Information on Arboviral Encephalitides
Perspectives
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.
Eastern Equine Encephalitis
Eastern equine encephalitis (EEE) is also caused by a virus transmitted to
humans and equines by the bite of an infected mosquito. EEE virus is an alphavirus
that was first identified in the 1930's and currently occurs in focal locations
along the eastern seaboard, the Gulf Coast and some inland Midwestern locations
of the United States. While small outbreaks of human disease have occurred in
the United States, equine epizootics can be a common occurrence during the summer
and fall.
It takes from 4-10 days after the bite of an infected mosquito for an individual
to develop symptoms of EEE. These symptoms begin with a sudden onset of fever,
general muscle pains, and a headache of increasing severity. Many individuals
will progress to more severe symptoms such as seizures and coma. Approximately
one-third of all people with clinical encephalitis caused by EEE will die from
the disease and of those who recover, many will suffer permanent brain damage
with many of those requiring permanent institutional care.
In addition to humans, EEE virus can produce severe disease in: horses, some
birds such as pheasants, quail, ostriches and emus, and even puppies. Because
horses are outdoors and attract hordes of biting mosquitoes, they are at high
risk of contracting EEE when the virus is present in mosquitoes. Human cases
are usually preceded by those in horses and exceeded in numbers by horse cases
which may be used as a surveillance tool.
EEE virus occurs in natural cycles involving birds and Culiseta melanura, in
some swampy areas nearly every year during the warm months. Where the virus
resides or how it survives in the winter is unknown. It may be introduced by
migratory birds in the spring or it may remain dormant in some yet undiscovered
part of its life cycle. With the onset of spring, the virus reappears in the
birds (native bird species do not seem to be affected by the virus) and mosquitoes
of the swamp. In this usual cycle of transmission, virus does not escape from
these areas because the mosquito involved prefers to feed upon birds and does
not usually bite humans or other mammals.
For reasons not fully understood, the virus may escape from enzootic foci in
swamp areas in birds or bridge vectors such as Coquilletidia perturbans and
Aedes sollicitans. These species feed on both birds and mammals and can transmit
the virus to humans, horses, and other hosts. Other mosquito species such as
Ae. vexans and Culex nigripalpus can also transmit EEE virus. When health officials
maintain surveillance for EEE virus activity, this movement out of the swamp
can be detected, and if the level of activity is sufficiently high, can recommend
and undertake measures to reduce the risk to humans.
Western Equine Encephalitis
The alphavirus western equine encephalitis (WEE) was first isolated in California
in 1930 from the brain of a horse with encephalitis, and remains an important
cause of encephalitis in horses and humans in North America, mainly in western
parts of the USA and Canada. In the western United States, the enzootic cycle
of WEE involves passerine birds, in which the infection is inapparent, and culicine
mosquitoes, principally Cx. tarsalis, a species that is associated with irrigated
agriculture and stream drainages. The virus has also been isolated from a variety
of mammal species. Other important mosquito vector species include Aedes melanimon
in California, Ae. dorsalis in Utah and New Mexico and Ae. campestris in New
Mexico. WEE virus was isolated from field collected larvae of Ae. dorsalis,
providing evidence that vertical transmission may play an important role in
the maintenance cycle of an alphavirus.
Expansion of irrigated agriculture in the North Platte River Valley during
the past several decades has created habitats and conditions favorable for increases
in populations of granivorous birds such as the house sparrow, Passer domesticus,
and mosquitoes such as Cx. tarsalis, Aedes dorsalis and Aedes melanimon. All
of these species may play a role in WEE virus transmission in irrigated areas.
In addition to Cx. tarsalis, Ae. dorsalis and Ae. melanimon, WEE virus also
has been isolated occasionally from some other mosquito species present in the
area. Two confirmed and several suspect cases of WEE were reported from Wyoming
in 1994. In 1995, two strains of WEE virus were isolated from Culex tarsalis
and neutralizing antibody to WEE virus was demonstrated in sera from pheasants
and house sparrows. During 1997, 35 strains of WEE virus were isolated from
mosquitoes collected in Scotts Bluff County, Nebraska.
Human WEE cases are usually first seen in June or July. Most WEE infections
are asymptomatic or present as mild, nonspecific illness. Patients with clinically
apparent illness usually have a sudden onset with fever, headache, nausea, vomiting,
anorexia and malaise, followed by altered mental status, weakness and signs
of meningeal irritation. Children, especially those under 1 year old, are affected
more severely than adults and may be left with permanent sequelae, which is
seen in 5 to 30% of young patients. The mortality rate is about 3%.
St. Louis Encephalitis
In the United States, the leading cause of epidemic flaviviral encephalitis
is St. Louis encephalitis (SLE) virus. SLE is the most common mosquito-transmitted
human pathogen in the U.S. While periodic SLE epidemics have occurred only in
the Midwest and southeast, SLE virus is distributed throughout the lower 48
states. Since 1964, there have been 4,437 confirmed cases of SLE with an average
of 193 cases per year (range 4 - 1,967). However, less than 1% of SLE viral
infections are clinically apparent and the vast majority of infections remain
undiagnosed. Illness ranges in severity from a simple febrile headache to meningoencephalitis,
with an overall case-fatality ratio of 5-15 %. The disease is generally milder
in children than in adults, but in those children who do have disease, there
is a high rate of encephalitis. The elderly are at highest risk for severe disease
and death. During the summer season, SLE virus is maintained in a mosquito-bird-mosquito
cycle, with periodic amplification by peridomestic birds and Culex mosquitoes.
In Florida, the principal vector is Cx. nigripalpus, in the Midwest, Cx. pipiens
pipiens and Cx. p. quinquefasciatus and in the western United States, Cx. tarsalis
and members of the Cx. pipiens complex.
Powassan Encephalitis
Powassan (POW) virus is a flavivirus and currently the only well documented
tick-borne transmitted arbovirus occurring in the United States and Canada.
Recently a Powassan-like virus was isolated from the deer tick, Ixodes scapularis.
Its relationship to POW and its ability to cause human disease has not been
fully elucidated. POW's range in the United States is primarily in the upper
tier States. In addition to isolations from man, the virus has been recovered
from ticks (Ixodes marxi, I. cookei and Dermacentor andersoni) and from the
tissues of a skunk (Spiligale putorius). It is a rare cause of acute viral encephalitis.
POW virus was first isolated from the brain of a 5-year-old child who died in
Ontario in 1958. Patients who recover may have residual neurological problems.
Venezuelan Equine Encephalitis
Like EEE and WEE viruses, Venezuelan equine encephalitis (VEE) is an alphavirus
and causes encephalitis in horses and humans and is an important veterinary
and public health problem in Central and South America. Occasionally, large
regional epizootics and epidemics can occur resulting in thousands of equine
and human infections. Epizootic strains of VEE virus can infect and be transmitted
by a large number of mosquito species. The natural reservoir host for the epizootic
strains is not known. A large epizootic that began in South America in 1969
reached Texas in 1971. It was estimated that over 200,000 horses died in that
outbreak, which was controlled by a massive equine vaccination program using
an experimental live attenuated VEE vaccine. There were several thousand human
infections. A more recent VEE epidemic occurred in the fall of 1995 in Venezuela
and Colombia with an estimated 90,000 human infections. Infection of man with
VEE virus is less severe than with EEE and WEE viruses, and fatalities are rare.
Adults usually develop only an influenza-like illness, and overt encephalitis
is usually confined to children. Effective VEE virus vaccines are available
for equines.
Enzootic strains of VEE virus have a wide geographic distribution in the Americas.
These viruses are maintained in cycles involving forest dwelling rodents and
mosquito vectors, mainly Culex (Melanoconion) species. Occasional cases or small
outbreaks of human disease are associated with there viruses, the most recent
outbreaks were in Venezuela in 1992, Peru in 1994 and Mexico in 1995-96.
Other Arboviral Encephalitides
Many other arboviral encephalitides occur throughout the world. Most of these
diseases are problems only for those individuals traveling to countries where
the viruses are endemic.
Japanese Encephalitis
Japanese encephalitis (JE) virus is a flavivirus, related to SLE, and is widespread
throughout Asia. Worldwide, it is the most important cause of arboviral encephalitis
with over 45,000 cases reported annually. In recent years, JE virus has expanded
its geographic distribution with outbreaks in the Pacific. Epidemics occur in
late summer in temperate regions, but the infection is enzootic and occurs throughout
the year in many tropical areas of Asia. The virus is maintained in a cycle
involving culicine mosquitoes and waterbirds. The virus is transmitted to man
by Culex mosquitoes, primarily Cx. tritaeniorhynchus, which breed in rice fields.
Pigs are the main amplifying hosts of JE virus in peridomestic environments.
The incubation period of JE is 5 to 14 days. Onset of symptoms is usually sudden,
with fever, headache and vomiting. The illness resolves in 5 to 7 days if there
is no CNS involvement. The mortality in most outbreaks is less than 10%, but
is higher in children and can exceed 30%. Neurologic sequelae in patients who
recover are reported in up to 30% of cases. A formalin-inactivated vaccine prepared
in mice is used widely in Japan, China, India, Korea, Taiwan and Thailand. This
vaccine is currently available for human use in the United States, for individuals
who might be traveling to endemic countries.
Tick-Borne Encephalitis
Tick-borne encephalitis (TBE) is caused by two closely related flaviviruses
which are distinct biologically. The eastern subtype causes Russian spring-summer
encephalitis (RSSE) and is transmitted by Ixodes persulcatus, whereas the western
subtype is transmitted by Ixodes ricinus and causes Central European encephalitis
(CEE). The name CEE is somewhat misleading, since the condition can occur throughout
much of Europe. Of the two subtypes, RSSE is the more severe infection, having
a mortality of up to 25% in some outbreaks, whereas mortality in CEE seldom
exceeds 5%.
The incubation period is 7 to 14 days. Infection usually presents as a mild,
influenza-type illness or as benign, aseptic meningitis, but may result in fatal
meningoencephalitis. Fever is often biphasic, and there may be severe headache
and neck rigidity, with transient paralysis of the limbs, shoulders or less
commonly the respiratory musculature. A few patients are left with residual
paralysis. Although the great majority of TBE infections follow exposure to
ticks, infection has occurred through the ingestion of infected cows' or goats'
milk. An inactivated TBE vaccine is currently available in Europe and Russia.
West Nile Encephalitis
WNV is a flavivirus belonging taxonomically to the Japanese encephalitis serocomplex
that includes the closely related St. Louis encephalitis (SLE) virus, Kunjin
and Murray Valley encephalitis viruses, as well as others. WNV was first isolated
in the West Nile Province of Uganda in 1937 (2). The first recorded epidemics
occurred in Israel during 1951-1954 and in 1957. Epidemics have been reported
in Europe in the Rhone delta of France in 1962 and in Romania in 1996 (3-5).
The largest recorded epidemic occurred in South Africa in 1974 (6).
An outbreak of arboviral encephalitis in New York City and neighboring counties
in New York state in late August and September 1999, was initially attributed
to St. Louis encephalitis virus based on positive serologic findings in cerebrospinal
fluid (CSF) and serum samples using a virus-specific IgM-capture enzyme-linked
immunosorbent assay (ELISA). The outbreak has been subsequently confirmed as
caused by West Nile virus based on the identification of virus in human, avian,
and mosquito samples. See also these MMWR articles Outbreak of West Nile-Like
Viral Encephalitis -- New York, 1999. MMWR, 1999:48(38);845-9 and Update: West
Nile-Like Viral Encephalitis -- New York, 1999. MMWR, 1999:48(39);890-2. A recent
outbreak WN encephalitis occurred in Bucharest, Romania in 1996.
The virus that caused the New York area outbreak has been definitively identified
as a strain of WNV. The genomic sequences identified to date from human brain,
virus isolates from zoo birds, dead crows, and mosquito pools are identical.
SLE and West Nile viruses are antigenically related, and cross reactions are
observed in most serologic tests. The isolation of viruses and genomic sequences
from birds, mosquitoes, and human brain tissue permitted the discovery of West
Nile virus in North America and prompted more specific testing. The limitations
of serologic assays emphasize the importance of isolating the virus from entomologic,
clinical, or veterinary material.
Although it is not known when and how West Nile virus was introduced into North
America, international travel of infected persons to New York or transport by
imported infected birds may have played a role. WNV can infect a wide range
of vertebrates; in humans it usually produces either asymptomatic infection
or mild febrile disease, but can cause severe and fatal infection in a small
percentage of patients. Within its normal geographic distribution of Africa,
the Middle East, western Asia, and Europe, WNV has not been documented to cause
epizootics in birds; crows and other birds with antibodies to WNV are common,
suggesting that asymptomatic or mild infection usually occurs among birds in
those regions. Similarly, substantial bird virulence of SLE virus has not been
reported. Therefore, an epizootic producing high mortality in crows and other
bird species is unusual for either WNV or SLE virus. For both viruses, migratory
birds may play an important role in the natural transmission cycles and spread.
Like SLE virus, WNV is transmitted principally by Culex species mosquitoes,
but also can be transmitted by Aedes, Anopheles, and other species. The predominance
of urban Culex pipiens mosquitoes trapped during this outbreak suggests an important
role for this species. Enhanced surveillance for early detection of virus activity
in birds and mosquitoes will be crucial to guide control measures.
Murray Valley Encephalitis
Murray Valley encephalitis (MVE) is endemic in New Guinea and in parts of Australia;
and is related to SLE, WN and JE viruses. Inapparent infections are common,
and the small number of fatalities have mostly been in children.
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