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CBRNE - Venezuelan Equine Encephalitis

Author: Robert W Derlet, MD, Professor of Emergency Medicine, University of California at Davis School of Medicine; Chief Emeritus, Emergency Department, University of California at Davis Health System
Coauthor(s): John R Richards, MD, FAAEM, Professor of Emergency Medicine, University of California at Davis School of Medicine
Contributor Information and Disclosures

Updated: Jan 7, 2010

Introduction

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.¹ The disease may progress from encephalitis to death.

Clinical symptoms are similar to those of many other zoonotic viral infections, which cause fever and headache, including St. Louis encephalitis, Japanese encephalitis, West Nile encephalitis, and dengue fever. Unlike these infections, which are caused by a Flavivirus, Venezuelan equine encephalitis (VEE) is caused by an enveloped single-stranded RNA virus of the Togaviridae family, Alphavirus genus.²

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 suitable 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.³ Unlike many other pathogenic viruses, these viruses are relatively stable in the environment.

Venezuelan equine encephalitis (VEE) remains a potentially potent biological weapon.⁴ 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.⁵

History of disease

Venezuelan equine encephalitis, first recognized in the 1930s, has been responsible for numerous outbreaks and thousands of cases of febrile illnesses and encephalitis. 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 Argentina, Colombia, Panama, Peru, Brazil, Venezuela, French Guiana, Guyana, and Surinam.^6,7,8 Mortality rates vary in horses but reportedly are as high as 80%. Hundreds of thousands of horses have died in epidemics.⁹

The potential impact of a Venezuelan equine encephalitis (VEE) epidemic is best illustrated by examining large Venezuelan and Colombian epidemics of 1962-63, 1967, and 1995.¹⁰ 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.¹¹ Clinically apparent but less severe neurologic manifestations occurred in additional patients.

Symptomatic manifestations are variable. The incidence among humans during epidemics has been as high as 300 per 1000 persons per month, especially among children younger than 15 years.¹² 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.¹³

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 Venezuelan equine encephalitis (VEE) viral RNA is enveloped in an icosahedral coat structure, with a diameter of about 60 nm.¹⁴ 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 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 Venezuelan equine encephalitis found in humans.¹⁵

Zoonotic transmission

Mosquitoes serve as the vector for transmission of Venezuelan equine encephalitis. Venezuelan equine encephalitis has a zoonotic reservoir in bats, birds, rodents, equines (horses, donkeys, mules), and certain tropical jungle mammals.¹⁶ 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.^17,18

Humans and horses are infected by a wide variety of mosquito vectors, including Culex, Mansonia, Psorophora, and Aedes species.¹⁹ 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. Venezuelan equine encephalitis (VEE) virus has been isolated from human pharynx.²⁰ 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 the aerosol form of Venezuelan equine encephalitis is highly infectious, making it a potential biowarfare agent. This could be especially worrisome if strains are genetically altered to increase pathogenicity.²¹

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.¹¹ 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.

The virus is lipid- and glycoprotein-enveloped; it contains RNA of approximately 12 kilobase pairs in length.²² The VEE virus gains access to a human's bloodstream after the person is bitten by an infected mosquito. The virus initially enters lymphatic and bone marrow cells by receptor-mediated endocytosis.²³ After the virus replicates and releases itself into the bloodstream, it infects other cells, causing symptoms typical of viral febrile illness. In a subset of patients, the virus gains entrance into the CNS, where it continues to replicate, resulting in acute encephalitis.²⁴

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.²⁵ 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.¹³

Frequency

United States

Venezuelan equine encephalitis (VEE) currently is rare in the United States. A major epidemic in horses occurred in Texas in 1971, but fewer than 100 laboratory-confirmed cases in humans are documented.²⁶ Data from international outbreaks suggest many more subclinical infections occurred. Unless a large-scale epidemic in horses occurs in the United States, VEE diagnosed in the United States will presumably have been acquired abroad or from 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 of Venezuelan equine encephalitis in endemic subtropical and tropical areas has not been clearly determined because isolated cases resulting from rodent-mosquito-human transmission remain undocumented.

Epidemic areas: Epidemics of Venezuelan equine encephalitis occurring every few years have demonstrated equines are highly susceptible to severe disease and fare poorly. Mosquito-exposed humans in these areas are also at risk, and most are believed to become infected; however, most human infection is subclinical.

Mortality/Morbidity

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

Race

No predilection.

Sex

Data regarding sex are nonspecific; however, many ranch and field workers in endemic areas are male, thus increasing the risk.

Age

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

Clinical

History

Symptoms of Venezuelan equine encephalitis (VEE) range from a mild flu-like illness to severe systemic disease, encephalitis, and death.^27,12,28,15

• Patients give a history of exposure to mosquitoes in an area endemic for VEE. Because the incubation period ranges from 1 day to 1 week, a patient who has been exposed in an endemic area may return to the United States with VEE.
• Suspect VEE and dengue fever in anyone with a febrile illness who has recently traveled in rural areas of Central America or tropical South America.
• Mild infection: Persons with the mild form of infection may be asymptomatic. Others may develop only minimal flu-like symptoms of low-grade fever, myalgias, or headache.
• Moderate infection: Typical symptoms include fever, intermittent chills, myalgias, back pain, headache, photophobia, vomiting, and/or hypesthesia. Less common complaints include sore throat.
• Severe infection: Patients present with acute-onset high fever (temperature, 39-40°C), severe myalgia, severe back pain, headache, photophobia, vomiting, weakness, prostration, and confusion.
• Biological warfare: Suspect biological warfare or terrorism when large numbers of patients present with VEE from a nonendemic region.³

Physical

The physical examination of patients with Venezuelan equine encephalitis results in nonspecific findings of an acute febrile illness. In patients with advanced disease in which encephalitis has developed, findings may include nuchal rigidity and ataxia.⁹

• Fever may be low grade in patients with mild cases and surpass 40°C in severe cases.
• Hypotension in dehydrated patients
• Nuchal rigidity in patients developing encephalitis
• Altered mental status in moderate and/or severe infections
• Coma in patients with progressed encephalitis

Causes

Venezuelan equine encephalitis (VEE) is caused by exposure to mosquitoes infected with VEE in endemic or epidemic areas or by intentional release of a VEE biological weapon.

• Endemic-acquired infections: These are the most difficult infections to diagnose. In many mosquito-infested areas of central and tropical South America, rodents dwelling in the jungle, swamp, marsh, or forest harbor VEE. Because many other infectious agents from these areas also cause febrile illnesses, VEE is not always considered early in the patient's course.
• Epidemic-acquired infections: These infections are usually well publicized, with public health and veterinary officials working to contain the outbreak. Patients with fever originating from these areas may present worried about VEE and may request diagnostic testing.

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• Brain and Nervous System Center
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