Rabies

Zoonotic Diseases

0195-5616/87 $0.00

+ .20

Rabies Brian D. Perry, B.V.M.&S ., D.T.V.M., M.Sc., M.R.C.V.S.*

The ancient disease of rabies is a perennial component of any review of zoonotic diseases and a subject on which the veterinary practitioner is approached almost daily for advice. In the United States, the number of cases of human and domestic animal rabies has been dramatically reduced over the last three decades. In spite of the fact that there have beeri less than two cases of human rabies on average per year over the last 10 years, the virtually inev,itable fatal outcome following the development of clinical sighs has ensured a high level of priority to the surveillance and control of this disease. Recent years have seen considerable improvements in rabies coritrol through improved vaccines and sophisticated disease surveillance, but they have also seen dramatic changes in the distribution and intensity of .the disease in the continental United States. Two excellent reviews of rabies directed at the medical and veterinary professions have recently been published. 5• 60 This article reviews current knowledge of the zoonotic aspects of rabies, with emphasis on epidemiology, case management, and preventive medicine.

THE SOURCE OF RABIES INFECTION IN MAN Rabies rarely affects human beings in the United States. However, this fact is dependent upori a variety of factors, including the low incidence of rabies in domestic pets, the infrequent close contact with the wild animal reservoirs of the disease, the relatively low susceptibility of man to the rabies virus, and the high efficacy of post-exposure immunization and therapy procedures in man. . Most warm-blooded animals are susceptible to infection with the rabies virus, and although clinical disease does not always result, the outcome is invariably fatal when it doesY Transmission usually occurs as a resuit of *Associate Professor, Department of Large Animal Clinicai Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia Veterinary Clinics of North America: Small Animal Practice-Yo!. 17, No. I, January 1987

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Rodents/ Domestic/Farm (8%)

L~gomorphs

(.6%)

Figure 1. Rabies diagnoses in the United States during 1984 by proportional categorization of species. Left, All species. ll.ight, Wild animals. (From Centers for Disease Control: Rabies Surveillance Summary, 1984; Atlanta, Georgia, 1985.)

the bite of a rabid animal; rabies virus from the saliva of the affected animal is introduced into the bite wounds, into existing cuts or wounds on skin, or through intact or abraded mucous membranes. 13 The clinical behavior of aQ animal is not necessarily a reliable indication of whether it is excreting rabies virus in its saliva, for virus has been recovered from saliva specimens of cats and dogs 1 to 3 days before the oQset of clinical signs. 55 In wild animals, the period before the onset of clinical signs during which virus may be excreted in saliva is unknown. The rabies virus is quite fragile in the environment and does not survive in dried saliva. In the dead animal, however, salivary glands and nervous tissue are particularly rich in virus, which is very resistant to autolysis and putrefaction and may remain viable in autolyzed brain tissue for 7 to 10 days. 13 Transmission can ocqu:. via other nonsalivary routes but this is thought to be rare. Oral infection has been shown experimentally in foxes and skunks following ingestion of mouse carcasses infected with rabies virus. 42 Air-borne rabies infection of man has occurred in laboratories in two instances 14 • 58 and was probably the route of transmission in two cases of rabies acquired in a bat-infested cave in Texas. 59 Exposure to rabies virus in peripheral nerves could potentially occur if a person with wounds on the hands does not wear gloves while skinning a rabid animal. Documented human-to-human transmission has only occurred when patients received corneal transplants from persons who died of rabies that was not diagnosed at the time of death. 16· 30 Currently, about 90 per cent of the 6000 or so reported cases in the United States occur in wild animal species, pri11cipally skunks, raccoons, bats, and foxes (Fig. 1). 19 · 61 However, this has not always been the case; in 1953, only 17 per cent of the 8837 reported cases were in wild animals. Since that time, there has been a steady decline in reported rabies cases in dogs and cats, from 6226 in 1953 to 811 in 1961, and to 237 in 1984. 18 · 19 • 49 This decline is due principally to the introduction of modified live virus vaccines for dogs in the late 1940s, which have been effectively used in combination with adjunct control measures such as stray dog control, the licensing of dogs, and leash laws. Since 1960, there has been an increase

75

RABIES

9.000

8.000

--TOTAL

7,000

· -- • • WILD -·-·- DOMESTIC

6,000

:3

s.ooo

1/)

< ()

4,000

3.000 2.000 1,000

1950

1955

1960

1965

1970

1975

1980

1985

YEAR Figure 2. Reported rabies cases in wild and domestic .animals in the United States by year, 1953 to 1984. (From Centers for Disease Control: Rabies Surveillance Summary, 1984; Atlanta, Georgia, 1985.)

in the number of reported cases of wild animal rabies (Fig. 2). This is probably due to an increased incidence of rabies in these species in certain regions of the United States as well as the greater intensity of rabies surveillance directed at wildlife. But a demonstration of the dynamic nature of the disease itself was provided in· the dramatic outbreak of raccoonassociated rabies in the mid-Atlantic states that started towards the end of the last decade and continues to advance on several fronts. During the years 1966 to 1984, there have been 35 cases of human rabies in the United States; the animal source of the exposure was identified in 22 cases. 18 • 19 Of these, 12 (54.5 per cent) were from dogs and acquired outside the continental United States. Five cases (22. 7 per cent) were acquired from bats, three cases (13.6 per cent) from skunks, and one case each from a cat and a bobcat. To date, no cases have been ascribed to exposure to a rabid raccoon. Although human rabies cases resulting from exposure to rabid animals within the United States are now predominantly of wildlife origin, the administration of post-exposure prophylaxis (PEP) to human 'beings is currently more likely to be as a result of exposure to a rabid or potentially rabid domestic pet. In a recent study of 5654 persons in 2i states who had received PEP between June 1980 and December 1981, the animal sources of human exposure did not reflect the frequency distribution of rabies amohg the various species of animals in the same area. 29 Domestic animals (dogs, cats, and other domestic animals) were responsible for 66 per cent of PEP but comprised only 13 per cent of proven rabid animals. Because of the frequent and prolonged contact people have with their pets and the exposure of numerous human beings, which often occurs when pets become

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Other Farm . (14%) Figure 3. Rabies diagnoses in the United States during 1984. Proportional categorization of domestic and farm animal species. (From Centers for Disease Control: Rabies Surveillance Summary, 1984; Atlanta, Georgia, 1985.)

rabid, these animals provide the greatest potential risk of infecting human beings with rabies. Rabies in domestic dogs and cats in the United States is not selfperpetuating, and, with the exception of some areas on the United StatesMexico border, the disease in these species «an be considered epidemiologically as a dead"end infection. In these areas on the United States-Mexico border and in other areas of Latin America, Africa, and Asia, however, this is not the case, and dogs often play the principal role in the maintenance of endemic rabies. 19• 25 In the United States, the domestic pet that is currently of greatest potential importance is the· cat. Since 1981, the number of cases of cat rabies has exceeded that of dogs 19 (Fig. 3), and these cases have shown some degree of geographical clustering in areas of the country where raccoon and skunk rabies predominate. Cats, like dogs and other domestic animals, usually acquire rabies infection from exposure to rabid wildlife. The principal wildlife species responsible for the maintenance of rabies in the United States (as measured by the frequency of rabies diagnosis in wild animals submitted to laboratories for testing) are (in the order of national importance) skunks, raccoons, bats, and foxes. 19 The relative importance of each species varies from state to state. These four species (in the order bats, raccoons, skunks, and foxes) also account for the most frequent wild animal exposures of man requiring PEP. Another group of wild animals, the rodents and lagomorphs, are also responsible for exposures of man requiring PEP, altho11gh rabies is infrequently reported in these species. Rodents (rats, mice, squirrels, muskrats, prairie dogs, gerbils, hamsters, and chipmunks) and lagomorphs (rabbits and hares) are known to be susceptible to rabies infection, and 29 diagnosed cases in these species were recorded in 1984. 19 Nevertheless, they are thought to play little role in the epidemiology of the disease. No cases of human rabies have ever been associated with these species in the United States to date. 18 However, the number oflaboratory-confirmed cases of rabies in rodents, particularly

RABIES

77

in woodchucks, has increased in recent years in association with the midAtlantic raccoon epidemic. 26 The main wildlife reservoirs of rabies for both domestic animals and man have fairly distinct geographical distributions. Skunk rabies involves a large area of the midwestern United States, and this species has been the most frequently reported rabid animal since 1961. 61 Fox rabies, the most prevalent of all species reported before that year, is now reported only at a low level, particularly in Ontario, upstate New York, and Texas, and with a less distinct geographical integrity. Raccoon rabies, which has recently become the most important wildlife species within certain distinct geographical foci, has dramatically changed the picture of the disease in the last few years. The disease was first recognized in this species during the late 1940s in Florida, and the ensuing two and a half decades saw a steady increase in its geographical distribution at the rate of approximately 25 miles per year so that by 1976 the states of Florida, Georgia, Alabama, and South Carolina were all reporting endemic raccoon rabies. 10 · 36 In 1977, a single case was reported in West Virginia several hundred miles north of the disease front. This was followed in 1978 by three cases in neighboring counties in Virginia. By 1983, the mid-Atlantic states were reporting an annual incidence of 1608 cases in raccoons alone. 18 Bat rabies, on the other hand, shows no defined pattern of geographical distribution and is currently reported from all of the continental United States and in most of the nearly 40 bat species occurring in North America. During the period 1975 to 1984, the number of reported rabies cases in bats increased by 102 per cent to 1038. 19 What do these variations in temporal, geographical, and species distributions mean with respect to the possible exposure of domestic pets and man to rabies? The greatest potential risk of rabies infection to the general public is the small risk presented by their domestic pets or "pet" wildlife. However, in areas of endemic raccoon rabies, this species with its cute appearance, scavenging habits, and consequent close cohabitation with human beings, provides a considerable risk of directly infecting man. In all areas, people whose work or pastimes bring them in close contact with terrestrial wildlife species are at greater risk than the general public. It is assumed that human beings are susceptible to the rabies virus originating from all of the affected domestic animal and wildlife species. 28 The risk of acquisition of infection by domestic cats and dogs is similarly greater in endemic raccoon rabies regions, particularly by hunting or roaming animals. Although epidemiologic evidence suggests that differences in virus strains, 45 as well as a variety of social and ecological fact9rs, 20 may account for the species and geographical associations seen in wild animals, domestic pets are apparently susceptible to rabies infections acquired from all wildlife species. The epidemiologic significance of differences in virus strains, which was recently demonstrated by the use of panels of monoclonal antibodies, is still unclear. 45· 47· 57 However, they do serve to show that most of the rabies cases that occur in a region are centered on one species of wildlife and that cases in other wild and domestic species are a result of a "spillover" of infection from the dominant wildlife species of the region. In a recent

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study, all the virus isolates taken from five different wild terrestrial species and domestic animals from the Southeast and mid-Atlantic regions where raccoon-associated rabies occurs were shown to be identical. 45 Virus isolates from terrestrial mammals in areas with endemic skunk rabies or endemic fox rabies could also be differentiated from each other and from the raccoonassociated virus isolates from the Southeast and mid-Atlantic. By contrast, there was a diversity of virus types found in the isolates from bats, and no species or geographical associations could be detected. Circumstances have occasionally implicated bats as the source of infection to domestic cats in areas where terrestrial rabies is not reported, 22 • 35• 43 • 44 • 50 and a recent study confirmed that cat rabies can be caused by bat rabies virus. 51 The keeping of "pet" wildlife poses a considerable increase in potential risk of rabies exposure to man and other domestic animals. These animals may find social acceptance both within the sylvatic members of their own species, in which rabies may be endemic, and within the human households looking after them . Even when they are confined in cages, as is often the case with pet ferrets, if they are kept outside for any period of time within a region of endemic rabies, they provide a potential bridge between the wildlife reservoir and man. Another potential source of rabies for domestic dogs and cats is the use of modified live virus (MLV) vaccines; several such instances have been reported. 8 • 24 • 40 • 56 However, most of the low egg passage (LEP) Flury strain vaccines that were responsible for these cases are no longer recommended or available for use in the United States. Vaccine-induced rabies, now more convincingly differentiated from field virus by the retrospective typing of virus isolates using panels of monoclonal antibodies, 56 has also been associated with high egg passage (HEP) Flury strain vaccines that are still available, but this has often been reported in cats known to have concurrent infections with feline leukemia virus. 3 Vaccine-induced rabies has also been reported in wildlife following the use of MLV vaccines. PROPHYLACTIC IMMUNIZATION OF ANIMALS AND OTHER PREVENTIVE MEASURES As is apparent from the previous section, human beings stand the greatest chance of being infected with rabies from their domestic pets, although the main reservoir of the disease in the United States and Canada is in wildlife. In the absence of any approved vaccine or method for the immunization of wildlife, current preventive measures are directed towards the creation of an immune barrier around man by the vaccination of his carnivorous domestic pets, the dog and the cat. It is the ultimate goal to extend this immune barrier to wildlife species . Currently, researchers are examining ways of satisfactorily immunizing populations of wildlife using oral vaccines . 4· 6 · 32 • 46 A wide range of efficacious rabies vaccines are available in the United States, and revised lists of those currently marketed and recommendations for immunization procedures are published annually in The Compendium of Animal Rabies Vaccines by the National Association of State Public

RABIES

79

Health Veterinarians (NASPHV). 38 The majority of vaccines in general use are inactivated virus vaccines, which provide protection for 1 or 3 years, depending on the vaccine. The Committee of the NASPHV recommends the use of the vaccines with a 3-year duration of immunity "because their use constitutes the most effective method of increasing the proportion of immunized dogs and cats in comprehensive rabies control programs. "38 In all cases, it is recommended that cats and dogs be immunized first at 3 months of age, then 1 year later, with boosters given at subsequent intervals of 1 or 3 years. Although some MLV vaccines are still marketed, their use has dramatically declined in recent years owing to the availability of efficacious inactivated vaccines and the rare occurrence of rabies induced with MLV vaccines. All rabies vaccines should be administered by the intramuscular route at one site in the thigh, although recently some vaccines have been approved for subcutaneous injection. 38 In the days when rabies was poorly controlled in both dogs and cats, the ratio of dog to cat cases was approximately 10:1. In the first 4 years of this decade, this ratio had changed to 1:1.4. 19 This illustrates the current need to ensure that cats receive immunization, particularly in areas where epidemic or endemic wildlife rabies is present. Regulations concerning the immunization of dogs and other species vary considerably in the United States, 7 but in approximately 27 states, licensure of dogs by the age of 6 months is mandatory, and evidence of rabies vaccination is required in order to obtain a dog license. In many states, this is not the case with cats, and rabies vaccination for cats has often been left to the personal discretion of owners and veterinarians. In regions currently affected by the outbreak of raccoon rabies, many counties or local jurisdictions have introduced ordinances requiring rabies vaccination for cats, and some rabies vaccination clinics have been run in these areas. Generally, it must be advised that all cats should be vaccinated against rabies. In the past, it has been said that vaccination may not be indicated for cats living in urban areas. 3 However, the mid-Atlantic outbreak of raccoon rabies has shown that cities, which provide an excellent habitat for raccoons, are also foci of rabies in this species; Washington, D.C., for example, reported 158 cases of raccoon rabies in 1983. 31 A recent study showed that 81 per cent of rabies-positive raccoons diagnosed in Fairfax County, Virginia, during 1984 were encountered in residential areas. 41 In addition, the lesser but more widespread risk of bat rabies further justifies the need for vigilant vaccination of the urban pet populations. The term "urban rabies," which was originally coined by Tierkel and others to describe endemic dog rabies in cities, 48 has now assumed a different meaning. ' Veterinarians are regularly confronted with the problem of requests for immunization of other species kept as domestic pets, either true wildlife species or exotic species such as ferrets that have been kept under domesticated conditions for a long time. There is no rabies vaccine licensed for use in the United States in any wildlife species, and protective immunity from the available vaccines in these species has not been demonstrated. Because of this and the possibility that large numbers of people could be exposed if rabies occurred in a "pet" wild animal, the NASPHV recommends

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that neither wild nor exotic animals be kept as pets and that wild animals ·· not be crossbred with domestic dogs and cats. 38 In addition to the vaccination of cats and dogs, supplementary measures directed at rabies control are recommended by the NASPHV. 38 These measures include the removal of stray animals by local health departments and animal control officials, the vaccination of pets prior to interstate shipment, and the adoption of leash laws by local communities.

THE MANAGEMENT OF SUSPECTED CASES OF RABIES Exposure of Domestic Pets to Possible Rabies Infection First it is necessary to ascertain whether exposure to rabies infection has occurred. One should presume a domestic animal has been exposed if saliva or nervous tissue from a rabid or potentially rabid animal could have had direct contact with mucous membrane or a break in the skin, even though an actual bite was not witnessed or the rabid animal was not available for testing. Furthermore, NASPHV emphasizes that any domestic animal that is bitten or scratched by a bat or a wild carnivorous animal that is not available for testing should be regarded as having been exposed to a rabid animal. 38 The subsequent management of the dog or cat exposed to rabies will depend upon its vaccinal history. Animals that are currently immunized against rabies should receive an immediate booster dose of vaccine and be confined for 90 days of observation. This confinement should be such that strict observation of the animal can be carried out, and contact with other unvaccinated animals should not occur. This usually means keeping the pet in the house, the garage, or some other escape-proof building or enclosure and allowing it out only when on a leash and when under the immediate control of an adult. It is recommended that any unvaccinated dog or cat exposed to a rabid or potentially rabid animal be euthanatized immediately. 38 If the owner is unwilling to do this, the exposed, unvaccinated pet should be put into strict isolation for a period of 6 months. In this case, the isolation required is considerably more stringent than the confinement of exposed vaccinated pets. The animal should be confined in a pen at home or in a kennel at a veterinary hospital or other approved facility that completely isolates the animal from any human or animal contact but permits feeding, watering, cleaning, and daily inspection. Isolated animals must be vaccinated against rabies 1 month before release. All animal exposures should be reported to the local health department. The health department must also be notified if the animal sickens or dies during the periods of confinement or isolation, and the animal's brain should promptly be submitted for laboratory diagnostic procedures. Exposure of Human Beings to Possible Rabies Infection The evaluation of human exposures to possible rabies infection and the appropriate actions to be taken have recently been reviewed. 12• 33 • 34 The

81

RABIES STEP 1:

STEP II:

WHAT TYPE OF EXPOSURE TO THE ANIMAL ACTUALLY OCCURRED? .

~:u;rt~GN~f~~~~E ~:IMAL:

BITE LICK OF MUCOUS MEMBRANE LICK OF FRESH WOUND OTHER SIGNIFICA!IIT EXPOSURE TO SALIVA .

HANDLING WITHOUT BITE OR SIGNIFICANT SALIVA EXPOSURE

I

NO NEED FOR PROPHYLAXIS

I

Figure 4. Three-step evl!luation of animal exposures for rabies post-exposure prophylaxis. (From Mann J: Jmmunization against rabies, pre- and post-exposure. In Winkler WG (ed): Rabies Concepts for Medical Professionals. Miami, Florida, Merieux Institute, 1984 pp 5158; with permission.)

rationale for treatment is also considered by the Immunization Practices Advisory Committee of the U. S. Public Health Service. 54 Factors to be considered are (1) the species and type of animal involved, (2) )Nhether an exposure sufficient to transmit rabjes virus occurred, and (3) the current disposition of the animal (for example, is it available for diagnostic testing, is it a wild animal or a domestic dog or cat?). One of the recent review articles provides three useful flow charts for this evaluation procedure, which are illustrated in Figures 4, 5, and 6. 34 In consideration of the species involved, epidemiologic evidence suggests that although rodents and lagomorphs are frequently responsible for biting human beings, these bites are often provoked and present minimal risks of rabies infection. One can assume that these animals are rabies-free

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WILD CARNIVORE OR BAT EXPOSURE

DATA .SUPPORT ABSENCE OF RABIES RISK IN PARTICULAR SPECIES IN THE PARTICULAR GEOGRAPHIC AREA

ADMINISTER COMPLETE . POSTEXPOSURE PROPHYLACTIC REGIMEN

Figure 5. Evaluation of a wild carnivore or bat exposure. (From Mann J: Immunization against rabies, pre- and post-exposure. In Winkler We (ed): Rabies Concepts for Medical Professionals. Miami, Florida, Merieux Institute, 1984, pp 51-58; with permission)

CONSULTATION WITH HEALTH DEPARTMENT REGARDING EPIDEMIOLOGY OF DOG OR CAT RABIES IN THE SPECIFIC AREA

Figure 6. Evaluation of a cat exposure. (From Mann J: Immunization against rabies, preand post-exposure. In Winkler we (ed): Rabies Concepts for Medical Professionals. Miami, Florida, Merieux Institute, 1984, pp 51-58; with permission.)

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and they need not be submitted for testing unless the circumstances of the bite are unusual, such as a truly unprovoked attack by one of these species in the wild. An exception to this is in woodchucks, and it has recently been proposed that when humans are bitten by woodchucks in rabies epizootic areas, prophylaxis should be considered if the animals are not available for testing. 26 . Wild carnivores and bats, however, present a considerable rabies risk. Behavioral changes are not necessarily present or recognizable when these animals are rabid, 36 • 49 and the length of time wild animals excrete rabies virus in their saliva before showing any clinical signs is unknown. Hence, any wild animal that bites a person or a domestic animal or exposes them in any manner to rabies virus should, if feasible, be euthanatized without inflicting unnecessary damage to its head and tested for rabies. Some jurisdictions consider that any raccoon, skunk, bat, or fox that has exposed a person or domestic animal is rabid unless proven otherwise, but given the considerable geographical and temporal variations in wildlife rabies, local health departments should be regularly consulted on this matter. Exposures of human beings to rabies from their "pet" wildlife should be treated in the same way as those from their free-living cousins, although emotional attachment to the animal and the possibility that it may have been vaccinated against rabies often introduce potential complications to the decision. Some rabies vaccines are inevitably used in pet wildlife species such as ferrets, but these vaccines are not licensed for use in these animals, nor is there any evidence that they produce a satisfactory immunity against rabies in these species. Furthermore, MLV vaccines cah, in fact, induce rabies in these. species. In the event of any human or animal exposure involving such "vaccinated" wildlife, therefore, their vaccinal history should not influence any decision. In addition, it must be stressed that the period of virus excretion in the saliva prior to the onset of clinical signs is unknown for wildlife species; therefore, when a pet wild animal bites someone, the only safe course is to euthahatize the animal and test it for rabies. Much rnore data are available for dogs and cats on the period of rabies virus excretion in saliva and its association with behavioral changes; this, .in combination with the feasibility of quarantine for these species, allows for less drastic, although more complex, strategies. Any healthy dog or cat that bites a person, whether or not it is vaccinated against rabies, should be confined for a period of 10 days. The circumstances of confinement may be specified by local ordinance or state law but are usually similar to the confinement appropriate for exposed vaccinated animals, which was described previously. If the animal shows any clinical signs of rabies during that period, it should be humanely destroyed and its brain promptly submitted for diagnostic procedures. It must be emphasized that regulations concerning the confinement and observation of potentially rabid animals do vary from place to place and strict compliance with local regulations is crucial. If the dog or cat responsible for the exposure of a person is a stray or unwanted animal, it should be humanely destroyed immediately and submitted for laboratory diagnosis. In many instances, the biting animal

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escapes and is not immediately available for testing. It goes without saying that every effort should be made to locate it, but in the case of wild animals, this is often unsuccessful. The attending physician then relies on local knowledge of the epidemiology of rabies and data from the patient concerning the circumstances of the exposure in order to decide whether to implement post-exposure prophylaxis. PRE- AND POST-EXPOSURE PROPHYLAXIS IN MAN Decisions relating to the use of pre-exposure prophylaxis and postexposure prophylaxis are clearly in the hands of practicing physicians and local or state health authorities. Nevertheless, practicing veterinarians are integral members of the team on which the medical profession relies for data to help them reach such decisions. They are in the unique position of having daily contact with the pet-owning community, and, as a result of that position, they are often the first people consulted for advice. It is for these reasons that a section on pre- and post-exposure prophylaxis is included in this article. Animal rabies vaccines currently in general use are highly effective, and the immunity they stimulate is sufficient to withstand subsequent challenge with the rabies virus. 34 Their protective qualities have been clearly demonstrated in a series of controlled experiments in the species at which they are targeted-the dog and the cat. This is not the situation with human rabies vaccines. Firstly, although the Human Diploid Cell Vaccine (HDCV), the only vaccine currently available for rabies immunization in human beings in the United States, will reliably induce demonstrable antibody production, I. 2• 9 • 11 : 21 · 23 · 39• 52 the precise relationship between antibody presence and protection is unknown, and further stimulation of the immune system is thought to be necessary. Secondly, evidence of efficacy of this vaccine is based on the demonstration of antibody response in human subjects and on follow-up surveillance data, which clearly show that no human rabies has been reported in exposed individuals who have completed a post-exposure immunization program. Needless to say, there are no controlled experiments in the target species-mao-on the efficacy of the vaccine. Pre-Exposure Prophylaxis Previous rabies vaccines for human beings have had the disadvantages of dubious efficacy (as demonstrated by the poor antibody response to the duck embryo vaccine) 12• 27 or serious side effects (as seeh in about 1 in 4000 to 1 in 10,000 patients immunized with the phenol-inactivated vaccines derived from animal nervous tissue). 48 The HDCV, however, is highly immunogenic, and reactions to it are generally mild, with allergic or severe reactions a rarity. 15 Nevertheless, it is considered that further stimulation of the immune system following exposure to rabies infection is necessary to afford protection. In summary, pre-exposure prophylaxis cannot be relied upon following

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rabies exposure and must be supplemented by a limited post-exposure regimen. 54 With this and the high cost of the vaccine in mind, high-risk groups of the population are generally selected for pre-exposure prophylaxis. These groups include people whose jobs or hobbies put them at greater risk than the general public, such as veterinarians, animal control officers, and laboratory workers, or people traveling to countries in which dog rabies is endemic. 54 In pre-exposure prophylaxis, the HDCV can be administered by a series of three intramuscular or intradermal injections on days 0, 7, and 21 or 28. In the intramuscular injections, the dosage at each administration is 1.0 ml, which is reduced to 0.1 ml when delivered by the intradermal route. The efficacy of this regimen in producing a demonstrable antibody response is such that serologic confirmation of vaccine "take" need not be sought unless the recipient is known to be immunocompromised or is at risk of exposure to a high dose of virus, such as those people working closely with the rabies virus in a laboratory. Booster doses, administered via intramuscular (1.0 ml) or intradermal (0.1 ml) routes, should generally be given at 2-year intervals. It is extremely important to realize that the pre-exposure immunization series does require supplementation (post-exposure prophylaxis) should exposure to rabies occur. The post-exposure prophylaxis regimen in these circumstances is considerably less than for those individuals who have not received pre-exposure immunization, but it is nevertheless of paramount importance. The degree of importance was tragically illustrated recently when an American Peace Corp volunteer working in Kenya who had received pre-exposure prophylaxis was exposed to rabies infection. 17 She did not receive post-exposure immunization and subsequently died of rabies. Post-Exposure Prophylaxis There are three components of post-exposure prophylaxis: (1) local wound care, (2) administration of human rabies immunoglobulin (RIG), and (3) administration of rabies vaccine. Once the decision has been made to initiate post-exposure prophylaxis, it is important that all three of these activities be carried out under direct medical supervision. Local Wound Care. The rabies virus is susceptible to treatment with detergents, so the immediate, thorough cleaning of a wound with soap and water is extremely important. It also has the effect of mechanically flushing virus from the wound. ' Administration of Human Rabies Immunoglobulin. The administration of RIG at the initiation of post-exposure prophylaxis (day 0) allows the delivery of preformed anti-rabies antibody while the patient mounts an immune response. Several reports have demonstrated its efficacy by documenting the development of rabies in patients who did not receive RIG, but did receive HDCV following exposure. The dose is calculated according to body weight, and half of the dose should be injected around the bite

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Table 1. Guide to Post-Exposure Rabies Prophylaxis in Man ANIMAL SPECIES

Domestic dog and cat

CONDITION OF ANIMAL AT TIME

TREATMENT OF EXPOSED

OF ATTACK

PERSON*

1. Healthy and available for 10 days of observation 2. Rabid or suspected rabid 3. Unknown (e.g., escaped)

Skunk, bat, fox, raccoon, coyote, bobcat, or other wild carnivore

Regard as rabid unless proven negative by laboratory test

Other livestock, rodents, rabbits, and hares

Consider individually. Provoked bites of squirrels liamsters, guinea pigs, gerbils, chipmunks, rats, mice and other rodents, or rabbits and hares rarely call for anti-rabies prophylaxis. Consult local or state health officials

Nonet RIG and HDCVt RIG and HDCVt if treatment is considered indicated based on circumstances RIG and HDCVt

Adapted from Immunization Practices Advisory Committee on Rabies Prevention, U.S. Public Health Service, 1984. *All bites and wounds should be thoroughly cleaned immediately with soap and water. tBegin RIG and HDCV treatment at first signs of rabies in confinement period. tDiscontinue immunizations if rabies diagnosis is negative.

site if possible. The use of RIG is restricted to patients who have not received pre-exposure prophylaxis. Administration of Rabies Vaccine. The administration of HDCV as part of post-exposure prophylaxis is carried out by the intramuscular injection of 1.0 ml of vaccine on five occasions--on days 0, 3, 7, 14, and 28. If the patient has received pre-exposure prophylaxis, 1.0 ml of the vaccine is administered on two occasions, days 0 and 3, by the intramuscular route. The deltoid region is recommended for the intramuscular injections. When to Initiate Post-Exposure Prophylaxis. The decision as to whether to initiate post-exposure prophylaxis can be complex and requires systemic evaluation, but generally it is based on the following considerations: (1) What species or kind of animal is involved? (2) Did an exposure sufficient to transmit rabies actually occur? and (3) What is the current disposition of the animal? Factors affecting these considerations have been discussed earlier in the article. A guide to post-exposure prophylaxis is presented in Table 1. SUMMARY

The practicing veterinarian has a key role to play in rabies control in the maintenance of protection in the companion animal populations, in the education of the pet-owning community on rabies, and in the decision-

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making process that accompanies human exposure to potentially rabid animals. This role encompasses far more than the routine maintenance of health and well-being in pet animal populations. Although it is important to remain diligent in the immunization of domestic pets against rabies to provide a barrier between wildlife, the main reservoir of infection, and man, it is also important to be aware of the current trends in wildlife rabies within a region. Research is currently underway to investigate methods of immunizing wildlife populations, but the effective and widespread control of rabies in these species is still a long way off; in the meantime, there will be an increasing demand for practicing veterinarians to take the lead in the control of this most fearful zoonotic disease. REFERENCES 1. Ajjan N, Soulebot JP, Triau R, et al: Intradermal immunization with rabies vaccine: Inactivated Wistar strain cultivated in human diploid cells. J Am Med Assoc 244:24282531, 1980. 2. Aoki FY, Tyrrell DAJ, Hill LE, et al: Immunogenicity and acceptability of a human diploid-cell culture rabies vaccine in volunteers. Lancet 1:660-662, 1975. 3. August JR, Loar AS: Zoonotic diseases of cats. Vet Clin North Am [Small Anim Pract] 14(5):1117-1151, 1984. 4. Bacon PJ, MacDonald DW: To control rabies: Vaccinate foxes. New Scientist 424:640645, 1980. 5. Baer GM, Murphy FA, Abelseth MK, et al: Report on Rabies. Princeton Junction, New Jersey, Fromm Laboratories, 1983. 6. Baer GM: Wildlife control: New problems and strategies. In Koprowski H, Plotkin SA (eds): World's Debt to Pasteur. New York, Alan R Liss, 1985, pp 187-218. 7. Bech-Neilsen S, Hagstad H, Hubbert WJ': Vaccination against dog rabies in the United States. JAm Vet Med Assoc 174:695-699, 1979. 8. Bellinger DA, Chang J, Bunn TO, et al: Rabies induced in a cat by high-egg-passage Flury strain vaccine. J Am Vet Med Assoc 183:997-998, 1983. 9. Bernard KW, Roberts MA, Sumner JW, et al: Effectiveness of immunization with small intradermal or subcutaneous doses of a human diploid-cell rabies vaccine. J Am Med Assoc 247:1138-1142, 1982. 10. Bigler WJ, Mclean RG, Trevino HA: Epizootiologic aspects of raccoon rabies in Florida. Am J Epidemiol 98(5):326-335, 1973. 11. Burridge MJ Baer GM, Sumner JW, et al: Intradermal immunization with human diploid cell rabies vaccine: Serological and clinical responses of persons with and without prior vaccination with duck embryo vaccine. J Am Vet Med Assoc 248:1611-1614, 1982. 12. Burridge MJ: Public health aspects in prevention and control of rabies. In Report on Rabies. Princeton Junction, New Jersey, Fromm Laboratories, 1983, pp 28-32. 13. Buxton A, Fraser GF: Animal Microbiology. Volume 2. Rickettsias and Viruses. New York, Blackwell Scientific Publications, 1977, p 830. , 14. Centers for Disease Control: Rabies in a laboratory worker. Morbid Mortal Weekly Rep 26:183, 1977. 15. Centers for Disease Control: Recommendation of the immunization practices advisory committee (ACIP): Rabies prevention. Morbid Mortal Weekly Rep 29:265-280, 1980. 16. Centers for Disease Control: Human-to-human transmission of rabies via corneal transplant: Thailand. Morbid Mortal Weekly Rep 30:473-474, 1981. 17. Centers for Disease Control: Human rabies: Kenya. Morbid Mortal Weekly Rep 32:494495, 1983. 18. Centers for Disease Control: Rabies surveillance. Annual Summary 1983. Atlanta, Georgia, 1985.

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19. Centers for Disease Control: Rabies surveillance. Annual Summary, 1984. Atlanta, Georgia, 1985. 20. Chalmers AW, Scott GR: Ecology of rabies. Trop Anim Health Prod 1:33-55, 1969. 21. Cox JH, Schneider LG: Prophylactic immunization of humans against rabies by intradermal inoculation of human diploid cell culture vaccine. J Clin Microbiol 3:96-101, 1976. 22. Department of National Health and Welfare, Canada: Animal rabies-British Columbia 1968-1982. Can Dis Weekly Rep 9:11, 1983. 23. Dreesen DW, Sumner JW, Brown J, et al: Intradermal use of human diploid cell vaccine for pre-exposure rabies immunizations. J Am Vet Med Assoc 181:1519-1523, 1982. 24. Esh JB, Cunningham JG, Wiktor TJ: Vaccine induced rabies in four cats. JAm Vet Med Assoc 180:1336-1339, 1982. 25. Fernandes MV, Arambulo PV: Rabies as an international problem. In Koprowski H, Plotkin SA (eds): World's Debt to Pasteur. New York, Alan R Liss, 1985, pp 187-218. 26. Fishbein DB, Belotto AJ, Pacer RE, et al: Rabies in rodents and lagomorphs in the United States, 1971-1984: Increased cases in the woodchuck (Mannota monax) in MidAtlantic States. J Wildlife Dis 22(2):151-155, 1986. 27. Garner WR, Jones DO, PrattE: Problems associated with rabies pre-exposure prophylaxis. J Am Vet Med Assoc 235:1131-1132, 1976. 28. Hattwick MAW, Gregg MB: The disease in man. In Baer GM (ed): The Natural History of Rabies. Volume 2. New York, Academic Press, 1975, pp 281-304. 29. Helmick CG: The epidemiology of human rabies postexposure prophylaxis, 1980-1981. J Am Vet Med Assoc 250(15):1990-1996, 1983. 30. Houff SA, Burton RD, Wilson RW, et al: Human-to-human transmission of rabies virus by corneal transplant. N Eng! J Med 300:603-604, 1979. 31. Jenkins S: Mid-Atlantic States raccoon rabies outbreak. Rabies Information Exchange 9:47-59, 1984. 32. Johnston DH, Voight DR: A baiting system for the oral rabies vaccination of wild foxes and skunks. Comp Immun Microbiol Infect Dis 5(1-3):185-186, 1982. 33. Mann JM: Systematic decision-making in rabies prophylaxis. Pediatr Infect Dis 2:162167, 1983. 34. Mann J: Immunization against rabies, pre- and postexposure. In Rabies Concepts for Medical Professionals. Miami, Florida, Merieux Institute, 1984, pp 51-58. 35. Massachusetts State Laboratory Institute. 1980 Annual Report. Massachusetts Department of Public Health. 1980, pp 24-25. 36. McLean RG: Raccoon rabies. In BaerG (ed): The Natural History of Rabies. New York, Academic Press, 1975, pp 53-77. 37. Murphy FA: The pathogenesis ofrabies virus infection. In Koprowski H, Plotkin SA (eds): World's Debt to Pasteur. New York, Alan R Liss, 1985. 38. National Association of State Public Health Veterinarians: Compendium of Animal Rabies Vaccines. Baltimore, Maryland, NASPHV, 1986. 39. Nicholson KG, Turner GS, Aoki FY: Immunization with a human diploid cell strain of rabies virus vaccine: Two-year results. J Infect Dis 137:783-788, 1978. 40. Pedersen NC, Emmons RW, Selcer R et al: Rabies vaccine virus infection in three dogs. JAm Vet Med Assoc 172:1092-1096, 1978. 41. Perry BD, Jenkins S, Tan E: Epidemic raccoon-associated rabies in Virginia: A computerized surveillance study. Rabies Information Exchange 12:1, 1985. 42. Ramsden RO, Johnston DH: Studies on the oral infectivity of rabies virus in carnivora. J Wildlife Dis 11:318, 1975. 43. Robinson SJ, Disalvo AF: Rabies in South Carolina. Public Health Lab 38:315-321, 1980. 44. Scatterday JE, Schneider NJ, Jennings WL, et al: Sporadic animal rabies in Florida. Public Health Rep 75:945-953, 1960. 45. Smith JS, Sumner JW, Roumillat LF, et al: Antigenic characteris~ics of isolates associated with a new epizootic of raccoon rabies in the United States. J Infect Dis 149:769-774, 1984. 46. Steck F, Wandeler A, Bichsel P, et al: Oral immunization of foxes against rabies. Comp Immun Microbiol Infect Dis 5:165-171, 1982. 47. Surean P, Rollin P, Wiktor TJ: Epidemiologic analyses of antigenic variations of steer rabies virus: Detection by monoclonal antibodies. Am J Epidemiol117:605-609, 1983. 48. Tierkel ES: Rabies. Adv Vet Sci 5:183-226, 1968.

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49. Tierkel ES: Canine rabies. In Baer CM (ed): The Natural History of Rabies. New York, Academic Press, 1975. 50. Trimarchi CV: Epidemiology and Control of Bat Rabies in New York State. North American Symposium on Rabies in Wildlife. Baltimore, Maryland, Johns Hopkins University, Nov. 7-8, 1983. 51. Trimarchi CV, Rudd RJ, Abelseth MK: Experimentally induced rabies in four cats inoculated with a rabies virus isolated from a bat. J Am Vet Med Assoc 47:777-780, 1986. 52. Turner GS, Aoki FY, Nicholson KG, eta!: Human diploid cell strain rabies vaccine: Rapid prophylactic immunisation of volunteers with small doses. Lancet 1:1379-1381, 1976. 53. Turner GS, Nicholson KG, Tyrrell DAJ, eta!: Evaluation of a human diploid cell strain rabies vaccine: final report of a three year study of pre-exposure immunization. J Hyg (Lond) 89:101-110, 1982. 54. United States Public Health Service: Rabies Prevention. Recommendations of the Immunization Practices Advisory Committee (ACIP), 1984, pp 79-84. 55. Vaughn JB, Gerhardt P, Newell KW: Excretion of street rabies virus in the saliva of dog. J Am Vet Med Assoc 184:705, 1965. 56. Whetstone CA, Bunn TD, Emmons RW, et a!: Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats and one fox. JAm Vet Med Assoc 185:285288, 1984. 57. Wiktor TJ, Flamaud A, Koprowski H: Use of monoclonal antibodies in diagnosis of rabies virus infection and differentiation of rabies and rabies related viruses. J Virol Methods 1:3346, 1980. 58. Winkler WG, Fashinell TR, Leggintwell L, et a!: Airborne rabies transmission in a laboratory worker. JAm Vet Med Assoc 226:1219-1221, 1973. 59. Winkler WG: Airborne rabies. In Baer GM (ed): The Natural History of Rabies. New York, Academic Press, 1975. 60. Winkler WG (ed): Rabies Concepts for Medical Professionals. Miami, Florida, Merieux Institute, 1984. 61. Winkler WG: Current status of rabies in the United States. In Rabies Concepts for Medical Professionals. Miami, Florida, Merieux Institute, 1984. Department of Large Animal Clinical Sciences Virginia-Maryland Regional College of Veterinary Medicine Virginia Polytechnic Institute and State University Blacksburg, Virginia 24061