Rabies

Epidemiology

Rabies is present on all continents except Antarctica. Rabies predominantly afflicts underaged, poor, and geographically isolated populations. Approximately 59,000 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 United States, 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, gray foxes harbor rabies in Arizona and Texas, red foxes and arctic foxes harbor rabies in Alaska, and mongooses carry rabies 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 United States 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. Among inhabitants of the Peruvian Amazon region who have exposure to rabies-infected vampire bats, there are some who have rabies virus–neutralizing antibodies and have survived. Antibody-positive patients remember bat bites but do not recall symptoms of rabies.

In the United States, 30,000 episodes of rabies postexposure prophylaxis (PEP) occur annually. Between one and three endemic human cases are diagnosed annually, half postmortem. There have been five outbreaks of rabies associated with solid-organ and corneal transplantations.

Transmission

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 who are bitten by a known rabies-infected animal and receive no PEP actually contract 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 healthcare 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.

Pathogenesis

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 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 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, further exacerbating dysautonomia. It is through this route that the virus infects the salivary glands. Many victims of rabies die from uncontrolled cardiac dysrhythmia.

Deficiency of tetrahydrobiopterin, 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 the first hospitalization, at about the time coma supervenes in the natural history. Increased intracranial pressure is regularly measured early in rabies in association with elevated N -acetylaspartate in cerebrospinal fluid (CSF), but is rarely radiologically apparent. Metabolites in CSF consistent with ketogenesis are associated with demise.