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, unfortunately, with predictable 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. Rabies is recognized as a zoonosis worldwide. Animal-control and vaccination strategies currently supersede postexposure prophylaxis in preventing the spread of rabies. Through such programs, rabies has been eliminated in several nations and some areas in the US territories.

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. Raccoons, skunks, and insect-eating bats remain the prime vectors in the United States, followed by cats and cattle. Increasingly in the United States, the source of exposures cannot be identified, but the risk of death from rabies is exceedingly low, with fewer than 5 cases documented per year. Opossums are rarely infected and are not considered a likely risk for exposure.

Other very rare sources of exposure have included neurally derived tissues (eg, transplanted corneas) and laboratory aerosols. Recently, the first US instance of human rabies transmission via solid organ transplantation was documented in 3 recipients of a donor unsuspected of having rabies; transmission via organ transplantation has also been documented in other countries.

The rabies virus is a bullet-shaped virion with a single-stranded RNA nucleocapsid core and lipoprotein envelope. Its nucleocapsid material comprises the Negri bodies observed in the cytoplasm of infected neurons. 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.
Pathophysiology
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.
Frequency
United States
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. Since 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. In 2006, 3 cases of human rabies were reported in California, Indiana, and Texas. Bat rabies virus variants were implicated in the rabies cases in Texas and Indiana, whereas exposure to a dog in the Philippines was responsible for the case in California. Approximately 16,000-39,000 people receive rabies postexposure prophylaxis each year.

Some concern exists regarding occupational transmission of rabies from patients to health care workers. Despite the lack of proven occupational transmission, approximately 30% of health care worker contacts exposed to known cases of rabies have been treated with postexposure prophylaxis in the United States, some of which may have been unnecessary. The delivery of health care to a patient with rabies is not an indication for postexposure prophylaxis unless mucous membranes or open wounds are contaminated by saliva, tears, cerebrospinal fluid (CSF), or neurologic tissue. Adherence to standard infection-control precautions recommended by the US Centers for Disease Control and Prevention (CDC) is expected to minimize the risk for exposure to rabies in caregivers.
International
Rabies is more prevalent in the developing world than in the developed world. 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.
Mortality/Morbidity
If rabies treatment is not initiated before the onset of symptoms, death is imminent. Five cases of survival of human rabies have been documented in individuals who had been previously vaccinated or received postexposure prophylaxis. The survival of a teenaged girl from Wisconsin received substantial attention in October 2004 as the first case of human survival of rabies in the absence of preceding vaccination or postexposure prophylaxis. Notably, she received an investigational regimen of ribavirin, amantadine, and a ketamine-midazolam–induced coma; however, assessing whether this therapy was genuinely efficacious, whether other factors may have been involved, or whether these results are in fact reproducible is difficult.

In addition, bat rabies virus (isolated from the Wisconsin survivor) may be less neurovirulent than canine or other variants that are responsible for most human cases of rabies. The case, wherein the victim did not seek medical attention after handling a bat and being bitten, underscores the potentially long incubation period (in this case, 1 mo) and the need for ongoing public awareness of the risk of contracting this almost uniformly fatal infection.
Race
Rabies has no known racial predilection.
Sex
Rabies has no known sexual predilection.
Age
Rabies has no known age predilection.
Clinical
History

• Incubation period
  • The rabies virus transfers from peripheral areas to the CNS.
  • The infected individual remain asymptomatic.
  • The average duration of incubation is 20-90 days. Rarely, incubation lasts as long as 19 years. In more than 90% of cases, incubation is less than 1 year.
  • The incubation period is less than 50 days if the patient is bitten on the head or neck or if a heavy inoculum is transferred through multiple bites, deep wounds, or large wounds. A person with a scratch on the hand may take longer to develop symptoms of rabies than a person who receives a bite to the head.
  • The rabies virus is segregated from the immune system during this period, and no antibody response is observed.
  • Patients may not recall exposure because of the prolonged incubation period.
• Prodromal period
  • The virus enters the CNS.
  • The duration of this period is 2-10 days.
  • Nonspecific symptoms and signs develop.
  • Paresthesia or pain at the inoculation site is pathognomonic for rabies and occurs in 50% of cases during this phase; this may be the individual’s only presenting sign.
  • Symptoms may include malaise, anorexia, headaches, fever, chills, pharyngitis, nausea, emesis, diarrhea, anxiety, agitation, insomnia, and depression.
• Acute neurologic period
  • This period is associated with objective signs of developing CNS disease.
  • The duration is 2-7 days.
  • Furious rabies may develop in this period. Patients develop agitation, hyperactivity, restlessness, thrashing, biting, confusion, or hallucinations. After several hours to days, this becomes episodic and interspersed with calm, cooperative, lucid periods. Furious episodes last less than 5 minutes. Episodes may be triggered by visual, auditory, or tactile stimuli or may be spontaneous. Seizures may occur. This phase may end in cardiorespiratory arrest or may progress to paralysis.
  • Paralytic rabies is also known as dumb rabies or apathetic rabies because the patient is relatively quiet compared with a person with the furious form.
  • Twenty percent of patients do not develop the furious form.
  • Paralysis occurs from the outset.
  • Fever and headache are prominent.
• Coma
  • This begins within 10 days of onset; the duration varies.
  • Without intensive supportive care, respiratory depression, arrest, and death occur shortly after coma.
• Recovery
  • This is unlikely. A few reports indicate that persons who survived had preexposure or postexposure prophylaxis.
  • Most US cases result in death within 14 days because of complications, despite intensive supportive care.

Physical

• Incubation period: The virus transfers from peripheral areas to the CNS. Physical findings are not present.
• Prodromal period: The virus enters the CNS. Signs include fever, agitation, emesis, or diarrhea.
• Neurologic period
  • Furious rabies
    • Patients present with episodic delirium, psychosis, restlessness, thrashing, muscular fasciculations, seizures, and aphasia.
    • Hydrophobia and aerophobia are pathognomonic for rabies and occur in 50% of patients. Attempting to drink or having air blown in the face produces severe laryngeal or diaphragmatic spasms and a sensation of choking. This may be related to a violent response of the airway irritant mechanisms. Even the suggestion of drinking may induce hydrophobic spasm.
    • Autonomic instability is observed, including fever, tachycardia, hypertension, hyperventilation, drooling, anisocoria, mydriasis, lacrimation, salivation, perspiration, and postural hypotension.
    • Other neurologic signs include cranial nerve involvement with diplopia, facial palsy, and optic neuritis.
  • Paralytic rabies
    • Fever and nuchal rigidity may occur.
    • Paralysis is symmetric and may be either generalized or ascending and may be mistaken for Guillain-Barré syndrome. The sensory system is usually spared.
    • Calm clarity gradually progresses to delirium, stupor, and then coma.
• Coma: Respiratory failure occurs within one week of neurologic symptoms. Hypoventilation and metabolic acidosis predominate. Acute respiratory distress syndrome is common. Wide variations in blood pressure, cardiac arrhythmias, and hypothermia ensue. Bradycardia and cardiac arrest occur.

Causes

• High-risk exposures consist of contact with saliva or infected CNS tissue, including corneal transplants, via the following:
  • The bite of an rabid animal
  • Contact with broken skin
  • Contact with mucous membranes
  • Exposure to aerosolized secretions from an rabid animal
• Contact with unpasteurized milk from dairies: Each year since 1990, approximately 150 rabid cattle are been reported to the CDC.
• Transplant patients: The innate state of immunosuppression in this population often provides a favorable environment for viral replication.
  • Corneal transplants: Currently, donated corneas are not accepted if the donor died from an encephalitis that may be consistent with rabies.
  • Kidney and liver transplants: In 2004, organs 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.
  • Organ donation: Clinical screening of potential organ donors should include a history of animal bites, presence of clinical features of rabies, and a travel history (within a period of months) to areas where rabies is endemic. Pre-exposure rabies immunization of potential organ recipients is being evaluated as an alternative approach to prevent transmission associated with organ transplantation.
• High-risk animal species in the United States include the following:
  • Bats
    • 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.
    • In September 2005, a previously healthy 10-year-old boy in Mississippi died from encephalitis later attributed to rabies. Upon further questioning after the patient’s death, family members recalled that bats were commonly seen outside the home. On two occasions, dead bats also were discovered inside the home. Several family members and friends who possibly had contact with the patient’s saliva received postexposure prophylaxis.
    • At least 30 of the more than 39 species of bats in the United States have been reported as rabid at some time.
  • Raccoons: 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.
  • Skunks: Three areas are associated with skunk-borne rabies. These areas include the north-central United States, the south-central United States, and California.
  • Foxes
  • Dogs and cats along the Mexican border: Because of limited resources and minimal public health infrastructure in the bordering communities, efforts to maintain animal control through dog-vaccination programs are hindered. 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 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.
• The vaccinia-rabies glycoprotein virus used to bait wild animals is a self-replicating agent. Only one case has been documented of a pregnant woman developing a skin infection and needing surgery after she was bitten by her dog. Her history findings revealed that she was bitten when she took a vaccinia-rabies virus vaccine out of her dog’s mouth. This oral animal vaccine may cause adverse effects, particularly in hosts with altered immunocompetence and in persons in whom smallpox vaccination is contraindicated (eg, pregnant women, patients with an exfoliative skin condition).