1. Acute central nervous system disease including aseptic meningitis, encephalitis and encephalomyelitis

2. Undifferentiated febrile illness with or without rash, and

3. Haemorrhagic fever, a systemic febrile illness with haemorrhagic 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 viraemia). The primary viraemia seeds target organs which replicate virus and serve as a source of virus for release into 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 haemorrhage (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 harbour 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).

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.

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.

Schematics by Steve Folder

Recommended reading
Charles Calisher. 1994. Medically Important Arboviruses of the United States and Canada. Clinical Microbiology Reviews 7:89-116.