Etiology

 

Rabies results from infection by the rabies virus, a neurotropic virus in the genus

Lyssavirus, family Rhabdoviridae. It is classified as genotype 1, serotype 1 in this group.

There are many strains of the rabies virus, with each strain maintained in particular

reservoir host(s). Although these viruses can readily cause rabies in other species, they

usually die out during serial passage in species to which they are not adapted.

Closely related lyssaviruses can cause a neurologic disease identical to rabies.

Lagos bat virus (genotype 2, serotype 2): This virus is found in bats in parts of Africa.

It was also isolated from the brains of two cats that died of neurologic disease. Mokola

virus (genotype 3, serotype 3): Mokola virus has been isolated from rodents and shrews

in Africa. It caused a small outbreak of neurologic disease resembling rabies in dogs

and cats, and has been isolated from children with neurologic disease. Duvenhage virus

(genotype 4, serotype 4): Duvenhage virus has been found in bats in Africa. It has caused

the deaths of several people with rabies-like disease. The European bat lyssaviruses

(EBLV) are very similar to the Duvenhage virus, but are found in continental Europe.

They are subdivided into two biotypes: EBLV1, genotype 5 and EBLV2, genotype 6.

Clinical cases have been reported in animals (sheep, a stone marten) and humans. The

Australian bat lyssavirus (ABLV) has been isolated in Australia. It is classified as genotype

7, but is not yet classified into a serotype. Viruses of serotypes 2–4, EBLV and

ABLV are known as rabies-related viruses.

Other related viruses – the Obodhiang and Kotonkan viruses in Africa, and the

Rochambeau virus in South America – have not been associated with disease in humans

or domestic animals. Unless otherwise specified, the information in this outline refers to

the classical rabies virus.

 

Geographic Distribution

 

With some exceptions (particularly islands), the rabies virus is found worldwide.

Countries that have been free of the classical rabies virus for many years include the

United Kingdom, Ireland, Sweden, Norway (mainland), Finland, Iceland, Japan, Australia,

New Zealand, Singapore, most of Malaysia, Papua New Guinea, the Pacific Islands,

the Indonesian island chains east of Java and Irian Jaya. According to the World Health

Organization (WHO), a country is considered to be free of rabies if there have been no

indigenously acquired cases in humans or animals during the previous two years, in the

presence of adequate surveillance and import regulations. Using this definition, several

additional countries are considered to be free of rabies. In some cases, these countries

have conducted rabies vaccination programs in wildlife, but are susceptible to the reintroduction

of the virus from neighboring countries. Official lists should be consulted for

an up-to-date list of rabies-free countries and areas.

The presence of the rabies-related viruses does not prevent a nation from being

listed as rabies-free. Recently, European bat lyssaviruses were isolated from bats and a

human with neurologic disease in the United Kingdom. Other countries considered to be

rabies-free, such as Australia, also contain rabies-related viruses.

 

Transmission

 

Species to species transmission of the rabies virus occurs readily. This virus is usually

transmitted in the saliva, when an infected animal bites another. Less often, it is spread

by any contact between infectious saliva or neurological tissues, and mucous membranes

or breaks in the skin. The rabies virus is not transmitted through intact skin.

There are also rare reports of transmission by other routes. A few cases have been

reported after corneal transplantation and, recently, a single organ donor in the U.S.

infected three recipients of kidney or liver transplants. Aerosol transmission has been

documented in special circumstances, such as in laboratories and bat caves with a high

density of aerosolized virus particles. Rabies viruses have been transmitted by ingestion

in laboratory animals, and there is anecdotal evidence of transmission in milk in animals.

(More conventional routes of spread could not be ruled out in the latter case.) Although

there is some speculation that ingestion could play a role in wild animals, there are no records of human disease acquired by this route. Nevertheless,

in two incidents investigated by the U.S. Centers for Disease

Control and Prevention (CDC), people who drank unpasteurized

milk from rabid cows were given post-exposure prophylaxis.

Pasteurized milk and cooked meat are not expected to

pose a risk of infection, as the rabies virus is inactivated by

heat; however, as a precaution, the National Association of

State Public Health Veterinarians recommends against consuming

tissues and milk from rabid animals.

 

The dissemination of the rabies virus

within the body

 

Immediately after infection, the rabies virus enters an

eclipse phase during which it is not easily detected. During

this phase, it replicates in non-nervous tissue such as muscle.

It does not usually stimulate an immune response at this

time, but is susceptible to neutralization.

After several days or months, the virus enters the peripheral

nerves and is transported to the central nervous system

(CNS) by retrograde flow in the axons. After dissemination

within the CNS, where clinical signs develop as the neurons

are infected, the virus is distributed to highly innervated tissues

via the peripheral nerves. Most of the virus is found in

nervous tissue, salivary glands, saliva and cerebrospinal fluid

(CSF), which should all be handled with extreme caution.

Some virus has also been detected in other tissues and

organs, including the lungs, adrenal glands, kidneys, bladder,

heart, ovaries, testes, prostate, pancreas, intestinal tract,

cornea, germinal cells of hair follicles in the skin, sebaceous

glands, tongue papillae and the brown fat of bats. The rabies

virus is contained within the neurons, and handling most

body fluids or intact organs is thought to carry a low risk

of infection. However, a puncture could theoretically pierce

a neuron, and healthcare personnel are given post-exposure

prophylaxis after a needlestick or other puncture wound

received while caring for a rabies patient. The rabies virus is

not spread hematogenously, and blood, urine and feces are

not thought to be infectious.

 

Epidemiological cycles

 

Rabies is maintained in two epidemiological cycles,

the urban and sylvatic cycles. In the urban rabies cycle,

dogs are the main reservoir host. This cycle is predominant

in much of Africa, Asia, and Central and South America,

where the proportion of unvaccinated and semi-owned or

stray dogs is high. It has been virtually eliminated in North

America and Europe; although sporadic cases occur in dogs

infected by wild animals, the urban cycle is not perpetuated

in the dog population.

The sylvatic (or wildlife) cycle is the predominant cycle

in Europe and North America. It is also present simultaneously

with the urban cycle in some parts of the world. The

epidemiology of this cycle is complex; factors affecting it

include the virus strain, behavior of the host species, ecology and environmental factors. In any ecosystem, only one and

occasionally up to three wildlife species are responsible for

perpetuating a particular strain of rabies. The disease pattern

in wildlife can either be relatively stable, or occur as a slow

moving epidemic. Recent examples of epidemics include a

fox rabies epidemic that moved slowly west in Europe, and

a raccoon rabies epidemic that moved north along the east

coast of the U.S.

 

Disinfection

 

The rabies virus can be inactivated by lipid solvents

(soap solutions, ether, chloroform, acetone), 1% sodium

hypochlorite, 2% glutaraldehyde, 45-75% ethanol, iodine

preparations, quaternary ammonium compounds, formaldehyde

or a low pH. This virus is also susceptible to ultraviolet

radiation or heat of 1 hour at 50° C. It is rapidly inactivated

in sunlight, and does not survive for long periods in the environment

except in a cool dark area.

 

Infections in Humans

Incubation Period

 

In humans, the incubation period is a few days to several

years. Most cases become apparent after 1 to 3 months.

In one study, approximately 4-10% of cases had an incubation

period of 6 months or more.

 

Clinical Signs

 

The early symptoms may include nonspecific prodromal

signs such as malaise, fever or headache, as well as discomfort,

pain, pruritus or sensory alterations at the site of virus

entry. After several days, anxiety, confusion and agitation

may appear, and progress to insomnia, abnormal behavior,

hypersensitivity to light and sound, delirium, hallucinations,

slight or partial paralysis, hypersalivation, difficulty

swallowing, pharyngeal spasms upon exposure to liquids,

and convulsions. Either an encephalitic (furious) form with

hyperexcitability, autonomic dysfunction and hydrophobia,

or a paralytic (dumb) form characterized by generalized

paralysis, may predominate. Death usually occurs within 2

to 10 days; survival is extremely rare.

 

Communicability

 

Human saliva contains the rabies virus; person-to-person

transmission is theoretically possible but rare. Activities

that could pose a risk for exposure include bites, kisses or

other direct contact between saliva and mucous membranes

or broken skin, sexual activity, and sharing eating or drinking

utensils or cigarettes. The CDC also recommends prophylactic

treatment after a needlestick or other sharp object

injury during an autopsy or during patient care, due to the

possibility that the object could have passed through nervous

tissue. Feces, blood, urine and other body fluids are not thought to carry the virus. A few cases of transmission have

been reported in corneal transplants and, recently, several

cases of rabies resulting from a single infected organ donor.

It is not known how long humans can shed the virus

before becoming symptomatic; the CDC recommends postexposure

prophylaxis for anyone who had at-risk contact with

a person during the 14 days before the onset of clinical signs.

 

Diagnostic Tests

 

Antemortem diagnosis may include virus isolation,

antigen detection or serology. More than one test is usually

necessary for a diagnosis. RT-PCR may be able to detect

the rabies virus in serum or CSF. Viral antigens may also

be detected, using RT-PCR or immunofluorescence, in skin

biopsies taken from the nape of the neck; the antigens are

found in the cutaneous nerves at the base of the hair follicles.

Serological tests include indirect immunofluorescence and

virus neutralization, and can be performed on serum or CSF.

Circulating neutralizing antibodies usually do not appear

until late, and infected people may still be seronegative

when they die. Postmortem diagnosis is usually by immunofluorescence

to detect viral antigens in the brain. A RT-PCR

technique has also been published.

 

Treatment

 

Postexposure prophylaxis consists of immediate wound

cleansing and disinfection, followed by rabies vaccination

and the administration of human rabies immunoglobulin.

The rabies vaccine is given as five doses in the U.S., and

is usually administered intramuscularly in the arm. Fewer

doses and no rabies immunoglobulin are given if the person

was previously vaccinated. Postexposure prophylaxis is

highly effective if it is begun soon after exposure.

There is no effective treatment once the symptoms

develop. Treatment is palliative. Vaccines, antivirals, interferon,

antibodies and ketamine, with supportive care, may

be tried but have been ineffective in the past. There is a very

high probability of an unsuccessful outcome. If treatment is

successful, there may be permanent and possibly severe neurologic

defects.

 

Prevention

 

Rabies prevention depends on the vaccination of pets,

to prevent exposure and subsequent transmission to humans,

and the prevention of bites from rabid animals. Wild animals

should not be handled or fed, and wildlife behaving abnormally

should, in particular, be avoided. Bats should be kept

out of houses and public buildings. In some areas, oral vaccination

of wild animal reservoirs may be practiced.

Veterinarians and animal control officers should handle

potentially rabid animals with extreme caution. Protective

clothing such as thick rubber gloves, eye goggles and a plastic

or rubber apron should be worn when doing autopsies or in other circumstances when exposure to infectious tissues

could occur.

Bites or other exposure should be reported immediately.

Post-exposure prophylaxis consists of immediate

wound cleansing and disinfection, rabies vaccination and the

administration of human rabies immunoglobulin. The rabies

vaccine is given as five doses in the U.S., usually administered

intramuscularly in the arm. Fewer doses and no rabies

immunoglobulin are given if the person was previously vaccinated.

Asymptomatic dogs, cats or ferrets that have bitten

humans are currently observed for 10 days; if the animal

develops symptoms of rabies during this time, it is euthanized

and tested for rabies.

An inactivated human vaccine is available for veterinarians,

animal handlers, laboratory workers and others at a high

risk of exposure. International travelers may in some cases

also be vaccinated. There is little or no cross-protection with

some rabies-related viruses, particularly the Mokola virus.

Rabies vaccination does not prevent the need for post-exposure

prophylaxis, but does eliminate the requirement for

rabies immune globulin and decreases the number of postexposure

vaccinations. It may also provide some protection

for persons with inapparent exposure or enhance immunity

if postexposure prophylaxis is delayed.

 

Morbidity and Mortality

 

In the U.S., clinical rabies is rare in humans, with 0 to 3

cases usually reported each year. Deaths are usually reported

in people who did not realize they had been exposed or,

for some other reason, did not seek medical treatment. Postexposure

prophylaxis, begun promptly, is almost always successful.

Human rabies is also rare in Canada, most European

countries, and some countries in South America. The prevalence

rates are high in some parts of the developing world.

Worldwide, approximately 90% of rabies cases occur

after exposure to rabid dogs. In countries with a high percentage

of vaccinated dogs, they are much less important as

a vector. In the U.S., most recent human cases were associated

with exposure to bats.

Factors that affect the outcome of exposure include the

virus variant, dose of virus, route and location of exposure,

and host factors such as age and immune status. Without

post-exposure prophylaxis, an estimated 20% of people

bitten by rabid dogs develop rabies. Once the symptoms

appear, the disease is almost always fatal within three

weeks, even with intensive care. There have been only

six reported cases of survival through the acute illness,

and some of these people were left with severe neurologic

complications. All had been treated with a rabies vaccine

before or soon after exposure, and before the symptoms

developed. Some of these cases could have been post-vaccinal

encephalomyelitis rather than rabies

 

Infections in Animals

Species Affected

 

All mammals are susceptible to rabies. Important reservoir

hosts include members of the Canidae (dogs, jackals,

wolves, foxes), Mustelidae (skunks, martens, weasels and

stoats), Viverridae (mongooses and meerkats), and Procyonidae

(raccoons), and the order Chiroptera (bats).

Reservoir hosts important in various world regions

include: insectivorous bats, skunks, raccoons and foxes in

the U.S.; foxes in continental Europe, Canada, Greenland

and the former Soviet Union

Dogs in Africa, Asia, and Central and South America;

jackals in parts of Africa, Asia and the Middle East; vampire

bats in South America; wolves in Asia and eastern Europe;

mongooses in the Caribbean; meerkats in southern Africa;

raccoon dogs in Russia and adjacent countries.

 

Incubation Period

 

The incubation period varies with the amount of virus

transmitted, virus strain, site of inoculation (bites closer to

the head have a shorter incubation period), host immunity

and nature of the wound. In dogs and cats, the incubation

period is 10 days to six months; most cases become apparent

between two weeks and two months. In cattle, an incubation

period from 25 days to more than five months has been

reported in vampire bat-transmitted rabies.

 

Clinical Signs

 

The initial symptoms of rabies are often nonspecific

and may include apprehension, restlessness, anorexia or an

increased appetite, vomiting, a slight fever, dilation of the

pupils, hyperreactivity to stimuli, and excessive salivation.

The first sign of post-vaccinal rabies is usually lameness in

the vaccinated leg. Animals often have behavior and temperament

changes, and may either become unusually aggressive

or uncharacteristically affectionate. Pigs typically have

a very violent excitation phase at the onset of disease. These

symptoms usually last for 2 to 5 days, and may be followed

by a phase in which either the paralytic or the furious form

of rabies predominates.

The paralytic (“dumb”) form of rabies is characterized

by progressive paralysis. In this form, the throat and masseter

muscles become paralyzed; the animal may be unable to swallow

and can salivate profusely. There may be facial paralysis

or the lower jaw may drop. Ruminants may separate from the

herd, become somnolent or depressed, and rumination may

stop. Ataxia, incoordination and ascending spinal paresis or

paralysis are also typical of this form. The paralytic form of

rabies may be preceded by a brief excitatory phase, or none at

all. Biting is uncommon. Death usually occurs within 2 to 6

days, as the result of respiratory failure The furious form is associated with infection of the limbic

system, and is the predominant form in cats. It is characterized

by restlessness, wandering, howling, polypnea,

drooling and attacks on animals, people or inanimate objects.

Animals with this form often swallow foreign objects such

as sticks, stones, straw or feces. Wild animals often lose their

fear of humans and nocturnal animals may be seen in the

daylight. Cattle may appear unusually alert. Convulsions

can occur, particularly in the terminal stages. In the furious

form of rabies, death sometimes occurs during a seizure but,

in most cases, incoordination and ascending paralysis are

seen late in the disease. The animal usually dies 4 to 8 days

after the onset of symptoms.

The symptoms of rabies are rarely definitive, and it

may be difficult to distinguish the furious and dumb forms.

The most reliable clinical signs are behavioral changes and

unexplained paralysis. In some cases in cats, no behavioral

changes were noticed, and the illness appeared to begin as

ataxia or posterior weakness, followed by ascending paralysis.

Horses and mules are often distressed and extremely agitated,

which may be interpreted as colic. Laryngeal paralysis

can cause a change in vocalizations, including an abnormal

bellow in cattle or a hoarse howling in dogs. Some animals

may die within a day, without marked clinical signs. Survival

is extremely rare once the clinical signs appear.

 

Communicability

 

All species can infect humans and other animals, but the

efficiency of transmission varies with the host species and

the form of rabies. Animals with the furious form of rabies

are more likely to disseminate rabies than animals with the

paralytic form. Carnivores are also more efficient vectors, in

general, than herbivores. Herbivore-to-herbivore transmission

is uncommon. Insectivorous bats have been implicated

in most recent human cases in the U.S.

Virus shedding occurs in 50-90% of animals, depending

on the host species and the infecting strain; the amount of

virus found in the saliva varies from a trace to high titers.

Shedding can begin before the onset of clinical signs. Cats

excrete virus for 1 to 5 days before the symptoms appear,

cattle for 1 to 2 days, skunks for up to 14 days and bats

for two weeks. Virus shedding in dogs is usually said to be

limited to the 1 to 5 days before the onset of clinical signs;

however, in some experimental studies (using viruses of

Mexican or Ethiopian origin), the virus was present in the

saliva for up to 13 days before the first symptoms appeared.

Asymptomatic carriers are thought to be very rare among

domestic animals. Cases have been reported among dogs in

Ethiopia and India, including one experimentally infected dog

that recovered from rabies symptoms and carried the virus in

her saliva and tonsils, but not the brain or other organs.

 

Diagnostic Tests

 

The rabies virus is usually identified by immunofluorescence

in a brain sample. The virus can also be found in other

tissues such as the salivary gland, tactile facial hair follicles

and corneal impression smears but detection is less efficient.

Immunofluorescence can identify 98-100% of cases caused

by all genotypes of the rabies and rabies-related viruses, and

is most effective on fresh samples. Other tests to detect the

virus include immunohistochemistry and enzyme-linked

immunosorbent assays (ELISAs). The rapid rabies enzyme

immunodiagnosis (RREID) test, an ELISA, detects only

the rabies virus and not rabies-related viruses. Histology to

detect aggregates of viral material in neurons (Negri bodies)

is nonspecific and rarely used in developed countries, but

may be an important technique in less developed nations.

Electron microscopy is used in research laboratories. RTPCR-

based techniques have been published.

A single negative test does not rule out infection; therefore,

mouse inoculation or virus isolation in cell culture

(mouse neuroblastoma or baby hamster kidney cells) is

often done concurrently. Identification of variant strains is

performed in specialized laboratories with monoclonal antibodies,

specific nucleic acid probes, or RT-PCR followed by

DNA sequencing.

Serology is occasionally used in epidemiological surveys

or to test seroconversion in wildlife vaccination campaigns.

It is rarely useful for the diagnosis of clinical cases,

as the host usually dies before developing antibodies. Serological

tests include virus neutralization tests and ELISAs.

There is some cross-reactivity between the rabies virus and

rabies-related viruses.

 

Treatment

 

There is no treatment once the symptoms appear. Postexposure

vaccination protocols have not been validated in

animals, and are not recommended by most authorities.

Experimental studies suggest that post-exposure vaccination

alone will not prevent rabies in unvaccinated animals,

but vaccination combined with a monoclonal antibody may

be effective.

 

Prevention

 

In the U.S., rabies is prevented in domestic animals by

vaccination and the avoidance of contact with rabid wild

animals.

Rabies vaccines are available for dogs, cats, ferrets,

cattle, sheep and horses. Both inactivated and modified live

vaccines are effective, but rare cases of post-vaccinal rabies

have been reported with the modified live vaccines in dogs

and cats. Wild animals can be immunized with oral vaccines

distributed in bait. Conventional rabies vaccines may not

protect animals against rabies-related viruses, particularly

the Mokola virus. Preventing animals from roaming will reduce the risk

of exposure to rabid wild animals. Infected wild animals

often behave strangely, are active at unusual times of the day

or night, or attack species they would normally fear; such

wildlife should be avoided. Bats caught by cats should be

submitted for rabies testing.

To prevent the transmission of rabies to humans or other

animals, unvaccinated animals that have been exposed are

either euthanized and tested, or placed in strict isolation for

6 months, with vaccination one month before release. Vaccinated

animals are revaccinated and confined under observation

for at least 45 days. Animals with expired vaccinations

are evaluated on a case-by-case basis. Asymptomatic dogs,

cats or ferrets that have bitten humans (with no history of

exposure to rabies) are currently observed for 10 days; if the

animal develops symptoms of rabies during this time it is

euthanized and tested for rabies. Countries free of the rabies

virus may require a prolonged quarantine period before animals

can be imported.

 

Morbidity and Mortality

 

The majority of rabies cases in the U.S. occur in wildlife.

In 2001, 37% of all animal cases were reported in raccoons,

30% in skunks, 17% in bats, 6% in foxes and less

than 1% in other wild animals. Domestic animals account

for less than 10% of all cases reported annually. Vaccination

has decreased the incidence of rabies in dogs; the number of

rabid dogs reported in the U.S. dropped from 5,000 in 1946

to 338 in 1987. Currently, cats, cows, horses and captive

wild animals are more likely to develop rabies than dogs,

due to the lower vaccination rates in these species.

Factors that affect the outcome of exposure include the

virus variant, dose of virus, route and location of exposure,

and host factors such as age and immune status. Symptomatic

rabies is almost always fatal. A few, very rare, cases of

recovery after street virus or vaccine virus-induced rabies

have been reported in animals. In addition, one experimental

study reported that 8 of 47 dogs inoculated with rabies survived,

and were subsequently resistant to reinfection.

 

Post-Mortem Lesions

 

There are no characteristic gross lesions. The stomach

may contain various abnormal objects, such as sticks and

stones.

The typical histological signs, found in the central nervous

system, are multifocal, mild, polioencephalomyelitis

and craniospinal ganglionitis with mononuclear perivascular

infiltrates, diffuse glial proliferation, regressive changes in

neuronal cells, and glial nodules. Negri bodies can be seen

in some but not all cases.

 

References

 

Abelseth MK. Rabies. In: Holzworth J, editor. Diseases of

the cat. Philadelphia: WB Saunders; 1987. p. 238-241.

Acha PN, Szyfres B (Pan American Health Organization

[PAHO]). Zoonoses and communicable diseases common

to man and animals. Volume 3. Chlamydioses,

rickettsioses, and viroses. 3rd ed. Washington DC:

PAHO; 2003. Scientific and Technical Publication No.

580. Rabies; p.246-275.

Aiello SE, Mays A, editors. The Merck veterinary manual.

8th ed. Whitehouse Station, NJ: Merck and Co;

1998. Rabies; p 966-70.

Animal Health Australia. National Animal Health Information

System (NAHIS). Rabies. Available at: http://

www.aahc.com.au/nahis/disease/dislist.asp. Accessed

 

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