Rabies virus can infect all warm-blooded animals, and in nearly all instances the infection ends in death. Rabies occurs throughout the world, with the exception of Australia, fapan, Great Britain, and many smaller islands such as Hawaii and most of the islands of the Caribbean basin. Dog rabies is still important in many parts of the world; virus in the saliva of infected dogs causes most of the estimated 75,000 human rabies cases that occur each year worldwide. In many countries of Europe, and in the United States and Canada, wildlife rabies has become of increasing importance as a threat to humans.
Infection by the bite of a rabid animal usually results in deposition of rabies-infected saliva deep in the striated muscles, but rabies can also occur, albeit with less certainty, after superficial abrasion of the skin. Initially, virus replicates in the muscle cells or cells of the subepithelial tissues until it has reached a sufficient concentration to infect motor and sensory nerves in the muscle or skin by binding specifically to the acetylcholine receptor or other receptors and entering nerve endings. Neuronal infection and centripetal passive movement of the viral genome within axons delivers virus to the central nervous system, usually via the spinal cord initially. An ascending wave of neuronal infection and neuronal dysfunction then occurs. Virus reaches the limbic system, where it replicates extensively, and the release of cortical control of behavior leads to "furious" rabies. Spread within the central nervous system continues, and when replication occurs in the neocortex the clinical picture changes to "dumb" rabies. Depression, coma, and death from respiratory arrest follow.
In the many species of animals that transmit rabies by biting, virus moves centrifugally from the central nervous system down peripheral nerves to a variety of organs: adrenal cortex, pancreas, and most importantly the salivary glands. In the nervous system most virus is assembled on intracytoplasmic membranes; the cells are not lysed, so that little viral antigen is released to stimulate host defense mechanisms. In the salivary gland, however, virions bud apically from plasma membranes at the luminal surface of mucous cells and are released in high concentrations into the saliva. Thus, at the time when viral replication within the central nervous system causes the infected animal to become furious and to bite indiscriminately, the saliva is highly infectious.
On histopathologic examination there is little evidence of brain damage, yet electron microscopic or fluorescent antibody studies show that almost all neurons are infected. There is minimal cellular destruction to match the extensive neurologic dysfunction seen in the disease.
Although rabies proteins are highly immunogenic, neither humoral nor cell-mediated responses can be detected during the stage of movement of virus from the site of the bite to the central nervous system, probably because very little antigen is delivered to the immune system (most is sequestered in muscle cells or within nerve axons). However, this early stage of infection is accessible to antibody, hence the efficacy of the classic Pasteurian postinfection vaccination, especially if combined with the administration of hyperimmune immunoglobulin. Immunologic intervention is effective during the long incubation period because of the delay between the initial viral replication in muscle cells and the entry of virus into the protected environment of the nervous system.
Following the bite of a rabid animal the incubation period is usually between 14 and 90 days, but may be considerably longer. Cases have been observed in rabies-free countries, like Australia, in which the last opportunity of infection occurred up to 6 years earlier. After a prodromal phase of fever, malaise, and often paresthesia around the site of the bite, muscles become hypertonic and the patient becomes anxious, with episodes of hyperactivity, aggression, and convulsions. Paralysis is often a major feature. Delirium, coma, and death follow.
It is important that the laboratory diagnosis of rabies in animals be undertaken in approved laboratories by qualified, experienced personnel. The most common request is to determine whether an animal known to have bitten a human is rabid. If clinical observation by a veterinarian suggests rabies, the suspect animal must be killed and brain tissue collected for testing by direct immunofluorescence to demonstrate rabies antigen in touch impressions of brain tissue (medulla, cerebellum, and hippocampus; see Fig. 12-6). If necessary, postmortem diagnosis can also be performed using the polymerase chain reaction (PCR) with primers that amplify both genomic RNA and viral rnRNA sequences from the brain. For antemortem diagnosis in humans and animals, immunofluorescence or PCR assays on skin biopsy, corneal impression, or saliva specimens can be used. Paraesthesia at the site of a known animal bite is a strong indication for testing humans for rabies infection, but by the time signs of encephalitis appear it is too late to expect treatment to be effective. Only positive results are of diagnostic value, since the lack of sensitivity of these procedures does not exclude an infection. Virus can be isolated in a high-security laboratory by intracerebral inoculation of suckling mice, or in a neuroblastoma cell line, with confirmation by immunofluorescence.
Epidemiology, Prevention, and Control
Rabies virus is not stable in the environment and in usual circumstances is only a risk when transmitted by the bite or scratch of a rabid animal, although in bat caves, where the amounts of virus may be very high, it can be transmitted via aerosol. Human to human transmission (via saliva?) has been reported only very rarely and has never been proved, except iatrogenically, for example, via corneal transplantation from donors dying of undiagnosed rabies.
The control of rabies in different countries of the world poses very different problems, depending on whether they are free of the disease, whether they are industrialized or developing countries, and whether vampire bat rabies is a problem.
Rigidly enforced quarantine of all dogs and cats for 6 months before importation has been effectively used to exclude rabies from Australia, Japan, New Zealand, Hawaii, and several other islands. Rabies did not become endemic in wildlife in the United Kingdom and was eradicated from dogs in that country in 1902 and again in 1922, after its reestablishment in the dog population in 1918.
In most countries of Asia, Latin America, and Africa, enzootic dog rabies is a serious problem, marked by significant domestic animal and human mortality. In these countries, large numbers of doses of human vaccines are used, and there is a need for comprehensive, professionally organized, and publicly supported agencies active in the following areas: (1) stray dog and cat elimination, and control of the movement of pets (quarantine may be called for in emergencies); (2) immunization of dogs and cats, so as to break the chains of virus transmission; (3) laboratory diagnosis, to confirm clinical observations and obtain accurate incidence data; (4) surveillance, to measure the effectiveness of all control measures; and (5) public education programs to ensure cooperation.
Fox rabies is enzootic in several countries of Western Europe, in the Appalachian Mountain regions of the United States, in Ontario, and in polar areas inhabited by the arctic fox. Skunk rabies is common in central North America, from Texas to Saskatchewan, where if is the principal cause of rabies in cattle. Racoon rabies in the United States began a gradual northern movement from Florida in the 1950s, following the importation of raccoons for sporting purposes, causing an explosive epidemic in Virginia, Maryland, Pennsylvania, and the District of Columbia in the 1980s, and in New Jersey, New York, and Connecticut in the 1990s. Historically, rabies control in wildlife has been based on animal population reduction by trapping and poisoning, but in the past few years, fox immunization, by the distribution of baits containing an attenuated live-virus rabies vaccine, appears to have been highly successful in "reducing transmission in Switzerland and Germany The question of whether immunization of other wildlife species will be useful, especially in more complex ecosystems, will depend on (1) the population density of the target species, (2) further research on the safety and efficacy of orally ingested wildlife vaccines, (3) delivery systems appropriate for each reservoir host species, and (4) solution of legal and jurisdictional problems. Many of these problems are now being solved and comprehensive field studies are in progress, including trials with a vaccinia virus-rabies glycoprotein recombinant.
In several countries of Latin America vampire bat rabies is a problem to both humans and livestock industries. Here control efforts have depended on the use of bovine vaccines and more recently on the use of anticoagulants such as diphenadione and warfarin. When vampire bats feed on the blood of treated cattle, they suffer fatal hemorrhages in their wing capillaries.
Rabies is the only human disease that can be prevented by active immunization after infection ("postexposure" vaccination), because the infecting event
Rabies' Guide for Human Postexposure Prophylaxis"
Condition of animal Treatment of
Animal species at time of attack exposed person''
Domestic animals Dog, cat
Wild animals Skunk, bat, fox, coyote, raccoon, bobcat, wood-chuck, other carnivores
Livestock, rodents, rabbits, hares
Healthy and available for 10
days of observation Rabid or suspected rabid
Regard as rabid unless proved negative by laboratory tests' or from geographic area known to be rabies-free
Consider individually; public health officials should be consulted about the need for rabies prophylaxis; bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice, other rodents, rabbits, and hares almost never call for anti-rabies prophylaxis
None, unless animal devel ops signs of rabies1 Immediate rabies immune globulin'1 and vaccine' Consult public health official; if treatment is indicated, give rabies immune globulin and vaccine
Rabies immune globulin1' and vaccine''
" In applying these recommendations, take into account the animal species involved, the circumstances of the bite or exposure, the vaccination status of the animal, and presence of rabies in the region Public health officials should be consulted if questions arise about the need (or rabies prophylaxis
'' All bites and wounds should immediately be thoroughly cleansed with soap and water If antirabies treatment is indicated, both rabies immune globulin and vaccine should be given as soon as possible, regardless of the interval from exposure.
' [f during the 10-day observation period a dog ot cat should exhibit clinical signs of rabies, it should be immediately killed and tested, and treatment of the exposed individual with serum and vaccine should be started.
'' If rabies immune globulin is not available, use equine antirabies serum Do not use more than the recommended dosage Anticipate possible need to treat for serum sickness r Five 1-ml intramuscula r doses to be given on days 0, 3, 7, 14, and 28 The WHO recommends an optimal sixth dose at 90 days. Local reactions to vaccines are common and do not contraindícate continuing treatment. Discontinue vaccine if fluorescent antibody tests of the animal are negative
1 The animal should be killed and tested as soon as possible; holding for observation is not recommended.
is recognizable and the incubation period is long. In addition, "preexposure" vaccination of occupationally at-risk humans is regularly and successfully practiced.
Rabies vaccines have come a long way since the days of Pasteur. Early vaccines were made from infected brain material and were associated with serious side effects, but excellent cell culture vaccines are now available. Today's vaccines are grown from attenuated virus in human diploid fibroblasts or Vero cells, then inactivated with 0-propiolactone or split into subunits with tri~n-butyl phosphate. Moreover, poxvirus-rabies glycoprotein recombinant vaccines are undergoing clinical trials in humans. In addition to active immunization, persons at risk should be given rabies immune globulin intramuscularly and around the bite. Remarkably, prompt administration of rabies immune globulin (after thorough cleansing of (he wound) and commencement of a full course of vaccine reduce the mortality from this frightening disease from virtually 100% to zero. A comprehensive guide on human postexposure treatment is provided by the U.S. Centers for Disease Control (Table 29-2).
Individuals occupationally or otherwise at risk of rabies should be pro-phylactically immunized. These include laboratory personnel working with rabies virus, veterinarians, animal control and wildlife workers in rabies-enzootic areas, and certain travelers visiting such areas. Preexposure immunization consists of three doses of modern cell-culture vaccine, 1.0 ml intramuscularly, one each on days 0, 7, and 28, with a booster (or serological confirmation of adequate antibody level) every 2 years.
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