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Background

Rabies is a viral disease of the central nervous system (CNS); it is one of the oldest and most feared diseases reported in medical literature. Incidence of rabies is widespread throughout the world.

Human rabies cases have been documented on all continents except Australia and the Antarctic. Many cases are unreported (or greatly underreported) in third world countries.

Since control of canine rabies in the 1940s and 1950s, human rabies in the United States has become very rare. However, with recent raccoon rabies epizootic in the United States and high transmissibility of the rabies virus by bats, a fear of reemergence of rabies in humans continues to exist. Practicing physicians must understand the biology, pathogenesis, and epidemiology of the disease. Physicians also must have detailed knowledge regarding postexposure prophylaxis for patients who may have been exposed to the disease through animal contact.

Pathophysiology

Most rabies viruses belong to the genus Lyssavirus and the family Rhabdoviridae. They are bullet-shaped RNA viruses with an incubation period of 5 days to 1 year, with an average of 20-90 days. In some cases, the incubation period has been thought to be significantly longer than 1 year.

Susceptibility to infection appears to be related to several factors, including size of inoculum, size and depth of bite, and proximity to the CNS.

Since 1980, most patients with human rabies in the United States have not had definite exposure through a bite wound, making total understanding of the mechanism of transmission somewhat elusive.

After inoculation, viral glycoprotein attaches to the nicotinic acetylcholine receptor of skeletal muscle. Initial replication occurs in myocytes. The virus then enters the nervous system via unmyelinated sensory and motor terminals. At this point, the virus is sequestered from the immune system, and vaccination can no longer be effective. The exact time course of these events is unknown because incubation may take years.

Rabies spreads via retrograde axoplasmic flow at 8-20 mm/d until it reaches the spinal cord. Paresthesias then may begin at the wound site. Rabies continues to spread throughout the CNS, subsequently undergoing centrifugal spread along peripheral nerves to the skin, intestine, and into salivary glands, where it is shed in saliva.

Transmission

The risk of contracting rabies from a bite wound is 5-80%, depending on incidence of rabies in endemic species or other terrestrial animals in the region. Cases from nonbite exposures now are more common in the United States than bite exposures. Unfortunately, most patients with rabies are interviewed after encephalitis symptoms have begun, which complicates ascertaining history. Nonbite exposures include being scratched, being licked over an open wound or mucus membrane, or exposure to brain tissue or cerebrospinal fluid (CSF) of a rabid animal. Nonbite exposures from bats are the exception, and respiratory exposure from bats is a growing concern.

Rabies prophylaxis is now recommended for any routine contact with at-risk animals. Intact skin contact with urine, blood, or feces of an animal has not been shown to constitute exposure, except in bats.

Rodents and lagomorphs (eg, hares) seldom carry rabies, and their bites generally do not require postexposure prophylaxis. Woodchucks are an exception and have been shown to carry rabies. Contacting local or state health departments may be helpful when risk of rabies from a species in a specific geographic region is unknown. The 24-hour/7-day Centers for Disease Control and Prevention (CDC) clinician phone number is (877) 554-4625.

Direct human-to-human transmission of rabies has not been documented. However, 8 cases have been reported in which people died of rabies after transplantation of corneas from people who were diagnosed with the disease. All 8 occurred in transplanted corneas in 5 countries. Only one case was within the United States. Strict corneal transplant regulations are in place to prevent this occurrence.

Frequency

United States

To date, raccoons are the most frequent primary vectors in the eastern United States, with 9495 cases of rabid raccoons reported in 1993. Sixty percent of documented animal rabies cases in the United States occur in raccoons. However, only one case of documented human rabies in the United States is associated with the raccoon rabies variant. Lack of spread of raccoon rabies variant to humans is attributed to domestic animal immunization programs and rapid postexposure prophylaxis of bites to humans. Skunk epizootics appear to be widespread in north-central and south-central United States and California. In an attempt to control animal rabies, rabies vaccine–laden baits have been used in trials in the wild. A Florida trial published in 2000 showed that 57% of raccoons, 85% of opossums, and 50% of gray foxes trapped in a baited area had ingested the bait.¹

From 1980-2003, 40 cases of human rabies have been documented in the United States by the CDC, although this number is controversial based on questionable cases from other agencies. The animal sources in these cases have included predominantly bats and nondomestic dogs. Other animals rarely include skunks, foxes, and raccoon (one case).

In the 12 cases associated with dogs, actual exposure occurred outside of the United States, most commonly in Mexico. A total of 19 of the 34 reported cases (1997) have been associated with bats. The silver-haired bat (Lasionycteris noctivagans) accounted for 13 (68%) of 19 bat-related rabies cases. This bat is found throughout the United States, except in the southern coastal regions; it lives in trees and shrubs and can migrate overseas. In a study of 7047 bats in New York State, only 25 (0.4%) were silver-haired, and only 2 of these were rabid. These low figures are difficult to reconcile with the high incidence of the silver-haired bat rabies variant in documented human cases. History of a bite wound has only been documented in 1 of the 19 cases of bat-related human rabies. Eight of the remaining cases reported physical contact. No history of bat contact could be found for the remaining 10 cases.

The method of virus transmission in cases with no history of bat contact is unclear. Aerosolization of viral particles, unrecognized scratches or bites, and transmission through another animal species (eg, skunk, raccoon) of the bat rabies variant are possibilities.

From January to August 1997, 2 rabies cases were identified in the United States. Both cases were bat-related, with one occurring in Washington and the other in Montana. In neither case was a bite or definite contact with a bat reported. One case involved a viral strain found in the silver-haired bat, and the other was a variant associated with the big brown bat species; this was the first human rabies fatality involving the big brown bat. In 1996, 4 cases of human rabies were reported. Two cases involved nonbite exposure to the silver-haired bat, and 2 cases involved dog bites that occurred outside the United States.

A total of 18 cases were reported from 1980-1993, 6 cases were reported in 1994, 4 cases were reported in 1995, 4 cases were reported in 1996, and 3 cases were reported in 1997.

A total of 8 cases of rabies have occurred in the time frame of 2005-2007. Three of these were recipients of solid organ transplants from a single individual. In 2004, 4 recipients of solid organ transplants from a common individual died from encephalitis of unknown source. It was later concluded that the recipients were infected with rabies virus from the donor. Since the successful treatment in 2004 of an unvaccinated infected patient with the "Wisconsin rabies treatment protocol," no further successes have been reported. Two cases in 2006 attempted this treatment protocol in the United States but were unsuccessful.    

International

Worldwide, canine rabies is still epidemic and a major source of human rabies. A total of 1326 cases of human rabies were reported to the World Health Organization (WHO) in 1991; however, WHO estimates that as many as 35,000 deaths occur from rabies annually.

Mortality/Morbidity

Although rabies is considered to be a uniformly fatal disease, 3 cases of survival were reported in the 1970s. No additional survival cases have been reported in the 1980s and 1990s. These 3 cases involved patients who were given duck embryo vaccine or suckling mouse brain vaccine before onset of clinical symptoms. Three additional cases of survival, which were not clearly documented, were reported in the 1940s, 1950s, and 1960s.

An additional case in Wisconsin was reported in 2004; a 15-year-old adolescent girl survived rabies without preexposure or postexposure prophylaxis. The girl was bitten by a bat 1 month prior and was given intravenous ribavirin and kept comatose for 7 days. She has partially recovered. As stated above, this is the sixth known case of human recovery from rabies; however, this is the first patient who did not receive rabies prophylaxis either before or after the onset of symptoms.

Sex

No sex predilection for rabies exists.

Age

No age predilection for rabies exists.

History

Suspicion of rabies is clear when a history of an animal bite is given; however, because a history of an animal bite is obtained in less than one half of US cases, diagnosis is problematic. Presentation of a patient in the rabies prodromal stage without a clear exposure history is so nonspecific and rare that making the diagnosis in the ED is essentially impossible. Rabies progresses over 7-14 days, and the mean time between initial presentation and death is 16.2 days.

• Prodrome
• • Patients have presented to EDs with nonspecific fevers and pharyngitis.
  • Most prodromes last from 2-10 days.
  • Initial symptoms of pain or paresthesias at the site of bite or scratch begin during the prodrome. These are the only symptoms that specifically may raise the red flag of a rabies diagnosis.
  • Fever, headache, and anorexia also may be present.
• Neurologic stage (2-7 d)
• • Aphasia
  • Incoordination
  • Paresis
  • Paralysis
  • Mental status changes
  • Hyperactivity
• Late symptoms
• • Hypotension
  • Coma
  • Disseminated intravascular coagulation (DIC)
  • Cardiac arrhythmias
  • Cardiac arrest
  • Fatality

Physical

• High fevers with rapidly progressive encephalitis
• Myoclonus
• Increased lacrimation
• Hypersalivation
• Agitation
• Anxiety

Causes

Rabies is transmitted by contact with the rabies virus, although the method of virus transmission may be unclear in cases with no history of contact with the source animal.

Lab Studies

• Cerebrospinal fluid
• • The patient's CSF may be normal, but the protein level usually is elevated, and cases of mildly increased CSF white blood cell (WBC) and red blood cell (RBC) counts have been reported.
  • The CSF protein level may be normal or moderately elevated.
  • The virus may be isolated from saliva, CSF, serum, or nuchal skin samples.
  • A lumbar puncture can provide diagnosis with a rabies-neutralizing antibody titer higher than 5 in the serum or CSF of unvaccinated people (may be negative for 7 d after clinical illness has begun).
• In humans, detection of direct fluorescent antibody from the brain or nerves surrounding hair follicles in the nape of the neck assists in the definitive diagnosis.
• Diagnosis can be determined by isolating the rabies virus from saliva, CSF, or CNS tissue.

Imaging Studies

• Head CT scan findings are normal.

Other Tests

• In animals, the postmortem examination shows characteristic Negri bodies in the hippocampus and Purkinje cells of the cerebellum. These are found in 70-80% of cases along with perivascular inflammation of gray matter.

Procedures

• Lumbar puncture (LP)
• Skin biopsy to detect rabies antigen in hair follicles

Prehospital Care

Prehospital care is supportive depending on the stage of the virus. Typically, patients present with an unknown febrile illness with signs of encephalitis. Body fluid isolation should take place for these patients.

Emergency Department Care

Treatment discussed here focuses on animal exposures where rabies transmission is a possibility. This is the primary concern of the emergency physician. Treatment of human rabies is supportive and often involves therapy for other possible etiologies before specific diagnosis is made, usually postmortem or well into an intensive care unit (ICU) hospitalization.

Most recent patients described in the literature were initially sent home by the emergency department. This reinforces the important role of a history of recent animal or bite exposures.

• Immediate therapy consists of thoroughly cleaning all bite and scratch wounds with soap and water and/or 2% benzalkonium chloride. Provide wound care as needed. Tetanus prophylaxis is indicated; measures to prevent bacterial infection when warranted also are indicated. A decision must then be made regarding postexposure prophylaxis.
• Postexposure rabies prophylaxis
• • All unprovoked animal attacks are considered high risk for rabies.
  • If a bite or mucus membrane contact was inflicted by a domestic animal with known vaccination status, and if the owner can quarantine the animal for 10 days, postexposure prophylaxis can be withheld.
  • If signs of rabies occur, the animal (if captured) should be sacrificed and the head shipped to a qualified facility for testing. Regional poison control centers and local veterinarians are valuable resources regarding testing sites and procedures.
  • Exposures involving small rodents and lagomorphs (eg, squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice, rabbits, hares) do not require treatment. These animals can be infected with rabies virus in the laboratory but have never been associated with rabies virus transmission to humans.
  • Immediately treat bites or scratches from high-risk animals such as bats, raccoons, foxes, skunks, woodchucks, nondomestic dogs, or dogs near the United States–Mexican border.
  • Data suggest that insignificant contact with bats may result in viral transmission. Postexposure prophylaxis for bats is recommended, even in the absence of a bite or scratch. Any suspicion of bat contact, such as finding a bat in a room where someone has been sleeping or any contact with an unattended child, intoxicated person, or mentally disabled person, requires postexposure prophylaxis.
  • Human rabies immune globulin and vaccine are recommended for bites and exposures regardless of the period between exposure and treatment unless the individual is previously vaccinated and rabies antibodies can be detected. The average delay in the United States between exposure and treatment is 5 days, which does not appear to compromise successful prophylaxis.
  • Although no human-to-human nontransplant transmission has been documented clearly, anyone coming into contact with CSF, saliva, or mucus membranes of a person suspected of having rabies should receive complete prophylaxis. According to the CDC, the average number of people who receive postexposure prophylaxis secondary to contact with a single suspected human rabies case is 64.6.
  • Vaccines: The 3 rabies vaccines currently available in the United States are the human diploid cell vaccine (HDCV, Imovax), rabies vaccine adsorbed (RVA), and RabAvert (rabies vaccine produced by Chiron). They are equal in efficacy and safety.
  • • The vaccine takes 7-10 days to induce an active immune response, with immunity lasting approximately 2 years. Administer the vaccine in the deltoid region, with a dose of 1 mL on days 0, 3, 7, 14, and 28.
    • Slight erythema may be expected, but any further skin changes should be reported to the health department to determine actual necessity of vaccine.
    • For young children, outer aspect of the thigh may be used for injection. Do not administer in the gluteal area because of possible poor absorption if accidentally administered subcutaneously.
  • Passive immunization with human rabies immune globulin (HRIG, Hyperab) provides immediate protection with a serum half-life of 21 days.
  • • Administer rabies immune globulin (20 IU/kg) with as much of the dose as possible infiltrated in and around the wound (if wound location allows); administer the rest intramuscularly in the gluteal region, using a needle long enough to ensure an intramuscular injection. The syringes and needles used for vaccine and immune globulin should be different.
    • Case reports have documented safe administration of HRIG and HDCV during pregnancy.
    • In immunocompromised persons, measure serum antibodies to determine adequate immune response. Rabies immunoglobulin should be delivered in the same dosage. Immediate cleaning with soap and water is the most important way of decreasing rabies transmission in these patients.
  • Neural tissue rabies vaccines should no longer be used, although they may be still used in some developing countries. In countries that cannot afford the 5-dose regimen, the World Health Organization states that 2 regimens are available which fulfill their requirements. These have been used in developing countries as replacements for the more expensive injections. These injections should be administered in consultation with the CDC  
  • No postexposure vaccine failures in the United States have been reported since HDCV was licensed in 1980. Of 13 cases of postexposure treatment failure that occurred outside the United States, all were from not cleaning wounds, not giving rabies vaccine, or giving rabies vaccine into the gluteal rather than deltoid region.
  • Prophylaxis before exposure is recommended for persons whose occupations or environments put them at risk, such as veterinarians, animal handlers, laboratory workers where live rabies is common, travelers where medical care is difficult to find or where rabies is common in dogs. Preexposure prophylaxis consists of intramuscular vaccine with HDCV or RVA in the deltoid on days 0, 7, and 21 or 28. Note that preexposure prophylaxis obviates the need for postexposure rabies immune globulin but not postexposure vaccine. This can be a significant advantage to the traveler when human (versus equine) rabies immune globulin is unavailable.

Consultations

Consultations with infectious diseases specialists, critical care specialists, neurologists, and the CDC are appropriate.

Rabies immunoprophylaxis requires passive and active immunization.

Drug Category: Rabies immune globulin

Rabies immune globulin is used together with rabies vaccine in previously unvaccinated individuals to provide maximum coverage before an immune response to vaccine occurs.

Drug Category: Rabies vaccine

Rabies vaccine is available as RabAvert, Imovax, and Rabies Adsorbed Vaccine.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Prognosis

• Rabies is 100% fatal once symptoms develop.

Patient Education

• Avoid wild and unknown domestic animals.
• Seek treatment immediately if bitten.
• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Rabies.