Venezuelan Equine Encephalitis, Bioterrorism

SYMPTOMS

Incubation period 1-6 days. Acute systemic febrile illness with encephalitis developing in a small percentage (4% children; less than 1% adults). Generalized malaise, spiking fevers, rigors, severe headache, photophobia, and myalgias for 24-72 hours. Nausea, vomiting, cough, sore throat, and diarrhea may follow. Full recovery from malaise and fatigue takes 1-2 weeks. The incidence of CNS disease and associated morbidity and mortality would be much higher after a BW attack.

DIAGNOSIS

Clinical and epidemiological diagnosis. Physical findings nonspecific. The white blood cell count may show 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.

THERAPY

Treatment is supportive only. Treat uncomplicated VEE infections 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.

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 first vaccine. No post-exposure immunoprophylaxis. In experimental animals, alpha-interferon and the interferon-inducer poly-ICLC have proven highly effective as post-exposure prophylaxis. There are no human clinical data.

ISOLATION AND DECONTAMINATION

Patient isolation and quarantine is not required. Standard Precautions augmented with vector control while the patient is febrile. There is no evidence of direct human-to-human or horse-to-human transmission. The virus can be destroyed by heat (80oC for 30 min) and standard disinfectants.

OVERVIEW

  • The Venezuelan equine encephalitis (VEE) virus complex is a group of 8 mosquito-borne alphaviruses that are endemic in northern South America and Trinidad and causes rare cases of human encephalitis in Central America, Mexico, and Florida. These viruses can cause severe diseases in humans and Equidae (horses, mules, burros and donkeys). Natural infections are acquired by the bites of a wide variety of mosquitoes. Equidae serve as amplifying hosts and source of mosquito infection.

  • Western and Eastern Equine Encephalitis viruses are similar to the VEE complex, are often difficult to distinguish clinically, and share similar aspects of transmission and epidemiology. The human infective dose for VEE is considered to be 10-100 organisms, which is one of the principal reasons that VEE is considered a militarily effective BW agent. Neither the population density of infected mosquitoes nor the aerosol concentration of virus particles has to be great to allow significant transmission of VEE in a BW attack. There is no evidence of direct human-to-human or horse-to-human transmission. Natural aerosol transmission is not known to occur. VEE particles are not considered stable in the environment, and are thus not as persistent as the bacteria responsible for Q fever, tularemia or anthrax. Heat and standard disinfectants can easily kill the VEE virus complex.

HISTORY AND SIGNIFICANCE

  • Between 1969 and 1971, an epizootic of a "highly pathogenic strain" of VEE emerged in Guatemala, moved through Mexico, and entered Texas in June 1971. This strain was virulent in both equine species and humans. In Mexico, there were 8,000-10,000 equine deaths, "tens of thousands" of equine cases, and 17,000 human cases (no human deaths). Over 10,000 horses in Texas died. Once the Texas border was breached, a national emergency was declared and resources were mobilized to vaccinate equines in 20 states (95% of all horses and donkeys were vaccinated; over 3.2 million animals), establish equine quarantines, and control mosquito populations with broad-scale insecticide use in the Rio Grande Valley and along the Gulf Coast. A second VEE outbreak in 1995 in Venezuela and Columbia involved over 75,000 human cases and over 20 deaths.

  • VEE is better characterized than EEE or WEE, primarily because it was tested as a BW agent during the U.S. offensive program in the 1950's and 1960's. Other countries have also been or are suspected to have weaponized this agent. In compliance with President Nixon's National Security Decision No. 35 of November 1969 to destroy the BW microbial stockpile, all existing stocks of VEE in the U.S. were publicly destroyed.

  • These viruses could theoretically be produced in large amounts in either a wet or dried form by relatively unsophisticated and inexpensive systems. This form of the VEE virus complex could be intentionally disseminated as an aerosol and would be highly infectious. It could also be spread by the purposeful dissemination of infected mosquitoes, which can probably transmit the virus throughout their lives. The VEE complex is relatively stable during the storage and manipulation procedures necessary for weaponization.

  • In natural human epidemics, severe and often fatal encephalitis in Equidae (30-90% mortality) always precedes disease in humans. However, a biological warfare attack with virus intentionally disseminated as an aerosol would most likely cause human disease as a primary event or simultaneously with Equidae. 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. A biological warfare attack in a region populated by Equidae and appropriate mosquito vectors could initiate an epizootic/epidemic.

CLINICAL FEATURES

  • Susceptibility is high (90-100%), and nearly 100% of those infected develop overt illnesses. The overall case fatality rate for VEE is less than 1%, although it is somewhat higher in the very young or aged. Recovery from an infection results in excellent short-term and long-term immunity.

  • VEE is primarily an acute, incapacitating, febrile illness with encephalitis developing in only a small percentage of the infected population. Most VEE infections are mild (EEE and WEE are predominantly encephalitis infections). After an incubation period from 1-6 days, onset is usually sudden. The acute phase lasts 24-72 hours and is manifested by generalized malaise, chills, spiking high fevers (38oC-40.5oC), rigors, severe headache, photophobia, and myalgias in the legs and lumbosacral area. Nausea, vomiting, cough, sore throat, and diarrhea may follow. Physical signs include conjunctival injection, erythematous pharynx and muscle tenderness. Patients would be incapacitated by malaise and fatigue for 1-2 weeks before full recovery.

  • During natural epidemics, approximately 4% of infected children (less than 15 years old) and less than 1% of adults will develop signs of severe CNS infection (35% fatality for children and 10% for adults). Adults rarely develop neurologic complications during natural infections. Experimental aerosol challenges in animals suggest that the incidence of CNS disease and associated morbidity and mortality would be much higher after a BW attack, as the VEE virus would infect the olfactory nerve and spread directly to the CNS. Mild CNS findings would include lethargy, somnolence, or mild confusion, with or without nuchal rigidity. Seizures, ataxia, paralysis, or coma follow more severe CNS involvement. VEE infection during pregnancy may cause encephalitis in the fetus, placental damage, abortion, or severe congenital neuroanatomical anomalies.

DIAGNOSIS

  • Diagnosis of VEE is suspected on clinical and epidemiological grounds, but confirmed by virus isolation, serology and PCR. A variety of serological tests are applicable, including the IgM ELISA indirect FA, hemagglutination inhibition, complement-fixation, and IgG. For persons without prior known exposure to VEE complex viruses, a presumptive diagnosis may be made by identifying IgM antibody in a single serum sample taken 5-7 days after onset of illness. PCR procedures are available for confirmation, but are generally available only as a rear laboratory capability.

  • Samples suitable for performing diagnostic tests include blood culture (only in appropriate BSL-3 containment), acute and convalescent sera, and cerebrospinal fluid. Viremia during the acute phase of the illness (but not during encephalitis) is generally high enough to allow detection by antigen-capture enzyme-linked immunosorbent assay (ELISA). Virus isolation is time consuming, but can be performed from serum and throat swab specimens by inoculation of cell cultures or suckling mice (a Gold Standard identification assay for VEE). VEE should be isolated only in a BSL-3 laboratory.

  • The white blood cell count shows a striking leukopenia and lymphopenia. In cases with encephalitis, the cerebrospinal fluid pressure may be increased and contain up to 1,000 WBCs/mm3 (predominantly mononuclear cells) and a mildly elevated protein concentration.

  • An outbreak of VEE may be difficult to distinguish from influenza on clinical grounds. Clues to the diagnosis are the appearance of a small proportion of neurological cases, or disease in equine animals. However, these indicators may be absent in a BW attack. A BW aerosol attack could lead to an epidemic of febrile meningoencephalitis featuring seizures and coma. In a BW context, the differential diagnosis would include other causes of aseptic meningitis and meningoencephalitis.

MEDICAL MANAGEMENT

  • No specific viral therapy exists; hence treatment is supportive only. 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. Patient isolation and quarantine is not required; sufficient contagion control is provided by the implementation of Standard Precautions augmented with the need for vector control while the patient is febrile. Patient-to-patient transmission by means of respiratory droplet infection has not been proven. The virus can be destroyed by heat (80°C for 30 min) and standard disinfectants.

PROPHYLAXIS

  • Vaccine: There are two IND human unlicensed VEE vaccines. The first investigational vaccine (designated TC-83) was developed in the 1960's and is a live, attenuated cell-culture-propagated vaccine produced by the Salk Institute. This vaccine is not effective against all of the serotypes in the VEE complex. It has been used to protect several thousand persons against laboratory infections and is presently licensed for use in Equidae (and was used in the 1970-71 Texas epizootic in horses), but is an IND vaccine for humans. The vaccine is given as a single 0.5 mL subcutaneous dose. Fever, malaise, and headache occur in approximately 20 percent of vaccinees, and may be moderate to severe in 10 percent of those vaccinees to warrant bed rest for 1-2 days. Another 18 percent of vaccinees fail to develop detectable neutralizing antibodies, but it is unknown whether they are susceptible to clinical infection if challenged. Temporary contraindications for use include a concurrent viral infection or pregnancy.

  • A second investigational (IND) vaccine (designated C-84) has been tested but not licensed in humans and is prepared by formalin-inactivation of the TC-83 strain. This vaccine is not used for primary immunization, but is used to boost nonresponders to TC-83. Administer 0.5 mL subcutaneously at 2-4 week intervals for up to 3 inoculations or until an antibody response is measured. Periodic boosters are required. The C-84 vaccine alone does not protect rodents against experimental aerosol challenge. Therefore, C-83 is used only as a booster immunogen for the TC-84 vaccine.

  • 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 of the pathogen. Research is underway to produce a recombinant VEE vaccine.

  • Immunoprophylaxis: At present, there is no pre-exposure or post-exposure immunoprophylaxis available.

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

Most of this information is courtesy of US Government CDC. In times of an emergency much of this material may not apply when it comes to specialized care and testing. These are guidelines to help you when that care is not available. Some of this information is very technical and difficult to understand, but hopefully someone will be available for help in treatment and understanding.