EEEV was first isolated in 1933 from the brain of a horse that died of encephalitis.[5]Calisher CH. Medically important arboviruses of the United States and Canada. Clin Microbiol Rev. 1994 Jan;7(1):89-116.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC358307/?page=15
http://www.ncbi.nlm.nih.gov/pubmed/8118792?tool=bestpractice.com
The virus has subsequently been isolated from humans, wild birds, small mammals, and mosquitoes across much of eastern and midwestern North America. Isolates have also been obtained from the Caribbean and Central and South America, but these variants were observed many years ago and were rarely, if ever, implicated in human disease. Furthermore, they were noted to be antigenically distinct from North American EEEV isolates.[6]Casals J. Antigenic variants of eastern equine encephalitis virus. J Exp Med. 1964 Apr 1;119:547-65.
http://jem.rupress.org/content/119/4/547.long
http://www.ncbi.nlm.nih.gov/pubmed/14151098?tool=bestpractice.com
In North America, a human EEEV outbreak was first noted in 1938 in Massachusetts, resulting in 34 hospitalisations and nearly as many deaths.[7]Komar N, Spielman A. Emergence of eastern encephalitis in Massachusetts. Ann N Y Acad Sci. 1994 Dec 15;740:157-68.
http://www.ncbi.nlm.nih.gov/pubmed/7840447?tool=bestpractice.com
Twenty years later, an outbreak of EEEV in New Jersey resulted in 32 cases of encephalitis, including 22 deaths.[7]Komar N, Spielman A. Emergence of eastern encephalitis in Massachusetts. Ann N Y Acad Sci. 1994 Dec 15;740:157-68.
http://www.ncbi.nlm.nih.gov/pubmed/7840447?tool=bestpractice.com
During that outbreak, it was estimated that 11 children or 40 adults had asymptomatic or mild infection for every encephalitis case.[8]Goldfield M, Sussman O. The 1959 outbreak of Eastern encephalitis in New Jersey. I. Introduction and description of outbreak. Am J Epidemiol. 1968 Jan;87(1):1-10.
http://www.ncbi.nlm.nih.gov/pubmed/5637871?tool=bestpractice.com
Since then, sporadic human cases have been noted in these and other eastern states of North America, with an average of 7 human eastern equine encephalitis (EEE) cases reported per year in the US.[9]Centers for Disease Control and Prevention. Eastern equine encephalitis: statistics and maps. June 2020 [internet publication].
https://www.cdc.gov/easternequineencephalitis/tech/epi.html
Between 2010 and 2018, a total of 69 human cases were reported to the US national arboviral surveillance system, ArboNET. An additional 38 cases of EEEV are reported in provisional data from 2019, 19 of which were fatal.[9]Centers for Disease Control and Prevention. Eastern equine encephalitis: statistics and maps. June 2020 [internet publication].
https://www.cdc.gov/easternequineencephalitis/tech/epi.html
In 2019, in the state of Massachusetts, the first human infections with EEEV have been reported since 2013; between January to August, four cases of EEEV were confirmed, including one fatality, prompting warnings from medical officials about particularly intense levels of EEEV activity.[10]Martin E. Eastern equine encephalitis in the Northeast. Aug 2019 [internet publication].
https://www.outbreakobservatory.org/outbreakthursday-1/8/29/2019/eastern-equine-encephalitis-in-the-northeast
The average annual incidence is reported to be 0.04 cases per million children and 0.03 cases per million adults.[11]Gaensbauer JT, Lindsey NP, Messacar K, et al. Neuroinvasive arboviral disease in the United States: 2003 to 2012. Pediatrics. 2014 Sep;134(3):e642-50.
http://pediatrics.aappublications.org/content/134/3/e642.long
http://www.ncbi.nlm.nih.gov/pubmed/25113294?tool=bestpractice.com
US states with the highest incidence rates include Florida, Massachusetts, New York, North Carolina, and Michigan.[9]Centers for Disease Control and Prevention. Eastern equine encephalitis: statistics and maps. June 2020 [internet publication].
https://www.cdc.gov/easternequineencephalitis/tech/epi.html
In North America, EEEV transmission occurs mainly in and around wooded wetlands in the Atlantic and Gulf Coast states and the Great Lakes region, which is where the enzootic transmission cycle between passerine birds (the natural reservoir for EEEV) and the ornithophilic mosquito Culiseta melanura (the enzootic vector for EEEV) is maintained.
During epizootics, the virus is amplified in a broader range of avian hosts by ‘bridge’ vectors such as the mosquito species Coquillettidia perturbans, Aedes vexans, Aedes sollicitans, Aedes albopictus, and Culex erraticus.[12]Mitchell CJ, Niebylski ML, Smith GC, et al. Isolation of eastern equine encephalitis virus from Aedes albopictus in Florida. Science. 1992 Jul 24;257(5069):526-7.
http://www.ncbi.nlm.nih.gov/pubmed/1321985?tool=bestpractice.com
[13]Cupp EW, Klingler K, Hassan HK, et al. Transmission of eastern equine encephalomyelitis virus in central Alabama. Am J Trop Med Hyg. 2003 Apr;68(4):495-500.
http://www.ajtmh.org/content/68/4/495.long
http://www.ncbi.nlm.nih.gov/pubmed/12875303?tool=bestpractice.com
[14]Crans WJ, McNelly J, Schulze TL, et al. Isolation of eastern equine encephalitis virus from Aedes sollicitans during an epizootic in southern New Jersey. J Am Mosq Control Assoc. 1986 Mar;2(1):68-72.
http://www.ncbi.nlm.nih.gov/pubmed/2853203?tool=bestpractice.com
These species are more likely than the enzootic vector, C melanura, to bite mammals and cause equine and human disease. Most human infections occur between late spring and early autumn when the mosquito population is at its highest.[15]Centers for Disease Control and Prevention. Eastern equine encephalitis. Nov 2019 [internet publication].
https://www.cdc.gov/easternequineencephalitis/index.html
South American EEEV (now known as Madariaga virus [MADV]) is genetically distinct and more heterogeneous than its North American counterpart.[3]Arrigo NC, Adams AP, Weaver SC. Evolutionary patterns of eastern equine encephalitis virus in North versus South America suggest ecological differences and taxonomic revision. J Virol. 2010 Jan;84(2):1014-25.
http://jvi.asm.org/content/84/2/1014.long
http://www.ncbi.nlm.nih.gov/pubmed/19889755?tool=bestpractice.com
Prior to 2010, only three human cases had been reported. In 2010, an outbreak of MADV and Venezuelan equine encephalitis virus (an alphavirus that is endemic in Central and South America) occurred in the eastern province of Darién, Panama.[16]Carrera JP, Forrester N, Wang E, et al. Eastern equine encephalitis in Latin America. N Engl J Med. 2013 Aug 22;369(8):732-44.
http://www.nejm.org/doi/full/10.1056/NEJMoa1212628#t=article
http://www.ncbi.nlm.nih.gov/pubmed/23964935?tool=bestpractice.com
There were 14 confirmed human cases of MADV infection, 8 of whom were hospitalised. All of the hospitalised patients were children, and most suffered seizures and other neurological complications. Subsequently, a serosurvey in the region demonstrated that 16% of the population had evidence of prior MADV infection.[17]Vittor AY, Armien B, Gonzalez P, et al. Epidemiology of emergent Madariaga encephalitis in a region with endemic Venezuelan equine encephalitis: initial host studies and human cross-sectional study in Darien, Panama. PLoS Negl Trop Dis. 2016 Apr 21;10(4):e0004554.
http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004554
http://www.ncbi.nlm.nih.gov/pubmed/27101567?tool=bestpractice.com
Seroprevalence was not age-dependent, indicating that the disease had emerged in recent years. A key risk factor was exposure to farm or pasture land.[17]Vittor AY, Armien B, Gonzalez P, et al. Epidemiology of emergent Madariaga encephalitis in a region with endemic Venezuelan equine encephalitis: initial host studies and human cross-sectional study in Darien, Panama. PLoS Negl Trop Dis. 2016 Apr 21;10(4):e0004554.
http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004554
http://www.ncbi.nlm.nih.gov/pubmed/27101567?tool=bestpractice.com
MADV has been isolated from various Culex (Melanoconion) species, and it is thought that these are its main vector.[18]Turell MJ, O’Guinn ML, Dohm D, et al. Susceptibility of Peruvian mosquitoes to eastern equine encephalitis virus. J Med Entomol. 2008 Jul;45(4):720-5.
http://jme.oxfordjournals.org/content/45/4/720.long
http://www.ncbi.nlm.nih.gov/pubmed/18714873?tool=bestpractice.com
Evidence of MADV infection has been found in a wide range of vertebrates, including birds, bats, turtles, and rodents.[19]Monath TP, Sabattini MS, Pauli R, et al. Arbovirus investigations in Argentina, 1977-1980. IV. Serologic surveys and sentinel equine program. Am J Trop Med Hyg. 1985 Sep;34(5):966-75.
http://www.ncbi.nlm.nih.gov/pubmed/2863991?tool=bestpractice.com
In Panama, the highest rates of infection were seen in the Bolivar rice rat and short-tailed cane rat, pointing to these species as possible enzootic hosts.[17]Vittor AY, Armien B, Gonzalez P, et al. Epidemiology of emergent Madariaga encephalitis in a region with endemic Venezuelan equine encephalitis: initial host studies and human cross-sectional study in Darien, Panama. PLoS Negl Trop Dis. 2016 Apr 21;10(4):e0004554.
http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004554
http://www.ncbi.nlm.nih.gov/pubmed/27101567?tool=bestpractice.com