equine encephalomyelitis (Eastern)

International Common Names

• English: arboviral encephalitis in horses; eastern equine encephalitis; eastern equine encephalitis virus-associated haemorrhagic enterocolitis; eastern equine encephalomyelitis; eastern equine encephalomyelitis, eee, in horses and cattle; eastern equine encephalomyelitis, eee, in pigs; epizootic equine encephalomyelitis; sleeping sickness; swine viral hepatitis

English acronym

• EEE

Eastern equine encephalitis is caused by a member of the genus Alphavirus of the family Togaviridae. The disease was first recorded in the USA, possibly as early as 1831 in Massachusetts, and was first isolated after the outbreaks in Delaware, Maryland, and Virginia in 1933 and 1934 (Hanson, 1957; Ten Broeck, 1938). Epidemics of eastern equine encephalitis are recorded at periodic intervals (Calisher, 1994). It is mainly restricted to North, Central and South America where the virus cycles between birds and ornithophilic mosquitoes. Eastern equine encephalitis was first recognized in horses on the eastern coast of the US (Giltner and Shahan, 1933; TenBroeck and Merrill, 1933; Elvinger and Baldwin, 1999). It has also been diagnosed and reported in cattle, dogs, goats, swine and a variety of wild mammalian species (Pursell et al., 1972, 1976, 1983; Bigler et al., 1976; McGee et al., 1992). Wild and domestic birds are susceptible to the virus (Scott and Weaver, 1989), although generally do not suffer disease, apart from pheasants and sparrows, which develop encephalitis and may die.

The alphavirus causes flu-like disease in horses and humans from mid-summer to late autumn when infection builds up in the bird populations to a level which results in spillover to other species of mosquito which feed on both birds and mammals on the margins of swampy areas. Many infections in horses and humans are inapparent, resulting in viraemia lasting up to a week, followed by long-lasting immunity (Thomson, 1994). During 1996-1997 there were 19 cases (5 fatal) of eastern equine encephalitis in humans in 8 states of the USA. Enzootic arboviral activity was reported in 18 states including 274 cases of arboviral encephalitis in horses and several cases of epizootics or sporadic clinical cases of haemorrhagic enterocolitis associated with eastern equine encephalitis virus (Anon, 1998).

Naturally occurring eastern equine encephalitis in swine was first reported in 1972 (Pursell et al., 1972) in southern Georgia when 160 of 200 pigs in a herd died in an outbreak. Exposure of domestic and feral swine to the agent had been described earlier in serological surveys in Georgia, Massachusetts and Wisconsin (Karstad and Hanson, 1958, 1959; Feemster et al., 1958; Elvinger and Baldwin, 1999). The virus has also been implicated as a primary cause of swine viral hepatitis (Marcato and Perillo, 2000).

This disease is on the list of diseases notifiable to the World Organisation for Animal Health (OIE).

No gross lesions are found post-mortem. Four of 9 unweaned pigs inoculated with the eastern equine encephalitis isolant in cell culture fluid or 10% brain suspension developed CNS signs similar to those seen in a naturally infected pig in southern Georgia, USA, in 1972. Brain lesions in the pigs were characterized by neutrophils in perivascular cuffs and in necrotic areas (Pursell et al., 1972). Histological features in an experimentally infected calf conformed with those described for eastern equine encephalitis in the horse. (Pursell et al., 1976.). Histological lesions in birds include inflammation and haemorrhage or necrosis of visceral organs, which differs from the central nervous system disease seen in mammals (Dein et al., 1986; Tully et al., 1992; Guy et al., 1994).

Alphavirus infections can range from inapparent to severe fatal disease. Infection typically occurs following the bite of an infected insect, with primary virus replication occurring locally and in adjacent lymph nodes. The primary viraemia, which persists for several days, serves to infect various target organs throughout the body; it is followed by secondary viraemia. The encephalitis virus may gain entry into the central nervous system if the viraemia is of sufficient level. The virus appears to enter the nervous tissue via exposed nerve endings or neuromuscular junctions, resulting in a necrotizing encephalitis in one to three weeks. Lesions often develop throughout the grey matter of the brain and include neuronal degeneration, vascular cuffing, infiltration of neutrophils and lymphocytes, microglial proliferation and haemorrhage. Macroscopic lesions in the central nervous system may be absent or consist of necrosis and haemorrhage. Microscopically, a necrotizing encephalitis is characterized by perivascular cuffing and infiltration of cells, gliosis, haemorrhage, neuronal necrosis and swollen endothelial cells. Additional necrotic lesion may be found in non-neural tissues, including lymphoid tissues (with myeloid depletion of bone marrow, spleen and nodes), pancreas, adrenal cortex, liver, myocardium and small blood vessels.

Upon infection an inflammatory response ensues within 4 to 5 days and antibody production begins. Production of interferon and activation of natural killer cells starts, possibly playing a role in limiting early virus replication and dissemination. Antibody development appears to be important in limiting virus replication and spread, as well as preventing re-infection. Antibodies develop to all viral proteins and exhibit activities such as neutralization, inhibition of haemagglutination and complement fixation. Peak antibody titres develop typically within 2 weeks. This antibody may be effective in neutralizing virus, enhancing virus clearance, lysing virus in the presence of complement or lysing infected cells via complement or killer cells. In addition to systemic production, there may also be local antibody production in the CNS. Cell-mediated immunity also appears to play a role in virus clearance and protective immunity. Cytotoxic T cells can be identified as early as 3 to 4 days post infection. While most studies are of an indirect nature (in vitro and T cell transfer in mice), cytotoxic T cells probably contribute to both recovery and protective immunity (Biberstein and Zee, 1990).

Eastern equine encephalitis has caused fatal disease in ratites including ostriches (Smith, 1993), with infection having a short incubation period (20 h to 25 h), acute haemorhagic enterocolitis and a viraemia of up to two days. Birds aged from twenty to thirty-six months and juveniles are affected principally, with a morbidity rate of up to 70% and mortality of up to 87% (OIE, 2001, Tully and Shane, 1996). Multifocal areas of coagulative necrosis (hepatitis) in the liver have also been described in emus with eastern equine encephalitis (Veazey et al., 1994).

In horses, infection may result in an inapparent or mild infection (febrile response and mild depression) with no obvious signs of disease. Virus invasion of the nervous system is associated with clinical disease. Horses experiencing CNS involvement often move about aimlessly and may walk into obstacles. Later there is severe depression associated with unusual stances. Varying degrees of muscular paralysis may be observed prior to death, which typically occurs 2-4 days after onset of clinical signs. Horses that recover may have permanent CNS damage.

Eastern equine encephalitis cases were studied in man between 1988 and 1994. 36 patients were studied with 57 CT scans and 23 MRI scans from 22 patients. Mortality rate was 36% and 35% of survivors were moderately or severely disabled. Among MRI scans, results were abnormal for all 8 comatose patients and for 3 non-comatose patients who subsequently became comatose. CT results were abnormal in 21 of 32 patients with readable scans. Abnormal findings included focal lesions in basal ganglia , thalami and brain stem. Cortical lesions, meningeal enhancement and periventricular white-matter changes were less common (Deresiewicz et al., 1997).

Culiseta melanura is the documented enzootic vector of eastern equine encephalitis virus. Other species have been ranked as epidemic vectors (most to least likely): Culex salinarius, Anopheles quadrimaculatus, Aedes canadensis, Coquillettidia perturbans, Aedes vexans, Anopheles punctipennis, in test of susceptibility to per os infection and potential salivary transmission for eastern equine encephalitis (Vaidyanathan et al., 1997). Eastern equine encephalitis virus isolated from Aedesalbopictus in Florida, USA, in 1991 did infect and was transmitted by females of Aedes albopictus and Aedes taeniorhynchus in the laboratory (Turell, 1993). Scott and Lorenz (1998) demonstrated that eastern equine encephalitis virus reduces survival and reproduction (fitness) of Culiseta melanura, which is required for transmission of eastern equine encephalitis virus in North America. Mosquito virulence was not measurably attenuated in virus isolates recovered 55 years apart. The virus did not affect the ability of mosquitoes to obtain a blood meal (from chickens) or the rate of mosquito oocyte development.

The mosquito is of major importance in the epidemiology of eastern equine encephalitis. The cycle of infection is between water birds and mosquitoes in freshwater swamps, the mosquitoes then transfer the virus to humans and horses but both are considered 'dead-end' hosts as they do not develop sufficient viraemia to infect mosquitoes. Pheasants and water birds, rodents and other small mammals, reptiles and amphibians may also carry and transmit the virus. Peak times of the disease are routinely recorded in late summer with an abrupt halt when mosquito numbers are reduced due to adverse conditions such as cold or drought. Outbreaks of disease attributable to eastern equine encephalitis virus were evaluated in horses in Michigan, USA. Data on eastern equine encephalitis virus vectors, wild bird reservoir hosts, and incidental hosts, including horses and man were obtained from census reports and medical records compiled between 1942 and 1991. Michigan had all the elements required to sustain eastern equine encephalitis virus on a state-wide basis. Regions of Michigan with specific patterns for water drainage, specific mosquito species and areas with higher amounts of precipitation were associated with outbreaks of disease attributable to the virus in horses. Evaluation of environmental patterns, weather conditions and vector and reservoir host distributions may be useful to identify areas in Michigan and elsewhere in which horses and humans are at increased risk for an outbreak of the disease (Ross and Kaneene, 1996).

The mosquito vector must ingest an infective blood meal. The alphaviruses are biologically transmitted so the vector must be actually infected. The vector must obtain a blood meal from a host that is sufficiently viraemic. The level of viraemia required to infect the vector is dictated primarily by virus strain, the feeding insect or both. Upon ingestion, the virus initiates infection in the gut with eventual distribution to the salivary gland, where replication provides a ready source of virus to infect additional hosts upon feeding. The time required for this process is the extrinsic incubation period. Once infected, the vector remains infected for life. On pheasant farms, transmission may also occur by birds pecking each other. The overwintering reservoir of eastern equine encephalitis is probably wild swamp birds, though other mammalian and reptilian hosts may also play a role since virus has been isolated during winter months from cats, dogs, mice, foxes and skunks. (Biberstein and Zee, 1990).

Thirty six isolates of eastern equine encephalitis virus were obtained from 8 species of mosquitoes collected from 5 September to 18 October during an epizootic in southeastern Connecticut, USA. These included Culiseta melanura (19 isolates), Culex pipiens (8), Culiseta morsitans (3), Aedes sollicitans (2), Aedes cantator (1), Aedes trivittatus (1), Aedes vexans (1) and Coquillettidia perturbans (1). Isolations from Aedes cantator and Aedes trivittans were new to North American records, and those from Aedes cantator and Aedes solicitans represented the first infections of human-biting, salt-march mosquitoes with eastern equine encephalitis virus in Connecticut. With one exception, eastern equine encephalitis-infected Culiseta melanura were found at all sites where eastern equine encephalitis virus was isolated. Large numbers of eastern equine encephalitis isolates from Culiseta melanura and the collection of infected mosquitoes in residential woodlots and coastal salt marshes away from traditional red maple or white cedar swamp habitats, reaffirmed the importance of local populations of this mosquito for viral amplification and dispersal from swamp foci. No human or horses cases of eastern equine encephalitis were reported although this represented the largest number of isolations for eastern equine encephalitis ever recovered from field-collected mosquitoes in Connecticut (Andreadis et al., 1998).

In the laboratory Aedes sollicitans was more susceptible to infection with eastern equine encephalitis and viral dissemination than Aedes taeniorhynchus when fed on a chick with a viraemia of 107 +/- 0.1 pfu/ml. Infection rates in adults were not affected by rearing in salt concentrations ranging from fresh water to brackish water containing 2.4% sea salts. When fed on the same viraemic 6-day-old chicken, all 48 Aedes albopictus, reared in fresh water, became infected (Turell, 1998).

Geographic information system technology and remote sensing have identified wetlands as the most important element, accounting for up to 72.5% of the observed variation in the host-seeking populations of Aedes canadensis, Aedes vexans and Culiseta melanura when examining landscape features determining the risk of eastern equine encephalitis transmission in Massachusetts, USA. Stepwise linear regression demonstrated deciduous wetlands to be the specific wetland category contributing to the major class models (Moncayo et al., 2000). Population data in southeastern Massachusetts between 1982-90, showed Coquillettidiea pertubans, Aedes canadensis and Culex salinarius are more likely vectors of eastern equine encephalitis in Massachusetts than Aedes vexans, Anopheles punctipennis and Anopheles quadrimaculatus (Moncayo and Edman, 1999).

Tengelsen et al. (2001) studied immune responses to vaccination and challenge against eastern equine encephalitis in emus. An unvaccinated pen-mate became infected in the absence of mosquito vectors, presumably as a result of direct virus transmission between birds. Unvaccinated challenged birds developed viraemia (> 10 9 pfu/ml blood) and shed virus in faeces, oral secretions and regurgitated material.

Japanese quail (Coturnix coturnix) would facilitate sentinel-based eastern equine encephalitis surveillance programmes because of their small size and low cost, susceptibility to eastern equine encephalitis infection without mortality, and detectability of both virus and virus-neutralizing antibodies (Komar and Spielman, 1995).

Guy et al. (1995), inoculated tom turkeys with eastern equine encephalitis virus and examined their semen for the presence of the virus and its ability to transmit infection by artificial insemination. Mild depression and inappetance were observed. Toms were viraemic on days 1-2 days after inoculation and virus was shed in semen on days 1-5. Semen collected from eastern equine encephalitis-virus inoculated toms on days 1-2 was inseminated into turkey breeder hens. Eastern equine encephalitis virus was detected in one of the 10 hens after insemination. It was therefore concluded that semen is a potential vehicle for transmission of eastern equine encephalitis virus (Guy et al., 1995.)

A role is suggested for glossy ibis (Plegadis falcinellus) in the epidemiology of eastern equine encephalitis in New Jersey, USA, based upon blood infection rates (22.3%, n=130). They can come into contact with the vector species Culiseta melanura and Aedes sollicitans. The snowy egret (Egretta thula) was also found to be infected sometimes (1.8%, n=163) (Crans et al., 1991).

The costs of eastern equine encephalitis virus infection are known to be substantial, but are infrequently recorded. The costs in man were calculated for a series of residents in eastern Massachusetts, USA. The majority of the expense was hospital costs. In the early years the costs were US $0.4 million, with a projected total cost of US $3 million in a residual case, including lost personal income (Villari et al., 1994). Costs of insecticide applications can cost as much as US $1.4 million depending on the size of area treated (Center for Disease Control, 2001).

Eastern equine encephalitis is a zoonotic disease, but a vaccine is available for humans. In a vaccination study in emus (Tengelsen et al., 2001), infected emus shed eastern equine encephalitis virus in secretions and excretions, making them a direct hazard to pen-mates and attending humans. Reasonable precautions should therefore be taken when handling livestock in areas of potential outbreaks of the disease.

There is no treatment for eastern equine encephalitis virus, but the symptoms in horses can be treated supportively. Non-steroidal anti-inflammatory drugs may control pyrexia, inflammation and discomfort, for example, phenylbutazone, flunixin meglumine. Dimethyl sulfoxide can be useful in reducing inflammation and providing some analgesia and mild sedation. Convulsions may be controlled with pentobarbital, diazepam phenobarbital or phytoin. Secondary bacterial infections require appropriate antibiotics. Fluid solution, orally or intravenously, should be employed for fluid balance. Laxatives minimize the risk of gastrointestinal impaction, and oral or parenteral supplementation should be undertaken if anorexia persist for more than 48 hours. All animals should be provided with extra bedding, and protective leg wraps and head protection may be used to reduce self-induced trauma.