Flavivirus

Basic information and current topics regarding Flaviviridae

Medical Relevance

The flavivirus genus comes from the Flaviviridea family of viruses, which are classified as arthropod-borne viruses. Flavivirus species can be transmitted to humans via either a mosquito or tick vector. The flavivirus genera are of importance to the medical community because they have been found to be the causative agent of many endemic and epidemic illnesses across the world.

The first flavivirus discovered to infect humans was the yellow fever virus, which led to the descriptive naming of this entire family of these viruses (Flavi means “yellow” in Latin)1. Patients with severe infection were often yellow in color, as they became jaundice secondary to liver failure. Most of the flavivirus species have tissue tropism to neural tissue. This explains their most debilitating effects on humans, such as encephalitis. There are over 50 various flavivirus species, but not all of them are known to cause human disease1.  Some key species that do cause human disease will be the focus of this blog, and they include:

– Yellow fever Virus

– West Nile Virus

– Dengue Fever/Dengue Hemmorhagic Fever

– St. Louis Encephalitis

– Japanese Encephalitis

Many time, an individual may be infected with one of these flavivirus species and not ever be aware, as asymptomatic infections are common in regard to flavivirus infections.  However, severe infection of certain flaviviruses can lead to serious complications, such as inflammation of the brain, hemorrhage, and death.  Below are the signs, symptoms, and clinical information regarding the 5 flaviviruses listed above.

Yellow Fever

Yellow fever originated in Africa, and was the first flavivirus associated with human disease.  This disease presently occurs most commonly in Africa and S. America (tropical regions), and its last occurrence in N. America was in 1905.  There are two types of yellow fever:

Jungle Yellow Fever (JYF) occurs when humans enter deep into forests or jungles, and becoming infected by the bite of an Aedes agypti mosquito (Africa) or a Haemogogus mosquito (Americas).  Feeding off of an already infected monkey infects mosquitoes in the jungle! JYF can be seen in urban areas when an infected jungle go-er comes back to urban areas and mosquitoes become infected by this person, allowing for transmission to other individual to occur2.

Urban Yellow Fever describes the transmission of the yellow fever virus from mosquito to human, with no monkeys involved!

The incubation period for yellow fever is about 3-6 days, followed by 3 stages of infection, detailed below3:

  1. Early Stage:  The first symptoms that may appear after being infected with this flavivirus include fever, headache, muscle aches, vomiting, loss of appetite, and jaundice.  These symptoms usually last about 3-4 days.
  2. Remission Stage:  After the 3-4 days noted above, individuals often notice their fever has diminished, along with the symptoms from the early stage. At this time, many individuals will fully recover from the infection.  If the body does not clear the infection, the individual will most onto stage 3.
  3. Intoxication Stage:  This is obviously the most sever stage of yellow fever.  The infection has spread throughout the body and the patient will experience mutli-organ failure.  At this point, symptoms include liver, heart and kidney failure, hemorrhagic complications, brain disorder, coma, and death.  Severe infections leading to death have been reported in up to 50% of individuals infected with yellow fever virus.

Treatment

Although there are no specific treatments for this disease, patients may be given specific treatments based on their symptoms. For mild symptoms, fever reducers and pain medication can be given to offer some relief.  In more severe cases, blood transfusions may be given to a patient who is hemorrhaging, IV fluids to maintain electrolyte balance and prevent severe dehydration, or even dialysis upon diagnoses of kidney failure3.

Prevention

The following information can be found on the CDC website:

Vaccine:  People expecting to travel in areas where there is a high prevalence for yellow fever are encouraged to talk to their doctor about the yellow fever vaccine.  This vaccine must be given 10-14 days prior to travel, and is discussed in more detail on the vaccine page.

Other : Prevention against being bit by infected mosquitoes is another way to decrease risk of yellow fever.  People should use mosquito repellent, sleep within a screened enclosure and wear clothing that fully covers the skin, so the mosquito has no chance (well, decreased chance) at biting!

West Nile Virus

The first reported case of west nile virus came from the West Nile District of Uganda (1937).  A large outbreak in Isreal occurred in 1957, resulting in severe meningitis and encephalitis in many of the elderly people infected4.  Since these viruses can only infect humans via transmission through an arthropod, outbreaks are often seen in tropical climates, where mosquitoes thrive.  However, more recently it has been noted that flavivirus infections are becoming more common in less than optimal mosquito dwelling environments, suggesting the vectors may be becoming more adapted to climates other than the tropical.  For example, the first reported case of West Nile was in the Summer of 1999 in New York4,5.  As of 2004, the virus has been detected throughout the entire United States. The peak incidence in N. America falls between August and September. To date, WNV has been seen in Europe, Africa, parts of Asia, the Middle East, and N. America4.

The reservoir for this virus is a bird, and a recent study suggests the Picui Ground Doves and Shiny Cowbirds both serve as reservoirs, but the former produces 10 times as many infectious mosquitoes than the later6! Humans are not the only one’s vulnerable to this virus.  WNV can also infect domestic animals (cats and dogs), horses, and even bats, squirrels, and rabbits (with less frequency).

Although much more rare, it is important to note that the CDC has documented transmission of this virus to humans via organ transplants, blood transfusions, breast milk and transplacental infection.

The incubation period of WNV ranges from 2-14 days.  Of all people infected with WNV, most will not be aware of the infection and will clear it with no symptoms.  The CDC reports that in recent outbreaks (Northern Hemisphere), 80% of infected individuals did not develop symptoms4.

Asymptomatic = 4/5 people infected

Mild = up to 20% of infections people

Symptoms include:

Fever, headache, rash on the trunk, swollen lymph glands, fatigue, and pain of the eyes, and nausea/vomiting.

Severe = 1/150 people infected.

When symptoms become more severe, WNV can be classified based on the difference in area of inflammation.  For example West Nile meningitis involves inflammation of the meninges, West Nile Encephalitis involves inflammation of the brain, and West Nile poliomyelitis which can result in paralysis (infection targets nerves)4. Some general symptoms seen with the severe cases of WNV include:

High fever and headache, GI problems, inflammation of the optic nerve, muscles, heart pancreas and liver, seizures, mental status changes, and flaccid paralysis.  Many patients also experience stiffness in the neck, confusion, tremors, muscle weakness, numbness, and coma.

It appears that age may play a factor in the severity of West Nile Virus:

Children = usually only mild symptoms, like mild fever

Adults = may experience illness similar to dengue fever

Elderly = may progress to encephalitis and death

Treatment

As with the yellow fever virus, supportive treatment is the route that health care providers use to minimize the patients symptoms. These include IV fluids, fever reducers, and oxygen supplementation4.

Dengue Fever/Dengue Hemorrhagic Fever

Dengue is an emerging infectious disease, and is the most widely occurring flavivirus disease worldwide, with hundreds of thousands of cases reported each yr in tropical and subtropical regions of the world.  There are two types of mosquitoes that serve has vectors for this flavivirus species; Aedes agypti and Aedes ablopticus. In 2007 in the Americas alone, over 900,000 cases of DF and over 26,000 cases of DHF were reported7.  The CDC also suggests that about 100-200 new cases of these viruses are introduced into the US annually, via travelers that leave and then return home.  There are actually four very closely strains of flavivirus that can cause dengue: DENV-1, DENV-2, DENV-3 and DENV-47,8.  Interestingly, immunity from one strain occurs following recovery from that particular strain, and immunity from one strain results in a very brief immunity of the other three strains8.

Dengue Fever is the less severe form of this infection, but if symptoms progress and the body cannot fight off the infection, very severe complications arise, leading to hemorrhagic fever or dengue shock syndrome.  The age of the individual plays a large role in the clinical features of this infection7:

-Young children are at least risk, and often show symptoms of fever and rash.

– Older children and adults can display anything from a mild fever, to severe and abrupt onset of high fever, pain behind eyes, muscle and joint pain, rash, and severe headache.  If the infection persists, it becomes severe and is classified as DHF with the an enlarged liver, a sudden temperature drop (after a few days of high fever), circulatory failure, resulting in shock and death.

Once the virus is transmitted to a person (via mosquito bite) the incubation period lasts between 3-14 days.  Many people only have mild symptoms, like a fever.

Treatment

No specific treatment, just supportive care as previously mentioned

Prevention

Currently, the only method of prevention is to avoid being bitten by an infected mosquito.  Ways to prevent this include:

– Removing any possible breeding environment for mosquitoes  (ie plastic containers,  car tires, metal drums)

– Use of insecticides in areas that larval would be gound.

– Use of insect repellent when outdoors

St. Louis Encephalitis (SLEV)

SLEV is much less common flavivirus worldwide, however the CDC reports that it’s the most common mosquito-tranimissited pathogen infecting humans in the U.S.  Although  epidemics of SLEV have occurred in only the Midwest and Southeast U.S., the virus has been detected throughout the lower 48 states.  About 193 cases of SLEV are reported annually in the US since 1964, but almost all of them (about 99%!) go undetected, as they are asymptomatic9.

The incubation period of SLEV ranges from 5-15 days, with symptoms becoming more intense in the days and weeks to follow in people who do not clear the infection.  After this time, some patients recover spontaneoulsly, while the disease progresses further in others, seen as the development of symptoms of CNS infection (ie stiff neck, confuson, dizzines, tremors).   The symptoms of SLEV, like other flaviviruses, range from mild fever, to meningioencephalitis and death.  Children who are infected often show no signs or symptoms of the disease, but when symptoms do occur, they often result in encephalitis.  Overall, the elderly population has a much higher risk of infection that develops into enchaphalitis, resulting in death9.

Japanese Encephalitis (JEV)

JEV is the primary cause of viral encephalitis in Asia, accounting for 30-50,000 infections per year.  This virus is vary rare in the U.S., with less than 1 case reported per year.  The mosquito vector for JEV is Culex tritaeniorhynchus10. The incubation period for JEV is about 5-15 days; and like other flaviviruses, this virus commonly causes subclinical infections, with no apparent signs and symptoms.  However, in about 1/250 infections, acute encephalitis can occur and may ultimately lead to seizures, paralysis, come and death.  People who recover from a JEV infection have shown to confer immunity from this virus for the rest of their lives.  Again, no specific treatments are available for JEV, and supportive care if given depending on the complications occurring in the individual10,11.

References:

1. North Dakota Department of Health: Department of Preparedness & Response. Flavivirus Fact Sheet.  Accessed March 3, 2011. © 2005. North Dakota Department of Health. < http://www.ndhealth.gov/EPR/public/viral/FlavivirusFact.htm>

2.  National Center for Biotechnology Information – PubMed Health.  © 2011, A.D.A.M., Inc. Yellow Fever.  Accessed March 3, 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002341/&gt;

3.  Center for Disease Control and Prevention (CDC). Yellow Fever.  Accessed March 3, 2011. <http://www.cdc.gov/ncidod/dvbid/YellowFever/index.html&gt;

4. Center for Disease Control and Prevention (CDC). Division of Vector-Borne Infectious Disease. West Nile Virus – Background, Fact Sheet. Accessed March 3, 2011. <http://www.cdc.gov/ncidod/dvbid/westnile/index.htm&gt;

5. Microbe Wiki – Sense RNA Viruses: West Nile Virus.  Accessed March 5th, 2011. <http://microbewiki.kenyon.edu/index.php/Sense_RNA_Virus:_West_Nile_Virus&gt;

6.  Dias, L., Flores, F., et al. (2011). Viremia profiles and host competence index for West Nile Virus (Flavivirus, Flaviviridae) in three autochthonous birds species from Argentina. Journal of Ornithology. 152:1, 21-25.

7. Center for Disease Control (CDC). Division of Vector-Borne Infectious Disease. Dengue. Accessed March 5, 2011. <http://www.cdc.gov/Dengue/&gt;

8. World Health Organization (WHO). Dengue and Dengue Hemorrhagic Fever. Facto Sheet. Accessed on March 5, 2011. < http://www.who.int/mediacentre/factsheets/fs117/en/&gt;

9. Center for Disease Control and Prevention (CDC). Saint Louis Encephalitis.  Accessed March 10, 2011. <http://www.cdc.gov/sle/index.html&gt;

10. Center for Disease Control and Prevention (CDC). Traveler’s Health – Yellow Book.  Japanese Encephalitis.  Accessed March 12, 2011. <http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-2/japanese-encephalitis.aspx&gt;

11. Wikipedia. Japanese Encephalitis. Accessed March 12, 2011. < http://en.wikipedia.org/wiki/Japanese_encephalitis>

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