Arboviral Encephalitides

by CDC

Arthropod-borne viruses, i.e., arboviruses, are viruses that are maintained in nature through biological transmission between susceptible vertebrate hosts by blood feeding arthropods (mosquitoes, psychodids, ceratopogonids, and ticks). Vertebrate infection occurs when the infected arthropod takes a blood meal. The term 'arbovirus' has no taxonomic significance. Arboviruses that cause human encephalitis are members of three virus families: the Togaviridae (genus Alphavirus), Flaviviridae, and Bunyaviridae.

All arboviral encephalitides are zoonotic, being maintained in complex life cycles involving a nonhuman primary vertebrate host and a primary arthropod vector. These cycles usually remain undetected until humans encroach on a natural focus, or the virus escapes this focus via a secondary vector or vertebrate host as the result of some ecologic change. Humans and domestic animals can develop clinical illness but usually are "dead-end" hosts because they do not produce significant viremia, and do not contribute to the transmission cycle. Many arboviruses that cause encephalitis have a variety of different vertebrate hosts and some are transmitted by more than one vector. Maintenance of the viruses in nature may be facilitated by vertical transmission (e.g., the virus is transmitted from the female through the eggs to the offspring).

Arboviral encephalitides have a global distribution, but there are four main virus agents of encephalitis in the United States: eastern equine encephalitis (EEE), western equine encephalitis (WEE), St. Louis encephalitis (SLE) and La Crosse (LAC) encephalitis, all of which are transmitted by mosquitoes. Another virus, Powassan, is a minor cause of encephalitis in the northern United States, and is transmitted by ticks. A new Powassan-like virus has recently been isolated from deer ticks. Its relatedness to Powassan virus and its ability to cause disease has not been well documented. Most cases of arboviral encephalitis occur from June through September, when arthropods are most active. In milder (i.e., warmer) parts of the country, where arthropods are active late into the year, cases can occur into the winter months.

The majority of human infections are asymptomatic or may result in a nonspecific flu-like syndrome. Onset may be insidious or sudden with fever, headache, myalgias, malaise and occasionally prostration. Infection may, however, lead to encephalitis, with a fatal outcome or permanent neurologic sequelae. Fortunately, only a small proportion of infected persons progress to frank encephalitis.

Experimental studies have shown that invasion of the central nervous system (CNS), generally follows initial virus replication in various peripheral sites and a period of viremia. Viral transfer from the blood to the CNS through the olfactory tract has been suggested. Because the arboviral encephalitides are viral diseases, antibiotics are not effective for treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia.

There are no commercially available human vaccines for these U.S. diseases. There is a Japanese encephalitis vaccine available in the U.S. A tick-borne encephalitis vaccine is available in Europe. An equine vaccine is available for EEE, WEE and Venezuelan equine encephalitis (VEE). Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes.

Selection of mosquito control methods depends on what needs to be achieved; but, in most emergency situations, the preferred method to achieve maximum results over a wide area is aerial spraying. In many states aerial spraying may be available in certain locations as a means to control nuisance mosquitoes. Such resources can be redirected to areas of virus activity. When aerial spraying is not routinely used, such services are usually contracted for a given time period.

Financing of aerial spraying costs during large outbreaks is usually provided by state emergency contingency funds. Federal funding of emergency spraying is rare and almost always requires a federal disaster declaration. Such disaster declarations usually occur when the vector-borne disease has the potential to infect large numbers of people, when a large population is at risk and when the area requiring treatment is extensive. Special large planes maintained by the United States Air Force can be called upon to deliver the insecticide(s) chosen for such emergencies. Federal disaster declarations have relied heavily on risk assessment by the CDC.

Laboratory diagnosis of human arboviral encephalitis has changed greatly over the last few years. In the past, identification of antibody relied on four tests: hemagglutination-inhibition, complement fixation, plaque reduction neutralization test, and the indirect fluorescent antibody (IFA) test. Positive identification using these immunoglobulin M (IgM) - and IgG-based assays requires a four-fold increase in titer between acute and convalescent serum samples. With the advent of solid-phase antibody-binding assays, such as enzyme-linked immunosorbent assay (ELISA), the diagnostic algorithm for identification of viral activity has changed. Rapid serologic assays such as IgM-capture ELISA (MAC-ELISA) and IgG ELISA may now be employed soon after infection. Early in infection, IgM antibody is more specific, while later in infection, IgG antibody is more reactive. Inclusion of monoclonal antibodies (MAbs) with defined virus specificities in these solid phase assays has allowed for a level of standardization that was not previously possible.

Virus isolation and identification have also been useful in defining viral agents in serum, cerebrospinal fluid and mosquito vectors. While virus isolation still depends upon growth of an unknown virus in cell culture or neonatal mice, virus identification has also been greatly facilitated by the availability of virus-specific MAbs for use in IFA assays. Similarly, MAbs with avidities sufficiently high to allow for specific binding to virus antigens in a complex protein mixture (e.g., mosquito pool suspensions) have enhanced our ability to rapidly identify virus agents in situ. While polymerase chain reaction (PCR) has been developed to identify a number of viral agents, such tests have not yet been validated for routine rapid identification in the clinical setting.

Mosquito-borne encephalitis offers a rare opportunity in public health to detect the risk of a disease before it occurs and to intervene to reduce that risk substantially. The surveillance required to detect risk is being increasingly refined by the potential utilization of these new technologies which allows for rapid identification of dangerous viruses in mosquito populations. These rapid diagnostic techniques used in threat recognition can shorten public health response time and reduce the geographic spread of infected vectors and thereby the cost of containing them. The Arbovirus Diseases Branch of NCID's Division of Vector-Borne Infectious Diseases has responsibility for CDC's programs in surveillance, diagnosis, research and control of arboviral encephalitides.

La Crosse Encephalitis

La Crosse (LAC) encephalitis was discovered in La Crosse, Wisconsin in 1963. Since then, the virus has been identified in several Midwestern and Mid-Atlantic states. During an average year, about 75 cases of LAC encephalitis are reported to the CDC. Most cases of LAC encephalitis occur in children under 16 years of age. LAC virus is a Bunyavirus and is a zoonotic pathogen cycled between the daytime-biting treehole mosquito, Aedes triseriatus, and vertebrate amplifier hosts (chipmunks, tree squirrels) in deciduous forest habitats. The virus is maintained over the winter by transovarial transmission in mosquito eggs. If the female mosquito is infected, she may lay eggs that carry the virus, and the adults coming from those eggs may be able to transmit the virus to chipmunks and to humans.

Historically, most cases of LAC encephalitis occur in the upper Midwestern states (Minnesota, Wisconsin, Iowa, Illinois, Indiana, and Ohio). Recently, more cases are being reported from states in the mid-Atlantic (West Virginia, Virginia and North Carolina) and southeastern (Alabama and Mississippi) regions of the country. It has long been suspected that LAC encephalitis has a broader distribution and a higher incidence in the eastern United States, but is under-reported because the etiologic agent is often not specifically identified.

LAC encephalitis initially presents as a nonspecific summertime illness with fever, headache, nausea, vomiting and lethargy. Severe disease occurs most commonly in children under the age of 16 and is characterized by seizures, coma, paralysis, and a variety of neurological sequelae after recovery. Death from LAC encephalitis occurs in less than 1% of clinical cases. In many clinical settings, pediatric cases presenting with CNS involvement are routinely screened for herpes or enteroviral etiologies. Since there is no specific treatment for LAC encephalitis, physicians often do not request the tests required to specifically identify LAC virus, and the cases are reported as aseptic meningitis or viral encephalitis of unknown etiology.

Also found in the United States, Jamestown Canyon and Cache Valley viruses are related to LAC, but rarely cause encephalitis.

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