Eastern Equine Encephalitis

Although designated as an “eastern” virus, EEE has a wide geographic distribution. It is found as far north as eastern Canada, is dispersed throughout the Caribbean, and has been identified in Central and South America. Infection in the United States (U.S.) is primarily seen in the southeastern states but has been detected in all states east of the Mississippi River and also in a number of western states. In recent years, intense focal activity has been reported in Wisconsin, Ohio, Massachusetts, and New Hampshire.^48,49

In the U.S., most cases of EEE in horses occur in the northern parts of Florida and the Carolinas. In total, several hundred equine cases are confirmed each year, despite the widespread availability of vaccines. In Florida, many horses that succumb to EEE are not vaccinated, are less than 3 years of age, and are stock-type horses (Long, unpublished data). There is no gender predilection. The occurrence of human disease is sporadic, with approximately 10 fatal human cases per year reported for the entire U.S.

In North America, EEE virus is perpetuated in a sylvatic cycle between avian hosts (passerine birds) and mosquitoes, primarily the ornithophilic mosquito, Culiseta melanura.^50–52 Indigenous passerine birds do not develop disease but develop sufficient titer viremia to allow transmission to feeding mosquitoes.⁵³ Cs. melanura is not a mammalian feeder and is not responsible for transmission between birds and mammalian hosts. However, several species of secondary or epidemic mosquitoes that feed on both birds and mammals can act as biologic vectors. These likely transmit EEE to horses, humans, and other vertebrate species. Horses and humans are clinically affected but do not develop viremia sufficiently high enough to transmit virus back to vector mosquitoes and are considered “dead-end” hosts.

Disease caused by EEE was first identified in Connecticut in 1937 in the then recently introduced exotic ring-necked pheasant. Since that time, disease in sparrows, pigeons, Pekin ducks, and Chukar partridges (all old-world species) has been reported.⁵⁴ In 1991, EEE was the cause of fatal hemorrhagic colitis in commercial flocks of emus in Louisiana. Similar outbreaks have been reported in emus and ostriches in Georgia, Florida, and other states.^55,56 Outbreaks of EEE have been recorded in intensive swine herds in southern Georgia.⁵⁷ Isolated cases of EEE in cattle, sheep, and nondomestic ungulates have also been recorded.^58–60

The mechanism by which EEE virus overwinters (diapause) remains uncertain.^61,62 Transovarial transmission of EEE virus is not important, although it does occur in the mosquito host. In tropical and subtropical climates, the year-round mosquito/avian cycle likely obviates the need for a period of diapause in mosquito populations. In the many areas of North America with seasonal EEE activity, winters are long and severe enough such that no adult mosquito activity occurs for several months.

Culiseta melanura, a temperate breeding species of mosquito, does not readily breed in southern Florida and the Caribbean, and EEE is not an endemic disease in this relatively focal region.⁶³ Only sporadic reports or small epidemics of EEE disease in horses have been recorded in these areas, likely through migratory influx of viremic birds providing occasional sources of virus for secondary vectors. These secondary vectors can initiate short-term outbreaks but cannot maintain the disease endemically.

Comparatively few epidemics of EEE in horses have occurred in South America, with minimal disease reported in humans. Mosquitoes of the subgenus Culex (Melanoconion) in South and Central America are implicated as endemic vectors.⁶⁴ Antibody prevalence studies in birds and small rodents indicate that, in contrast with North America, small rodents are involved in the primary virus life cycle.

Western Equine Encephalitis

Since 1964, WEE has been reported in 640 people. The highest number of cases has been reported in Colorado and Texas, followed by Minnesota and California. Historically, large outbreaks of WEE have been described in horses. The virus was first identified in association with a large epizootic that occurred in the San Joaquin Valley of California in 1930. Approximately 6000 horses were affected, with a case-fatality rate of 50%.⁶⁵ This outbreak continued and spread to several western states from 1931 to 1934. Within a decade, another 300,000 equid cases were reported, with several thousand human cases. Over the last decade, reports of WEE in horses have been limited and sporadic, likely reflecting vaccination and protective immunity gained by subclinical exposure.^66,67

Culex tarsalis is the primary vector that maintains WEE virus in an enzootic cycle with birds, especially nestling passerines,^68,69 Cx. tarsalis population abundance is favored by a rapid increase in temperature following a cool, wet spring, resulting in the rapid melting of snow and flooding of rivers.^70,71 This species of mosquito also has a predilection for irrigated lands as breeding sites.⁷² Other ornithophilic mosquitoes become infected as the summer progresses, and the infection eventually spills over to other types of birds, mammals, and possibly reptiles and amphibians. Most, if not all, of these infections are inapparent. This in turn results in the virus becoming established in species of mosquitoes with host preferences other than birds. Transovarial transmission of WEE in North American mosquitoes, including Cx. tarsalis, has not been proved, and interepidemic maintenance in temperate areas by mosquitoes is therefore in doubt. Horses, even those that are obviously clinically affected, do not produce viremia high enough to infect mosquitoes.

At least two variants of WEE virus (Fort Morgan and Buggy Creek) have been isolated in western North America and are transmitted between birds by swallow nest bugs (Oeciacus vicarius).²⁴ Neither variant is considered to be pathogenic for humans or horses. A third variant, Highlands J virus, is mainly found east of the Mississippi River and has been isolated from horses dying of encephalitis.^{20,24–26,73} Information is limited on the number of horses infected with HJ virus on an annual basis.

In South America, where Cx. tarsalis does not occur, antibody prevalence rates in birds are lower than in North America, and the species (vertebrate and invertebrate) responsible for maintaining the virus on that continent have not been identified.⁷⁴ Aedes albasfaciatus has experimentally transmitted WEE virus to chickens in Argentina.⁷⁵ Other studies have demonstrated mosquitoes of the Culex pipiens complex are refractory to oral WEE virus inoculation. The species of mosquitoes from which WEE virus has mostly been isolated feeds principally on mammals rather than birds.

Venezuelan Equine Encephalitis

Venezuelan equine encephalitis virus is one of the most important human and veterinary pathogens in the New World.⁷⁶ The virus, both historically and very recently, has been responsible for large outbreaks of disease in both humans and horses over large geographic areas. The first recognized outbreak of VEE occurred initially in equids in Colombia and then in Venezuela in 1935 and 1936, although it is speculated to have been active in this area since 1920.⁷⁷ Documentation of human disease occurred in a Columbian outbreak in the 1960s, when an estimated 50,000 to 100,000 equids (horses, mules, donkeys) died and 250,000 humans were affected (mainly an influenza-like disease, but some cases of encephalitis and death). It is uncertain whether the 1969–1971 epidemic that was first reported in Ecuador and subsequently spread to Central America, Mexico, and Texas was directly related to this outbreak in Colombia or was caused by the use of an incorrectly inactivated subtype IAB strain vaccine.^78,79 Regardless of its cause, however, this epidemic revealed the potential for VEE to spread rapidly within an equine population, with a case-fatality rate approaching 90% in some areas.

The availability of vaccines and active surveillance throughout the Americas since the early 1970s have arguably reduced the impact of the disease in the rural regions, where VEE has traditionally been described. Nevertheless, after a long period with no evidence of clinical disease in horses, outbreaks of VEE were reported in 1993 in Chiapas, southern Mexico; in 1995 in Venezuela and Colombia; and in 1996 in Oaxaca, Mexico.^80–84 The geographically extensive outbreak in 1995 had all the initial hallmarks of the 1969–1971 epidemic. Not only did large numbers of horses, mules, and donkeys die, but there were also an estimated 75,000 to 100,000 human cases of disease. VEE viruses isolated in 1995 were genetically similar to those associated with disease in the 1960s. Although the cause of these severe cyclic disease occurrences is still a matter of intense research, it can be assumed that severe epizootic VEE may continue to occur with approximately one- to two-decade-long interepizootic periods.

Key to understanding the epidemiology of VEE is recognition of the differences in the basic biology of two transmission cycles, enzootic and epizootic, of this virus⁷⁶ (Fig. 20-1). The enzootic cycle centers around sylvatic rodents such as spiny and cotton rats, which have high natural infection rates and can develop viremia high enough to transmit VEE to mosquitoes.^85,86 Even opossums, bats, and shore birds likely are important in dispersal of enzootic virus.^87,88 The subgenus Melanoconion (Culex cedecci) is likely to be the most important vector of enzootic VEE.⁸⁹ This vector resides in tropical forests and swamps and feeds on small forest mammals at night. Some species of this mosquito have broader feeding patterns. Activity for this vector peaks with high ambient temperature and rainfall. Table 20-1 indicates that certain strains of virus are found only in the enzootic cycle. These viruses, subtypes I-E, II, III, and IV, tend to be of low pathogenicity for equids and do not result in high levels of viremia in horses.

Fig. 20-1 Life cycle of Venezuelan equine encephalitis virus (VEE). During the endemic cycle, VEE is maintained in a sylvatic ecosystem with a rodent reservoir (spiny rat) and mosquito vector, generally Culex spp. (Melanoconion). On generation of an epizootic strain of VEE, multiple-vector species transmit the virus. The horse generates a sufficiently high-titer viremia to amplify the virus significantly. Several other terrestrial mammals also are susceptible to infection and develop significant viremia (including human and dog).

Many theories exist on the origin of epizootic VEE viruses, primarily of the subtypes IAB and IC.^90,91 These viruses are associated with variable but often quite high equine mortality (20%-85%).⁹² In contrast to most arboviruses in the horse, efficient amplification of the virus by equids is the hallmark of epizootic VEE. Humans usually develop a flulike illness, with only 4% to 14% exhibiting neurologic signs and symptoms.⁸⁸ Case-fatality rate for humans is approximately 1%. Several other species of mammals, including domestic rabbits, small ruminants, and dogs, develop potentially fatal clinical disease after VEE virus infection.⁹² More than 100 species of birds have been either virologically or serologically associated with transmission of epidemic VEE virus. Shore birds in general and herons in particular appear to be capable of serving as amplifier hosts.^93,94 Birds may develop viremia as high as 10⁸ TCID₅₀/mL of blood.

The importance of equine infection in maintenance of epizootic VEE is evidenced by the observation that human disease has never been demonstrated in the absence of equine disease.²⁹ All mammalian hosts are capable of developing a high-titer viremia of approximately 10⁵ to 10⁷ pfu/mL for up to 5 days, but the horse is likely to be the most important mammalian host in terms of vector capacity.⁷⁶ In contrast to EEE and WEE, where horses are not considered to be a major source of virus for the vector, in VEE epidemics, horses are the most important amplifiers of virus activity.

Several species of mosquitoes from at least 11 genera have been determined to be naturally infected with epidemic strains of VEE virus.^95–102 In particular, Psorophora confinnis, P. columbiae, Ochlerotatus sollicitans, O. taeniorhynchus, and Culex spp. have been associated with epizootics. Virus has also been isolated from Culicoides spp. (Ceratopogonidae) and blackflies (Simuliidae), but it is not known whether insects in these families are capable of biologic transmission of VEE virus.⁹⁵ During an epidemic, dogs regularly become infected and may be capable of virus amplification.^103–106 In addition, ticks, including the species Ambylomma cajennense and Hyalomma truncatum, may be capable of viral transmission.^107–111

Several theories exist regarding the source of IAB and IC strains and how they persist in the environment between outbreaks.¹¹² Although molecular analyses have been used to address this, a comprehensive understanding of how epidemics in horses originate remains elusive. Isolates that are virulent for horses do not appear to be transmitted in the interepizootic period.^113,114 There is some evidence for circulation of these viruses in the interepizootic period, but no latency is associated with these infections. No evidence suggests that the epizootic strains coexist in the enzootic cycle. Mutation of enzootic strains may allow the emergence of highly pathogenic virus and initiation of epizootics.¹¹⁵ This has been identified as the source of four epizootics. Some of these epizootics may have occurred secondary to the use of a modified live vaccine derived from the IAB strain.⁷⁹