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Chapter 266 Rabies
Rodney E. Willoughby, Jr.
Rabies virus is a bullet-shaped, negative-sense, single-stranded, enveloped RNA virus from the family Rhabdoviridae, genus Lyssavirus. There currently are 7 known genotypes of Lyssavirus; more are under taxonomic consideration. The classic rabies virus (genotype 1) is distributed worldwide and naturally infects a large variety of animals. The other 6 genotypes are more geographically confined, with none found in the Americas. All 7 Lyssavirus genotypes have been associated with rabies in humans, although type 1 accounts for the great majority of cases. Within genotype 1, a number of genetic variants have been defined. Each variant is specific to a particular animal reservoir, although cross-species transmission can occur.
Rabies is present on all continents except Antarctica. Rabies predominantly afflicts under-aged, poor, and geographically isolated populations. Approximately 50,000 cases of human rabies occur in Africa and Asia annually. Theoretically, rabies virus can infect any mammal (which then can transmit disease to humans), but true animal reservoirs that maintain the presence of rabies virus in the population are limited to terrestrial carnivores and bats. Worldwide, transmission from dogs accounts for >90% of human cases. In Africa and Asia, other animals serve as prominent reservoirs, such as jackals, mongooses, and raccoon dogs. In industrialized nations canine rabies has been largely controlled through the routine immunization of pets. In the USA, raccoons are the most commonly infected wild animal along the eastern seaboard. Three phylogenies of skunk rabies are endemic in the Midwest (north and south) and California, and gray foxes harbor rabies in Arizona and Texas and mongooses in Puerto Rico. Rabies occurs infrequently in livestock. Among American domestic pets, infected cats outnumber infected dogs, probably because cats frequently prowl unsupervised and are not uniformly subject to vaccine laws. Rabies is rare in small mammals, including mice, squirrels, and rabbits; to date, no animal-to-human transmission from these animals has been documented.
The epidemiology of human rabies in the USA is dominated by cryptogenic bat rabies. Bats are migratory in the spring and fall; rabid bats are identified in every state of the union except Hawaii. In one study, the largest proportion of cases of human rabies were infected with a bat variant, and in almost all cases of bat-associated human rabies there was no history of a bat bite.
In the USA, 30,000 episodes of rabies postexposure prophylaxis (PEP) occur annually. Between 1 and 3 human cases are diagnosed annually, half postmortem. There have been two outbreaks of rabies associated with solid organ and corneal transplantations.
Rabies virus is found in large quantities in the saliva of infected animals, and transmission occurs almost exclusively through inoculation of the infected saliva through a bite or scratch from a rabid mammal. Approximately 35-50% of people bitten by a known rabies-infected animal and receiving no PEP experience rabies. The transmission rate is increased if the victim has suffered multiple bites and if the inoculation occurs in highly innervated parts of the body such as the face and the hands. Infection does not occur after exposure of intact skin to infected secretions, but virus may enter the body through intact mucous membranes. Claims that spelunkers may experience rabies after inhaling bat excreta have come under doubt, although inhalational exposure can occur during laboratory accidents.
No case of nosocomial transmission to a health care worker has been documented to date, but caregivers of a patient with rabies are advised to use full barrier precautions. The virus is rapidly inactivated in the environment, and contamination of fomites is not a mechanism of spread.
After inoculation, rabies virus replicates slowly and at low levels in muscle or skin. This slow initial step likely accounts for the disease’s long incubation period. Virus then enters the peripheral motor nerve, utilizing the nicotinic acetylcholine receptor and possibly several other receptors for entry. Once in the nerve, the virus travels by fast axonal transport, crossing synapses roughly every 12 hr. Rapid dissemination occurs throughout the brain and spinal cord before symptoms appear. Infection of the dorsal root ganglia is apparently futile but causes the characteristic radiculitis. Infection concentrates in the brainstem, accounting for autonomic dysfunction and relative sparing of cognition. Despite severe neurologic dysfunction with rabies, histopathology reveals limited damage, inflammation, or apoptosis. The pathologic hallmark of rabies, the Negri body, is composed of clumped viral nucleocapsids that create cytoplasmic inclusions on routine histology. Negri bodies can be absent in documented rabies virus infection. Rabies may be a metabolic disorder of neurotransmission; tetrahydrobiopterin (BH4) deficiency in human rabies causes severe deficiencies in dopamine, norepinephrine, and serotonin metabolism.
After infection of the central nervous system, the virus travels anterograde through the peripheral nervous system to virtually all innervated organs. It is through this route that the virus infects the salivary glands. Many victims of rabies die from uncontrolled cardiac dysrhythmia.
Deficiency of BH4, an essential cofactor for neuronal nitric oxide synthase, is predicted to lead to spasm of the basilar arteries. Onset of vasospasm has been confirmed in a few patients within 5-8 days of first hospitalization, at about the time coma supervenes in the natural history.
The incubation period for rabies is 1-3 mo but is variable. In severe wounds to the head, symptoms may occur within 5 days after exposure, and occasionally the incubation period can extend to >6 mo. Rabies has 2 principal clinical forms. Encephalitic or “furious” rabies begins with nonspecific symptoms, including fever, sore throat, malaise, headache, nausea and vomiting, and weakness. These symptoms are often accompanied by paresthesias and pruritus at or near the site of the bite that then extend along the affected limb. Soon thereafter the patient begins to demonstrate typical symptoms of severe encephalitis, with agitation, depressed mentation, and occasionally seizures. Characteristically patients with rabies encephalitis initially have periods of lucidity intermittent with periods of profound encephalopathy. Hydrophobia and aerophobia are the cardinal signs of rabies; they are unique to humans and are not universal. Phobic spasms are manifested by agitation and fear created by being offered a drink or fanning of air in the face, which in turn produce choking and aspiration through spasms of the pharynx, neck, and diaphragm. The illness is relentlessly progressive. There is a dissociation of electrophysiologic or encephalographic activity with findings of brainstem coma caused by anterograde denervation. Death almost always occurs within 1-2 days of hospitalization in developing countries and by 18 days of hospitalization with intensive care.
A 2nd form of rabies known as paralytic or “dumb” rabies is seen much less frequently and is characterized principally by fevers and ascending motor weakness affecting both the limbs and the cranial nerves. Most patients with paralytic rabies also have some element of encephalopathy as the disease progresses subacutely.
The differential diagnosis of rabies encephalitis includes all forms of severe cerebral infections, tetanus, and some intoxications and envenomations. Rabies can be confused with psychiatric illness, drug abuse, and conversion disorders. Paralytic rabies is most frequently confused with Guillain-Barré syndrome. The diagnosis of rabies is frequently delayed in Western countries because of its rarity and the unfamiliarity of the medical staff with the infection. These considerations highlight the need to pursue a history of contact with an animal belonging to one of the known reservoirs for rabies or to establish a travel history to a rabies-endemic region.
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