Excerpt from CBRNE - Venezuelan Equine Encephalitis

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Background

Venezuelan equine encephalitis (VEE) is a mosquito-borne viral disease characterized by fever and other symptoms that may include severe headache, back pain, myalgias, prostration, chills, nausea, vomiting, and weakness. The disease may progress to encephalitis and death.

Clinical symptoms are similar to those of many other zoonotic viral infections that cause fever and headache, including St Louis encephalitis, Japanese encephalitis, West Nile encephalitis, and dengue. Unlike these infections, which are caused by a Flavivirus, VEE is caused by an enveloped single-stranded RNA virus of the Togaviridae family, Alphavirus genus.

Alphaviruses include eastern equine encephalitis, western equine encephalitis, Chikungunya fever, Semliki Forest disease, Barmah Forest fever, and Ross River fever. Some species of the Alphavirus genus have characteristics that make them suited for weaponization, a fact that was recognized in the 1930s and 1940s. Alphaviruses could potentially be produced in large quantities and delivered effectively via an aerosol route. Unlike many other pathogenic viruses, these viruses are relatively stable in the environment.

VEE remains a potentially potent biological weapon. If this virus was deployed efficiently, it could incapacitate thousands of people for a week or more and cause untold psychologic stress to millions. VEE is potentially susceptible to genetic manipulation in advanced laboratories. This characteristic has proven useful for researchers aiming to develop more effective vaccines; however, it could also be exploited to produce more effective biological weapons. A live-attenuated VEE vaccine has been used in horses. A formalin-inactivated vaccine has been developed for use in humans, although further investigation of its protective effects is needed.

History of disease

VEE, first recognized in the 1930s, has been responsible for numerous outbreaks of febrile illnesses and encephalitis involving thousands of cases. VEE viruses are transmitted among equines and rodents by a variety of mosquito species.

Human and animal infections have occurred in equatorial South America and Central America, including Colombia, Panama, Peru, Brazil, Venezuela, French Guiana, Guyana, and Surinam. Mortality rates vary in horses but reportedly are as high as 80%. Hundreds of thousands of equines have died in epidemics.

The impact caused by VEE epidemics is best illustrated by examining large Venezuelan and Colombian epidemics that occurred in 1962-63, 1967, and 1995. In the 3 epidemics combined, more than 300,000 humans were infected, with more than 4% experiencing severe neurologic symptoms and more than 2000 (<1%) deaths reported. Clinically apparent but less severe neurologic manifestations occurred in additional patients.

Symptomatic manifestations of disease are variable. The incidence among humans during epidemics has been as high as 300 in 1000 persons per month, especially among children younger than 15 years. In some epidemics, more than 50% of persons residing in rural villages have become ill, while during other outbreaks, the incidence has been less, although minimally infected persons may not have been reported.

Initial diagnosis may be difficult; therefore, a high index of suspicion is required in examining a symptomatic patient with a history of travel to an endemic area or an area experiencing an active epidemic.

For more information, see Medscape's Bioterrorism Resource Center.

Pathophysiology

The VEE RNA is enveloped in an icosahedral coat structure, with a diameter of about 60 nm. Surface spikes are recognized by host receptors, which afford adsorption of the particle into the host cells. Chronologic pathophysiology is described under Virus action below. Thirteen distinct subtypes have currently been identified; however, only subtype I is associated with human disease. Numerous groups exist within this subtype; groups I-A and I-B cause most cases of VEE found in humans.

Zoonotic transmission

Mosquitoes serve as a vector for transmission of VEE. VEE has a zoonotic reservoir in bats, birds, rodents, equines (horses, donkeys, mules), and certain tropical jungle mammals. Rodents and other small animals are the most important amplifiers in endemic preservation of the virus in tropical forests, swamps, and marshlands. Horses are the most important amplifier hosts in large epidemic outbreaks.

Humans and horses are infected by a wide variety of mosquito vectors, including Culex, Mansonia, Psorophora, and Aedes species. The principal vector for humans is Aedes aegypti. Humans acquire infection as an incidental dead-end infection of the normal animal-mosquito-animal cycle in nature. Blood viral loads of infected patients may exceed the threshold level required to infect mosquitoes, and human-mosquito-human transmission has been suspected in some epidemics.

Other potential modes of transmission

The potential for person-to-person transmission exists. VEE virus has been isolated from throat washings of patients. Furthermore, aerosol transmission of the virus has occurred as a result of laboratory accidents or lack of laboratory precautions. An analysis of laboratory incidents suggests that the aerosol form of VEE is highly infectious, making VEE a potential biowarfare agent. This could be especially worrisome if strains are genetically altered to increase pathogenicity.

The Centers for Disease Control and Prevention (CDC) extensively analyzed the 1995 VEE outbreak in northwest Colombia and reported a 5% secondary household attack rate. Whether these secondary attacks were from bites by mosquitoes infected from animals or humans was unclear. At the present time, direct human-to-human transmission is not scientifically proven but is suspected.

Virus action

The virus gains access to a human's bloodstream after he or she is bitten by an infected mosquito. VEE is lipid- and glycoprotein-enveloped; it contains RNA of approximately 12 kilobase pairs in length. The virus initially enters lymphatic and bone marrow cells by receptor-mediated endocytosis. After the virus replicates and releases itself into the bloodstream, it infects other cells, causing fever and the other symptoms typical of febrile illnesses. In a subset of patients, the virus gains entrance into the CNS, where it continues to replicate, resulting in acute encephalitis.

An initial immune response with immunoglobulin M (IgM) occurs specific to viral surface components, followed by neutralizing antibody and other immune defenses against the virus infection. Serologic studies of populations exposed during epidemics have demonstrated a high seroconversion rate, with most persons experiencing only flulike symptoms or no symptoms at all.

Frequency

United States

VEE currently is rare in the United States. A major epidemic in horses occurred in Texas in the past, but fewer than 100 laboratory-confirmed cases in humans are documented. Data from international outbreaks suggest that many more infections occurred that were subclinical or mild. Unless a large-scale epidemic in horses occurs in the United States, VEE observed in US EDs will have been acquired abroad or due to an intentional release of the pathogen. However, changing climatic patterns may favor establishment of the virus in wild rodents in warmer areas of the United States.

International

Endemic areas: The incidence in endemic subtropical and tropical areas has not been clearly determined because isolated cases resulting from rodent-mosquito-human transmission may remain undocumented.

Epidemic areas: Epidemics that occur every few years have demonstrated that equines are highly susceptible to severe disease and respond poorly. Mosquito-exposed humans in these areas are also at risk, and most are believed to become infected; however, most human infection is subclinical or mild.

Mortality/Morbidity

• The overall mortality rate from epidemics is 0.5-1%. In patients who develop encephalitis, the mortality rate is in the range of 20%.
• Encephalitis is clinically diagnosed in 2-4% of adults and in 3-5% of children.

Sex

Data regarding sex are nonspecific; however, many ranch workers in at-risk areas are male, thus increasing the risk in males.

Age

Data from epidemics demonstrate that children have the highest risk of acquiring moderate or severe forms of the infection.

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