Eastern equine encephalitis (EEE), also called triple E and sleeping sickness, is a viral disease caused mainly by the Eastern equine encephalitis virus (EEEV). Most infections in humans are asymptomatic, but about 5% of the time the infection progresses to severe neuroinvasive disease. Symptoms typically appear 3–10 days after being bitten by an infected mosquito and initially include fever, headache, nausea, vomiting, fatigue, muscle pain, and joint pain. Neurological symptoms usually appear a few days later and include altered mental state, encephalitis, photophobia, seizures, paralysis, and loss of consciousness and coma. The case fatality rate is 30–75% depending on age, with disease severity greatest in young children and the elderly. About 50 to 90% of survivors experience long-term neurological complications that range from minor to severe. EEE is most common in horses, in which the disease carries a 70–90% case fatality rate and permanent brain damage for survivors.
Most human cases are caused by EEEV. Traditionally, four lineages of EEEV were recognized: I, II, III, and IV. Lineage I corresponds to EEEV and the other lineages are classified as a different virus: Madariaga virus (MADV). EEEV is found in North America, the Caribbean, and Central America, and MADV is found in Central America and South America. While both EEEV and MADV cause disease in horses, it is very rare for MADV to cause disease in humans. EEEV and MADV are single-stranded, positive-sense RNA viruses of the genus Alphavirus in the family Togaviridae. Alphaviruses are sorted into Old World alphaviruses and New World alphaviruses, and considered arthritogenic (affecting the joints) or encephalitic (affecting the brain). EEEV and MADV are New World encephalitic alphaviruses. Among encephalitic alphaviruses, EEEV causes the most severe disease in humans.
EEEV is maintained in nature in an enzootic cycle between natural reservoirs of the virus and mosquitos that feed on the blood of those animals. In North America, passerine birds are the main reservoirs of the virus, and Culiseta melanura is the main enzootic vector. In South America, rodents and marsupials may be reservoirs of MADV, and Culex mosquitos of the subgenus Melanoconion are likely the main enzootic vectors. The disease is occasionally transmitted to mammals and other non-reservoir species by other species of mosquitos, called bridge vectors. These mosquitos feed on the blood of both avian and mammalian hosts and include Coquillettidia perturbans and various species of the Aedes, Anopheles, and Culex genera. Humans, horses, and other incidental carriers of EEEV are considered dead-end hosts because they cannot transmit the virus back to mosquitos.
EEE is usually diagnosed by using enzyme-linked immunosorbent assay (ELISA) to test for anti-EEEV antibodies in serum or cerebrospinal fluid. The results of ELISA are then verified with plaque reduction neutralization tests. Other methods such as viral cultures and nucleic acid amplification assays may be used post-mortem. Neuroimaging and electroencephalogram (EEG) tests are useful for identify the severity of disease. There are no specific antiviral drugs used to treat EEE, so treatment is supportive in nature and includes corticosteroids, anti-convulsant drugs, intravenous fluids, tracheal intubation, and fever-reducing drugs. Physical therapy, occupational therapy, and speech therapy are often needed during the recovery process. Prevention methods include insecticides, larvicides, and eliminating mosquito breeding sites. A vaccine that protects against EEEV, but not MADV, is available for horses.
EEE was first recorded during an outbreak in horses in Massachusetts, USA in 1831. EEEV was first isolated from horse brains and linked to EEE during another outbreak in 1933. The first documented human cases were in 1938 in Massachusetts, and isolation from mosquitos first came in 1949 from Cq. perturbans and then in 1951 from Cs. melanura. The disease occurs along the eastern side of the Americas, mainly in the USA in states bordering the Atlantic Ocean, Gulf of Mexico, and Great Lakes. Fewer than ten human cases occur in a typical year, usually in close proximity to hardwood freshwater swamps and marshes where Cs. melanura and other vectors lives. Periodic outbreaks occur in years following years with heavy rainfall, likely due to creating a favorable environment for Cs. melanura. Outbreaks in horses usually precede those in humans, so an increase in cases in horses may be predictive of an upcoming human outbreak.
Signs and symptoms
In most cases, infection with Eastern equine encephalitis virus (EEEV) is self-limiting with no symptoms. In about 5% of cases, though, the virus invades the central nervous system, where it causes Eastern equine encephalitis (EEE), also called triple E or sleeping sickness. This disease is severe and carries with it a high likelihood of death or long-term neurological complications for survivors. Neuroinvasive disease is most likely to occur for people under the age of 15 and over the age of 50. but may appear up to three weeks later. Usually within a few days, central nervous system involvement becomes apparent due to the emergence of neurological symptoms such as alterations in mental state, heightened irritability and agitation, personality changes, confusion, encephalitis, convulsions, seizures, paralysis, and loss of consciousness and coma. A stiff neck is indicative of infection in the meninges and meningitis.
EEE is caused primarily by Eastern equine encephalitis virus (EEEV) and secondarily by Madariaga virus (MADV). EEEV and MADV belong to the genus Alphavirus in the family Togaviridae. which is the most severe alphavirus to affect humans. The non-structural proteins are nsP1, nsP2, nsP3, and nsP4. The structural proteins are the capsid protein (CP), E3, E2, 6K/TF, and E1.
The functions of each protein are described hereafter. and Central America and is responsible for most human cases. The other types are found in Central America and South America, where they mainly cause disease in horses. Lineage I is Eastern equine encephalitis virus, while lineages II–IV are classified as a different species, Madariaga virus. These birds are the natural reservoirs of the virus and serve as amplification hosts since the virus multiplies easily in their bodies, and marshlands, environments favorable for growth of mosquito larvae. Most transmission of EEEV occurs in these environments. While it is not known whether green herons are infected or develop viremia, there is some evidence that certain migratory ardeids are susceptible to EEEV in the southern United States.
EEEV can infect osteoblasts, dendritic cells, fibroblasts, skin proximal keratinocytes, ventricular interstitial cells, and ovarian stromal cells. Other receptors that EEEV binds to include the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). the United States, and Mexico. Cases have also been identified in Jamaica, but permanent enzootic circulation has not been verified there or in the Dominican Republic.