Rabies is a viral disease that affects the central nervous system (CNS). The genus Lyssavirus contains more than 80 viruses. Classic rabies, the focus of this article, is the prototypical human Lyssavirus pathogen. (See Etiology.)
There are 10 viruses in the rabies serogroup, most of which only rarely cause human disease. The genus Lyssavirus, rabies serogroup, includes the classic rabies virus, Mokola virus, Duvenhage virus, Obodhiang virus, Kotonkan virus, Rochambeau virus, European bat Lyssavirus types 1 and 2, and Australian bat Lyssavirus. (See Etiology.) Five antigenic variants of rabies strains are recognized in the United States (see the image below).
The rabies virus is a bullet-shaped virion with a single-stranded ribonucleic acid (RNA) nucleocapsid core and lipoprotein envelope. Its nucleocapsid material consists of Negri bodies, which are observed in the cytoplasm of infected neurons (see the image below). The virus is transmitted in saliva or in aerosolized secretions from infected animals, typically via a bite. The virus is not hardy and is quickly inactivated by drying, ultraviolet rays, x-rays, trypsin, detergents, and ether. (See Etiology.)
The fatal madness of rabies has been described throughout recorded history, and its association with rabid canines is well known. For centuries, dog bites were treated prophylactically with cautery, with predictable and unfortunate results. In the 19th century, Pasteur developed a vaccine that successfully prevented rabies after inoculation and launched a new era of hope in the management of this uniformly fatal disease. (See Treatment and Medications.)
Rabies is a highly neurotropic virus that evades immune surveillance by its sequestration in the nervous system. Upon inoculation, it enters the peripheral nerves. A prolonged incubation follows, the length of which depends on the size of the inoculum and its proximity to the CNS. Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor and sensory axons. At this point, prophylactic therapy becomes futile, and rabies can be expected to follow its fatal course, with a mortality rate of 100%.
The rabies virus travels along these axons at a rate of 12-24 mm/d to enter the spinal ganglion. Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at the site of the inoculum, which is the first clinical symptom and a hallmark finding. From here, the rabies virus spreads quickly, at a rate of 200-400 mm/d, into the CNS, and spread is marked by rapidly progressive encephalitis. Thereafter, the virus spreads to the periphery and salivary glands.
From the standpoint of diagnosis and therapeutic opportunities, it is important to understand that rabies does not cause cytotoxicity. Neuronal morphology and lifespan is normal throughout the course of the disease. Death occurs from global neurologic and organ dysfunction. The virion acts in the synaptic space, where homology in amino acid sequences between neurotransmitter receptors for acetylcholine, GABA, and glycine may afford a mechanism for viral binding of these receptors. Thus, its action is neurotoxic, rather than direct damage.
Further, as disease progresses, virus may no longer be viable or replicating in tissue, although Negri bodies are present. If the virus could be contained or the binding action reversed, a cure might indeed be possible.
Rabies is recognized as global zoonosis yet remains remarkably neglected, despite unmatched lethality. It remains a threat underappreciated by healthcare practitioners in many endemic areas, often owing to lack of rapid diagnostic tools, postmortem evaluation, and public health reporting. Further, few resources have been devoted to its mechanisms of disease and potential therapeutic targets; the therapeutic approach remains a crude guess at best, based on anecdotal experiences shared across the globe. Most attention has focused on preventive strategies, which are fortunately highly effective where implemented.
The prevalence of rabies varies by location depending on animal-control effectiveness and immunization programs. The largest number of human deaths annually was recorded during the first half of the 20th century, with an average of 50 documented cases per year. Most were related to rabid-dog exposure. After 1940, when canine rabies vaccination programs began, the average number of documented cases declined to 2 per year. From 2001-2005, 15 cases of human rabies were reported in the United States.
Human rabies reflects the prevalence of animal infection and the extent of contact this population has with humans. Less than 5% of cases in developed nations occur in domesticated dogs; however, unvaccinated dogs serve as the main reservoir worldwide. Undomesticated canines, such as coyotes, wolves, jackals, and foxes, are most prone to rabies and serve as reservoirs. These reservoirs allow rabies to remain an indefinite public health concern, and ongoing public health measures are critical to its control.Animal-control and vaccination strategies currently supersede postexposure prophylaxis in preventing the spread of rabies. Through such programs, rabies has been eliminated in some parts of the United States, as well as several nations.
Terrestrial rabies in the United States is most common in raccoons on the eastern coast and in skunks, foxes, coyotes, and dogs on the Texas-Mexico border. Canine rabies, and to a lesser extent, bat rabies are significant problems in Mexico and around the world. (Opossums are rarely infected and are not considered a likely risk for exposure.)
The only rodent in the United States that can carry rabies long enough to transmit it to humans is the groundhog. Other small rodents (eg, squirrels, chipmunks, rats, mice) and lagomorphs (eg, rabbits, hares) usually die before being able to transmit rabies virus to humans, and human disease has not been documented from these mammals.
Domestic animals usually succumb to the virus strain predominant in their geographic region. Other cases have been associated with dog or animal bites in travelers returning from abroad, especially in countries where wild canine rabies is endemic. In other countries, canines are the most common source of rabies. Other animals, such as mongooses, jackals, ferrets, and domestic farm animals, may be common sources. Human-to-human transmission has only occurred with corneal and other organ transplants. [1, 2] Transmission of virus in saliva through mucous membranes, open wounds, or scratches is possible but rarely documented.
Rabies continues to adapt to new hosts and evolve transmissibility in previously “dead-end” hosts. In Arizona 2001, a mutated bat strain was confirmed to have developed both pathogenicity and transmissibility in both foxes and skunks, which previously were not seriously affected or contagious upon infection. Human encroachments into natural areas, as in suburban development, have been associated with the spread of rabies strains in the past. 
In addition, changes in epidemiology are expected to follow global climate change and are most likely to be detected in areas of climate extremes. This is being illustrated in Alaska, as increased viral transmission shifts from red fox to arctic fox populations following warming trends. Increased surveillance is needed to improve predictive models of epidemiology and human risk. 
Bat (avian) rabies appears to be widespread in the 49 continental states, and since 1980, most endemic rabies cases in humans in the United States have been associated with bat strains. 
Bat bites, if noticed by the patient, are generally thought to be trivial injuries because of the small size of most temperate-zone species (eg, silver-haired bats, eastern pipistrelles). In addition, bat bites can go completely unrecognized by the patient; consequently, appropriate postexposure prophylaxis is not administered.
One third of rabies cases occur in children, and most have no known exposure to a rabid animal. Because children may not be able to recall contact with a bat, if a bat is found in a room where a child has been sleeping, the bat should be captured and submitted for examination to the county or state health authorities. In 60% of cases, testing of the bat can avoid the need for rabies immunization. 
At least 30 of the more than 39 species of bats in the United States have been reported as rabid at some time.
Raccoons have been recognized a reservoir for rabies in the southeastern United States since the 1950s.  Currently, the risk of raccoon transmission exists in all of the eastern coastal states and Alabama, Pennsylvania, Vermont, West Virginia, and Ohio.
Three areas are associated with skunk-borne rabies: the north-central United States, the south-central United States, and California. As recently as 2001, a new skunk-borne variant arose from a bat strain and has since been quickly spreading.
Dogs and cats
Dogs and cats along the Mexican border
Limited resources and minimal public health infrastructure in the bordering communities have hindered efforts to maintain animal control through dog-vaccination programs. Viral studies of human cases reported from US border states implicate an urban canine rabies strain and a link to coyote rabies in southern Texas. 
Lower-risk animal species in the United States
Any mammal is potentially at risk for rabies, some more than others. Lower-risk animal species in the United States include dogs, cats, and ferrets in areas not near a border. No person in the United States has ever contracted rabies from a dog, cat, or ferret held in quarantine for 10 days. American opossums are especially at low risk, because the species’ low body temperature hinders replication.
Animal rabies vaccine
The vaccinia-rabies glycoprotein virus used in rabies vaccine–laden baits for wild animals is a self-replicating agent. This oral animal vaccine may cause adverse effects in some humans exposed to it through animal bits, particularly in hosts with altered immunocompetence and persons in whom smallpox vaccination is contraindicated (eg, pregnant women, patients with an exfoliative skin condition). 
The innate state of immunosuppression in this population often provides a favorable environment for viral replication. Recipients of neurally derived tissues are at highest risk; however, any tissue poses a risk. In 2004, kidneys and liver were inadvertently transplanted from a donor from Texas with rabies that had gone undiagnosed; the recipients developed clinical rabies within 30 days, resulting in 100% mortality. 
Rabies is more prevalent in the developing world than in industrialized countries. The World Health Organization (WHO) estimates that rabies is responsible for 35,000-50,000 deaths annually worldwide and that gross underreporting is likely. An estimated 10 million people receive postexposure prophylaxis each year after being exposed to animals with suspected rabies. Unvaccinated dogs are the major reservoir for rabies.
Europe - Foxes, bats
Middle East - Wolves, dogs
Asia - Dogs
Africa - Dogs, mongooses, antelopes
North America - Foxes, skunks, raccoons, insectivorous bats
South America - Dogs, vampire bats
Encounters with rabid animal vectors may be increased in males, who may have greater contact in certain geographic areas. Evidence to support this is found in data on dog bites, which are observed more frequently in males than in females.
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