Rabies is an acute, progressive viral encephalomyelitis that principally affects carnivores and bats, although any mammal can be affected. The disease is fatal once clinical signs appear. Rabies is found throughout the world, with the exception of Antarctica. A few countries claim to be free of the disease because of either successful elimination programs or their island status and enforcement of rigorous quarantine regulations. Globally, the dog is the most important reservoir, particularly in less developed countries. Integrated veterinary management of local animal populations, by mass vaccination of dogs and community promotion of responsible pet ownership, is the most cost-effective, humane, longterm solution toward eliminating regional canine rabies in a One Health context.
Etiology and Epidemiology of Rabies
Rabies is caused by lyssaviruses in the Rhabdovirus family, Lyssavirus genus. Lyssaviruses are usually confined to one major reservoir species in a given geographic area, although spillover to other species is common. Identification of different virus variants by laboratory procedures, such as monoclonal antibody analysis or genetic sequencing, has greatly enhanced understanding of rabies epidemiology. Generally, each virus variant is responsible for virus transmission between members of the same species in a given geographic area. To date, >16 different lyssaviruses have been described. Globally, rabies virus is the most important member of the genus. Information presented here on the diagnosis, pathogenesis, clinical signs, and prevention of rabies virus infection are generally applicable to other lyssaviruses as well.
From an epidemiologic perspective, the name of the mammalian species acting as the reservoir and vector is used as an adjective to describe involvement in the infection process. For example, rabies maintained by dog-to-dog transmission is termed canine rabies, whereas rabies in a dog as a result of infection with a variant from a different reservoir mammal, eg, skunk (or raccoon or fox), would be referred to as skunk (or raccoon or fox, etc) rabies in a dog.
In North America, distinct virus variants are responsible for rabies perpetuation in red and Arctic foxes in Canada and Alaska, raccoons along the eastern seaboard from Maine to Florida, and gray foxes in the southwest, including Arizona, Colorado, and Texas. Two different variants are responsible for rabies in striped skunks, one in the south central states and the other in the north central states, which often extends into the Canadian prairies. Another skunk rabies virus variant is found in California. By comparison, the epidemiology of rabies in bats is complex. In general, each variant found in bats may be characterized with a predominant bat species. Spillover from bats to other mammals is seen infrequently. Most human cases of rabies in the USA in the past decade have been caused by bat rabies virus variants (especially viruses associated with Lasionycteris noctivagans, the silver-haired bat, and Perimyotis subflavus, the tricolored bat).
Rabies emergence may be affected by changes in virus-host dynamics or human translocation of infected species. For many years, skunks were the most commonly reported rabid animal in the USA, but during 1990, rabid raccoons became the most numerous carnivore. Canine rabies became established in dogs and coyotes (Canis latrans) in southern Texas but was eliminated by the end of the 20th century. Canine rabies exists in parts of central America, with the potential to spread throughout the USA if reintroduced. Skunk, raccoon, and fox rabies are each found in fairly distinct geographic regions of North America, although some overlap occurs. Bat rabies is distributed throughout the Americas. The vampire bat is an important reservoir in Latin America and is the source of multiple outbreaks in cattle, as well as in people, particularly in parts of Amazonia.
In western Europe, red fox rabies predominated before its elimination by oral vaccination. In parts of eastern Europe, rabies in raccoon dogs is of increasing concern. Bat rabies, maintained by several different lyssaviruses in insectivorous Chiroptera, appears to be widely distributed throughout Europe.
Other wildlife play an important role in the transmission of rabies in certain areas, including different species of mongooses in the Caribbean, southern Africa, and parts of Asia; jackals in parts of Africa; wolves in parts of northern Europe; marmosets in Brazil; and ferret badgers in China.
All rabies reservoirs are also vectors of the virus, but not all vectors are reservoirs. For example, cats can effectively transmit rabies virus, but no cat-to-cat transmission of rabies perpetuates in lieu of a predominant reservoir (such as infected dogs), and no unique feline rabies virus variant has been documented. However, cats are the most commonly reported rabid domestic animal in the USA. Virus is present in the saliva of rabid cats, and people have developed rabies after being bitten by rabid cats. Reported cases in domestic cats have outnumbered those in dogs in the USA every year since 1990.
Transmission and Pathogenesis of Rabies
Lyssaviruses are highly neurotropic. Transmission of rabies almost always occurs via introduction of virus-laden saliva into tissues, usually by the bite of a rabid animal. Although much less likely, virus from saliva, salivary glands, or brain can cause infection by entering the body through fresh wounds or intact mucous membranes. Saliva is infectious at, or before, the time clinical signs occur. Domestic dogs, cats, and ferrets may shed virus up to 10 days before onset of clinical signs. Viral shedding in wildlife has been reported for several weeks before onset of signs. Rabies virus has not been isolated from skunk musk (spray).
The incubation period is both prolonged and variable. Typically, rabies virus remains at the inoculation site for a considerable time. The unusual length of the incubation period helps to explain the effective action of local infiltration of rabies immune globulin during human postexposure prophylaxis, even days after exposure. Most rabies cases in dogs develop within 21–80 days after exposure, but the incubation period may be shorter or considerably longer. One recorded case of rabies in a person in the USA had an incubation period estimated reliably to be >8 years.
Rabies virus travels via the peripheral nerves to the spinal cord and ascends to the brain. After reaching the brain, the virus travels via peripheral nerves to the salivary glands and other organs. If an animal is capable of transmitting rabies via its saliva, virus will be detectable in the brain. Virus is shed intermittently in the saliva.
Hematogenous spread does not occur. Under most circumstances, there is no danger of aerosol transmission of rabies virus. However, aerosol transmission has occurred under very specialized conditions in which the air contained a high concentration of suspended particles or droplets carrying viral particles. Such conditions have been responsible for laboratory transmission under less than ideal containment situations. There has been a suggestion of very rare natural aerosol transmission in a cave inhabited by millions of bats. Oral and nasal secretions containing virus were probably aerosolized from tens of thousands of rabid bats in a confined roost space within a cave. Aerosol infection may occur via direct attachment of the virus to olfactory nerve endings.
Near the end of the clinical phase, after replication in the CNS, rabies virus may be found in nearly every innervated organ. Rabies virus has been transmitted by transplantation of tissues and organs from infected people.
Clinical Findings of Rabies
Clinical signs of rabies are rarely definitive. Rabid animals of all species usually exhibit typical signs of CNS disturbance, with minor variations among species. The most reliable signs, regardless of species, are acute behavioral changes and unexplained progressive paralysis. Behavioral changes may include sudden anorexia, signs of apprehension or nervousness, irritability, and hyperexcitability (including priapism). The animal may seek solitude. Ataxia, altered phonation, and changes in temperament are apparent. Uncharacteristic aggressiveness may develop—a normally docile animal may suddenly become vicious. Commonly, rabid wild animals may lose their fear of people, and normally nocturnal species may be seen wandering about during the daytime.
The clinical course may be divided into three general phases—prodromal, acute excitative, and paralytic/endstage. However, this division is of limited practical value because of the variability of signs and the irregular lengths of the phases. During the prodromal period, which lasts ~1–3 days, animals show only vague nonspecific signs, which intensify rapidly. The disease progresses rapidly after the onset of paralysis, and death is virtually certain a few days thereafter. Some animals die rapidly without marked clinical signs.
The furious form of rabies refers to animals in which aggression (the acute neural excitative phase) is pronounced. This is the classic “mad-dog syndrome,” although it may be seen in all species. There is rarely evidence of paralysis during this stage. The animal becomes irritable and, with the slightest provocation, may viciously and aggressively use its teeth, claws, horns, or hooves. The posture and expression is one of alertness and anxiety, with pupils dilated. Noise may invite attack. Such animals lose caution and fear of people and other animals.
Carnivores with the furious form of rabies frequently roam extensively, attacking other animals, including people, and any moving object. They commonly swallow foreign objects, eg, feces, straw, sticks, and stones. Rabid dogs may chew the wire and frame of their cages, breaking their teeth, and will follow a hand moved in front of the cage, attempting to bite. Young pups can seek human companionship and are overly playful, but bite even when petted, usually becoming vicious in a few hours. Rabid skunks may seek out and attack litters of puppies or kittens. Rabid domestic cats and bobcats can attack suddenly, biting and scratching viciously. As the disease progresses, muscular incoordination and seizures are common. Death results from progressive paralysis.
The paralytic form of rabies is manifest by ataxia and paralysis of the throat and masseter muscles, often with profuse salivation and the inability to swallow. Dropping of the lower jaw is common in dogs. Owners frequently examine the mouth of dogs and livestock searching for a foreign body or administer medication with their bare hands, thereby exposing themselves to rabies. These animals may not be vicious and rarely attempt to bite. The paralysis progresses rapidly to all parts of the body, and coma and death follow in a few hours.
Cattle with furious rabies can be dangerous, attacking and pursuing people and other animals. Lactation ceases abruptly in dairy cattle. The usual placid expression is replaced by one of alertness. The eyes and ears follow sounds and movement. A common clinical sign is a characteristic abnormal bellowing, which may continue intermittently until shortly before death.
Horses and mules frequently show evidence of distress and extreme agitation. These signs, especially when accompanied by rolling, may be interpreted as evidence of colic. As in other species, horses may bite or strike viciously and, because of their size and strength, become unmanageable in a few hours. People have been killed outright by such animals. These animals frequently have self-inflicted wounds.
Rabid foxes and coyotes often invade yards or even enter houses, attacking dogs and people. One abnormal behavior that can occur is demonstrated by an animal that attacks a porcupine; finding a fox, or another animal, with porcupine quills can, in many cases, support a diagnosis of rabies.
Rabid raccoons, foxes, and skunks typically show no fear of people and are ataxic, frequently aggressive, and active during the day, despite their often crepuscular nature. In urban areas, they may attack domestic pets.
In general, rabies should be suspected in terrestrial wildlife acting abnormally. The same is true of bats that can be seen flying in the daytime, resting on the ground, paralyzed and unable to fly, attacking people or other animals, or fighting.
Rodents and lagomorphs rarely constitute a risk of exposure to rabies virus. However, each incident should be evaluated individually. Reports of laboratory-confirmed rabies in woodchucks are not uncommon in association with the raccoon rabies epizootic in the eastern USA.
Diagnosis of Rabies
Immunofluorescence microscopy on fresh brain tissue is the test of choice
Clinical diagnosis may be suggestive of an apparent encephalitis to the skilled practitioner but is difficult for the practicing veterinarian within developed countries, especially in areas where rabies is uncommon. Diagnosis based on clinical signs should not be relied on when making public health decisions. In the early stages, rabies can easily be confused with other diseases or with individual aggressive tendencies. Therefore, when rabies is suspected and definitive diagnosis is required, laboratory confirmation is indicated. Suspect animals should be euthanized, and the head removed for laboratory shipment.
Rabies virus diagnosis should only be done by a qualified laboratory, designated by the local or state health department in accordance with established standardized national protocols for such viral testing. Typically, the suspect animal is euthanized, and the brain is removed as the preferred organ for testing. Immunofluorescence microscopy on fresh brain tissue, which allows direct visual observation of a specific antigen-antibody reaction, is the current test of choice. When properly used, it can establish a highly specific diagnosis within a few hours. Brain tissues examined must include the medulla oblongata and cerebellum (and should be preserved by refrigeration with wet ice or cold packs). Virus isolation by tissue culture techniques using mouse neuroblastoma cells may be used for confirmation of indeterminate fluorescent antibody results, but it is no longer in common use in the USA. Molecular testing, including real-time PCR, is becoming more standard in modern diagnostic laboratories. The World Health Organization recommends methods for the detection of rabies virus antigens, amplicons, and antibodies .
Prevention and Control of Rabies
Vaccination and registration of dogs, with control of stray populations
Oral vaccination of wildlife can reduce rabies in reservoir populations
Domestic Animal Management
Comprehensive guidelines for control in dogs have been prepared internationally by the World Health Organization and in the USA by the National Association of State Public Health Veterinarians (NASPHV). The guidelines include the following:
Notification of suspected cases, and euthanasia of dogs with clinical signs and dogs bitten by a suspected rabid animal
Reduction of contact rates between susceptible dogs by leash laws, dog movement control, and quarantine
Mass immunization of dogs by campaigns and by continuing vaccination of young dogs
Stray dog control and euthanasia of unvaccinated dogs with low levels of dependency on, or restriction by, people
The Compendium of Animal Rabies Control, compiled and updated regularly by the NASPHV, summarizes the most current recommendations for the USA and lists all USDA-licensed animal rabies vaccines marketed in the USA. Many effective vaccines, such as modified-live virus, recombinant, and inactivated types, are available for use throughout the world; in the USA, no modified-live rabies virus vaccines are currently marketed (for any species). Recommended vaccination frequency is every 3 years, after an initial series of two vaccines 1 year apart. Several vaccines are also available for use in cats, and a few for use in ferrets, horses, cattle, and sheep. Because of the increasing importance of rabies in cats, vaccination of cats is critical. No parenteral vaccine is approved for use in wildlife. Protective immunity from the commercially available vaccines for domestic species has not been definitively demonstrated in wildlife species.
Oral Vaccination of Wildlife
Until recently, the control of rabies in wildlife populations relied on population reduction of wildlife in an attempt to reduce the contact rate between susceptible animals; however, this proved difficult and often not publicly acceptable, ecologically sound, economically warranted, or programmatically effective. In Europe and Canada, use of oral vaccines distributed in baits to control fox rabies has been widespread and effective. The disease in foxes has been eliminated from most of western Europe and curtailed significantly in Ontario. Use of a vaccinia-rabies glycoprotein recombinant virus vaccine in the USA has successfully eliminated coyote rabies in southern Texas and has limited the western expansion of raccoon rabies from the eastern USA. Another product, a human adenovirus-rabies recombinant vaccine, has also been used successfully for the oral vaccination of wildlife within North America.
At present,the licenses limit use of these vaccines to state or federal rabies programs; they are not available to private veterinarians or for individual animal use. Together with other biologics, such oral vaccines may also be used to assist in the control of dog rabies in developing countries.
Management of Suspected Rabies Cases—Exposure of Pets
Where carnivore or bat rabies is known to occur, any animal bitten or otherwise exposed by a wild, carnivorous mammal (or a bat) not available for testing should be regarded as having been exposed to rabies virus. The NASPHV recommends that any unvaccinated dog, cat, or ferret exposed to rabies be euthanized immediately. If the owner is unwilling to do this, the animal should be placed in strict isolation (ie, no human or animal contact) for 4-–6 months and vaccinated against rabies as soon as possible upon entry into quarantine. If an exposed domestic animal is currently vaccinated, it should receive medical assessment and wound care, be revaccinated immediately, and be closely observed for 45 days.
Zoonotic Risk of Rabies
Rabies has the highest case fatality of any infectious disease. When a person is exposed to an animal suspected of having rabies, the risk of rabies virus transmission should be evaluated carefully. Risk assessment should include consideration of the species of animal involved, the prevalence of rabies in the area, whether exposure sufficient to transmit rabies virus occurred, and the current status of the animal and its availability for diagnostic testing.
Wild carnivores and bats present a considerable risk where the disease is found, regardless of whether abnormal behavior has been observed. Insectivorous bats, though small, can inflict wounds with their teeth and should never be caught or handled with bare hands. Bat bites may be ignored or go unnoticed, so direct contact with bats could be considered a risk of virus exposure. Any wild carnivore or bat suspected of exposing a person to rabies should be considered rabid unless proved otherwise by laboratory diagnosis; ideally, this includes bats in direct contact with people, such as those found in rooms with sleeping or otherwise unaware persons. Wildlife, including wolf hybrids, should never be kept as pets; if one of those animals exposes a person or domestic animal, the wild animal should be managed like free-ranging wildlife.
Any healthy domestic dog, cat, or ferret, whether vaccinated against rabies or not, that exposes (bites or deposits saliva in a fresh wound or on a mucous membrane) a person should be confined for 10 days; if the animal develops any signs of rabies during that period, it should be euthanized and its brain promptly submitted for rabies diagnosis. If the dog, cat, or ferret responsible for the exposure is stray or unwanted, it may be euthanized as soon as possible and submitted for rabies diagnosis. Since the advent of testing by immunofluorescence microscopy, there is no value in holding such animals to “let the disease progress” as an aid to diagnosis.
Internationally, the World Health Organization recommends several types of cell-culture vaccines for human groups at risk. In the USA, guidelines for human rabies prevention follow recommendations prepared by the Advisory Council on Immunization Practices. Preexposure immunization is strongly recommended for people in high-risk groups, such as veterinary staff, animal control officers, rabies and diagnostic laboratory workers, and, under certain circumstances, some travelers working in countries in which canine rabies is enzootic. Preexposure vaccine is administered on days 0, 7, and 21 or 28. However, preexposure prophylaxis alone cannot be relied on in the event of subsequent rabies virus exposure and must be supplemented by a limited postexposure regimen (two doses of vaccine, IM, on days 0 and 3). For healthy, unvaccinated patients bitten by a rabid animal, postexposure prophylaxis consists of wound care, local infiltration of rabies immune globulin, and vaccine administration on days 0, 3, 7, and 14. When provided in a timely and appropriate manner, modern postexposure prophylaxis virtually assures human survival.
Rabies is an acute, progressive, incurable viral encephalitis. This zoonosis has the highest case fatality of any infectious disease.
All mammals are believed susceptible to rabies virus and other lyssaviruses. Dog vaccination is the single most useful and cost-effective measure for modern rabies prevention and control.
Preexposure vaccination should be given to all persons at risk of rabies exposure, including veterinarians.
Human rabies can be prevented after exposure by proper wound care, infiltration of all bite sites with rabies immune globulin, and the administration of several doses of human rabies vaccine.
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