What is rabies?

Causes and Symptoms

Rabies is caused by a bullet-shaped virus that attacks warm-blooded animals, especially mammals. The virus can enter many types of mammal cells and cause them to produce and bud off new viruses, but it is particularly adept at attacking nerve cells and glandular cells. This combination enhances the virus’s chance of being transmitted to another host.

The following sequence of events occurs in an untreated human being after being bitten by a rabid animal. The bite introduces large amounts of saliva, which contains abundant rabies virus because of the virus’s efficient growth in salivary glands. The virus enters muscle cells in the vicinity of the bite and replicates there. The new viruses then enter the nerve cells that carry signals from the brain and spinal cord to the muscle cells. They move along these nerve cells to the spinal cord, eventually making their way to the brain. The viruses replicate at certain sites as they ascend the nerve and spinal cord. In the brain, they replicate especially well in the centers that control emotions. Once established in the brain and spinal cord, the virus moves out of these organs along the nerves to most organs of the body. The salivary glands are favored targets in this migration.

As a result of its extensive migrations, the virus is present in many tissues of the body, but the critical ones for the pathology and transmission of the disease are the brain and salivary glands, where the virus reproduces especially well. To understand this relationship between transmission and pathology, consider the dog or other animal that bit the human being described above. A sequence of events similar to that described for the human being has occurred in the animal. The viruses attacking the emotional centers of the animal’s brain initiated the characteristic aggressive state in which it wandered aimlessly, attacking anything it encountered. Viruses attacking the brain also stimulated the production and release of copious amounts of saliva, giving rise to another familiar symptom of rabies: frothing at the mouth. The viruses reproducing in the salivary glands, along with the excessive salivation, assured that an abundance of virus would be chewed into the wound.

The time sequence and pathology of a human victim include an incubation period that may range from ten days to a year; in most victims, however, it is between two and eight weeks. During this time, the virus is replicating in cells at the site of the bite and moving to the central nervous system. As the nervous system begins to be involved, generalized symptoms begin. These include fever, headaches, and nausea and last about a week. Neurologic symptoms then develop, including hyperactivity, seizures, and hallucinations. The throat sometimes becomes so sore and prone to spasms that the patient has trouble swallowing and fears choking while drinking. Another common name for rabies, hydrophobia (literally, fear of water), is based on this aspect of the disease. Paralysis and
coma occur about a week after the onset of the neurologic symptoms, and death follows a few days later. Once the symptoms begin in a human being, the disease is nearly always fatal.

In dogs, a similar sequence of events occurs, though the timing is somewhat different and dogs occasionally recover. The aggressive stage described above is called the furious stage in animals, and the gradual development of paralysis is called the paralytic, or dumb, stage. Both phases may occur in dogs or the furious stage may be bypassed, but death commonly occurs shortly after symptoms begin.

Rabies in wildlife is called sylvatic rabies, and the species of wildlife involved differ according to geographic area. Some species act as the virus’s reservoir and as the source of rabies epidemics in humans or their pets. In arctic regions of North America and Eurasia, arctic foxes and wolves are the most important hosts of sylvatic rabies. Red and gray foxes and skunks play important roles in spreading the disease in various parts of eastern Canada and the United States, as do raccoons. Some investigators believe that weasels and their relatives are important carriers in maintaining the virus in nature in many areas, although they are not particularly important in the direct transfer of the virus to humans.
Bats are common sources of rabies throughout the United States, but especially in the southern part of the country. They play a major role in rabies epidemiology in Mexico and Central and South America, where the disease often occurs in vampire bats.

In 2010, there were 6,153 cases of rabies in animals and only 2 cases of rabies in humans reported in the United States and Puerto Rico. Raccoons (36.5 percent), bats (23.2 percent), skunks (23.5 percent), and foxes (7 percent) were the most commonly infected animals. In 2010 8 percent of rabies reports were for demestic species. Surprisingly, there were more cats than dogs reported with rabies, undoubtedly due to rabies vaccination programs for dogs.

Other mammals, both wild and domestic, are attacked by the virus, but they are not important in transmitting rabies between species or in acting as reservoirs. Examples of these species are grazing and browsing animals such as cattle and deer, which seldom bite other animals and so are not likely to pass the virus to other creatures. Many of these animals die from rabies, however, and the economic and ecological impact of these deaths may be great.

These animals are attacked by the virus in the same manner as are humans and dogs, and they show similar symptoms. Rabid wild animals do not always suffer a furious stage. Raccoons, for example, often skip the furious stage and go directly into the dumb stage. Early in this stage they may lose their fear of humans and appear to be friendly. If left alone, they seldom attack, but humans who approach these “friendly” raccoons may be bitten and exposed to rabies. Many bat species also do not go through the furious stage; a bat suffering from dumb rabies is easily caught and may bite if handled, exposing the handler to rabies. Unlike humans, bats, skunks, raccoons, and other wildlife often survive the symptoms of rabies.

In addition to the disease it causes in humans and their pets, the rabies virus has had other negative impacts on human society. Rabies transmitted to cattle by vampire bats has had a devastating economic effect on the cattle industry in all of Latin America. Rabies in red foxes has occasionally had a detrimental effect on Canada’s fur industry. Wildlife populations in many parts of the world may be periodically decimated by rabies epidemics, which sometimes reduces the population of a species of recreational importance to humans or one critical to the ecological stability of a region.

Treatment and Therapy

Active immunization by vaccination can be used after exposure to rabies because of the relatively long latency period of the virus. If a person has been bitten by a rabid animal, symptoms usually do not appear for two or more weeks. Prompt vaccination after the bite induces the production of antibodies that attack the virus and neutralize it before it reaches the central nervous system. Two other precautions are often taken. The wound is cleaned and treated with antiviral agents, and passive immunity is often produced by injecting antirabies antiserum into the victim.

The rabies inoculations of early immunization series were numerous, extremely painful, and not always successful. Since the early twentieth century, it has been possible to determine whether the attacking animal was rabid and thus whether this painful treatment was necessary. The animal was sacrificed, and its brain was sectioned and stained. Treated in this way, a rabid animal’s brain cells often display Negri bodies, named for the scientist who first described them. They are the sites of production of new virus in the brain cell, and their presence indicates the need for vaccination of the victim. Even though the immunization sequence that was first developed was painful, the certain death that followed the onset of symptoms made immunization imperative if there was any possibility of rabies exposure.

Improved immunization sequences and rabies tests have been developed. Refined and nearly infallible, these immunization sequences require only three inoculations and are no more painful than most shots. Tests using antibodies are more rapid and reliable at detecting the presence of the rabies virus than the test for Negri bodies.

Preexposure immunization, in contrast to the postexposure immunization described above, is used to protect persons who might be exposed to rabies in their normal activities and to protect pets from contracting rabies. Since the overwhelming majority of human cases of rabies come from dog bites, pet vaccination is the most important part of the successful rabies control programs of developed countries. Laws requiring the immunization of pets against rabies and leash laws (which require that pets be controlled and not allowed to wander freely) have been very effective in reducing human rabies in these countries.

Because wildlife may harbor rabies, attempts have been made to control or eliminate the disease by killing (culling) or immunizing wildlife. Neither approach has been particularly successful, and the first is accompanied by troublesome side effects. The purpose of culling members of host species is to reduce the host population below the point that will sustain the rabies virus’s population. This method is based on the idea that each infected host must, on the average, infect at least one other susceptible host before it dies in order for the parasite to persist in the population. The lower the host population, the lower the chance of one host meeting another and thus the lower the probability of an infected host infecting other members of the population. Yet many of the methods of culling (trapping and poisoning, for example) are not species-specific, and members of other species are killed, sometimes in large numbers. Culling has also been ineffective in many cases. It is most successful in small, isolated areas with a low probability of reinvasion.

Instead of reducing the population size of the host, the goal of immunization is to reduce the number of members that are susceptible to rabies by increasing the number that are immune. Oral immunization by scattering bait containing rabies vaccine has shown promising results in reducing rabies in foxes, coyotes, and raccoons.

An argument against immunization of wildlife to control human rabies is based on the success of the control programs in effect and can be stated as follows. Immunization and regulation of pets, preexposure immunization for humans regularly exposed to rabies, and effective postexposure treatment have already minimized the incidence of human rabies in developed nations. Therefore, wildlife immunization is not necessary for the control of human rabies. In developing nations, where human rabies is still a serious disease, all the potential solutions strain the available resources, but the most cost-effective solution would be the one in use in developed countries. There is general agreement, however, that wildlife immunization might be an effective way to increase the population size of a wildlife species that is normally susceptible to rabies, if desirable.

To control vampire bats in Latin America, where rabies carried by vampire bats burdens the cattle industry, culling has been attempted repeatedly, often unsuccessfully, and with serious side effects. For example, other bat species, some of which are important to insect control and the pollination of fruit trees, have been regular victims of indiscriminate attempts at vampire bat control by culling.

A more effective, and less ecologically disruptive, method for the control of vampire bats employs anticoagulants. These chemicals stimulate bleeding in the digestive tract of vampire bats that swallow them, resulting in death. The anticoagulant can be applied directly to the backs of the vampire bats and will spread through the bat population when the bats groom one another at the roosting colony. Alternatively, anticoagulant can be injected into a cow’s rumen, the enlarged first chamber of its four-part stomach. The anticoagulant is then absorbed into the animal’s blood and spread to vampire bats when they feed on the cattle.

In test areas, each method has reduced the number of vampire bat bites in cattle by 90 percent, but each has drawbacks. Direct application to these bats requires extensive netting or trapping, special equipment, and workers skilled in vampire bat identification. The rumen injection technique requires expensive equipment for, and workers experienced in, handling large numbers of cattle. In developing countries, either combination can be difficult to finance.

Education is another important aspect of rabies control. While dogs are the most common source of human rabies, humans occasionally contract the disease after being bitten by a wild animal. In addition, there are potential avenues of transfer other than bites. These include skinning rabid animals, being licked by a rabid animal on broken skin, and breathing air infested with the rabies virus. All these alternative transmission mechanisms are exceptionally infrequent, but there are documented cases of aerial transmission to humans. For example, two men who were not bitten died of rabies contracted while exploring a bat cave in Texas. To be transmitted in this way, the rabies virus must be highly concentrated in the air. These concentrations probably occur only in caves occupied by a large number of bats, and many of them must be carrying the rabies virus.

While educating spelunkers and hunters to these dangers would have a minimal effect on the incidence of rabies, as these transmission mechanisms are so infrequent, such educating could be of the utmost importance to an individual who is spared a rabies infection by the knowledge. Educating people, especially children, to leave animals acting in an unnatural fashion alone would have a somewhat greater effect on rabies incidence. Most wild animals that can be caught or approached closely are sick and may be suffering from dumb or paralytic rabies. They should be avoided and reported to the appropriate authorities, as should any dog or cat that behaves unnaturally. Educating the public about the importance of pet vaccination and pet control is the most important role of education in the regulation of rabies.

Perspective and Prospects

Rabies in humans and its association with attacks by mad dogs have been known for more than two thousand years. Despite the fact that rabies has never caused epidemics accompanied by mass mortality as have smallpox and bubonic plague, its frightful symptoms and ability to turn a loving family pet into a vicious animal have given the disease a terrifying and mysterious aura. As a result, cures and preventions have been sought throughout history.

In the late nineteenth century,
Louis Pasteur and his associates performed a series of experiments in which the rabies virus was isolated from a dog and injected into rabbit brains. Pasteur called this virus a “street” virus because it was isolated directly from dogs in the street. The virus replicated in the rabbit brain and could be transferred into another rabbit’s brain, where it again replicated. Growth of the virus in one of the rabbit brains was called a “passage.” A sequence of such passages resulted in a virus which had a more predictable and shorter incubation period. This virus was called a “fixed” virus because of its fixed incubation period. After a hundred such passages, the virus had lost much of its ability to infect dogs.

Pasteur then developed an immunization sequence that protected dogs from the street virus. He air-dried rabbit spinal cord tissue infected with the fixed virus for varying amounts of time and developed a series of virus solutions, ranging from those that could not infect rabbits through those that could occasionally establish weak infections to those that were maximally infective. He then injected dogs daily for ten days, beginning with the noninfective preparation the first day and increasing the infectivity with each day’s injection until, on the tenth day, he was injecting highly infective virus. Dogs so treated were resistant to experimentally injected street virus.

Pasteur was still refining his immunization system when a boy who had been attacked by a rabid dog was brought to him. Knowing that the latency period of the virus might allow time for the development of immunity before the symptoms appeared, and aware of the almost certain fatal result if nothing was done, Pasteur treated the boy with the sequence that he had used on the dogs. The boy lived, with no apparent side effects, and Pasteur’s treatment became the standard for rabies. The modern treatment sequence is a refinement of Pasteur’s. While the immunization sequence for rabies was not the first to be used successfully—smallpox immunization nearly a century earlier holds that distinction—the possibility of immunization after exposure to diseases with long incubation periods was established by Pasteur’s work.

Considerable work has been done on the epidemiology of rabies. Mathematical and computer models have been developed that attempt to predict the characteristics of the disease spread under different conditions, and thus suggest means of controlling and preventing rabies epidemics. Arguments over the effectiveness of wildlife vaccination are partially based on such models. The usefulness of these models is not restricted to rabies epidemiology but instead contributes to an understanding of epidemiology in general. Thus research on rabies continues to enhance the control and prevention of that terrifying disease and to add to the general knowledge base of medicine as well.

Bibliography:

Bacon, Philip J., ed. Population Dynamics of Rabies in Wildlife. New York: Academic Press, 1985.

Badash, Michelle. "Rabies." Health Library, December 30, 2011.

Baer, George M., ed. The Natural History of Rabies. 2d ed. Boca Raton, Fla.: CRC Press, 1991.

Biddle, Wayne. A Field Guide to Germs. 2d ed. New York: Anchor Books, 2002.

Blanton, Jesse D., et al. “Rabies Surveillance in the United States During 2007.” Journal of the American Veterinary Medical Association 233 (2008): 884-897.

Constantine, Denny G. “Health Precautions for Bat Researchers.” In Ecological and Behavioral Methods for the Study of Bats, edited by Thomas H. Kunz. Washington, D.C.: Smithsonian Institution Press, 1988.

Finley, Don. Mad Dogs: The New Rabies Plague. College Station: Texas A&M University Press, 1998.

Jackson, Alan C., and William H. Wunner, eds. Rabies. Boston: Academic Press, 2002.

Kaplan, Colin, G. S. Turner, and D. A. Warrell. Rabies: The Facts. 2d ed. New York: Oxford University Press, 1986.

Pace, Brian, and Richard M. Glass. “Rabies.” Journal of the American Medical Association 284, no. 8 (August 30, 2000): 1052.

Parker, James N., and Philip M. Parker, eds. The Official Patient’s Sourcebook on Rabies. San Diego, Calif.: Icon Health, 2002.

"Rabies." Centers for Disease Control and Prevention, March 15, 2013.

"Rabies." Mayo Clinic, January 28, 2011.