Continuing Education Activity

Venezuelan equine encephalitis (VEE) is a mosquito-borne disease endemic in regions of Central and South America that causes sporadic outbreaks of equine and human encephalitis. This activity outlines the pathophysiology, evaluation, and treatment of Venezuelan equine encephalitis and reviews the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of Venezuelan equine encephalitis.
• Review the evaluation of a patient with Venezuelan equine encephalitis.
• Describe the common complications of Venezuelan equine encephalitis.

Introduction

Venezuelan Equine Encephalitis Virus (VEEV) is the causative viral pathogen of Venezuelan Equine Encephalitis (VEE). Outbreaks frequently involve both equines – including horses, donkeys, mules, zebras – and humans.[1][2] Outbreaks may range over a large geographic area and may last for several months to years.[1] Sporadic epidemic outbreaks occur most commonly in Central and South America. VEEV exists as both a natural pathogen and a laboratory-developed biologic weapon.[1] Outbreaks have been reported in several South and Central American countries, including Venezuela, Colombia, Peru, Ecuador, Costa Rica, Nicaragua, Honduras, El Salvador, Guatemala, Panama, Mexico, and the United States.[3] Previous outbreaks of epizootic strains have affected up to 75,000 people during a single epidemic.

Etiology

VEEV is a single-stranded positive-sense RNA alphavirus in the Togaviridae family.[1][2] Alphaviruses are mosquito-borne pathogens; transmission between species and between individual humans occurs via mosquitos. Thus VEEV is also classified as an arbovirus.[2] Arboviruses replicate in arthropod vectors before transfer to vertebrates.[4] New World alphaviruses – including VEEV, Eastern Equine Encephalitis Virus (EEEV), and Western Equine Encephalitis Virus (WEEV) – are found in the Americas and can cause severe encephalomyelitis. Old World alphaviruses – including chikungunya virus – are found in Europe, Asia, and Africa and typically cause fever and polyarthritis. VEEV was discovered in 1935 after equine outbreaks in Venezuela, Columbia, and Trinidad.[2] It was not isolated from humans until 1950 during an outbreak in Colombia.[3]

There are six subtypes (I-VI) and many antigenic variants within each subtype. The epizootic strains IAB and IC are responsible for causing encephalitis in equines and humans. These subtypes of VEE are highly pathogenic and can spread quickly through equine populations. Horses are the key reservoir species and amplification hosts for epizootic viral strains.[5]

The enzootic strains (ID, IE, subtypes II-VI) are usually avirulent in horses and produce mild or no equine illness. However, these strains may still cause significant disease in humans. Enzootic strains are typically found circulating in rodents. Spillover from these enzootic transmission cycles between rodents and mosquitos may lead to human epidemics. There appears to be no clinical difference in disease caused by epizootic and enzootic strains of VEEV in humans.[3]

Epidemiology

Epizootic subtypes IAB and IC can cause significant disease in both humans and equines.[1] VEE can occur in all age groups, and there is usually no sex bias during outbreaks. However, infected children are more likely than adults to develop lasting neurological sequelae and fatal encephalitis. Pregnant women infected with VEEV are at risk for congenital disabilities, spontaneous abortions, preterm deliveries, and stillbirths.[1][6]

Pathophysiology

Several species of mosquitos are capable of transmitting both the enzootic and epizootic strains of VEEV.[3] Ochlerotatus taeniorhynchus appears to be the primary mosquito vector during epizootics, while Culex species transmit enzootic strains.[7] Mosquitos feed on infected rodents or equines, infecting the mosquito midgut. Following initial infection, the virus matures and disseminates to secondary organs, including the salivary glands. Virus accumulates in the salivary glands, and blood-feeding releases virions through the mosquito salivary ducts into the new host. The virus then gains entry to a host cell and replicates in the cellular cytoplasm.[2] Infected equines are viral amplification hosts for epizootic strains, while sylvatic rodents are the primary reservoir hosts for enzootic strains.[1] Infected equines and humans develop high viremia loads that can, in turn, be a source of further mosquito infections. Infected horses shed the virus in body fluids, and humans can then become infected by direct contact or aerosolized fluids. 

VEEV can cause a spectrum of disease from mild febrile flu-like illness to severe or fatal encephalitis.[4][5][7] The incubation period for human VEEV infection is typically 2 to 5 days.[1] Between 4 to 14% of infected individuals will develop neurologic disease.[2][7]

Histopathology

Examination of the spleen, GI tract, and lymph nodes of infected equines, rodents, and humans shows a significant depletion of lymphocytes.[1] VEEV replicates in lymphoid tissue and causes an inflammatory cell response and cellular necrosis.[8] Additional pathological findings include interstitial pneumonia and alveolar hemorrhage in the lungs and hepatocellular degeneration in the liver in fatal human cases.[7][8] As the virus clears, tissues recover.[8]

History and Physical

Clinical signs of VEEV infection include leukopenia, tachycardia, and fever. Patients may develop interstitial pneumonia. The physical exam may reveal conjunctival injection, pharyngeal inflammation, and muscle tenderness. The patient may complain of myalgias most typically in the thighs or lumbar back, occipital or retro-orbital headache, fever, and chills.[1] This flu-like prodrome may progress to encephalitis in up to 14% of patients. Children are more likely to develop encephalitis and have a higher rate of morbidity and mortality from fulminant disease than do adults.[4] Symptoms of more severe disease include tremors, seizures, behavioral changes, hemiparesis, hemichorea, cranial nerve palsies, ataxia, myoclonus, confusion, somnolence, and coma.[1][8] Generalized congestion, edema, hemorrhage, and vasculitis in the brain, GI tract, and lungs are seen in lethal cases, which comprise less than 1% of human infections.[1][7] Signs and symptoms of VEE may overlap with other circulating arbovirus infections.

Evaluation

Many cases of Venezuelan equine encephalitis are diagnosed clinically, and cases are probably frequently misdiagnosed as other more common febrile illnesses.[3] Laboratory confirmatory tests do exist. VEEV may be diagnosed by virus isolation or detection in serum or CSF or by serological analysis.[3][7] A VEEV-specific blocking ELISA has been used to identify the serotype of VEEV in serum.[7] These diagnostic tests are cost-prohibitive, especially in resource-poor countries.[3]

Laboratory testing may reveal leukopenia, lymphopenia, and elevated transaminases.[8] A lumbar puncture to obtain CSF for analysis may be necessary. CSF may demonstrate a lymphocytic pleocytosis and elevated protein.

Treatment / Management

Currently, no specific treatment exists for any of the encephalitic arboviruses, including Venezuelan equine encephalitis. Treatment is supportive or palliative.[7] Most infections are self-limiting, though neurological sequelae may persist.[1]

Vaccine development for VEEV is ongoing. Though there is currently no FDA-approved human vaccine, TC-83 is a live-attenuated vaccine strain that has been used in both humans and equines.[7] The vaccine is not widely available and is typically reserved for laboratory and military personnel at high risk of exposure. Up to 40% of individuals may develop flu-like symptoms following vaccination. Approximately 80% of vaccinated individuals will seroconvert. There is also a risk that the vaccine strain may revert to a wildtype virulent strain and potentially cause outbreaks of disease.[2] Formalin-inactivated TC-83 has also been used in equines and humans who do not seroconvert with the live-attenuated vaccine. However, boosters are necessary to maintain immunity.[3] Post-infection, immunity to a specific serotype appears to be lifelong; however, cross-immunity between serotypes may be poor.

Differential Diagnosis

Several arboviruses circulate in overlapping regions throughout Central and South America. VEE clinically presents like other tropical arboviral diseases and may be indistinguishable without expensive confirmatory testing.[3] The differential diagnosis for VEE is extensive. A thorough travel history should be obtained in patients presenting with febrile illness in endemic regions. The clinician should elicit any exposure to ill equids. Careful history-taking and physical examination may aid in differentiating VEEV from other arbovirus infections, but laboratory diagnosis remains most specific.

• Bacterial meningitis
• Chikungunya
• Dengue
• Eastern equine encephalitis
• HSV encephalitis
• Lyme disease
• Malaria
• Rocky mountain spotted fever
• Western equine encephalitis
• Yellow fever
• Zika

Prognosis

Equine mortality is significant and is estimated to be 19-83% during epizootic outbreaks. Fatality rates are much lower in humans, and less than 1% of cases are lethal. Adults are more likely to develop febrile flu-like illness. Children are at greater risk for developing neurological disease or encephalitis.[7] Symptoms of CNS disease may include ataxia, depression, altered mentation, coma, and seizures.[2] Children are also more likely to suffer from neurological sequelae following recovery from disease.[9]

Complications

Neurological sequelae may persist following recovery from initial infection with VEEV. Though there is no specific therapy for VEEV, modern medical technology has improved supportive treatments, and many patients will survive even encephalitic disease.[9] Patients may then develop permanent neurological sequelae. These can include seizures, confusion, intellectual disabilities, and behavioral changes. The spectrum of VEEV-induced sequalae ranges from mild and manageable to life-altering. These post-infectious sequelae can develop irrespective of the severity of the preceding febrile illness.[9]

Pregnant women may be at distinct risk of complications from arbovirus infections. VEEV was classified as the first teratogenic arbovirus. Pregnant women are at risk for congenital disabilities, miscarriage, preterm delivery, and stillbirth. Vertical transmission from mother to fetus has been documented. Ten fetal autopsies performed during an outbreak demonstrated VEEV in the brains of aborted fetuses.[3][6] Infants born to mothers with Venezuelan Equine Encephalitis may have neurological sequelae or fatal cerebral lesions. Worldwide, infectious diseases remain one of the most common causes of maternal mortality, and it is estimated that up to 90% of pregnancies occur in regions where arboviruses are endemic or epidemic.[6]

Deterrence and Patient Education

As there is no specific treatment for Venezuelan equine encephalitis, avoiding infection is the best prevention. Outbreaks may be controlled by reducing mosquito populations, as arthropods serve as the primary vector of infection. Humans, especially those who have frequent contact with equines, should limit physical exposure to mosquitos, wear protective clothing, and use frequent applications of repellants. Aerosolized insecticide applications in endemic areas will also contribute to a reduction in mosquito populations.[3]

Epizootic outbreaks may also be prevented through mass vaccination of horses with the TC-83 live-attenuated vaccine.[1] TC-83 is licensed and available for equines in endemic regions.[4] Sustained vaccine programs between outbreaks may be necessary to develop herd immunity in equines to limit spillover into humans.[3]

Pearls and Other Issues

Global warming may facilitate the emergence of VEEV epidemics. Climate change can lead to longer transmission seasons, changes in rainy seasons, which increase mosquito populations, and increased geographic distributions of tropical mosquito vectors.[3][10]

Enzootic VEEV exists continuously in tropical regions, and there is a risk of emergence of epizootic strains leading to equine and human outbreaks. In endemic regions, surveillance programs for early detection and implementation of mosquito control and equine vaccination will help control outbreaks.

VEEV was developed as a biological weapon by the United States and the former Soviet Union during the Cold War. It is classified as a biosafety level 3 by the Centers for Disease Control and as a category B priority pathogen by the National Institute of Allergies and Infectious Diseases.[2] Laboratory accidents have been reported, with infections occurring from small-volume aerosolized samples.

Enhancing Healthcare Team Outcomes

The diagnosis and treatment of Venezuelan equine encephalitis require a multidisciplinary approach. Healthcare providers in endemic areas must maintain a high degree of suspicion for the diagnosis. Patients will require supportive care for any degree of disease they develop, from mild illness to fulminant encephalitis. Following recovery, some patients will suffer from neurological sequelae and will require continued support from healthcare providers and the community. [Level 5]