INFECTIOUS DISEASE

VIDEO LECTURE

VIROLOGY - CHAPTER  TWENTY ONE  

ARBOVIRUSES

Dr. Margaret Hunt

En Español

Logo image © Jeffrey Nelson, Rush University, Chicago, Illinois  and The MicrobeLibrary

READING: Murray et al., Microbiology, 5th Ed., appropriate parts of chapters 62 (Reoviruses), 63 (Toga- and Flavi- viruses), 64 (Bunya- and Hanta- viruses) and 64 (Filo- and Arena- viruses)

TEACHING OBJECTIVES
Introduction to viral zoonoses
Brief overview of general features of togaviruses, bunyaviruses, reoviruses, arenaviruses and filoviruses
Discussion of ecology, epidemiology and public health
Arbovirus encephalitis, febrile and hemorrhagic disease
Rodent borne hemorrhagic fever, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome.
Other filovirus-associated hemorrhagic fevers

INTRODUCTION

 Zoonotic viruses are viruses which are transmissible from animals (arthropods, vertebrates) to man. Many are transmitted by means of an infected, blood-sucking, arthropod vector (arthropod borne = arboviruses). Others may be transmitted by inhalation, or conjunctival contact with infected excretions, or by direct contact with infected animal (e.g. rabies).  

Constant vigilance and surveillance are important components in reducing the public health impact of these viruses

The term arboviruses is used to describe viruses from various families which are transmitted via arthropods. Diseases caused by arboviruses include encephalitis, febrile diseases (sometimes with an associated rash), and hemorrhagic fevers.

ARTHROPOD VECTORS

The virus replicates in the vector but usually does not harm it. In the mosquito-borne diseases, the virus establishes a persistent infection in the salivary glands and there is sufficient virus in the saliva to infect another host during feeding. Each virus usually only grows in a limited number of mosquito species.

The natural habitat of the vector (rural or around dwellings), its diurnal activity patterns and its preferred targets for a blood meal, affect the transmission pattern of the disease. Many vectors are only active during part of the year and so this will affect the seasonal incidence of the disease. Insect vectors may over-winter as eggs; in this case the virus must either be transmitted transovarially (which happens in some cases), or survive the winter in the vertebrate host and infect the vector the following year.

VERTEBRATE HOSTS

The virus is usually maintained in a vertebrate host. There is often a persistent viremia and the host can act as a long term reservoir. In many cases the reservoir host is not severely affected by the viral infection. If the vertebrate reservoir is migratory, this will affect the timing of infections in a particular locale.

In many cases, if the virus is transmitted to an animal other than its normal host, viremia is low or transient and there is little chance of the infected animal being able to pass enough virus to a blood sucking arthropod to establish an infection. In this case, the animal is said to be a dead-end host. Man is a dead-end host in the case of most arbovirus diseases (exceptions include yellow fever and dengue fever).

PREVENTION

Methods include surveillance, vector control, public education about reducing breeding sites for vectors and reducing exposure to vectors (by wearing suitable clothing, using insect repellents, timing activities for low risk time of day, etc.), and use of vaccines in few cases where available.

Sylvatic life cycle

Urban life cycle

There are several types of life cycles, but many arboviruses have a sylvatic cycle while some also have an urban cycle.

1. Sylvatic cycle (sometimes known as the jungle cycle). In this the virus cycles between an arthropod and a mammalian host with man usually a dead-end host infected by the arthropod

2. Urban cycle. In this the virus cycles between man and an arthropod species.

There is an urban cycle for yellow fever and dengue fever (both of these also have a sylvatic/jungle cycle).  If there is an urban cycle, using window screens, bed nets, etc. to prevent access of mosquitos to viremic patients may reduce transmission.

ARBOVIRUS DISEASE

Diseases caused by arboviruses include:

• encephalitis

• febrile diseases (sometimes associated with rash)

• hemorrhagic fevers

There is some overlap of symptoms between various virus types; for example viruses not usually classed as encephalitis viruses may cause CNS symptoms, etc.

More than 100 arboviruses are known to infect man but only a few will be mentioned here. Disease outbreaks caused by arboviruses are sporadic and unpredictable. Usually, infection is followed by replication in endothelial cells and macrophage/monocyte lineage cells. Frequently, these infections are associated with flu-like symptoms since these RNA viruses are good inducers on interferon. Often the infection stops here but it may produce enough virus for secondary viremia which can then cause a major infection of target organs (brain, endothelial cells, liver). Which organs are targeted depends on the tropism of the virus. Access to the brain tends to be via infection of the endothelial cells in the blood vessels supplying the brain.

RECOVERY

Recovery involves the cell-mediated immune system. The arboviruses are generally good inducers of interferon, which may partially explain early influenza-like symptoms common to so many of these viruses (fever, headache, fatigue, myalgia). Antibody can be important in controlling the secondary viremia and limiting disease.


DIAGNOSIS 

Diagnosis is difficult because many other agents cause similar symptoms. Arbovirus infection is usually confirmed by immunological methods (complement fixation, ELISA, immune fluorescence assay, etc) or by PCR of the viral nucleic acid. The tests are usually done in a State Laboratory or at the Centers for Disease Control. Awareness of an arbovirus associated disease in a particular area enables risk reduction procedures to be put in place (vector-control, insect repellents, protective clothing, change in human activity patterns).

RESISTANCE

Resistance to arboviruses is mediated by antibodies and recovery involves the cell-mediated immune system.

ARBOVIRUS-ASSOCIATED ENCEPHALITIS

All of the arboviruses in the above table are transmitted by mosquitoes; however, some arbovirus encephalitides are transmitted by ticks or other insect vectors such as sandflies.

Human St Louis Encephalitis cases by state 1964-98 CDC

St Louis encephalitis virus transmission cycle CDC

ARBOVIRUS ENCEPHALITIS IN THE UNITED STATES

For all of the viruses listed below, most infections are sub-clinical, but if  clinical cases do occur, the consequences may be very serious. Initial symptoms are flu-like including fever, but can progress to encephalitis. The following are the most  frequently reported in humans in United States 

California serogroup / La Crosse encephalitis (Bunyavirus family)
Recent cases have been predominantly in the Eastern United States. The reservoir is small mammals (chipmunks and squirrels) and the virus is transmitted by mosquitoes. Children more often develop symptoms than adults but  morbidity and fatality are low (case fatality rate is less than 1%). In the US, there are about 70 cases per year

St. Louis encephalitis (Flavivirus family)
The elderly are most severely affected by a St. Louis encephalitis virus infection since they often have weaker immune systems. The case fatality rate varies from 3-25%. The reservoir is birds and the virus is transmitted by mosquitoes. This virus can have an urban cycle as well as well as a sylvatic cycle. Infections occur in the northern parts of the United States in the late summer and early fall but in the south, infections occur all year.

In many cases of St Louis virus infection, mild infections occur without apparent symptoms other than fever and headache. In more severe cases, there is high fever, neck stiffness, stupor, disorientation, coma, tremors, occasional convulsions (which occur mainly in infants) and spastic (but rarely flaccid) paralysis. The symptoms are therefore similar to West Nile encephalitis which is also caused by a flavivirus (see below). The CDC reports that since 1964 there have been 4,478 reported human cases of St. Louis encephalitis, with an average of 128 cases reported annually. There is no vaccine for this virus for use in humans.
 

WEB RESOURCES
St Louis Encephalitis
CDC Information - St Louis Encephalitis

Western Equine Encephalitis
CDC information

Eastern equine encephalitis (Alphavirus genus of Togavirus family)
The reservoir of this virus is birds and it is transmitted by mosquitoes. Horses are a dead end host.  Many cases result in mild flu-like symptoms but children are more likely to have severe clinical symptoms that adults. People under 15 or older than 50 are more likely to have severe clinical symptoms. If there is clinical disease, death may occur relatively frequently (Case fatality rate is about 35%). Sequelae (mild to severe neurologic deficits) are common in survivors. There have been 200 confirmed human cases of Eastern Equine encephalitis in the United States since 1964.

Western equine encephalitis (Alphavirus genus of Togavirus family)
Again the reservoir is birds and the virus is transmitted by mosquitoes. The horse is a dead end host. As with eastern equine encephalitis, children are more likely to have severe clinical symptoms that adults. The case fatality rate is 3-7%. In the young, death or sequelae (mild to severe neurological impairment) are more common. There have been 639 confirmed cases in the U.S. since 1964; however the number has dropped off in recent years.

Venezuelan equine encephalitis (Alphavirus genus of Togavirus family)
This virus is predominantly a problem in central and South America, but it periodically occurs in the southern US (Texas, Florida). Its reservoir is small mammals and horses.

CASE REPORT
Cases of Eastern Equine Encephalitis in the Young and the Old

WEB RESOURCES
West Nile Virus 
Q&A West Nile Virus 
CDC
Current case count in the US 
 CDC 

Case definition
Encephalitis or Meningitis, Arboviral (includes California serogroup, Eastern equine, St. Louis, Western equine, West Nile, Powassan)

Five Common Myths about West Nile Virus
CDC
West Nile Virus: A Primer for the Clinician
Annals of Internal Medicine

West Nile encephalitis (Flavivirus family)

West Nile virus is closely related to St. Louis encephalitis virus and until 1999 was found in Africa, west Asia/eastern Europe and the Middle East. Most (75%) of people who become infected show no symptoms and mount a successful immune attack against the virus. Most of the remainder have flu-like symptoms (fever, headache and general malaise) with an incubation period of 3 to 14 days. Sometimes there is swelling of the lymph glands (lymphadenopathy) and there may also be a rash. In less than 1% of patients, the infection is life-threatening as a result of encephalitis. The symptoms are high fever, headache, stiff neck. These are followed by confusion, coma, tremors, convulsions, paralysis, and, in some cases, death.  Persons over 50 years of age are most severely affected by West Nile encephalitis and the case fatality rate is approximately 2 - 5%. 

Some people who become infected with West Nile Virus can develop “acute flaccid paralysis”. This is a sudden onset of weakness in the limbs and/or breathing muscles. In most persons, this syndrome is due to the development of West Nile poliomyelitis—an inflammation of the spinal cord that causes a syndrome similar to that caused by the poliovirus. West Nile poliomyelitis was first widely recognized in the United States in 2002. Persons with West Nile poliomyelitis may develop sudden or rapidly progressing weakness. The weakness tends to affect one side of the body more than the other, and may involve only one limb. The weakness is generally not associated with any numbness or loss of sensation, but may be associated with severe pain. In very severe cases, the nerves going to the muscles that control breathing may be affected, resulting in rapid onset of respiratory failure. It is important to recognize that this weakness may occur in the absence of meningitis, encephalitis, or even fever or headache—there may be few other clues that the weakness is due to West Nile Virus infection.

The natural reservoir of the virus is birds and the virus is transmitted by mosquitoes (most likely by Culex pipiens, in the North of the US and Culex quinquefasciatus, in the South; however, through spring 2002, West Nile virus had been detected in 29 North American mosquito species). The first human cases in the United States were in 1999 in New York but in 2002, there were 4156 reported cases of West Nile virus human infection including 284 deaths, with the virus reaching 44 states. In 2003, it spread into all parts of the United States except Oregon, Washington and Idaho and in 2004 it was found in all states except Washington. In 1999- 2001, the peak incidence of human West Nile virus disease was in late August and early September  The spread of the virus is likely to be due to migration patterns of birds. In 2003, the number of human cases of the disease was much higher in western states than in the eastern states in which the  disease was found predominantly in earlier years; for example, Colorado reported over 1500 cases while South Carolina has reported only one.  This is probably because the bird population in eastern states has developed immunity against the virus.

Treatment for West Nile virus infection is supportive although it has been suggested that ribavirin may be active against the virus. In an outbreak in Israel, however, patients treated with ribavirin had a higher mortality than those not treated, although this could have been due to other factors.

The best control for West Nile is reducing the incidence of mosquitoes by spraying (methoprene) or bacterial larvicides such as Bacillus thuringiensis var. israelensis and Bacillus sphaericus. Reduction of mosquito breeding sites such as pools of stagnant water is useful, as is the use of DEET-containing insect repellents.

Spread of West Nile Virus 2003-2005 in humans

Spread of West Nile Virus 2003-2005 in birds

Spread of West Nile Virus 2003-2005 in mosquitoes

 

VIDEO
Surveillance and control in Pennsylvania
  Real Video
Eliminating mosquito breeding areas
Real Video

CDC Responds: Update on West Nile Virus - For Clinicians and Laboratorians
Non-Closed Caption
Closed Caption
Real Video

Preparing for West Nile Virus: Will Your Community Be Next?
Public Health Grand Rounds
CDC Real Video

For latest data go here

  West Nile Virus in the United States as of October 26, 2004 CDC

   West Nile virus transmission cycle    CDC

West Nile virus is a flavivirus commonly found in Africa, West Asia, and the Middle East. It is closely related to St. Louis encephalitis virus found in the United States.  CDC/Cynthia Goldsmith

 
Brain tissue from a West Nile encephalitis patient, showing antigen-positive neurons and neuronal processes (in red)  CDC/W.-J. Shieh and S. Zaki

Human West Nile Virus Disease Cases
Top: Cumulative results for calendar year reported as of September 18, 2002. Bottom: Cumulative results for calendar year reported as of 3:00 a.m. MDT September 17, 2003

ARBOVIRUSES ASSOCIATED WITH FEVER

Colorado tick fever (Reovirus family) 
This occurs in the Rocky Mountain States. It is a mild disease resulting in fever, headache, myalgia and often rash. The virus is transmitted by ticks. In diagnosis, the physician must consider the much more serious Rocky Mountain spotted fever (rickettsial disease) which may have similar initial symptoms and should be treated promptly. See also Ticks

Mature Dengue-2 virus particles replicating in five day old tissue culture cells. The original magnification is 123,000 times. CDC

  High-power view of heavy fibrin depositis in small arteries, almost occluding the lumen. From a section of pancreas of a patient who died from dengue hemorrhagic fever. (Image courtesy of the Wellcome Trust/WHO)

ARBOVIRUSES ASSOCIATED WITH HEMORRHAGIC DISEASE

Dengue fever  (Dengue virus - Flavivirus family)

The natural hosts are monkeys and man and mosquitoes are the vector. Dengue virus has an urban  and a jungle cycle. There are four serotypes (1,2,3,4). It is one of the more rapidly increasing diseases in the tropics and occurs worldwide (50-100 million cases per year). Every year there are cases of dengue fever imported by travelers into the United States. Usually illness is ~1-8 days after infection and IgM may not be present until somewhat later. Symptoms include fever, headache, rash, bone pain (hence the name: "breakbone fever"), myalgias and arthralgia. The infection can sometimes progress to encephalitis/encephalopathy.

Clinical features (edited extract from CDC guidelines for healthcare practitioners):

Classical dengue fever is characterized by acute onset of high-grade fever, frontal headache, retro-orbital pain, myalgias, arthralgias, and often a maculopapular rash. In addition, many patients may notice a change in taste sensation. Symptoms tend to be milder in children than in adults, and the illness may be clinically indistinguishable from influenza, measles, or rubella. The acute phase may last up to one week, with a prolonged convalescence characterized by weakness, malaise, and anorexia. Treatment based on symptoms is recommended.

Dengue Hemorrhagic Fever (DHF) 

DHF - potentially a deadly complication of dengue. It appears to be an immunopathological consequence of infection of a person who has already developed immunity to one serotype of Dengue virus with a virus of another serotype, although the mechanism is not fully understood. It may well involve an immune enhancement whereby there is increased uptake of virus coated with non-neutralizing antibody (developed during an earlier infection with a different serotype) into macrophages via the Fc receptor. Virus replicates in macrophages and so there is an increased virus load. Also macrophages become activated and release inflammatory cytokines. The immune enhancement by non-neutralizing antibody complicates prospects for vaccine development. Disease is more severe in children and the presence of maternal antibody in infants may result in DHF even from a first infection with Dengue virus. There are four serotypes of dengue virus, multiple serotypes circulate in Asia, Africa and the Americas. In DHF, increased vascular permeability is a major problem.

Clinical features (edited extract from CDC guidelines for healthcare practioners):

Dengue hemorrhagic fever (DHF) may resemble classical dengue or other viral syndromes in the first few days of illness. Patients with DHF may have fever lasting 2 to 7 days and a variety of nonspecific signs and symptoms; At about the time the fever begins to break, however, the patient becomes restless and lethargic, shows signs of circulatory failure, and develops hemorrhagic manifestations. The most common of these manifestations are skin hemorrhages such as petechiae, and purpura or ecchymoses. Most patients develop thrombocytopenia and hemoconcentration, the latter as a result of plasma leakage from the vascular compartment. These patients have dengue shock syndrome (DSS), which if not immediately corrected, can lead to profound shock and death. Early signs of DSS include restlessness, cold clammy skin, rapid weak pulse, and narrowing of pulse pressure and/or hypotension. Fatality rates in countries that are not prepared for this disease may be very high. Dengue hemorrhagic fever/DSS is most severe in children under 15 years old, but it can also occur in adults. Fortunately, DHF/DSS can be effectively treated by fluid replacement therapy, and if diagnosis is made early, fatality rates can be kept below 1%. Thus, it becomes very important that both the medical and lay communities learn to recognize this disease. Once a person is infected, the key to survival is early diagnosis.

Patients thought to have dengue should be given acetaminophen preparations rather than aspirin, because the anticoagulant effects of the latter may aggravate the bleeding tendency associated with dengue infection.

WEB RESOURCES
Dengue Fever
CDC Information - Dengue Fever

VIDEO
Dengue Fever 
patients - symptoms - treatment - prevention - research - vectors - parasites
List of sequences
WHO-RealVideo

Aedes albopictus mosquito feeding. This mosquito is a secondary vector for dengue in South-east Asia. It recently extended its range into Africa, the New World and Australia, increasing the risk of the spread of arbovirus infections. (Image courtesy of the Wellcome Trust)

World distribution of dengue fever CDC

Distribution of Aedes aegypti (red shaded areas) in the Americas in 1970, at the end of the mosquito eradication program, and in 1997. CDC

Reported cases of Dengue hemorrhagic fever -  1970's to 1900's

  Yellow fever virus (magnification: 234,000x)

Yellow fever (hemorrhagic fever)

This is a disease that is only found in Africa and South America. In South America, the disease is sporadic and occurs in forested areas. In Africa, yellow fever occurs mostly in the rainy season in the west and central areas of the continent
This disease is transmitted by mosquitoes. Natural hosts of the virus include monkeys and man. It has an urban  and a jungle cycle. Infection results in severe systemic disease, hemorrhages, degeneration of the liver, kidney and heart. The case-fatality rate can be 50%. There is an effective vaccine (attenuated strain called 17D). There are sometimes mild effects (head ache, malaise) of the vaccine within days of administration in a few recipients (less than 5%) but there have been reports of severe illness (fever, hepatitis and multiple organ failure) in seven patients in the past six years 

WEB RESOURCES
Yellow Fever
CDC Information - Yellow fever

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