115 Rabies

Rabies is an acute viral encephalomyelitis or inflam­mation of the brain and spinal cord of humans and other mammals, especially carnivores. The disease, known since antiquity, is almost always transmitted to human beings in the saliva of biting animals and is almost invariably fatal.

Distribution and Incidence

Rabies occurs in most of the world, including Africa, Asia, the Americas, and most of Europe. It has never occurred in, or has been eliminated from, Britain, Ireland, Sweden, Norway, Japan, Australia, New Zealand, Hawaii, and many other islands in the Pa­cific and the Caribbean. Rabies is primarily a dis­ease of wild carnivores, particularly canids such as the fox, wolf, jackal, and coyote. Skunks and rac­coons are also common hosts, as are many species of bats. Virtually any species of mammal can contract the disease when bitten by an infected animal. Do­mestic dogs are the major threat to humans; cats are a growing danger in North America. Cattle, horses, sheep, and other livestock may also be affected. Out­breaks among farm animals may cause considerable economic loss, but bovine or equine rabies usually poses little danger for humans.

Rabies is a relatively uncommon disease in hu­mans, occurring sporadically as isolated cases or in small clusters. Epizootics develop at irregular inter­vals in wild carnivores, and may infect humans mainly through dogs or rarely directly. Persons working alone in remote areas, such as hunters, trappers, or shepherds, are vulnerable to attack by infected animals. Wolves are especially dangerous because their size and strength allow them to inflict multiple bites. Most human cases, particularly in developing countries, are acquired by the bites of “mad dogs,” which were themselves victims of at­tacks by feral animals.

Human rabies has become a rare disease in devel­oped countries. There were 236 cases in the United States between 1946 and 1965; only 11 occurred after 1960, and no cases at all have been reported in many of the subsequent years. Canada reported only 21 cases from 1924 to 1986, but Mexico recorded 76 fatalities in 1985 and 81 in 1986. In Africa, Ghana confirmed 102 cases from 1977 to 1981, whereas Ethiopia recorded 412 in 1982. India reported the highest annual number of cases in the early 1980s - that is, 20,000 - as well as the highest rate of infection - 28.8 per million individuals.

Etiology

Rabies is caused by a virus of the rhabdovirus group. The virus is a rod-shaped particle with a single StrandofRNA for its genetic material. Large concen­trations of virus are present in the saliva of sick animals and enter a new host through bite wounds. The virus is neurotrophic; it migrates along nerves to the brain, where it multiplies, causing grave dam­age manifested in part by behavioral changes in the victim. New viruses descend through efferent nerves to the salivary glands and hence into the saliva.

Epidemiology

Rabies circulates primarily in wild carnivores and only incidentally attacks domestic ones. Canids- notably foxes, wolves, and jackals - are the major reservoir in much of the world, although skunks, raccoons, mongooses, and other carnivores can also be significant hosts. Human beings are accidental and terminal hosts. The spread of rabies in skunks and raccoons, two species that have adapted with great success to suburban habitats, has caused con­cern in the United States during the 1970s and 1980s, but so far no human cases have been attrib­uted. Opossums, rabbits and hares, rodents, and hoofed mammals can suffer and die from rabies, but they rarely transmit it.

Bats in Europe and the Americas are commonly infected, but, except for the blood-feeding “vampire” bats that plague cattle and even people in the Carib­bean and parts of northern South America, their epidemiological significance is unclear. Transmis­sion to humans and other animals is possible, but serologic studies of viral strains in the United States and Canada suggest that bat rabies is largely self­contained. Slightly different area-specific strains are found in terrestrial species in given areas, sug­gesting, for example, that foxes and skunks ex­change a specific viral type. Species of bats in the same region tend to have a greater variety of strains, with none identical to that prevailing in local ground-dwelling animals. High-resolution sero­logic studies have been possible only since the early 1980s, and much more research will be needed to clarify fully the epizootiology of wildlife rabies.

Wildlife rabies tends to occur in irregular waves, and may spread over thousands of miles in a matter of a few decades. Control of rabies in wild animals by population reduction has generally been unsuccess­ful, and vaccines for use in wild mammals are still in the experimental stage. Monitoring local reservoir hosts can, however, alert public health authorities to the danger of possible cases among dogs and cats, and provide time to warn people to avoid wild ani­mals and to control and vaccinate their pets. In the United States, where canine rabies has steadily de­clined for decades, the number of cases in cats began to exceed cases in dogs in 1980. This has resulted in widespread campaigns to vaccinate felines.

Animals may exhibit either “furious rabies,” with agitated, aggressive behavoir preceding paralysis and death, or “dumb rabies,” where the victim is lethargic and progressively immobile. The classic “mad dog,” foaming at the mouth and wandering menacingly in the streets, does exist, but not all sick dogs display such dramatic symptoms. In northern Canada rabid foxes and wolves may become “crazy,” wandering about settlements, mingling with sled dogs, and sometimes attacking the dogs or their own­ers.

Although infection by virus-laden saliva is the only common way to contact rabies, two other mechanisms have been reported. Inhalation of virus in dust and contamination in surgery are possible, but both are very rare. High concentrations of virus may occur in dust in caves heavily populated by bats, and spelunk- ers have died of rabies after inhaling the virus. Labo­ratory inhalation of virus-laden aerosols has also caused infections. Comea transplants from the cadav­ers of undiagnosed rabies victims have caused at least two deaths in recipients, but immunologic test­ing of donors should prevent future incidents.

Pathology and Clinical Manifestations

If infective saliva enters a break in the skin, viruses are carried from the site of the wound through the nerves to the brain. The incubation period of the disease varies from 2 to 16 weeks, depending on the site, severity, and location of the wound, and the size of the viral inoculation. Severe bites on the face and head are the most dangerous and have the shortest incubation periods, because the virus does not have far to travel. Infection results in destruction of cells in several regions of the brain and spinal cord and damage to the myelin sheaths of nerves. Clumps of viruses called Negri bodies are often seen on micro­scopic examination of affected cells and are useful in diagnosis.

Rabies patients commonly show restless, agitated behavior and hypersensitivity to minor stimuli. They frequently become extremely apprehensive or aggressive shortly after the onset of the disease. Convulsions and excessive salivation are common. Patients often suffer intense thirst, but have severe muscle spasms in the throat when they attempt to drink.

There have been a handful of reports of survivors, but even the most intensive supportive care is gener­ally futile, and there are no specific drugs or other therapies. Prevention is the only solution. Vaccinat­ing dogs and cats, controlling strays, monitoring wildlife populations, and education are all essential. A preexposure human vaccine is available for per­sons at special risk, such as game wardens, veteri­narians, and laboratory workers.

Fortunately, persons bitten by a rabid or possibly rabid animal can still be effectively vaccinated be­fore the disease completes its long incubation period. If the biting animal is captured and shown to be rabid, or if it escapes but there are grounds to sus­pect that it might be rabid, prompt treatment is essential. Careful cleansing of the wound to remove as much virus as possible is followed by a series of injections of a serum (gamma globulin) that contains preformed antibodies to the virus. Human rabies immune globulin (RIG) has replaced an equine preparation in recent years. The key measure, a series of shots with a specific vaccine, is then begun.

The earliest vaccines were developed by Louis Pas­teur in the 1880s, using rabbit spinal cord tissue. Preparations from brain tissues of sheep, goats, or mice are still used in some developing countries, but these vaccines are being replaced because they can cause severe allergic reactions. Duck embryo cul­tures were used to produce vaccine until human diploid cell vaccine (HDCV) was developed in France and the United States in the late 1970s. This vaccine is cheaper and safer, and requires a shorter series of injections.

Proper postexposure prophylaxis is very effective, and must be given if there is any reasonable possibil­ity of infection. It is, however, time-consuming and expensive. In the United States, where cases have averaged only one or two per year since 1965, some 20,000 to 30,000 people are treated annually, at a cost of about $400 each. India provided treatment to about 3 million victims of animal bites annually in the early 1980s, whereas El Salvador treated the world’s highest rate of 4,570 persons per million population. A World Health Organization survey of 30 developing countries in 1980 showed an average of 3.7 rabies cases and 867 treatments per million population. The costs of rabies in lives, terror, and medical resources are considerable, especially in the Third World.

History

Literature

Rabies is one of the oldest documented diseases of humankind. Rare, but with spectacular symptoms and fatal outcome, it was and is an easily observed disease. Although some cases (particularly when an animal bite was not documented) could be confused with tetanus or with a neurological disorder like epilepsy, rabies cases are generally easy to recog­nize, even in old accounts.

Antiquity. Rabies may have been described in Mesopotamian texts as early as 2300 B.C., and was well known to ancient writers from China to Rome. The first certain reference in Chinese texts dates from the sixth century B.C., and the disease is de­scribed in a first-century Indian text. Rabies is also mentioned in a number of literary works from an­cient Greece, including plays by Euripides, Xeno­phon’s Anabasis, and perhaps Homer’s Iliad. Aris­totle’s fourth-century History of Animals describes rabies in dogs and other domestic animals.

Roman medical writers of the first and second centuries, such as Dioscorides, Pliny, Galen, and es­pecially Celsus, wrote extensively on rabies and es­tablished a number of ideas about the disease, which were influential in European and Islamic medicine well into the eighteenth century. In accordance with prevailing humoral doctrines, it was believed that dogs (or other animals) developed the disease from a “corruption” of their humors, due to factors such as stress, cold, heat, or poisoning. Their saliva became poisonous, and bites carried the rabies poison or “virus” to humans or other animals. Celsus advo­cated bloodletting and cauterizing the wound with hot irons, a practice that, although harsh, might at times have cleansed the bite and one that was fol­lowed well into the nineteenth century. Celsus also suggested sudden immersion of the victim in hot or cold water, a practice that was also employed, at least sporadically, into the nineteenth century. Like his contemporaries, Celsus described a wide array of internal and external remedies of animal, mineral, and vegetable origins, none of which, based on mod­ern knowledge, could have done any good. Pliny’s unfounded belief that a “tongueworm” of dogs was responsible for rabies lasted as long as the ideas of Celsus.

Medieval Period Through the Sixteenth Century. Rabies continued to interest many medical and other writers after the fall of Rome and into the Middle Ages. Jewish authorities wrote about rabies in several passages of the Talmud. Numerous Chris­tian writers in the West and the Byzantine Empire discussed the disease, following the humoral theo­ries of Classical times. Medieval Islamic authorities such as Rhazes in the tenth century and Avicenna (Ibn Sina) in the eleventh century also worked in the Galenic humoral tradition and were strongly influ­enced by the views of Celsus. Avicenna gave good accounts of rabies in dogs, wolves, foxes, and jackals. He thought that their humors, notably the black bile, were disrupted by heat, cold, or ingesting putrified food or polluted water, resulting in rabies and “mad” behavior.

As in most medical matters, commentators on ra­bies in medieval western Europe had little to add to the comments of ancient and Islamic writers. In the thirteenth century, Arnold of Villanova wrote wrongly that dogs became rabid after eating corpses, but he did rightly stress the importance of thor­oughly washing the bite wounds. Once symptoms of rabies appeared, many persons resorted to religious methods of healing. In much of western Europe, pil­grimages and prayers were directed to the shrine of Saint Hubert (who died in 727), a patron of hunters whose relics were kept in the Ardennes. Other saints were invoked elsewhere in Europe and among the Coptic Christians of Egypt.

Early modern medical authorities had little to add to the works of their predecessors. Girolamo Fra- castoro, sometimes hailed as a sixteenth-century forerunner of the formulators of the germ theory, con­sidered rabies one of many diseases caused by “semi­naria,” something more like a seed or a self­replicating poison than a microorganism. He thought that it affected the heart and advocated cauterization of the wound. The sixteenth-century French surgeon Ambrose Pare gave a good clinical description and recognized central nervous system involvement.

Eighteenth Through Mid-Nineteenth Century. Per­haps because the disease was more common, or per­haps because of the growing volume of medical research and writing in general, the literature on ra­bies became much more abundant in the eighteenth and early nineteenth centuries. Autopsy studies were done (although without results, as the lesions are mi­croscopic) and many more case reports and epidemio­logical observations were published. The growth of the literature was especially notable in France, where the Societe Royale de Medecine, founded in 1776, took considerable interest in the problem. As of about 1750, many French and other physicians be­lieved in the spontaneous appearance of rabies, possi­bly because some apparent cases were really tetanus, resulting from puncture wounds rather than animal bites. But within a few decades it was generally recog­nized that rabies resulted only from bites of rabid animals and that not all such bites, especially bites through clothes, transmitted the disease. Joseph- Ignace Guillotin, the inventor of the execution device popularized during the French Revolution, proposed an experimental approach to therapy. He wanted con­demned criminals to be bitten by mad dogs so that clinical trials of various remedies could be conducted on them.

This scheme was not adopted, but some important experiments were undertaken in the 1790s and the first two decades of the 1800s. The prominent En­glish physician John Hunter proposed saliva inocula­tion experiments in 1793 and in 1799. An Italian investigator, Eusebio Valli, claimed that the “virus” in saliva was made less virulent by gastric juice from frogs. He did not, however, publish his results, and his work seems to have had little impact. The first saliva inoculation experiments are credited to the German investigator Georg Gottfried Zinke, who published in 1804. Zinke, who was aware of Hunter’s work and may have been inspired by it, was able to infect dogs, cats, rabbits, and birds; saliva treated with acids was not infective. In 1813 the French researchers Franςois Magendie and Gilbert Breschet infected dogs and several other animals with saliva from a human rabies victim. Such results, repeated and extended by others, discredited the views of some students of mental disease, who believed that rabies was not a physical disease but only the prod­uct of terror and imagination.

Nineteenth-century therapy, however, remained a hopeless melange of useless remedies, many inher­ited from medieval and ancient times. Doctors tried every possible treatment from drugs and purges to electric shock and immersion in the sea. Sedatives were often employed to ease the patient’s suffering, and euthanasia may have been practiced.

Late Nineteenth Century. Modem knowledge of ra­bies etiology and prevention dates from the last half of the nineteenth century and is closely linked to the rise of experimental methodology and germ theory. Rabies was not common enough to be a major public health hazard, but it was spectacular enough to at­tract a fair amount of research. The work of Pierre- Victor Galtier, a French veterinarian, was especially important. In 1879 he published the results of experi­ments in which he maintained rabies in a series of rabbits. Galtier continued to publish on rabies, but the development of a vaccine was the climax of the career of another person, Louis Pasteur.

Pasteur published his first paper on rabies in 1881. Working with rabbits as advocated by Galtier, Pasteur was able to use dried spinal cord material as a dependable source of infectious material. By 1884 he had developed a method of attenuating the still unknown agent in dried rabbit spinal cords. The weakened infective agent, suspected by Pasteur of being a “microbe of infinite smallness,” was injected into dogs. Unlike fresh preparations, it did not cause sickness, but instead provided protection against in­jections of virulent virus.

The first human trials were conducted in 1885. Pasteur and his associates could not inject a person with the virus in order to test the vaccine but, rather, had to treat a victim of a recent attack in hopes that the weakened virus in the vaccine would convey immunity before the virulent virus from the bite could cause disease. In July 1885, a 9-year-old boy, who had been badly bitten by a rabid dog, was brought to Paris within 2 days of exposure. Doctors were convinced that he had been infected, and Pas­teur knew that the prognosis was hopeless unless the new vaccine was effective. The boy was given a series of injections with progressively fresher rabbit spinal cord vaccine. He lived, and eventually became concierge at the Institut Pasteur. A second victim was treated successfully in October, and 350 others were inoculated over the next several months. Only one died - a girl who did not receive vaccine until over a month after exposure.

The Pasteur treatment was a major theoretical and practical breakthrough. It caused a public sensation, and people bitten by rabid or suspicious animals flocked to Pasteur’s laboratory from all over Europe. Success rates were consistently high, especially if vaccine was promptly administered and if wounds were not on the head. Even with a long train ride to delay treatment, 35 of 38 Russians who had been bit­ten by rabid wolves were saved by injections. The French government promptly began to fund the work of the Institut Pasteur, branches of which were soon established elsewhere in France and its empire as centers of vaccine production and medical research.

Pasteur’s associates, notably Emile Roux, and other workers developed methods of vaccine produc­tion and treatment. Research suggested a route from the bite through the nerves to the brain, but this was not proven until well into the twentieth century. The etiology of rabies remained a mystery.

Twentieth Century. In 1903 Adelchi Negri working in Italy discovered microscopic dark bodies in nerve cells of rabid dogs. He thought they were protozoans that caused the disease, but, although this proved erroneous, the Negri bodies were a useful diagnostic sign. Tests with mouse inoculation of suspect tissue, introduced in 1935, and various serologic methods have largely replaced histological examination for Negri bodies as tests for rabies in dogs and other animals.

Although Negri’s protozoan theory attracted some attention, the search for the etiologic agent centered around the concept of “filterable viruses” - entities too minute to be retained by filters with pores small enough to hold bacteria. The virus was first seen in 1962; electron microscope studies in 1965 showed that the Negri bodies were clumps of viruses and antibodies.

Epidemics and Epizootics

Rabies epidemics and epizootics are difficult to trace before the twentieth century. In Europe, although there are many case reports, most descriptions are of isolated cases or small outbreaks. In 1271 rabid wolves invaded towns in Franconia (Germany), at­tacking herds and flocks and killing 30 persons. There was a fox epizootic in Frankfurt in 1563. Ra­bies seems to have been widespread in western Eu­rope during the eighteenth and nineteenth centuries, possibly because population growth was disturbing the wildlife habitat and causing greater contact be­tween feral mammals and domestic dogs. In 1701 Nancy, France, was beset by canine rabies and en­acted laws against stray dogs. Paris responded to ra­bies cases in 1725 with a leash law, and other Euro­pean cities followed with similar ordinances. Such restraints, as well as campaigns to rid the streets of strays, were seldom strictly enforced until there was a rabies scare.

A widespread epizootic in 1719-28 involved France, Germany, Silesia, and Hungary, and there also were many animal and human cases in Britain in 1734-5. Rabies was common in the greater Lon­don area in 1759-62 and in France, Italy, and Spain in 1763. A major epizootic developed in foxes in the Jura region of France in 1803; this outbreak appar­ently lasted until the late 1830s and spread over Switzerland and much of Germany and Austria. Out­breaks among wolves, foxes, and dogs continued throughout the century and caused hundreds of hu­man deaths.

Rabies declined in the twentieth century, in wild and domestic animals as well as in humans. The disease was exterminated in Britain in 1922 and became rare throughout western Europe. In the early 1940s, however, a fox epizootic developed in Poland and since then has spread westward at a rate of 30 to 60 kilometers a year, reaching France in 1968. Denmark has defended itself by intensive fox control in a belt of territory near the German border; Britain is still protected by the Channel.

The history of rabies on other continents is little known. Sporadic cases and scattered epidemics oc­curred in Ethiopia prior to the twentieth century, a pattern that must have been common in other Afri­can and Asian countries. Rabies did not exist in Australia or New Zealand prior to English coloniza­tion in 1788, and seems to have been absent from the Pacific islands as well.

The antiquity of rabies in the New World is unclear. It is certainly possible that bat rabies existed in pre­Columbian times, and Arctic foxes and wolves could just as possibly have carried the virus from Siberia to Alaska and northern Canada centuries or millennia ago. Eskimo oral traditions suggest that the Eskimos were aware of rabies long before European contact. However, early European sources do not mention ra­bies among the American fauna, and a Spanish work published in 1579 specifically denied the existence of rabies anywhere in the “Indies.” The first accounts of the disease are from Mexico in 1709, Cuba in 1719, Barbados in 1741, Virginia in 1753, North Carolina in 1762, New England in 1768, Jamaica and Hispan­iola in 1783, and Peru in 1803. Because rabies is such

an obvious disease, at least when it afflicts domestic animals and people, and because it was so well known to both lay and medical observers, the absence of early reports could well indicate that rabies, at least in temperate and tropical America, was a late biologi­cal importation from Europe.

Fox rabies was known in the eighteenth century, and the disease was widespread in North American wildlife populations in the nineteenth century. Ra­bid skunks (hydrophobic or “phobey cats”) were de­scribed in the Great Plains in the 1830s and in California in the 1850s. Most U.S. cases in the twen­tieth century have been reported in dogs, but since canine rabies is in decline as a result of vaccination and animal control measures, greater attention has been given to wild animals. Raccoon rabies was first described in 1936, and bat rabies, now recognized in 47 states, was first detected in 1953. An epizootic developed among raccoons in Florida in 1955, and spread slowly northward into Georgia and South Carolina in the 1960s and 1970s. Sportsmen trans­ported infected raccoons from this focus to the Virginia-West Virginia border for hunting in the mid-1970s; and rabies has spread in both states and into Pennsylvania, Maryland, and Washington, D.C. Skunk rabies has been spreading slowly from two foci in the Midwest for several decades, and now extends from Texas and Tennessee to Montana and Manitoba. Fox rabies is widespread in the Appalachi­ans. In Canada, an epizootic was recognized in the far north in 1947, but probably began in the 1930s or earlier. Foxes and wolves are the primary victims, and the epizootic has spread south into Ontario, Que­bec, and the northeastern United States.

Wildlife rabies still represents a potential threat to Europeans and North Americans, but vaccination of pets should prevent more than an occasional hu­man case. In developing countries such as Mexico or India, canine rabies is still a real danger, and rela­tively little attention has been given to wildlife reser­voirs of the virus.

K. David Patterson

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