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ARBOVIRUSES
These viruses are spread by hematophagous arthropod vectors
(blood sucking insects). In the U.S. the tick and the mosquito
are the vectors involved in virus transmission. But other
vectors such as biting flies have been implicated in other
countries for other illnesses. Arboviruses are vector specific
and will replicate in the tick or mosquito but not in both. The
virus is usually transmitted to the vector by a blood meal and
replicates in the vector eventually making its way to the
salivary glands where it can be transmitted to a second animal
upon feeding. Thus the virus is actually amplified by the
vector. The vector is usually infected for life and does not
display any signs of sickness due to infection. During winter
months in cold climates the vector numbers decrease or the vector
disappears. Thus arbovirus infections tend to be epidemic and
seasonal based on the presence of a large number of infected
vectors during warmer months. The virus must have some mechanism
for overwintering: this may involve transovarial transmission
(adult female to egg) or reintroduction of virus by infected
migratory birds. For many arboviruses vector transmission can
also occur sexually or trans-stadially (larva to nymph to adult).
Most arboviruses exist in enzootic cycles (natural cycles) of
transmission in which virus is transmitted by insect vectors from
bird to bird or among small mammals. If the vector should feed
on a human or equine the virus may be transmitted (epizootic
infection) with illness resulting. Equines and humans are
usually dead end hosts. Transmission from human to human does
not occur and vector transmission among humans usually does not
occur because levels of virus in the blood are very low or
undetectable. Exceptions include Dengue and Yellow Fever where
virus levels in the blood are sufficient for man to vector to man
transmission.
Arboviral infections can manifest as three types of
illnesses in humans. These are 1)acute central nervous system
disease including aseptic meningitis, encephalitis and
encephalomyelitis, 2) undifferentiated febrile illness with or
without rash, and 3) hemorrhagic fever, a systemic febrile
illness with hemorrhagic manifestations, cardiovascular
instability and varying degrees of hepatic and renal
insufficiency.
Pathogenesis
Following the arthropod bite virus replicates
locally then spreads to regional lymph nodes and is disseminated
via the lymphatic system into the bloodstream (primary viremia).
The primary viremia seeds target organs which replicate virus and
serve as a source of virus for release in the circulation. Virus
can then enter the neural tissue causing encephalitis.
The symptoms of arbovirus infection usually have an abrupt
onset. With constitutional symptoms occurring first (fever,
chills, headache, generalized aches and malaise) followed in some
cases by more severe symptoms of encephalitis ( drowsiness,
nuchal rigidity, confusion, convulsions, tremors, coma, death) or
hemorrhage (yellow fever and dengue [rare]). The incubation
period can vary from 3 to 21 days. Sequelae of encephalitis can
be severe. Most arbovirus infections are inapparent and immunity
is life-long.
There are four virus families that harbor arboviruses:
Togaviridae; Flaviviridae; Bunyaviridae and Reoviridae. Although
63 arboviruses have been isolated within the U.S. and Canada,
only six cause significant illness - St. Louis encephalitis
(SLE), Eastern Equine encephalitis (EEE), Western Equine
encephalitis (WEE), Powassan encephalitis (POW), California
encephalitis (Lacrosse virus) and Colorado tick fever (CTF). MMWR arboviruses in the U.S.
TOGAVIRIDAE
The virus is enveloped with a single segment ssRNA
genome that is positive sense (i.e. functions like mRNA) and is
capped and polyadenylated. The virus replicates in the cytoplasm
with the genomic RNA translating nonstructural proteins and a
subgenomic RNA from the 3' end encoding structural polypeptides.
Three genera of Togaviruses exist: alphaviruses, rubriviruses
(rubella) and pestiviruses (hog cholera). The arboviruses reside
within the alphavirus family. Their are three major alphaviruses
which are arthropod borne. EEE, WEE and VEE (Venezuelan equine
encephalitis).
Eastern Equine encephalitis (EEE)
Is a rare but deadly disease
with severe sequelae for survivors. The virus was first isolated
in the U.S. in 1933 and is maintained in an enzootic cycle
involving wild birds and mosquitoes in fresh water swamps. The
vector involved is Culiseta melanura which rarely bites mammals,
explaining the rare transmission to humans and equines. This
natural cycle may change with the recent introduction (1985) of
the Asian tiger mosquito (Aedes albopictus) into the U.S. which
has more relaxed feeding preferences. Since 1955 their has been
and average of 7 cases per year in the U.S. Most infections are
inapparent (infection/case = 23/1). The infection can be
systemic or encephalitic, with most systemic cases being
inapparent. In cases that progress to encephalitis mortality is
high and if sequelae are included mortality may reach 90%.
Mortality in horses is 90%. Children seem to show a higher
susceptibility and a more abrupt onset of symptoms than adults.
A vaccine is available for horses and also for laboratory workers
who culture the virus. In MS the first confirmed case of EEE
occurred in 1989, their were no cases in 1990 and 1 case in 1991.
Western Equine encephalitis (WEE)
Was first isolated in the U.S.
in 1930. In 1941 their was a U.S. epidemic involving 300,000
horses and 3,336 humans. It is most prevalent in the western
plain states where human cases may follow outbreaks in horses.
The vast majority of cases are inapparent ( adults case/infection
= 1/1150, children 1/58). Fatality rates can reach 3-4% with
higher mortality seen in individuals over 55. Convulsions can
occur in patients under 1 yr. Five documented cases of in utero
transmission. The natural cycle involves birds and mosquitoes
(Culex tarsalis; breeds in ditches). An inactivated vaccine is
available for equines and human lab workers. No MS cases have
been reported.
Venezuelan Equine encephalitis (VEE)
Is not a significant problem
in the U.S. The virus is maintained in an enzootic cycle with
rodents and the mosquito (Culex melanoconion). Mortality in
humans varies from .5% in adults to 4% in children. Recently a
related virus known as the VEE II Everglades virus has been
documented in Florida in three CNS cases. The virus is highly
infectious by the aerosol route and there is a high sero
prevalence in Florida. The last major epidemic of VEE occurred
in horses in south Texas (1971) and was extinguished by
vaccination. A vaccine is available for horses.
Togaviruses outside U.S. These include Chikungunya, Mayaro,
O'nyong-nyong, Igbo Ora, Ross River and Sindbis. All cause an
acute arthralgia with fever. Togavirus genome structure
FLAVIVIRIDAE
The flaviviruses were once listed as Togaviruses
but were found to be different enough to merit inclusion as a
separate family. They are enveloped ssRNA viruses of positive
sense which contain only a single RNA segment and replicate in
the cytoplasm. The viral genome is capped but not polyadenylated
and during replication a single polyprotein is synthesized than
cleaved to form viral proteins (there is no subgenomic RNA).
In the U.S. the major flavivirus pathogens are St. Louis
encephalitis (SLE, mosquito borne) and Powassan encephalitis
(tick borne).
St. Louis Encephalitis (SLE)
Is the most important arbovirus
disease in North America. The natural cycle is maintained in
birds(sparrows, finches, blue jays, robins and doves) by
transmission mosquitoes (Culex). The virus was first recognized
in 1932 (Paris, Illinois) and first isolated in 1933 during the
St. Louis epidemic from a human brain. Most cases are inapparent
(case/infection = 1/100) but 75% with clinical illness will
develop encephalitis. In adults over 60 the fatality rate can
approach 7%. Between 1964 and 1992 the U.S. averaged 86 cases
per year. In 1975 there was an epidemic with 1800 documented
infections. 10% of patients have convulsions and SLE is
sometimes misdiagnosed as stroke. Last outbreak in MS was in
1975 but there have been no cases in recent years. In 1991 there
was an outbreak in Pine Bluff, Arkansas.
Powassan encephalitis (POW)
This virus is tick borne (Ixodes).
It was first isolated in 1958 in Ontario. Its enzootic cycle
involves small mammals such as squirrels and ground hogs. It is
widely distributed in eastern and western U.S. The virus can
infect dogs and goats. Transmission by goat's milk is a
possibility. Their have been 21 symptomatic infections
documented since 1958. The seroprevalence is low < 1% (range .5-
3.3%) but the young appear to be much more susceptible. The
virus has also been isolated in Russia.
Yellow Fever virus (YF)
YF was the first arthropod-borne viral
disease identified. It has caused major epidemics in the U.S. in
New york, Philadelphia, Memphis (1870's) and New Orleans (1905).
It delayed the development of the Panama canal and is still a
major problem in South America and Africa. The virus can occur
in two cycles- urban and jungle. In the urban cycle transmission
is human - mosquito - human. In the jungle cycle transmission is
monkey - mosquito - monkey. Thus unlike most other arboviruses
YF reaches high titers in human blood. The mosquito vector is
Aedes aegypti which lives in close association with humans.
Yellow fever has not been documented in the U.S. for 30-40 years
but the vector (Aedes aegypti) exists here. The clinical
spectrum following YF infection varies from inapparent to fatal.
In severe cases fever is high, blood pressure drops and there are
signs of hemorrhage. The major organ target is the liver. A
vaccine is available for yellow fever known as the 17D vaccine.
Dengue fever
Dengue continues to be a world wide public health
problem. Transmission is by Aedes eagypti and Dengue can occur
in both an urban and jungle cycle similar to YF. Their are four
serotypes of Dengue based on neutralization tests. Complication
and deaths are rare but convalescence can take weeks. In young
children (age 2-13) Dengue infection can take the form of a
hemorrhagic fever or shock syndrome (DHF/DSS). This is thought
to occur in individuals with non-neutralizing heterologous
antibody. In 1990-1991 184 cases of imported Dengue were
reported. Epidemics of Dengue have occurred in Jamaica, Puerto
Rico and Cuba (1981).
Russian-Spring-Summer-Encephalitis
It is transmitted by ticks
and also by consumption of unpasteurized goats milk. It is found
in Russia where it is associated with a high mortality.
Japanese Encephalitis
it is mosquito borne. Pigs and birds are
its natural hosts. It has been documented in U.S. servicemen.
Mortality varies from 2-11%. Flavirus genome structure
BUNYAVIRIDAE
Five genera of have been described - Bunyavirus
(California Encephalitis group [LaCrosse virus], Hantavirus,
Nairovirus (Crimean-Congo hemorrhagic fever, Nairobi sheep
disease), Phlebovirus (sandfly fever and rift valley fever), and
Tospovirus (tomato spotted wilt). Over 258 recognized members of
the Bunyaviridae exist. The only member of medical importance
for the U.S. is the LaCrosse virus of the Bunyavirus genus.
The bunyaviridae are enveloped viruses which contain three
distinct segments of negative polarity ssRNA designated as large
(L), medium (M) and small (S). These are enclosed within the
virion as helical nucleocapsids. L encodes the viral RNA
dependent RNA polymerase. M encodes glycoprotein one (G1),
glycoprotein two (G2), and a nonstructural protein (NSm). S
encodes the nucleocapsid protein (N) and a nonstructural protein
(NSs). The G1 and G2 glycoproteins are present as spikes in the
viral envelope. Bunyaviruses replicate in the cytoplasm and
obtain their envelope by budding from the golgi. Like the
influenza virus Bunyaviruses pirate the 5' ends of their mRNAs
from the cells mRNA.
LaCrosse virus (LAC)
{California encephalitis group of the
Bunyaviruses}:localized to the midwest. Most important cause of
arboviral pediatric encephalitis in the U.S. LAC exists in a
natural cycle involving the mosquito (Aedes triseriatus) and
small mammals (chipmunks, gray squirrel). between 1964 and 1992
2,032 cases were reported to the CDC (70 cases per year). Most
infections are subclinical. Fatality rate of .3%. Seizures
occur in 50% of the cases.
Phleboviruses
Transmitted by phlebotomus flies and mosquitoes.
- Sandfly fever: common in Africa and some parts of Asia.
Symtoms include fever and malaise but recovery is complete.
- Rift Valley fever is a serious pathogen (mainly in Africa) of
cattle, sheep and goats and can also cause human disease.
Usually the illness is benign although there have been isolated
reports of mortality. Virus can be spread by aerosols.
Nairoviruses
These viruses are all tick borne
- Crimean-Congo hemorrhagic fever [CCHF] is widespread throughout
Africa and Asia and Europe. It is maintained in a natural cycle
involving rodents such as bank voles. Bunyavirus genome structure
REOVIRIDAE
Genus = coltivirus. Colorado tick fever. The insect
vector is the tick Dermacentor andersoni. The enzootic cycle
involves the tick and small mammals (e.g. ground squirrel,
porcupine, deer mouse). Between 1985 and 1989 there were 441
cases in the U.S. Symptoms include abrupt high fever chills and
muscle pain with loss of fever and relapse in 2-3 days. Very few
fatalities although children may display hemorrhagic
manifestations. There is a prolonged viremia and virus can be
isolated from the serum.
ARBOVIRUSES
Prevention and Control
The most success has been with efforts
directed at eradication of the vector particularly the mosquito.
Other important steps involve the use of barriers (screens) to
deny vector entry to homes or of insect repellant to discourage
biting. Monitoring of wild birds and mosquitoes for the presence
of virus can also indicate when levels of infection are high
enough to present a danger of epizootic transmission to humans.
Sentinel birds (usually chickens) have been used to monitor virus
infection rates. Finally, vaccination of horses, when vaccines
are available and the horse is a source of infection is highly
effective.
Laboratory Diagnosis
Most laboratory diagnoses are based on
serological conversion. Conclusive serology depends on acute and
convalescent blood samples from the patient which show at least a
4 fold rise in titer. Isolation of the virus in culture is the
most dependable method of laboratory confirmation, but is very
difficult and even dangerous for arboviruses. Viremias in
arbovirus infections are short and are rapidly quenched by
antibody to the virus. With exception of YF, Dengue and CTF
where there are prolonged viremias isolation of the virus will be
extremely difficult. In most cases if virus is isolated it is
post mortem from infected brain tissue from which a number of the
encephalitic arboviruses can be readily isolated.
Immunofluorescence, ELISA, nucleic acid hybridization and PCR are
now commonly used by laboratories for diagnosis and surveillance.
Differential diagnosis: The critical task is to eliminate
treatable from non-treatable encephalitic illnesses. There are
no pathognomonic profiles for arbovirus disease likely to occur
in the U.S. Therefore, differential diagnosis can be very
difficult. However, the knowledge of arbovirus disease and
epidemiology should permit an attentive clinician to make a
rational differential diagnosis. Slow-wave background activity
by electroencephalogram and a mild lymphocytic pleocytosis in CSF
are indicators of encephalitis. A careful case history
documenting travel abroad, exposure to animals or recollection of
a tick bite can be very helpful.
Treatment
Therapeutic efforts are directed towards managing
symptoms, such as reducing fever maintaining hydration, assuring
adequate respiratory function, administering anticonvulsants, or
giving diuretics to decrease intracranial pressure.
test questions on arboviruses
schematics by Steve Folder
Recommended reading
Charles Calisher. 1994. Medically Important
Arboviruses of the United States and Canada. Clinical
Microbiology Reviews 7:89-116.
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