Venezuelan Equine Encephalitis

VENEZUELAN EQUINE ENCEPHALITIS

SUMMARY

Signs and Symptoms: Sudden onset of illness with generalized malaise, spiking fevers, rigors, severe headache, photophobia, and myalgias. Nausea, vomiting, cough, sore throat, and diarrhea may follow. Full recovery takes 1-2 weeks.

Diagnosis: Clinical diagnosis. Physical findings are usually non-specific. The white blood cell count often shows a striking leukopenia and lymphopenia. Virus isolation may be made from serum, and in some cases throat swab specimens. Both neutralizing or IgG antibody in paired sera or VEE specific IgM present in a single serum sample indicate recent infection.

Treatment: Supportive only.

Prophylaxis: A live, attenuated vaccine is available as an investigational new drug. A second, formalin-inactivated, killed vaccine is available for boosting antibody titers in those initially receiving the live vaccine.

Isolation and Decontamination: Standard Precautions for healthcare workers. Human cases are infectious for mosquitoes for at least 72 hours. The virus can be destroyed by heat (80 degrees centigrade for 30 minutes) and standard disinfectants.

OVERVIEW

Venezuelan equine encephalitis (VEE) virus is an arthropod-borne alphavirus that is endemic in northern South America, Trinidad, Central America, Mexico, and Florida. Eight serologically distinct viruses belonging to the VEE complex have been associated with human disease; the two most important of these pathogens are designated subtype I, variants A/B, and C. These agents also cause severe disease in horses, mules, burros and donkeys (Equidae). Natural infections are acquired by the bites of a wide variety of mosquitoes. Equidae serve as amplifying hosts and source of mosquito infection. In natural human epidemics, severe and often fatal encephalitis in Equidae always precedes disease in humans. The virus is rather easily killed by heat and disinfectants.

HISTORY AND SIGNIFICANCE

VEE was weaponized by the United States in the 1950's and 1960's before the U.S. offensive biowarfare program was terminated, and other countries have been or are suspected to have weaponized this agent. This virus could theoretically be produced in either a wet or dried form and potentially stabilized for weaponization. This agent could then theoretically be delivered against friendly forces in a manner similar to the other agents already discussed.

As mentioned above, in natural human epidemics, disease in Equidae always precedes that in humans. A biological warfare attack with virus disseminated as an aerosol would almost certainly cause human disease as a primary event. If Equidae were present, disease in these animals would occur simultaneously with human disease. However, during natural epidemics, illness or death in wild or free ranging Equidae may not be recognized before the onset of human disease, thus a natural epidemic could be confused with a BW event, and data on onset of disease should be considered with caution. A more reliable method for determining the likelihood of a BW event would be the presence of VEE outside of its natural geographic range. Secondary spread by person-to-person contact has not been conclusively shown to occur; however, observations during a recent outbreak in Columbia suggest that it may occur often enough to sustain epidemics in the absence of Equidae. A BW attack in a region populated by Equidae and appropriate mosquito vectors could initiate an epizootic/epidemic.

CLINICAL FEATURES

VEE is characterized by inflammation of the meninges of the brain and of the brain itself, thus accounting for the predominance of CNS symptoms in the small percentage of infections that develop encephalitis. The disease is usually acute, prostrating and of short duration. The case fatality rate is less than 1 percent, although is somewhat higher in the very young or aged. Nearly 100 percent of those infected suffer an overt illness. Recovery from an infection results in excellent short-term and long-term immunity.

DIAGNOSIS

After an incubation period varying from 2-6 days, onset is usually sudden. It is manifested by generalized malaise, spiking fever, rigors, severe headache, photophobia, and myalgias in the legs and lumbosacral area. Nausea, vomiting, cough, sore throat, and diarrhea may follow. This acute phase lasts 24-72 hours. A prolonged period of asthenia and lethargy may follow, with full health and activity regained after 1-2 weeks. Approximately 4 percent of children during natural epidemics develop signs of central nervous system infection, with meningismus, convulsions, coma, and paralysis. Adults rarely develop neurologic complications. In children manifesting severe encephalitis, the fatality rate may reach 20 percent. Permanent neurologic sequelae are reported in survivors. Experimental aerosol challenges in animals suggest that the incidence of CNS disease and associated morbidity and mortality would be high after a BW attack, as the VEE virus would infect the olfactory nerve and spread directly to the CNS. A VEE infection during pregnancy may cause encephalitis in the fetus, placental damage, abortion, or severe congenital neuroanatomical anomalies.

The white blood cell count shows a striking leukopenia and lymphopenia. In cases with encephalitis, the cerebrospinal fluid may be under increased pressure and contain up to 1,000 white cells/mm3 (predominantly mononuclear cells) and a mildly elevated protein concentration. Viremia during the acute phase of the illness (but not during encephalitis) is generally high enough to allow detection by antigen-capture enzyme immunoassay. Virus isolation may be made from serum, and in some cases throat swab specimens, by inoculation of cell cultures or suckling mice. A variety of serological tests are applicable, including the IgM ELISA indirect FA, hemagglutination inhibition, complement-fixation, and neutralization. For persons without prior exposure to VEE complex viruses, a presumptive diagnosis may be made by finding IgM antibody in a single serum sample taken 5 to 7 days after onset of illness.

MEDICAL MANAGEMENT

Standard Precautions are recommended for healthcare workers. Person-to-person transmission may theoretically occur by means of respiratory droplet infection. There is no specific therapy. Patients with uncomplicated VEE infection may be treated with analgesics to relieve headache and myalgia. Patients who develop encephalitis may require anticonvulsants and intensive supportive care to maintain fluid and electrolyte balance, ensure adequate ventilation, and avoid complicating secondary bacterial infections. Patients should be treated in a screened room or in quarters treated with a residual insecticide for at least 5 days after onset, or until afebrile, as human cases may be infectious for mosquitoes for at least 72 hours. The virus can be destroyed by heat and disinfectants.

PROPHYLAXIS

Vaccine: An investigational vaccine, designated TC-83, is a live, attenuated cell-culture-propagated vaccine which has been used in several thousand persons to prevent laboratory infections. The vaccine is given as a single 0.5 ml subcutaneous dose. Febrile reactions occur in up to 18 percent of persons vaccinated, and may be moderate to severe in 5 percent, with fever, myalgias, headache, and prostration. Approximately 18 percent of vaccinees fail to develop detectable neutralizing antibodies, but it is unknown whether they are susceptible to clinical infection if challenged. Contraindications for use include an intercurrent viral infection or pregnancy. TC-83 is a licensed vaccine for Equidae.

A second investigational product that has been tested in humans is the C-84 vaccine, prepared by formalin-inactivation of the TC-83 strain. The vaccine is not used for primary immunization, but is currently used to boost nonresponders to TC-83 (0.5 ml subcutaneously at 2-4 week intervals for up to 3 inoculations or until an antibody response is measured), and probably affords complete protection against aerosol infection from homologous strains in these individuals. As with all vaccines, the degree of protection depends upon the magnitude of the challenge dose; vaccine-induced protection could be overwhelmed by extremely high doses.

Antiviral Drugs: In experimental animals, alpha-interferon and the interferon-inducer poly-ICLC have proven highly effective for post-exposure prophylaxis of VEE. There are no clinical data on which to assess efficacy in humans.