild form of dengue (in some cases, there is no apparent illness) seems to sensitize the immune system to the hemorrhagic form of the disease.

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Location.    Mostly in tropical and subtropical climes:  Asia, Africa, South America, the Caribbean (including Puerto Rico and the U.S. Virgin Islands).  Dengue is predominantly found in urban areas, but can also be found in rural areas.  Epidemics are usually seasonal, during and shortly after the rainy season. Because the dengue vector (mosquitoes) cannot survive prolonged or extreme cold, dengue is rarely found at elevations above 4000 feet, and is limited to a global range below 42N latitude.  Global warming will likely expand the range of the vector mosquito.

Dengue is present in the U.S.  Most cases are imported from travelers; however, confirmed cases of mosquito-transmitted disease have occurred in south Texas in 1980, 1986, and 1995.  Mosquito-borne epidemics have occurred in northern Mexico.

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Vector.   Aedes aegypti mosquitoes, which are most active during the day, are usually found near human dwellings, and are often present indoors.  Elevated temperatures significantly shorten the incubation periods for the dengue virus in mosquitoes.  (This increases the rate of mosquito-human transmission of the virus.)   A. aegypti cannot withstand temperatures below 48 F, and will die after less than an hour of 32 F.  It is currently limited to a range below 35N latitude.

The Aedes albopictus (Asian tiger mosquito) was introduced to the U.S. in 1982 in Houston, Texas, in shipments of used tires imported from Asia.  The used tires contained rainwater which harbored mosquito larvae.  The mosquito has now established itself in at least 18 states.  Although the tiger mosquito has not yet been identified as directly responsible for dengue in America, the proliferation of the mosquito may make it a significant vector.  

A. albopictus is a proven carrier of the following diseases in the United States:  dengue, yellow fever, Mayaro, Venezuelan equine encephalitis, Eastern equine encephalomyelitis (EEE), and others.  The tiger mosquito, which feeds on animal blood, not just human blood, is slightly hardier than A. aegypti, and is currently limited to below 42N latitude.

Dengue is also imported to the U.S. via tourists from endemic areas.

Dengue has a second, natural host in monkeys and treehold-breeding mosquitoes; but this natural forest cycle is not yet understood.

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Incubation Period.  5-8 days.

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Mechanism -- Hemorrhagic Variant.  The hemorrhagic dengue variant seems to be able to replicate in the human body only in macrophages.  It is possible that the virus-antibody interactions actually help hemorrhagic viral replication by promoting cell infection.  This is via specific macrophage receptors--the Fc portion of the antibody molecule, or possibly via a protease-sensitive receptor.  

Apparently, the antibodies attach to the virus's outer envelope, then signal the larger macrophages.  When a macrophage responds to the antibody signal and arrives on the viral scene, it engulfs the virus.  However, the virus then takes control of the macrophage and replicates inside the macrophage instead of being destroyed by it.  The virus is then carried throughout the body via the macrophage transports.  

Physical reactions triggered by this involvement of the immune system include fevers from 104-107 F, convulsions, shock, and death.

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Symptoms.  Characterized by sudden onset of high fever, weakness and prostration, severe headaches, retro-orbital pain, joint and muscle pain (myalgia), nausea, vomiting, and rash.  The fever rises rapidly to as high as 104 F, and may be accompanied by bradycardia.  The petechiae rash appears 3-4 days after the onset of fever, and usually appears on the trunk first, before spreading peripherally.  Symptoms usually persist for 7 days, hence one of the common names for the disease:  seven-day fever.

Symptoms of hemorrhagic dengue are initially indistinguishable from dengue fever, but progress to faintness, shock, and systemic bleeding (gastrointestinal hemorrhage, etc.).  The mortality rate for hemorrhagic dengue is 5%.  

Dengue does not produce long-term complications.

Dengue can be confused clinically with influenza, measles, malaria, Colorado tick fever, scarlet fever, typhus, yellow fever, and other hemorrhagic fevers.

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Diagnosis.  Diagnosis is made by blood test for the presence of the virus or antibodies, or by serologic testing.  

Lab results may indicate that fibrinogen and clotting factors V, VII, IX, and X are reduced.

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Treatment.  There is no specific treatment for dengue.  At best, bed rest, fluids, and medications to reduce fever can be adminstered.  Anticoagulants, such as aspirin, should be avoided.  Severe bleeding can sometimes be controlled with transfusions of packed red blood cells or platelets.

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Outbreaks and History of Infection.  The interval between epidemics in South and Central America and in Asia has shortened until there are annual major epidemics.  Massive outbreaks have occurred when a susceptible population (one already exposed and innoculated against one serotype) is exposed to a new dengue serotype.  Some of the first notable outbreaks occurred:
   - 1779, Asia, Java, and Africa, epidemics
   - 1780, Philadelphia, U.S., epidemic
   - 1897, Australia, epidemic

Dengue then became endemic throughout the Americas.  When the vector (A. aegypti) was identified, countries began eradication campaigns during the early 1900's.  However, after mosquito-eradication programs were effective, funding for the programs dropped off, and programs were discontinued throughout most of the world. 

The next major outbreak of dengue occurred in Manila, in 1953, and introduced viral strain dengue-2, hemorrhagic dengue.  By 1981, dengue was reentrenched in Manila.  The virus now reemerges at the onset of every rainy season, affecting tens of thousands of children each year, killing approximately 15% of those affected.

Following the 1953 Manila outbreak, an epidemic occurred in 1958 in Bangkok, affecting 2,297 (mostly children), and leaving 240 dead. The hemorrhagic form of dengue persisted in Bangkok from 1958 to 1963, affecting over 10,300 people and killing almost 700.  Almost all victims in the Bangkok epidemic had been exposed to other, less pathogenic strains of dengue.

Since the 1960's, dengue has reemerged throughout the world.   Some notable outbreaks in the last two decades:
   - 1977, Cuba:  mild epidemic of dengue-1.
   - 1977, Seychelles (Africa) - first major epidemic
   - 1979, Laredo, Texas:  two residents developed hemorrhagic fever.
   - 1981, Havana, Cuba:  A new strain of dengue-2 from Southeast Asia causes its first major epidemic:  350,000 infected; 115,000 hospitalizations; 156 dead.  It was later found that 44.5% of Havana's residents had been exposed previously to dengue-1 during the 1977 epidemic.
   - 1982, New Delhi, India:  20% of the 5.6 million residents fall ill to dengue-2
   - 1982, Keyna - first major epidemic of dengue-2
   - 1982-1984, Somalia - dengue-2
   - 1985 - Mozambique, first major epidemic (dengue-3)
   - 1985-1986, Nicaragua:  indigenous population of Managuans
   - 1985, Hainan Island, China - first major epidemic of dengue-2
   - 1988, U.S.: 124 suspected cases of imported dengue, of which 27 (in 7 states) were definite, and 25 were uncertain.
   - 1990, Venezuela
   - 1991, Brazil:  epidemic, indigenous population.
   - 1991-1992, Djibouti (Africa) - first major epidemic
   - 1993, Somalia:  U.S. troops.  
   - 1994, Pakistan, first epidemic
   - 1994, Nicaragua:  dengue-3 reappears (a new strain genetically distinct from previous dengue-3 strains in the Americas) and causes an epidemic of dengue hemorrhagic fever.
   - 1994, Saudi Arabia, first major epidemic of dengue-2

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Vaccine.  None currently available.  However, some attenuated candidate vaccine viruses have been developed in Thailand.  Human trials of the attenuated vaccine have not yet been performed.

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Varients.  The dengue virus has significant genetic variants, and there is evidence of genetic drift in specific countries over time.  Genetic differences between strains do not appear to be associated with differences in symptoms or clinical features of the disease.  The endemic strains of certain varients appear to be specific to geographic locations.  

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     •  Fact sheet, DVBID/CDC
     •  History and current trends in infections and geographic distribution, DVBID/CDC
     •  Electron micrographs of virus, DVBID/CDC

Copyright 2004 Tara K. Harper

All rights reserved.  It is illegal to reproduce or transmit in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, any part of this copyrighted file without permission in writing from Tara K. Harper.  Permission to download this file for personal use only is hereby granted by Tara K. Harper.

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